Industrial Pharmacy PAPER - 910201: CHAPTER NO. - 1, 6, 7 & 8

INDUSTRIAL PHARMACY PAPER 910201
M. PHARM PART I (2009-10)
CHAPTER NO. - 1, 6, 7 & 8.

(1) PHARMACEUTICAL FACTORY LOCATION (6) GMP & ITs IMPLEMENTATION (7) PRODUCTION PLANNING & MATERIAL CONTROLS (8) PILOT PLANT, SCALE UP TECHNIQUE
DEPT.OF PHARMACEUTICS & PCEUTICALTECHNOLOGY L. M. COLLEGE OF PHARMACY, ABAD- 09
SEMINAR ON INDUSTRIAL PHARMACY (PAPER-910201) CHAPTER NO.: 1, 6, 7 & 8
INDEX
No. 1 2 3 4 5 6 7 8 Seminar Topic Pharmaceutical factory location: Selection , layout & planning Utility Services & Service facilities HVAC & Personnel facilities GMP & Its implementation Process Analytical Techniques(PAT) & cGMP World class GMP & Flexible GMP Production Planning Material Control Prepared By Sanjay Krupa Nitu Kalpesh Saurabh Shweta Himaxi Himanshu Jignasha & Vijay Page no. 1 13 49 78 99 116 122 138 165
9,10 Pilot Plant & Scale-Up techniques
SIGNATURE OF GUIDE:- _______________
PAPER-910201
Chapter-1,6,7&8
PCEUTICAL FACTORY LOCATION BY : SANJAY C. MODI
Seminar on
PHARMACEUTICAL FACTORY LOCATION: SELECTION LAYOUT PLANNING
GUIDED BY:
Dr. R. K. PARIKH
PREPARED BY:
SANJAY C. MODI M.PHARM I ROLL NO. 07 YEAR:- 2009-10
DEPT. OF PHARMACEUTICS AND TECHNOLOGY L.M.COLLEGE OF PHARMACY AHMEDABAD-09.

M.PHARM. PART-I (2009-10) L.M.COLLEGE OF PHARMACY, AHMEDABAD-09
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[1] INTRODUCTION:-
The pharmaceutical industry is a major global economic force, which increasingly relies on the safe and efficient production of technically advanced products. This environment challenges the facilities professional who is charged to plan, design ,construct, validate, and operate complex manufacturing facilities that meet world class pharmaceutical standards. The facilities professional must master the many dynamic, interacting industry forces and understand how they influence pharmaceutical manufacturing facilities, and must apply prudently good design practices in response to these challenges. The pharmaceutical industry is an economic entity comprised of multiproduct,multi-market companies. The industrys operating environment is complex because of economic, political, technical, and social influences within a growing global environment for product development and delivery. The pharma industry has grown in the last several decades and has become quite complex, promising to deliver valuable products that enhance the quality of life to an expanding global population that demands greater access and more affordable choices. The role of the facilities professional is increasingly important to the industry as it addresses sourcing and manufacturing delivery objectives. Pharmaceutical manufacturing facilities are charged with meeting two significant objectives: They must perform and conform. Facilities deliver increasingly complex and valuable products configured in evolving, technically complicated dosage forms and therapies. Facilities must also comply with ever-changing and demanding regulatory overview from the worlds statutory bodies. These two fundamental challenges are addressed by facility professionals keen appreciation of the dynamic forces shaping the industry and by prudent facility designs that contribute to the enterprises strategic long-term viability. This seminar presents a broad overview of strategic industry driving forces to develop a solid informational framework for the facility professionals guidance. Key issues and concepts covered include speed to market, performance and conformance, cost of goods, risk management, and supply chain, as well as other issues that bear on facilities planning, design, delivery, and operation.
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[2] PLANT LOCATION:Plant location means the establishment of an industry at a particular place. The performance of an enterprise is considerably affected by its location. The selection of site for any enterprise mainly depends on its size and nature. Sometimes, The nature of the product itself suggest some suitable location. A Small scale industry mainly select the site where in accordance with its capacity, the local market for the product is available. It can easily be shifted to other place, when there is any change in the market. But in the case of Large scale industries, Where huge amount of investment has already been done the selection of proper site is very important.
IMPORTANCE OF PLANT LOCATION:

The selection of appropriate location is important due to the following reasons :- Location of plant partially determines operating and capital costs. It determines the nature of investment costs to be incurred and also the levels of operating costs. Location fixes some of the physical factors of the overall plant designs. e.g. heating and ventilation requirements, storage capacity of raw material taking into consideration their local availability, transportation need for raw materials and finished goods, power needs ,cost of labours, taxes, land construction, fuel, etc. Each prospective location implies a news allocation of capacity to respective market area. Government sometimes plays an important role in the choice of location keeping in view the national benefits.
FACTORS RESPONSIBLE FOR THE PLANT LOCATION CHOICES:

The choices of the plant location is based on the following factors :----- Availability of Raw material: An ideal location is one where the main raw material required to manufacture the product is adequately available. This will ensure regular supply of the material and will reduce the transportation costs. Nearness to the potential market: marketing of finished goods efficiently is an important function of an enterprise. If the plant is located near the market, then the management can keep close touch with their changes in market environment and formulate its production policies accordingly. Moreover, the transportation and other overhead expenses are reduced. Location should be near to source of operating power: in some industries, continuous and adequate power supply is needed. There are certain industries for which cheap electricity may be very important. In such situation, location of the plant near to the hydel-power situation will provide cheap electricity. Supply of labour: labour is one of the most important inputs in any industrial enterprise. There should be regular and cheap supply of labour, specifically the unskilled labour. If there is adequate supply of local labour near the plant, then naturally it will be available at cheaper rates.
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Transport and communication facilities: Transport is very important for bringing raw materials, fuel from different places, marketing of finished products etc. The region well connected with rail, road, water and air transport system is considered to be more appropriate for the location of the plants. Similarly good communication facilities, such as, postal and telecommunication links are of great significance towards the success of an enterprise. Regions with good communication system should be given priority for the selection of the sites. Similarly, industries producing goods for exports may be located near ports or airports. Suitability of land and climate: sub-soil of the location should be able to support the load likely to be placed on it. Similarly, climatic conditions viz humidity, temperature and other atmospheric conditions should be favourable for the plant. For the example, humid atmosphere is not suitable for the formation of pharmaceuticals. Integration with other group of companies: new enterprise owned or operated by a single group of companies should be so located that its work can be integrated with the work of the associated establishments. Availability of housing, other amenities and services: good housing facility, adequate shopping centre, theatres, cinema halls, restaurants, local transport facilities, rail services and sufficient availability of gas, water supply, drainage, disposal of waste, can easily attract good staff. Local building and planning regulations: proposed location should not be infringe local regulations and bye-laws. A discussion with survey department of the local authority is most desirable. Laws for the construction of buildings, local taxes etc. should be taken into consideration for the selection of site. Safety requirements: industries likely to cause pollution or processes explosives in nature should be located in remote areas. Miscellaneous considerations: The consideration like low interest on loans, special grants, low rentals, attitude of residents, towards the industry, living standards etc. helps in locating in the site of plants.
SELECTION OF SITE:
Once an appropriate area is chosen for certain plant, next step is location analysis to choose suitable site in that area. The choice of site is important both for objective and subjective reasons. The following points should be kept in mind for the selection of the site:--It should be well connected with rail, road and river transports. There should be efficient sewage system for the disposal of water and waste materials. The surroundings should be good and peaceful. The sub-soil should be capable of bearing the load of the building plant and equipment.
1. 2. 3. 4.
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5. There should be sufficient land to meet the present as well as the future space requirements of the plant. There should be provision for the parking of transport and sufficient space for residential accommodation for staff and labour.
Geography Neighbours Factory location Pollution Economic factors
Climate
SEZ
Site can be selected both in urban or rural areas. Urban area can provide better transport and communication system with sufficient labour supply. There can also be adequate security arrangements as well as other social services like medical, entertainment, restaurants, educational etc. But in urban area, cost of land and labour wages are likely to be on higher side. Rural area can provide cheaper land and labour with scope for further expansion. The local taxes and expenditure on other amenities is likely to be very low. The main shortcomings of rural plant site lies in scarcity of skilled labour, good shopping complexes, entertainment facilities, school and colleges and other amenities. In general, rural location is good for large plants.
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[3] PLANT LAYOUT:Once a decision about location of the plant has been taken, next important problem before the management is to plan suitable layout for the plant. Efficiency and performance of good machines and sturdy building depend to a great extent on the layout of a plant. Plant layout is the method of allocating machines and equipment, various production processes and other necessary service involved in transformation process of a product with the available space of the factory, so as to perform various operations in the most efficient and convenient manner providing output of high quality and minimum cost. Planning the layout of a plant is a continuous process as there are always chances of making improvements over the existing arrangement. The disposition of the various parts of a plant along with all the equipment used is known as plant layout. It should be so designed that the functioning of plant would become very efficient. A good layout results in comforts, convenience, safety, efficiency, compactness and profits. A poor layout results in congestion, waste, frustration and inefficiency.
ADVANTAGES OF A GOOD LAYOUT:

A good layout can provide a number of advantages to workers and management. Some of these are given below:----I. To the worker: 1. There are lesser number of operation and material handling. 2. There is reduction in length of hauls and motions between operations, which minimize production time as well as the activities of workers. 3. There is more labour productivity i.e. more output per man hour. 4. There is more safety and security to workers from accidents. 5. Better working conditions resulting in improved efficiency. II. In manufacturing costs: 1. Maintenance and replacement costs are reduced. 2. Loss due to waste and spoilage is minimised. 3. Improved quality of product with reduction in handling w.r.t. movement, time and cost. 4. Better cost control. III. In production control and supervision: 1. It provides more space for production operation. 2. There is efficient arrangement for receipt, transportation, and delivery of raw material and finished goods. 3. The cost and efforts in the supervision of production are minimized. 4. There is a better and convenient storage facility. 5. Control and supervision operations are provided at appropriate points.
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FEATURES OF A GOOD LAYOUT:

1. The good layout should possess the following basic characters:-There should be sufficient space for the workers as well as for the equipment to perform their functions. This will ensure smooth and continuous flow of production process. It must provide adequate safety and security to workers against accidents or injury. For example, provision of fire fighting equipment, first aid boxes, etc. The arrangement of machines and equipment should be such that minimum material handling is necessary for low cost processing. The store for in-process material should be such that minimum material handling is necessary for low cost processing. The supervision, coordination and control of the activity should be effectively and easily executed. There should be sufficient scope for making adjustment and modifications whenever any need arises.
SAMPLE LAYOUT OF A PHARMACEUTICAL FACTORY
2. 3. 4. 5. 6.
Good cGMP Design Features Include: Clear layouts Appropriate detailing and finishes Adequate room sizes and staging areas Presentation drawings that illustrate flows for people, product and equipment. Flexibility: Able to adapt to different uses Able to bring new services to the rooms Ease off clean up Modulations
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SAMPLE LAYOUT OF A PRODUCTION DEPARTMENT
SAMPLE LAYOUT OF F&D DEPARTMENT
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[4] PLANNING:A plan is a course of action to be taken in future. It is a prescribed course of action. Planning is the process of deciding in advance what to do, how to do it, when to do it and who is to do it. It involves the selection of objectives, policies, procedures, and programmes from among alternatives. Planning is a mental exercise that requires imagination, foresight and sound judgments. It is thinking before doing.
SALIENT FEATURES OF PLANNING:

The following points highlight the nature of planning: 1. Planning is goal oriented : planning is done to achieve certain objectives and all plans are linked with the goals of the organization. Planning identifies the action that would lead to the desired results quickly and economically. 2. Planning is future oriented : planning seeks to manage future events to the best advantage of the organization. Scientific anticipation of future events is called forecasting which serves as the basis of planning. For example, manufacturer prepares the production plan of the next year after forecasting the demand. 3. Planning is intellectual process : planning is a mental exercise and it involves the creative thinking and imagination. Management can prepare sound plans only when it has sound judgment, foresight and vision. Planning requires mental predisposition to think before acting. Planning is not mere guess work but involves logic and systemic thinking. 4. Planning is a primary function of management : planning serves as the basis for all other functions of management. It precedes organizing, staffing, directing and controlling. All these function are preformed within frame work of plans. Thus planning is the most basic function. 5. Planning is pervasive : planning is required in all types of organization and at all levels of management. Every department prepares plans. However, the scope of planning may differ from one level to another. For example, top management plans for the whole of the organization, middle management prepares departmental plans, whereas the lower management prepares day to day operational plans. 6. Planning is continuous : planning is ongoing process. Plans are prepared for a specified period say for one year. At the end of that period, new plans have to be prepared. Similarly, existing plans are required to be changed, if the conditions are changed. Thus planning is never ending exercise. 7. Planning involves choice : planning is essentially the process of choosing from among alternatives course of action. If there is only one possible alternatives, there is no need for planning as there is no choice. The planning is needed when there are various alternatives to reach to a definite goal.
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8. Planning aims at efficiency : plans are prepared to achieve the objectives in the best way. Sound planning helps to achieve desired objectives at the minimum possible cost. It helps in optimization of resources. A good plan should provide maximum satisfaction to those responsible for its execution.
ADVANTAGES:
1. Planning makes goals clear and specific. Plans serves as a guide for deciding what actions should be taken. With clear goals, activities become meaningful. 2. Planning helps the organization to keep on the right path. 3. Planning reduces the risks and uncertainly. Business enterprises operate in an uncertain environment. Planning enables to predict future events and prepares to face the unexpected events. 4. It improves the efficiency of operation because planning involves selection of the best possible course of action. 5. It provides basis of control. Planning provides the standard against which the actual performance can be measured and evaluated. 6. It promotes creativity, because only sound planning encourages creative thinking. This leads to growth and expansion of business. 7. It facilitates decision making. Planning involves forecasting of future conditions and helps the management to take correct decision. 8. It helps in coordinations. Planned targets and programmes serves as the basis of harmonizing the efforts of different departments, sections and individuals to achieve it.
LIMITATIONS :
1. Planning is an expensive process. Money is involved in forecasting, collection of information and evaluation of alternatives. The cost of planning should not exceeds the gain expected from it. 2. Planning is a time consuming process. So it is not practicable during emergencies and crises, when quick decisions are necessary. 3. Planning creates a rigid frame work in the organization. Once the plans are formulated people tend to strictly adhere to them irrespective of changes in the environment. 4. Changes in business environment restrict freedom of planning for the management. 5. Planning creates a false sense of security because detailed planning gives a feeling among employees that everything has been taken care of. 6. Planning creates a psychological barriers, because executive have more regard for the present than future. Planning often involve changes which executives would like to ignore, hoping they would not materialize. 7. Planning is based on forecast which are estimates about the future. When forecasts are inaccurate, plans became misleading; therefore, blind reliance on plans may be dangerous.
STEPS INVOLVED IN PLANNING:

Systematic approach to planning is necessary in order to prepare a sound plans. The steps involved in systematic planning are as follows:--1. Definition and description of objectives: plans are prepared to achieve certain objectives or goals. The first step in planning is to define clearly the objectives of the business organization. The planning is required either to solve a problem or to
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exploit an opportunity to be utilized to achieve the objectives. For example, main objective of the company is to increase profits by 25% during the next year. So the production and sales targets should be decided on this basis. 2. Determination of planning premises: this is next step of planning. Planning premises are the assumptions about the future. The provide the environment or boundaries in which plans will be implemented. Planning premises are established with the help of forecasting. Planning premises may be of following types: a) Tangible and intangible premises: assumption which can be expressed in quantitative terms are called tangible premises e.g. units of production, capital investments, time available etc. Intangible premises are employees morale, goodwill of the enterprise, motivation etc. b) Internal and external premises: assumption about the internal working of the enterprise are known as internal premises. E.g. capital, machines, personnel etc. On the other hand factors outside the enterprise are called external premise e.g. changes in technology, population growth, changes in competition, government policies etc. c) Controllable and uncontrollable premises: policies and programmes of the organization which can be fully regulated by the management are controllable premises. Uncontrollable premises are the external factors like trade cycles, political changes etc. which are beyond the control of management. 3. Discovering alternatives courses of action: once the objectives and planning premises are established, the various courses of action are discovered in order to achieve the established objectives. Information may be collected from primary and secondary sources. The data so collected will serve as the basis for development of an alternative course of action. The strength and weakness of an alternative course of action also need to be examined by the management at this stage. 4. Evaluation of alternative courses: the various alternatives are evaluated and compared in terms of their expected costs and benefits, after objectives and scientific evaluation of different alternatives, the best alternatives is selected. 5. Formulation of derivative plans: once the basic plan is decided, the next step is to develop detailed plans for its implementation. These detailed plans refers to the policies, procedures, rules, programmes, schedules, budgets etc. for example, when pharmaceutical company decides to develop a new product, planning concerning the product design, procurement of funds, purchase of raw materials, training of personnel, advertising for the product have to be prepared. 6. Communicating the plan: plan should be explained to the subordinates in order to get their support in the execution of plans. Successful implementation of plans requires whole hearted cooperation and understanding of personnel. 7. Receiving the planning process: continuous evaluation of plans and the process of planning helps to detect shortcomings of the plans. All plans should be reviewed from time to time in the light of current circumstances and necessary action should be taken to keep them up-to-date.
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[5] QUESTIONS :
1. Draw a simple layout of pharmaceutical production plant along with F & D section? Write a note on utility services & sanitation programme in manufacturing premises?(2nd internal exam 2007) 2. Enlist the factors to be considered while selecting site for pharm.Plant what is utility services?(University exam 2005) 3.Discuss the factors affecting selection of pharma.plant site & design.Discuss about personnel facilities & personnel protection as per GMP. How the sanitation program in mfg, premises is carried out?(2nd internal exam ,2005)
[6] REFERENCES :
GMP FOR PHARMACEUTICALS BY:- JAMES SWARBRICK VOL-2, PAGE NO.:- 15 to19. GOOD DESIGN PRACTISES FOR GMP PHARMACEUTICAL FACILITIES BY:- ANDREW. A.SIGNORE & TERRY JACOBS VOL-146, PAGE NOS:- 80 to 85. Pharmaceutical industrial management by R.M.Mehta
www.who.org www.fda.com
www.wikipedia.com
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UTILITY SERVICES BY: KRUPA
UTILITY SERVICES AND SERVICE FACILITIES
GUIDED BY: Dr. R.K.Parikh

PREPARED BY: Krupa P. Mehta
Department Of Pharmaceutics L.M.College Of Pharmacy,Ahmedabad

M.PHARM PART-I (2009-10) L.M.COLLEGE OF PHARMACY, AHMEDABAD-09
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UTILITY SERVICES:
All utilities that could affect product quality should be qualified and appropriately monitored and action should be taken when these utility limits are exceeded. UTILITY SERVICES include 1. HEATING, VENTILATION AND AIR CONDITIONING 2. PLUMBING 3. DRAINAGE SYSTEMS 4. GAS SYSTEMS 5. SANITATION 6. WATER FOR PHARMACEUTICAL USE. 7. PESTICIDES etc Services used by a factory include compressed gases, water, vacuum, electricity and room air conditioning. 1.HVAC has been covered in other seminar.
2.PLUMBING:
Potable water shall be supplied under continuous positive pressure in a plumbing system free of defects that could contribute contamination to any drug product. The pipes and fittings must be of quality good enough to withstand the pressure and heat conditions. Metals are often included in pharmaceutical facility waste water permitting criteria but are not commonly a discharge issue. Compatibility of the materials of construction with the characteristics of the waste water must be considered during the design of the facility. For example: Copper plumbing should not be used in drain line for acidic waste water because it might fail from corrosion but also may result in waste water discharge above copper concentratin limits. The pipes should be colour coded according to the material it carries.
Grey Orange Green Insulated White
Raw water Distilled Water Cooling water Steam Air
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3.DRAINAGE SYSTEMS:
They remove effluent from spaces ,systems, or process.
- Drains shall be of adequate size and, where, connected directly to sewer, shall be
provided with an air break or other mechanical device to prevent back-siphon age. - They should be easy to clean. And they must be cleaned at a proper interval. They must be well closed and air tight. - For biological waste, it should be treated in a proper manner before disposal to not to harm the environment. - Dissolved oxygen content in the waste to be disposed in lake or river must be within limits.
Sanitary waste system

A separate sanitary waste drainage and vent system is provided to convey waste from toilets, lavatories, non-process service sinks and floor drains. Sanitary drainage is connected to the site sanitary sewer system generally without treatment. Any other materials or product that may present a hazard or environmental problem in the sewer system must be conveyed by a separate waste and vent system.
Laboratory waste system:

A separate laboratory waste drainage and vent system is often provided in cases where acids or caustics used in laboratory processes must be sampled and potentially neutralized before disposal into the sanitary waste system. A batch or continuous neutralization system may be utilized.
Process Waste System

A separate process waste drainage and vent system is often provided in cases where products used in the manufacturing process must either be contained separately or treated before disposal into the sanitary waste system. If they are contained, they are usually removed by tanker truck and disposed of offsite. Because the drainage may be potentially hazardous and certainly possess a potential contamination and environmental threat, the piping distribution system must either be protected (double wall piping system) or provided in a location that is easily monitored (i.e., exposed service corridors).
Hazardous Material Waste and Retention

Separate hazardous waste drainage and vent systems are provided in cases where hazardous materials such as solvents, toxins, radioactives, high concentrations, etc. must be contained. Generally these systems are limited in distribution and highly contained. They can either be local such as in-lab safety containers or larger as in the case of a solvent spill retention system in a dispensing area. These systems must maintain isolation of the hazardous material for other drainage systems.
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Storm Drainage System

A separate storm drainage system is provided to drain rainwater from all roof and area drains. This system is generally not combined with any other drainage system All precautions must be taken to ensure that contaminated fluids cannot flow into the storm drainage system. In case of potentially hazardous material spills, valving is generally provided in the drainage system to isolate the drainage area.
4.GAS SYSTEMS
Many types of gases are utilized in the manufacturing process. The most prevalent of these include compressed air use in process and controls, breathing air for hazardous environments, nitrogen, vacuum, vacuum cleaning, natural gas, propane, and other process systems. All gases used in manufacturing and processing operations, including the sterilization process, should be sterile filtered at points of use to meet the requirements of the specific area. Gases to be used in sterilizers after the sterilization OR used at the filling line or microbiological testing area must also be sterile filtered.
Compressed Air
In general compressed air should be supplied by an oil-free type compressor and must be free of oil and oil vapor unless vented directly to a non-controlled environment area. It should also be dehumidified to prevent condensation of water vapor (generally to around -40(F dewpoint). Centrally distributed compressed air is generally provided at 100 to 125 psig and reduced as required.
Breathing Air
Breathing air is generally provided for use to personnel working in hazardous environments. It can be provided centrally through a breathing air distribution system or at the local level with backpack type breathing air units worn by each person. Personal units are more cumbersome but less expensive than central units. Air must be purified to meet OSHA Grade D breathing air requirements. System reliability must be provided in the design with redundancy or storage to provide for escape time in case of equipment failure.
Nitrogen
Nitrogen is an inert gas generally utilized in the pharmaceutical laboratory and manufacturing environments primarily for the purging of electrical equipment in volatile or explosive environments. Cryogenic uses are limited in the pharmaceutical manufacturing industry. Nitrogen, however, can be provided locally utilizing small individual bottles or generators. In the central system, nitrogen may be distributed at 100 to 125 psig with pressure regulation as required. Laboratory nitrogen is generally provided at lower pressures (40 to 90 psig).
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Vaccum
Vacuum is utilized throughout pharmaceutical laboratory and manufacturing facilities. A great deal of vacuum is utilized in the encapsulation and tablet compression areas. Vacuum is generally generated at between 20 and 25 inches Hg and provided at between 15 and 20 inches Hg at the inlet.
Vaccum Cleaning
Vacuum cleaning is utilized throughout the pharmaceutical manufacturing environment for dry particulate and powder pickup. Individual units are more cumbersome, require stricter cleaning regimens between uses, can be a source of cross contamination, but are less expensive than central units. Vacuum cleaning is generally generated at between 5 and 10 inches Hg and provided at about 2 inches Hg at the inlet. This reduced pressure range compared to the vacuum system described above may be more conducive to some processes..
Natural Gas and Propane

Natural gas and propane are sometimes required in the pharmaceutical laboratory environment for such processes as maintaining solvent oxidization and heating hot water and steam. Gas is generally distributed to laboratory outlets at 5 to 10 inches wg.
5.SANITATION IN THE MANUFACTURING PREMISES

The manufacturing premises shall be maintained clean and in orderly manner, free from accumulated waste, dust, debris, etc; Eating, chewing, smoking or any unhygienic practices shall not be permitted in manufacturing area; The manufacturing area shall not be used for general thoroughfare for personnel or storage for storage of materials, except for material being processed; Routine sanitation programme shall be drawn up and observed which shall be properly recorded and which shall indicate: Specific areas to be cleaned and cleaning intervals; Cleaning procedure to be followed, including equipment and materials to be used for cleaning; Personnel assigned to and responsible for cleaning operations. Records of compliance in respect of sanitation shall be maintained for inspection.
Objectives of sanitation are:

Removal of dirt and other waste material; Minimize the risk of cross contamination between different products in the same area; Reduce the number of micro-organisms in work area;
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Control pests so that these do not affect the quality of materials tp be used in the manufacture of drugs.
Sanitation in the manufacturing premises doesnt obviate necessity of sanitation in other areas. However, sanitation in manufacturing areas is more important than other areas because of risk of contamination is more in these areas, protection from outside environment too is necessary. For protection of premises from outside environment, some important measures are: Effectively seal manufacturing plant from outside environment by :Avoiding multiple entry/ exit positions, Installing air curtain at each main entrance, Providing air-lock at each entry point. Install insectocutors at effective positions like main entrances, entrances to manufacturing areas including packaging section, inside manufacturing areas. Keep surrounding of the building clean. Maintenance of lawn will keep incidence of dust low. Carry out pest control periodically. Services of pest control agency can be availed for this purpose.
CLEANING AGENTS AND DISINFECTANTS

Cleaning agents help to remove extraneous materials from surfaces some of the commonly used cleaning agents their chemical nature, concentration in which they are used and their uses are given below:
Name of cleaning agent Teepol
Active ingredients
Conc.
Uses
Avipol
Liquid soap
Sodium benzene sulphonate, alcohol, ether sulphate and alcohol ethoxylate Liquid detergent of the sodium alkyl sulphate type Soap
0.1 %
Multipurpose cleaning agent can be used for equipment, floors, glass wares
Vim
Mixture of detergents
Tanks and vessels in liquid oral manufacturing As Can be used for required washing hands, gloves, machine parts As Toilets, floors, sinks, required etc.
1%
Disinfectants destroy pathogenic and other micro organisms and are used to
reduce microbial count in manufacturing area. Commonly used disinfectants their chemical nature and uses are given here under:
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Name of disinfectant Dettol
Active ingredients Chloroxylenol and terpineol
Uses
Savlon
Farigenol
Formalin
2.5 % solution can be used for hands and spray. Chlorhexidine 2.5 % solution can be gluconate and used for treating all cetrimide surfaces in aseptic area. Dichloro meta 2% solution can be xylenol, terpineol and used for treating all soap surfaces in aseptic area. Formaldehyde A mixture of potassium permanganate and formalin is used for disinfection of sterile areas.
It is advisable to use these disinfectants on a rotation bawsis with predetermined periodicity. For sterile areas the periodicity of change of disinfectant should be of higher frequency like change on alternate days. Typical cleaning schedule for tablet manufacturing areas are given below. Similar schedules can be prepared for other manufacturing areas.
AREA Floors
FREQUENCY OF CLEANING Minimum once a day
Walls Ceilings Windows Exhaust fans Light fixture, ducts of air conditioning Equipment washing area
Twice a week Weekly Daily Weekly Weekly Daily
METHOD OF CLEANING Vacuum cleaning and damp mop with disinfectant Vaccum cleaning, jet wash and damp mop. Vaccum cleaning Vaccum cleaning and dry mop Wet mop with disinfectant Vaccum cleaning Scrubbing, jet washing and disinfection with disinfectant.
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Records of sanitation should be maintained. Records can be maintained in the form of log-book. A separate log-book can be maintained for each section. Format of log book is given below:-
LOG BOOK FOR SANITATION Work Area ___________________________

Date Code* no. of SOP for sanitation Sign of person Who executed Job responsible for the job
* SOP for sanitation can be given code numbers
6.WATER FOR PHARMACEUTICAL USE:

INTRODUCTION:
The importance of process water to a pharmaceutical manufacturing facility cannot be overstated. Water is most widely used material in pharmaceutical manufacturing. A greater volume of water is used in cleaning and rinsing processes than in formulation in most facilities. Regardless of the water volume used in actual drug formulation , all pharmaceutical water is subject to cGMPs even when the water does not remain in the finished product.
GOOD MANUFACTURING PRACTICES(GMPs):

Most of the GMP requirements for water derived from broad statements in 21CFR Part211:cGMP for finished pharmaceuticals. These general statements relate to the requirements for water used in production or cleaning processes to not alter the safety, identity, strength, quality or purity of the drug product. These statements open all water system unit operations, contact surfaces of equipments and piping, installation, and maintenance to FDA scrutiny. All materials must be proven to be compatible with the product and process, and must not contribute objectionable contaminants. Additional 21 CFR Part 211 GMP requirements for verification of proper cleaning and sanitization procedures mandate written records and procedures for these steps. All rinse and cleaning water qualities must be proven to be appropriate.
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WATER QUALITY REQUIREMENTS:

The types of water defined in the pharmacopoeial monographs such as Purified Water and Water for Injection (WFI) are known as compendial waters. Other quality waters used in manufacturing, not defined by USP or other recognized compendia,are known as non-compendial waters. Non-compendial waters can be used in many applications such as production of many Active Pharmaceutical Ingredients (APIs) and in many cleaning and rinsing steps. Non-compendial waters are not necessarily lower quality than compendial waters. Non-compendial waters range from water that is required only to meet the U.S. Environmental Protection Agency (EPA) National Primary Drinking Water Requirements (NPDWR), to water that is specified to exceed the requirements for Water for Injection. Non-compendial water systems are not necessarily less tested, maintained or validated than compendial waters, and they are subject to the same cGMP requirements.
MONOGRAPH REQUIREMENTS:
The monographs require that the water purity is proven by conductivity and total organic carbon (TOC). The conductivity requirement using USP <645> can be met with online testing (Stage 1) or in laboratory testing (Stages 1, 2, or 3). The Stage 1 conductivity test requires measurement of conductivity and water temperature. The conductivity limit varies from 0.6 microsiemens/centimeter (S/cm) at 0C to 3.1 S/cm at 100C.Intermediate values include 1.3 S/cm at 25C and 2.7 S/cm at 80C. The TOC test is a limit response test with a theoretical limit of 500 parts per billion (ppb). The test is designed to accommodate virtually any TOC analyzer that meets the USP suitability requirements. The microbial limits for USP Purified Water (PW) are not defined in the legally binding monograph. The General Information Chapter <1231> Water for Pharmaceutical Purposes states that a maximum of 100 colony forming units per milliliter (mL) may be used as an action level . Some products and processes require an absence of certain objectionable species such as Pseudomonas aeruginosa as well as a low total viable plate count. Water for Injection (WFI) has the same chemical requirements as PW and has a limit of 0.25 endotoxin units per milliliter (EU/mL). The microbial level for WFI also is absent from the monograph but is stated to be a maximum action level of 10 cfu/100 Ml. The USP 28 WFI monograph states Water for Injection is water purified by distillation or a purification process that is equivalent or superior to distillation in the
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removal of chemicals and microorganisms. Several prior volumes of USP limited WFI production to distillation or reverse osmosis. Distillation currently produces over 99% of USP WFI. Other processes such as a combination of reverse osmosis, deionization, and ultrafiltration have a significant history of production of WFI quality water for rinsing, API production, and other uses. Distillation was the only allowable process for WFI production for decades and became the standard method of production. The revised USP 28 WFI monograph may stimulate an increase in alternative system designs if the alternative designs are evaluated to be as reliable as distillation and more cost effective.
WATER QUALITY SELECTION:
The water quality or qualities selected for the pharmaceutical process must be consistent with the final product requirements. The final rinse water must be the same quality as the water used in manufacturing. Oral products must use a minimum of USP PW for manufacturing and PW is normally used as final rinse water. Since the method of manufacture for PW is not stated by USP, there is little advantage to use of non-compendial water for final rinse water where PW is acceptable.
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Parenteral products must use a minimum water quality of USP WFI for manufacturing and WFI is used in most plants for final rinse water. It is acceptable to use WFI quality non-compendial water for final rinse in parenteral processes if practical. The water quality requirements for Active Pharmaceutical Ingredients (API) and Bulk Pharmaceutical Chemicals (BPC) are complex. The minimum water quality permitted in API or BPC manufacturing is water meeting the U.S.Environmental Protection Agency (EPA) National Primary Drinking Water Requirements (NPDWR) or equivalent. APIs use a wide range of waters for manufacturing, initial rinses and final rinses, up to and including WFI. FDA may expect WFI to be used in certain inhalation products depending upon use. Water quality exceeding USP, PW, or WFI requirements may be required for some products such as intrathecals. A large volume parenteral product may have to be produced with water with endotoxin limits well below WFI limits dependent upon the expected patient weight and the dosage volume. The manufacturer is required to determine the appropriate water quality.
TYPES OF WATER: A) POTABLE WATER (drinking water) being the source for obtaining various
higher qualities of water, adequate pretreatment are essential before it is used. It may be used for synthesis of active ingredients and also used for cleaning of equipments and facilities. B) PURIFIED WATER monograph identify quality attributes that include ionic and organic contaminants and limits the level of microbiological contaminants. This water is used in preparation of nonparenteral dosage forms.
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C) WATER FOR INJECTION (WFI)

o Monograph includes the same chemical attributes as purified water. Additionally, they include attributes for bacterial Endotoxin and lower level of microbiological contamination. o It is used in parenteral products. In bulk, this type of water is also called Pyrogen free water or PFU and if it is sterilized, it is called sterile WFI. o WFI must be free from pyrogens, and so should pass the rabbit pyrogen test, or the LAL limit of less than 0.25EU/mL. o It is recommended that WFI water systems be tested at predetermined intervals. The inspector should check the frequency of these tests. o Storage time for all water must be less than 24 hrs unless stored at 80C. The GMP guideline of some countries, however, indicates that at or above 70oC is acceptable. D) SOFTENED WATER, which has its Calcium and Magnesium removed. Such a water can be used e.g. for first washing steps. Certain processes require special well-defined qualities of water. E) CLEAN STEAM is a form of water that may be used for sterilization purpose and prepared from deionized water. F) WATER FOR FINAL RINSE is used for rinsing equipment after washing. It must be of the same quality as the water used for manufacturing the product. G) STERILE WATER FOR INJECTION water for injection which is sterilized within 12 hours of collection and distributed in sterile containers. It is intended mainly for use as a solvent for injectable preparations such as powders for injection that are distributed dry because of limited stability of their solutions. It should be packaged only in single dose containers of not larger than 1-litre size.
H) BACTERIOSTATIC WATER FOR INJECTION I) STERILE WATER FOR IRRIGATION

Now the pharmacopoeia may additionally include monographs for water for specific applications, such as hemodialysis, inhalation, or irrigation. The types of water produced and the steps required are shown in flow chart.
WATER SYSTEMS:USER REQUIREMENT SPECIFICATIONS AND DESIGN QUALIFICATION:

It is the designing of water generation and treatment system which consistently supports water quality. Seasonal variations in feed water quality , change of source due to supply issues also affect output water quality. An ideal water system should
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have robust design which takes care of any such considerations and consistently gives water of desired water quality. Designing a water system involves identification of needs with respect to end resultsqualitative and quantitative. It should also incorporate treatment systems and controls at appropriate stages to ensure consistency in output water quality. Designing starts from conceiving the ideas in a systematic manner. When this conception documented, forms User Requirement Specifications(URS).
URS: ISPE( International Society of Pharmaceutical Engineering) defines URS as a

description of requirements of conditions , systems and facilities to get the required quality output consistently. URS therefore forms a part of Validation Master Plan.
URS for water systems: URS is driven by:

a. b. c. d. Input water quality considering seasonal variations Organic matter Compliance to pharmaceutical requirements End usage of water.
URS team should consist of members with specialized knowledge from

a. System water b. Designer of the system c. Validation team d. QA and e. Project management In generating URS for water system, it is necessary to classify the components and then define the sub components. Each sub component has to be then defined in terms of quantifiable parameters that substantiate end requirements of the user system. The following can be the broad guideline for classification of components 1. Process control parameters 2. Purification /Treatment requirements 3. Materials of construction for the system 4. Distribution system 5. Sanitization
1.Process Control Parameters: 1.1 pH- This is indirect measure of ionic content and hence conductivity. Ideally the
measurements are done post RO stage. The contamination with the buffer is likely and hence the location of measuring device should be in a side stream which is drained. The flow rate also needs control for stable measurements.
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1.2Conductivity- It is valuable tool for measuring total ionic quality of water. USP
and BP specify the values which are useful in developing controls. Since measurements are temperature dependent, due care must be taken in URS data. Location of measurement is generally after the final treatment step to verify the acceptable quality prior to delivery to final storage tank. In addition, conductivity meters are often installed in the return piping of distribution loops, downstream of the final point of use. The conduction of electric current depends on the ions contained (org. comp. dissolved) in water. The purer is the water, the lower is the concentration of such ions and, therefore, the lower is conductivity. For low conductivity, the reciprocal applies, high resistivity, as they are different expressions for the same phenomena. The water conductivity at the purification theoretical limit, that is, when almost all ions have been removed and only H+ and OH- remains, is 0.055 micro Siemens/cm or 18.2 Megohm.cm, at 25 C. This is called ultra pure water
1.3TOC- Installation of on line TOC instrumentation need careful evaluation for cost
reasons. However the measurement provides useful control for biofilms. USP describes instrument precision, system suitability, test methodology and calibration procedure. This is useful for URS documentation. Location of measurement is generally after the final treatment step to verify the acceptable quality prior to delivery to final storage tank. In addition, TOC meters are also installed. Feed water TOC monitoring helps to detect seasonal quality changes that could impact pre treatment or membrane fouling. Total organic carbon (TOC) is an indirect measure of organic molecules present in pharmaceutical waters measured as carbon. Analytical technologies utilized to measure TOC share the objective of completely oxidizing the organic molecules in an aliquot of sample water to carbon dioxide (CO2), measuring the resultant CO2 levels, and expressing this response as carbon concentration. All technologies must discriminate between the inorganic carbon, which may be present in the water from sources such as dissolved CO2 and bicarbonate, and the CO2 generated from the oxidation of organic molecules in the sample. The water used for the preparation of solution must have a TOC level below 0.25mg/L.
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1.4Microbial Load-Measurements of certain strains helps to ideally judge the

robustness of the system. In spite of TOC meters it is widely accepted that microbial determination is critical and TOC cannot substitute for these measurements. Method: The common methods for microbial total count are Most Probable Number Test (not reliable for low numbers), Spread or Pour Plate (can only test only 1 or 10mL respectively; not reliable for low counts) or membrane filtration, which is preferred. Media: There are various types of test media that can be used.
Incubation time and temperature:
Preferably 32oC or lower (higher temperatures than this inhibit aquatic microflora) and up to 5 days (sub-lethally damaged organisms may not revive quickly). Objectionable and indicator organisms: Any organism, which can grow in the final product, or can cause physical and chemical changes to the product, or is pathogenic, is unacceptable in purified water. Indicator organisms, such as Escherichia coli or pseudomonas auriginosa or coliforms, point to faecal contamination. They indicate possible contamination by other pathogenic organisms. The manufacturer must set specifications for total count and absence of objectionable and indicator organisms.
1.5BET(Bacterial Endotoxin Test)- BP and USP define limits for purified

water and WFI which serve as useful guide. Like microbial measurements, BET measurement is also an important tool for controls.
PYROGEN AND ENDOTOXINS

o Any compound injected into mammals which gives rise to fever is a Pyrogen o Endotoxin are pyrogenic, come from Gram negative bacterial cell wall fragments o Detect Endotoxin using a test for lipopolysaccharides (LPS) Rabbit test detects pyrogen LAL test detects Endotoxin o Ultrafiltration , distillation, & RO may remove pyrogen
1.6Hardness
Hardness of water is due to the presence of calcium and magnesium salts. The concentration of these salts makes water hard or soft. Hardness is expressed as mg/l or ppm of Calcium Carbonate (CaCO3).
Water hardness classification Soft Moderate Hard Very Hard mg/L or ppm as CaCO3 0-60 61-120 121-180 > 180
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Very hard water has the potential for forming scale in equipment, especially if evaporation occurs, for example, in boilers. Hard water must be softened before further treatment, since the calcium and magnesium salts can interfere with other purification processes. Removal is usually by water softeners that exchange the calcium and magnesium for sodium. Sodium salts are more soluble than calcium and magnesium salts, which can precipitate to form scale, or which can chelate drug products. Sodium is later removed in the deionizer or reverse osmosis units.
2.Purification /Treatment requirements:

Raw water used for generation of purified water or WFI comes from varied sources like supply from municipal storages, bore well and river water etc..
CONSIDERATION IN SELECTING WATER TREATMENT METHODS

o o o o o o Water quality specified Yield or efficiency required Nature and quantity of contaminants Reliability and robustness of equipment Availability of water treatment equipments Operation cost.
2.1Pretreatment- This involves sand filters for preliminary filtration. Further

pretreatment depends upon feed water quality which is source specific. Chlorination is done to control bacterial growth. However , it is necessary to remove the traces of chlorine to avoid damage to system membranes like RO. Charcoal bed is to be provided to remove the excess chlorine. Pretreatment equipment typically is implemented to control scale, fouling, and oxidation of final treatment equipment.
Scale Control:
Scale or precipitation occurs when the solubility of sparingly soluble salts is exceeded in the concentrate streams of RO and distillation units. The most common form of scale control is the use of water softeners. Water softeners utilize cation exchange resin in the sodium form to remove divalent cations such as calcium, magnesium, barium, and strontium. The most common forms of scale in reverse osmosis units and stills are calcium carbonate, calcium sulfate, calcium fluoride, barium sulfate, strontium sulfate, and silica. Softeners cannot control silica scale but can prevent formation of the other forms of scale through the removal of calcium, magnesium, barium, and strontium from the feed water in exchange for sodium. Sodium salts are highly soluble. Softener construction varies broadly. Vessel construction is typically plastic lined, reinforced fiberglass (FRP), lined carbon steel, or stainless steel. Piping materials
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are typically PVC, copper, or stainless steel. Multi-port valve units are used as well as individual valves. o Hard water is made water soften by removal of Ca and Mg salts. o Using zeolite exchange column-Ca &Mg exchanged for Na & Na is removed by deionizer or RO o Improves performance of RO o Does Not Remove, Exchange only o It is sanitizable but can grow bacteria. Anti-scalant/anti-foulant chemicals can also be used to control scale and fouling in RO units. These chemicals also have anti-foulant properties and can be very useful in minimizing particulate fouling. The anti-foulant properties limit deposition of inorganic and organic particulates and colloids. The capital cost of anti-scalant systems is generally significantly less than the capital cost of water softeners. Under application of the chemical may result in significant scaling of the RO or dis tillation equipment, and over application may lead to significant membrane fouling requiring frequent cleaning.
"soft" water to deioniser
by pass valve brine and salt tank
brin e
"hard" water in
zeolite water softener - exchange s - Ca and Mg for Na
drain
Adjustment of feed water pH can also be utilized to minimize scale in RO systems. Lowering of the pH increases the solubility of most sparingly soluble salts. Lowering of pH converts some bicarbonate to carbon dioxide that is not removed by RO. The system design must address this carbon dioxide or an alternate scale control method must be implemented.
Fouling Control:
Fouling is a mechanical coating of membranes rather than a chemical precipitation such as scale. Fouling occurs from common feed water contaminants such as silt, dissolved organics, colloids, heavy metals, and
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Microorganisms. Silt, colloids, and other types of particulate are generally controlled through different methods of filtration. Large particulate or suspended solids are typically minimized through pretreatment steps such as multi-media filtration, disposable cartridge filtration, nanofiltration, and ultrafiltration, or through a clarification or flocculation process.
1.Multimedia Filtration: -The most common particulate fouling control is use of a multi-media filter as the first
component of the pharmaceutical water system. Multi-media filters are pressure filters generally employing three active layers of media filtration in a pressure vessel utilized in a downward service flow. The active layers vary but are most commonly anthracite followed by a layer of sand with a final filtration layer of fine garnet. Multimedia filters can generally filter down to the 710 micron range, although not on an absolute basis. -Multi-media filters are sized as a function of the pretreatment requirement and the feed water quality. Multi-media filters are generally sized larger to provide better filtration ahead of reverse osmosis systems than ahead of either distillation units or demineralizers.
2.Disposable Cartridge Filters/Bag Filters: -The most common alternative to multi-media filtration is an inexpensive disposable
cartridge filter or bag filter. These filters reduce the capital cost and reduce the generation of wastewater, but generally increase operating cost. -Disposable cartridge filters and bag filters can filter just as effectively as multi-media filters or better as a function of the disposable filter micron rating. In cases of high flow and high suspended solids, multi-media filters are generally the better choice since they are typically automatically backwashed and necessitate very little labor.
3.Carbon filters(Organic scavangers):

-When organic fouling reduction is included, it is generally an organic scavenger, activated carbon filtration, or ultrafiltration. -Organic scavengers utilize specially selected anion resins in a pressure vessel configuration very similar to water softeners. The anion resin selected has the ability to remove a wide variety of dissolved organics from feed water and have the ability to have the organics eluted from the resin during a regeneration process. -Activated carbon has been used in several applications for organic reduction as well as dechlorination. The reduction of organics varies greatly with time in service, carbon type, application, and feed water properties. The reduction of organics through use of activated carbon may range from only a few percent to as high as perhaps 80%. It is difficult to predict the effectiveness of organic reduction with activated carbon without pilot testing.
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Microbial fouling is an issue in membrane systems .Microbial fouling can be

effectively controlled through the presence of residual chlorine in the feed water to many processes. Some of the processes such as multimedia filters, disposable cartridge filters, and softeners generally tolerate levels of chlorine that are high enough to control microbial growth and low enough to avoid significant media oxidation. Other processes such as some RO, ultrafiltration, or microfiltration processes frequently incorporate membranes or media that are not chlorine tolerant. Microbial fouling control methods in these cases often include the use of ultraviolet light upstream of the process in order to moderate the microbial
Ultraviolet (UV) light has been utilized for decades to control microorganism
growth in water systems. The UV light spectrum includes several wavelengths that are effective in minimizing the replication of microorganisms in the water stream. UV units typically incorporate UV lamps housed inside of quartz sleeves that allow penetration of UV light into the water stream that surrounds the quartz sleeves. The microbial control of UV units is based upon UV radiation penetration of the cell wall of the microorganisms. UV light is absorbed by DNA, RNA, and enzyme modules. The absorption of UV energy inhibits the ability of the microorganisms to replicate.
Oxidation Control:
-Another critical part of pretreatment systems is the implementation of a process to remove feed water disinfectants from the process stream. Most municipal feed waters utilize chlorine or chloramines for bacterial control. Many private supply systems utilize injection of chlorine for the same microbial control purpose. The chlorine or chloramines are damaging to many pretreatment and final treatment components. Ammonia can be a byproduct of dechloramination and the system must be designed to remove the ammonia or USP conductivity limits may not be met. -Distillation units and RO units that include the widely used thin film composite membranes are subject to extreme damage from chlorine compounds. Most distillation units are only rated up to 0.02 ppm free chlorine The reality is that chlorine should be at non-detectable levels ahead of all distillation and thin film composite RO systems for the most reliable operation. -Dechlorination or dechloramination is accomplished in most pharmaceutical systems through implementation of activated carbon, injection of sodium sulfite compounds, or through the use of UV light.
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A) Carbon Filtration Or Sodium sulphite
-Activated carbon beds to remove some organic compounds, chlorine that is

generally present as an antimicrobial agent and other particles. -Removal of chlorine is recommended because further treatment steps such as deionization, reverse osmosis, and distillation are affected by its presence. -Carbon beds provide a nutrient-rich environment for microbial growth and absence of antimicrobial agent makes the water susceptible to contamination. -So periodic sanitization to control the microbial levels and replacement of carbon that no longer remains organic compounds. -OR -Sodium Bisulphate does not facilitate the microbial growth as does an AC filter and less costly then AC. -Dechlorination reactions
-NaHSO3 + CL2 + H2O NaHSO4 + 2 HCL -When bisulphite is injected into the process stream, it is oxidized to sulphate, and it
also reduces free chlorine to the chloride ion. The by-products, sulphate and chloride, are removed or reduced by a de-ionizer or an RO system. -The by-products, sulphate and chloride, are removed or reduced by a de-ionizer or an RO system. -Note that bisulphite does not remove organic contaminants, whereas AC does remove organic contaminants.
B)UV Light: -Extremely high intensity levels are required for quantitative reduction of free or
combined chlorine. The range of UV light energy can vary from 10 times the energy required for microbial control to as high as 150 times the energy required for germicidal control. -The greatest advantage of UV dechlorination is that no microbial risk exists, The massive doses of UV light applied are lethal to feed water microbes. The capital cost is generally higher than sodium sulfite injection but lower than or equal to thermally
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sanitized activated carbon units. -The principal disadvantage of UV light dechlorination is that attainment of chlorine levels below the limit of detection is quite difficult without using significant UV light energy levels. The effectiveness of UV dechlorination is a direct function of the feed water disinfectant level and the UV energy level applied. Significant increases in feed water disinfectant level such as those encountered when coliform microorganisms are detected in municipal feed water may present a challenge to UV light dechlorination. Sodium sulfite injection can be used as a supplemental dechlorination method when peak chlorine levels are encountered.
Prefiltration:
o o o o Water is polished through a 5 micron filter Multiple Prefilters with different micron ratings in series can length filter life Final micron size determined by RO membrane requirements Removal of Suspended particles and Microorganisms
ADVANTAGES:
1. Removes all particles > pore size, 2. Minimal maintenance, 3. Sterilisable
DISADVANTAGES:
1. Expensive, 2. Non-regenerable does not remove Endotoxin & 3. Dissolved inorganic
2.2Final Treatment(Purification systems):

a. b. c. d. e. o o o o Deionization Reverse osmosis(RO) Ultrafiltration Distillation Electrodeionization
A) DEIONIZATION
The deionization process is performed using ion exchange porous globular resins Removes ions & ionized organic comp. The performance of the deionizer is monitored by conductivity measurement. The resin is periodically recharged to remove accumulated ions with strong acids and bases.
ADVANTAGES:
1. Simple installation, 2. Low investment, 3. Regenerable
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DISADVANTAGES:
1. Promote bacterial growth 2. High operation cost 3. Do not remove organic material or Microorganism
B) REVERSE OSMOSIS
o Removal of ions, organics comp., Endotoxin, dissolved inorganic and Microorganisms. o Physical separation of impurities through semipermeable membrane. o The most economical way of removing variety of contaminants in a water system.
ADVANTAGES
1. Minimal maintenance 2. Can eliminate ion exchange 3. Good control of operation parameters 4. More effective microbial control than ion exchange
DISADVANTAGES
1. Membrane may subjected to encrusting &clogging 2. Consumption of heat and electricity 3. Low flow rates
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4. Can support bacterial growth 5. Permeate will concentrate CO2 from feed water
USES
1. Purifies water that meets pharmacopoeia specifications 2. Feeding of distillation units prevents scaling and ensures quality WFI 3. Water for final rinse 4. Water for injection only permitted by local regulations
C) ULTRAFILTRATION
o Same principle of RO but lower pressure and more permeable membranes o Pore size of membrane is 10 to 200 0A. o UF membrane is a thin polymeric material either polysulfone or polyacrylonitrile with an anisotropic pore structure. o But cannot remove ions, gases and low molecular weight organic matter o Can produce water that meets the microbial & bacterial end toxins of WFI &/or water for final rinse for parenteral mfg o Its main features are: 1. Removal of organic contaminants such as Endotoxin 2. Operation at 80C possible 3. Sterilization at 121C possible
ADVANTAGES
1. Effective removal (>99%) of all organic molecules having a molecular weight above the NMWL. Very effective removal of pyrogen and virus, as well as particles. 2. No risk of incrustation. 3. Low consumption of water and electricity. 4. Low maintenance; well documented/accepted procedures
DISADVANTAGES
Almost no removal of ions, gases and low molecular weight organic matter (UF membranes provided with a narrower mesh have a cut-off of 1.000 dalton)
D) DISTILLATION
o Classic method for producing WFI o Principle: - phase change, mechanical separation & in some designs, centrifugal separation o Water evaporated & steamed is condensed into WFI. A portion of feed water is discharge with concentrated contaminants
ADVANTAGES
1. Remove all types of contaminants medium investment 2. Easy to operate
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DISADVANTAGES
1. Water quality is not controlled 2. High operation cost regular maintenance
E) ELECTRODEIONIZATION
Deionizes water by means of applied electrical current removal of dissolved inorganic compound
ADVANTAGES
1. No chemical regeneration, 2. Low operating cost, 3. Sanitizable
DISADVANTAGES
Needs RO or DI pretreatment relatively high capital cost
3.Materials for Construction: -Primary source of contamination. It should be compatible with the processes
adopted for sanitization, cleaning and passivation. -Materials for construction should be resistant to the chemicals or additives and temperatures used in sanitization. Turbulent flow and elevated velocities accelerate wear and tear. -Stainless steel of suitable grade is the material recommended. Electro polishing provides resistance against corrosion and limits bacterial growth. Materials should be selected to avoid shedding, extractability and microbial activity.
4.Distribution system: 4.1Storage TankAbility to withstand full vacuum is desirable so that ozonisation or steam penetration can be effective. In hot water circulation system, return flow is through spray nozzle which ensures permanent rinsing of the internal surface and keeps it hot. Storage tanks are to be fitted with hydrophobic vent filter to reduce bioburden and particles. Inert blanket over the tank head space is a must to avoid absorption of CO2 and thus its effect on conductivity. In WFI storage tanks, 0.2 microns hydrophobic vent filter is recommended. The filters should be capable of withstanding sterilization.
1] Continuous Hot Storage:

The continuous hot system is self-sanitizing and microbial problems are virtually always external to the sanitary system. A continuous hot system is generally considered to be the most conservative and lowest risk storage system design. Use point heat exchangers for cooling or cooled sub-loops are commonly employed where hot water is not suitable for manufacturing.
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2] Ozonated Storage:
An excellent alternative to continuous hot storage with cooled water for usage is continuously ozonated storage as shown below. The continuous application of ozone ensures low microbial counts in storage and the stored ozonated water can be used to periodically sanitize the distribution system. Ozone can destroy most (i.e., those not embedded in biofilm) microorganisms in seconds of contact time, is easily removed from manufacturing water with UV light, and has been successfully documented in many installations. Microorganisms embedded in biofilm necessitate significantly longer ozone contact time for destruction. The residual ozone in water from storage is removed with inline UV units downstream of the distribution pump. These UV units use approximately three times the energy, per gallon processed, as UV units sized for microbial control. Continuous addition of ozone to stored water will cause an increase in conductivity. The increase may cause the conductivity to rise above the USP conductivity limit during lengthy periods of low or no water usage. This issue is eliminated or minimized through repurification of some of the stored water, use of appropriately low applied ozone levels. Since ozone is an extremely strong oxidizing agent, material compatibility must be addressed in system design. Most ozonated systems use components constructed of 316L or 316 stainless steel. PVDF piping, fittings, and valves are also very compatible with ozone.
3]Ambient Storage:
Many systems utilize ambient temperature water storage without continuous or intermittent ozone. These systems rely on periodic hot water sanitization (80 to 121C) or chemical sanitization. Properly designed sanitary 316 stainless steel systems with daily hot sanitization are commonly used with great success in both WFI and PW applications. Many systems operate successfully with hot sanitization less frequently than daily, but the microbial risk increases.
4.2Distribution LoopThis is the most important part of the water system since incidences of stagnation and dead legs cause failures due to microbial growth.URS should cover-whether hot(65C-80C), ambient(18-28C) or cold(4-10C) loop is required -piping slope to avoid stagnation -drain points -pump design to deliver turbulent flow to retard the development of biofilm -velocity of water flow -usage points in distribution loop and minimum dead legs -sanitization methods -User points -sampling points
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4.3Heat ExchangersThese are provided to reduce the temperature of output water. It also conserves energy by exchanging heat from outlet water to inlet water. The possibility of mix-up at the inter phase should be avoided by providing proper material and design to the exchanger.
5.Sanitization: 5.2HEAT
o Heat is the preferred disinfection method because it is safe, inexpensive, and effective and leaves no residues. o The most reliable method and disinfection by products. o Time and temp. of the heat disinfection cycle: >60c for purified water for 1 hr. and > 70c for WFI for 1 hr. in continuous circulation
5.2OZONE
o It is highly unstable, and is one of the strongest oxidizing agents. It leaves no residue. However, because it is highly reactive, O3 must be stripped from the water before the water is used to manufacture pharmaceuticals. Otherwise it will quickly degrade the actives. o The use of Ozone in storage and distribution systems is growing because of its relatively low capital and operating costs, compared to hot water generation and storage.
5.3UV LIGHT (254 nm UV light use)

o UV light is bactericidal, but water can attenuate the radiation quickly. The design and maintenance of the system is important. The units do not sterilize water as is sometimes claimed; at best the manufacturer can expect about a 3 log reduction of bacteria for properly installed and maintained equipment. o Some organisms have efficient UV repair mechanisms, and so sub-lethally damaged organisms can grow again if they pass through the unit too quickly. They can then colonise the water treatment system downstream of the UV light unit, causing considerable problems.
5.4CHLORINATION
This is an effective pre-treatment for control of microbial load in fed water. It is also given if there is intermediate storage.
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5.5DISINFECTION OTHER CHEMICALS

o XO2-the peroxygen family of hydrogen peroxide, peracetic acid and perxitane.good disinfectant o Halogen strong and good disinfectants, but leaves residues that have corrosive effect. o Formaldehyde- good effect but has a toxic vapour at low levels and persistent residues so system becomes re-contaminated therefore not used widespread.
VALIDATION OF WATER SYSTEM:

Major components
Installation Qualification (IQ) Operational Qualification (OQ) Performance Qualification (OP) Validation maintenance
Validation is a program for assuring that the product is acceptable by systematically verifying the installation, operation, and performance of the water treatment and distribution process.
A) MAJOR COMPONENTS 1. Installation Qualification (IQ)

IQ verifying and documents that the system has been properly installed. Operating procedures, instrument calibration, and preliminary operating range should be established prior to implementation of the test protocol.
2. Operational Qualification (OQ)

OQ tests and documents that the system functions properly and ensure that the control sequences for equipment function in the correct order.
3. Performance Qualification (OP)

PQ generates data to characterize the ability of the system to repeatability produce, hold and distribute water over an extended period of time
4. Validation Maintenance
Validation of water systems is an ongoing activity that the system continuously produces water which meets the quality standards.
B) VALIDATION FOR WATER SYSTEMS CONSISTS OF THREE PHASES Phase 1: 2 4 weeks Phase 2: 4 weeks Phase 3: 1 year 1. Phase 1 Investigational Phase (2 4 Weeks)
o IQ and OQ o Develop operational parameters cleaning and sanitization procedures and frequencies o Sample daily at each point of use o End of Phase I, develop SOPs for the water system
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2. Phase 2 (Verifying Control), (4 Weeks)

o Demonstrate the system is in control o Same sampling as in phase 1
3. Phase 3 Verifying Long-Term Control (1 Year)

o PQ o Demonstrate the system in control over a long period of time o Weekly sampling
C) INSPECTION
When commencing an inspection, start with the use of water the inspection approach will be different according to the products being made. Options may include: 1. Sterile products: Production of WFI is the most challenging. Check pyrogen and Endotoxin requirements for the water. 2. Non-sterile products: Check if there are any special requirements for the pharmaceutical products, such as aluminium limit test for dialysis products. 3. Liquid products: These are more susceptible to microbiological contamination so more stringent bacterial limits may be appropriate. 4. Solid dose products: e.g. tablets and capsules may use water as part of the granulation step. 5. Water is also used for washing and rinsing equipment. It is necessary to have specifications for these types of water. 6. Check specifications and trends, especially the requirements for pyrogen or endotoxins for sterile manufacturing, and microbial limits. Microbial limits are always a problem. Only a few of the pharmacopoeia recommend microbial limits but the pharmaceutical manufacturer should be setting its own limits and frequency of monitoring.
D) CHECK FOR
1. Check for weld quality. Electropolished internal welds smooth internal surface which helps in reducing bacterial colonization. 2. Hygienic couplings - no threaded fittings in the water flow which can become contaminated. Example on next slide. 3. "Passivation" records. Whenever equipment in contact with water is repaired or changed, passivation should be considered, especially for systems producing water of very high purity. Passivation is the removal of free iron from the surface of the steel. This is performed by immersing the steel in an oxidant, such as nitric acid or citric acid solution. Since the top layer of iron is removed, passivation diminishes surface discoloration. While passivation does not affect the thickness or effectiveness of the passive layer, it is useful in producing a clean surface for a further treatment. WFI systems may need to be periodically re-passivated.
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4. No direct connections to drains or sewers, and that non-return valves and backflow preventers are working or have been properly checked. Tundish is the engineering term for an air break to a fixed funnel, to prevent bacteria from a drain or sewer growing into the water treatment plant. 5. Check pipes and pumps: There are hygienic couplings (Ladish or TriClover clamps), welded pipes and hygienic pumps. Note also hygienic sampling points. 6. Assess physical condition of equipment. Look for stains and leaks that could indicate problems. 7. Check to make sure heat exchangers are double tube or double shell. If not, there should be continuous pressure monitoring to ensure the heating or cooling liquid does not contaminate the pure water through any pinholes. For single plate heat exchangers, the pressure of the heating or cooling liquid must be LOWER than the purified water at all times. An exception may be where the liquid is of a higher purity than the water being produced. 8. Note from the heat exchanger example above that even high grade stainless steel, such as 318SS, can be subject to pit corrosion! 9. Check maintenance of the entire system by examining the maintenance procedure and records. For example, check the O rings of connections and the maintenance of the pump seals. The pump on the left shows good connections and a good standard of engineering. 10. The one on the right shows a threaded coupling, called a milk coupling or sanitary coupling. Threaded couplings and couplings in general should be avoided whenever possible. 11. Where welding is impossible, hygienic couplings should be used or milk (sanitary) coupling, which are acceptable since the threaded fitting is not part of the fluid pathway, and so should not contaminate the water. 12. The inspector must be satisfied that hidden seals and O rings have actually been removed, examined and/or replaced during maintenance. 13. Check air filters which should be hydrophobic (otherwise, they can be blocked by a film of water condensate) and should be able to be sanitized. Those on WFI plants should be able to be sterilized and integrity-tested. 14. Check replacement frequency, which the pharmaceutical manufacturer should determine with assistance from the filter supplier. 15. Check burst discs because if they have ruptured without being noted the storage system can become contaminated. 16. By-pass valves and by-pass lines are often used for maintenance procedures. In critical situations there may be, for example, two pumps in parallel, in case one breaks down.
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Additionally, engineers like to be able to replace a pump or a filter without dismantling large sections of the system. However, valves in bypass lines can leak, be left open, or be contaminated, and so they are undesirable. A blanking piece is often better during operation of the system, so that there is no physical connection.
17. Activated carbon bed sanitization these can become overgrown with bacteria quite quickly.
Check sanitization frequency to ensure the AC remains uncontaminated. 18. Calibration of temperature-compensated conductivity meters is often overlooked or not done properly. 19. Influence of plastic pipe adhesive on Total Organic Carbon (TOC) compliance - some adhesives will leach into the water and these can be volatile. 20. Non-condensable gases in pure steam for example nitrogen and oxygen. They affect the apparent pressure of sterilization processes, lowering their effectiveness. 21. Polypropylene welding inspection. If polypropylene pipe is used and welded, has the manufacturer checked for pin holes? 22. Retrospective validation of WFI system. Many water plants are 10 20 years old and may not have been properly validated. Can they be properly retrospectively validated? 23. Rouging of WFI Systems. The high temperatures of these storage and distribution systems seem to lead to a build up of a deposit known as rouge. Check to see if the manufacturer carries out a periodic physical check for this effect, and what steps are taken to remove the rouge. Sometimes repassivation is effective. 24. Spray ball efficacy. This is not easy to determine and must be assessable. If the spray ball is jammed it will not work properly, but because it cannot be seen it is not easy to check. There are non-rotating or fixed spray balls or sprays cones which may be better in small systems. 25. UV light monitoring performance and lamp life. The lethal radiant energy from UV lights drops off quickly, so many have to be replaced approximately every 6 months. Does the manufacturer have an hour meter and is the lamp replaced according to the suppliers recommendations? Can the intensity of the light be measured? 26. Validating ozone dosage is difficult. It may be possible for the manufacturer to get the suppliers validation studies showing worst case lethal effects.
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27.
Water softener sodium chloride specifications. Like any ancillary
material, the salt, acids and alkalis used as consumables in water treatment plant should have purchase specifications. Note: testing is not required unless for trouble shooting purposes. 28. Check the drawings to see if valves are marked as Normally Open or
Normally closed, and then physically check the valve position. It is

surprising sometimes those valves are not returned to the correct operating position; for example, after de-ionizer regeneration.
BIOFILMS:
Biofilms are a collection of micro organisms surrounded by the slime they secrete, attached to either an inert or living surface. Biofilms exist wherever surfaces contact water. When microbial levels are not controlled in a water supply system, they will eventually forms biofilms. Slime (glycocalyx) enhances the bacterial cell ability to adhere to the surface. The slime layer helps adhere other bacterial cells and nutrients which float past, and also acts as a protective layer, which resists chemical disinfectant penetration.
Biofilm Development Factors: Surface material has no or little effect. Surface area is one of the primary factor. RO membranes, DI resins, storage
tanks, cartridge filters and joints in pipe fittings etc all provide surfaces suitable for m.o. growth.
Dead leg is an area in a piping system where water can become stagnant and
where water is not exchanged during flushing. Modern piping design limits the length of any dead end pipe to 6 times the pipes diameter. This is known as the sixdiameter rule.
Smoothness- smoother surfaces delay the initial build up of attached bacteria,

but does not affect the total amount of biofilm after several days.
Flow velocity High flow will not prevent the bacteria attachment nor completely
remove the existing films but it will limit the thickness of the film.
Nutrients limiting will limit the growth of bacteria. Detecting and Counting: -Routine monitoring of bacterial levels is an essential part.
-The most common way to enumerate bacteria in water is PLATE COUNT.
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-But a low plate count doesnt mean that bacteria are less because more than 99% of bacteria in the water systems are attached to the pipe surfaces which cannot be counted by plate count method. -If recent flushing has not distrupted the integrity of mature film, it may not slough off the cells in the water. -As biofilms grow, single cells or rafts of cells are sloughed off during flushing. This resulted in random particle showers of bacteria, which can explain day-to-day fluctuations and occasional high bacteria count results.
Biofilm Recovery(Regrowth):
it is common to observe a rapid regrowth of biofilm immediately following sanitization. Incomplete removal of the biofilm will allow it to quickly return to its equilibrium state, causing rebound in total plate counts following sanitization.
What we can do?

-use of biocide -Purify water -Flush -Minimize crevices and avoid dead legs -Sanitize -Take expert advise
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7.SERVICE FACILITIES:
Medical services, canteen facilities, washing and toilet facilities, protective clothing , change rooms, educational programmes and training, and safety programmes will be covered in the personal facilities.
FIRE PROTECTION SYSTEMS:

Pharmaceutical manufacturing facilities are typically provided with automatic fire suppression and protection system throughout.
Sprinkler Systems Wet Sprinkler System: A sprinkler system with automatic sprinkler heads
attached to a piping system containing water and connected to a water supply, so that water discharges immediately from sprinkler heads that are opened directly by heat from a fire.
Dry Pipe Sprinkler System: A sprinkler system using automatic sprinklers

attached to a piping system containing air or nitrogen under pressure which, when released during the opening of the sprinkler heads, permits the water pressure to open a dry pipe valve. The water then flows into the piping system and out of the opened sprinkler heads.
Preaction Sprinkler System: A sprinkler system using automatic sprinklers

attached to a piping system containing air that may or may not be under pressure, with a supplemental detection system (smoke, heat, or flame detectors) installed in the same areas as the sprinklers. Actuation of the detection system opens a valve that permits water to flow into the sprinkler piping system and to be discharged from any sprinkler heads that may be open. Preaction systems can operate by one of the following three basic means: Systems that admit water to the sprinkler piping upon operation of detection devices(single interlock). Systems that admit water to the sprinkler piping upon operation of detection devices or automatic sprinklers (non-interlock). Systems that admit water to sprinkler piping upon operation of both detection devices and automatic sprinklers (double interlock). Deluge Sprinkler System: A sprinkler system using open sprinkler heads attached to a piping system connected to a water supply through a valve that is opened by the operation of a detection system (smoke, heat, flame detectors, etc.) installed in the same areas as the sprinklers. When the valve opens, water flows into the piping system and discharges from all attached sprinkler heads.
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Antifreeze Sprinkler System: A wet pipe sprinkler system using automatic

sprinkler heads attached to a piping system containing an antifreeze solution and connected to a water supply. The antifreeze solution is discharged, followed by water, immediately upon operation of sprinkler heads opened directly by heat from a fire
Deluge Foam-Water Sprinkler and Foam-Water Spray Systems Foam-Water Sprinkler System: A special system of piping connected to a
source of foam concentrate and a water supply, and equipped with appropriate discharge devices for extinguishing agent discharge and for distribution over the area to be protected. The piping system is connected to the water supply through a control valve that is usually actuated by operation of automatic detection equipment (smoke, heat, flame detectors, etc.) installed in the same areas as the sprinklers. When this valve opens, water flows into the piping system and foam concentrate is injected into the water; the resulting foam solution discharging through the discharge devices generates and distributes foam. Upon exhaustion of the foam concentrate supply, water discharge will follow the foam and continue until the system is shut off manually.
Foam-Water Spray System: A special system of piping connected to a source

of foam concentrate and to a water supply and equipped with foam-water spray nozzles for extinguishing agent discharge (foam or water sequentially in that order or in reverse order) and for distribution over the area to be protected. System operation arrangements parallel those for foam-water sprinkler systems as described previously.
Closed-Head Foam-Water Sprinkler System: A sprinkler system with

standard automatic sprinklers attached to a piping system containing air, water, or foam solution up to the closed-head sprinklers, that discharges foam or water directly onto the fire after the operation of a sprinkler(s). This system can also be a dry-pipe or preaction type system.
General Design Requirements

The building will typically be provided with one or a combination of systems to provide automatic fire suppression and protection throughout the building. Suppressing agents other than those mentioned above (such as CO2, Dry Chemical, Foam and Halon alternatives) can be used to address specific hazards, and would not be used as a suppression agent throughout. In general the first choice for automatic fire suppression is a wet-pipe sprinkler system. This most common type of system provides the quickest actuating, most reliable, and least expensive type of suppression for most applications. In areas which are susceptible to water damage or where contamination is a concern, the use of preaction sprinkler systems are appropriate. These space
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may include, computer rooms, high voltage electric rooms, telecommunications rooms, sterile areas, containment areas, and other GMP spaces. At a minimum, a single interlock preaction system can be provided. Where the accidental or unnecessary discharge of water is a concern, a double-interlock preaction system can be provided.
Dry-pipe valve systems are appropriate for use in unheated spaces such as
remote detached buildings, warehouses, outside loading docks, combustible concealed spaces, parking garages, etc.
Antifreeze sprinkler systems are also appropriate for unheated spaces but
are typically limited for applications requiring twenty sprinkler heads or less, such as small loading dock areas or a vestibule. Caution must be taken with the application of these systems to support local water company requirements regarding to crossconnection control (backflow prevention) due to the addition of the antifreeze to the sprinkler system.
Control and monitoring:

Water flow detection and alarms are typically provided for each floor, zone, or specific hazard space and are monitored by the building fire alarm system. Each floor or zone is equipped with electrically supervised water supply control valves that are also monitored by the building fire alarm system. Other items such as fire detection and loss of air pressure are monitored for preaction, dry and deluge type systems.
Portable Fire Extinguishers

Portable fire extinguishers are provided to suit the type of hazard and are provided in accordance with locally adopted building codes and NFPA 10 Portable Fire Extinguishers. Extinguishers are typically the dry chemical multi-purpose ABC type, but can be water, CO2or other substance depending on the occupancy and hazard involved.
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References:
1. Good Design Practices for GMP pharmaceutical Facilities by Signore and Jacob 2. www.who.org 3. www.fda.gov 4. Encyclopaedia of pharmaceutical technology vol-16 water for pharmaceutical use 293-306 5. Types of water and its applications in oral and parenteral dosage forms; pharma times vol.36; December 2004 6. WHO GMP: water for pharmaceutical use (WPU) 7. Water system design and planning-ppt. 8. Pharma Times, Vol. -37, August -2005, pg -9-13 9. ftp://ftp.who.int/medicines/GMP/gmptraining/m09.ppt 10.Production and Operations Management Vol. 5, No. I. Spring 1996 11.Manufacturing Strategy Concepts ( PDF) Massachusetts Institute of Technology Sloan School of Management 12.GMPs for Pharmaceuticals by James Swardbrick. 13.How to practice GMP by P. P. Sharma, 14. Drugs & Cosmetics Act 1940 , by Vijay Malik 17 th edition eastern book company
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HVAC NITU K. CHANGOIWALA
Seminar On
HVAC & PERSONNEL FACILITIES
GUIDED BY: Dr. R. K. PARIKH
PREPARED BY: NITU K. CHANGOIWALA M.PHARM I ROLL NO. 04 YEAR:- 2009-10
DEPT. OF PHARMACEUTICS & TECHNOLOGY L.M.COLLEGE OF PHARMACY AHMEDABAD-09.
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HEATING, VENTILATING & AIR- CONDITIONING SYSTEM HVAC (pronounced either "H-V-A-C" or "aitch-vak") is an acronym that stands for the closely related functions of "Heating, Ventilating, and Air Conditioning"the technology of indoor environmental comfort. HVAC system design is a major subdiscipline of mechanical engineering, based on the principles of thermodynamics, fluid mechanics, and heat transfer. Refrigeration is sometimes added to the field's abbreviation as HVAC&R or HVACR, or ventilating is dropped as in HACR. Heating:There are different types of standard heating systems. Central heating is often used in cold climates to heat private houses and public buildings. Such a system contains a boiler, furnace, or heat pump to heat water, steam, or air, all in a central location such as a furnace room in a home or a mechanical room in a large building. The system also contains either ductwork, for forced air systems, or piping to distribute a heated fluid and radiators to transfer this heat to the air. The term radiator in this context is misleading since most heat transfer from the heat exchanger is by convection, not radiation. The radiators may be mounted on walls or buried in the floor to give under-floor heat. Ventilating:It is the process of "changing" or replacing air in any space to control temperature or remove moisture, odors, smoke, heat, dust and airborne bacteria. Ventilation includes both the exchange of air to the outside as well as circulation of air within the building. Methods for ventilating a building may be divided into mechanical/forced and natural types. Air- conditioning:Air conditioning and refrigeration are provided through the removal of heat. The definition of cold is the absence of heat and all air conditioning systems work on this basic principle. Heat can be removed through the process of radiation, convection, and Heat cooling through a process called the refrigeration cycle. The conduction using mediums such as water, air, ice, and chemicals referred to as refrigerants. An air conditioning system, or a standalone air conditioner, provides cooling, ventilation, and humidity control for all or part of an industry, house or building
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Heating, ventilation and air conditioning (HVAC) constitutes up to 35 percent of energy used in manufacturing facilities..When the opportunity exists, energy conservation should be a factor in the original equipment selection and system design. The best HVAC design considers the interrelationship of building systems while addressing energy consumption, indoor air quality, and environmental benefit .HVAC systems can vary in design and complexity. Modifications can be added to the basic system to reach the desired HVAC operation. DESIGNING OF HVAC IN BUILDING SHOULD CONSIDER FOLLOWING:1. Air intake should be designed & situated to protect from sabotage. 2. Consider the need for filtration. 3. Units should be located in restricted access areas.
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System Design Criteria

Specific facility and process criteria define the system solutions that are provided. These criteria are defined as follows.
Temperature and Moisture :Space and process temperature and moisture (or relative humidity) conditions are generally determined by the product or process performed. Personnel comfort is also important, though secondary to the product requirements. In general, most product or processes can be performed within temperature and relative humidity conditions comparable to human comfort and system control parameters. On occasion, products or processes are sensitive to moisture and may even attract moisture hygroscopically. If product or process requirements are significantly outside of these parameters, an independent enclosed process environment is often provided. Generally, process operators may be gowned at levels from laboratory coats to full coveralls with head, face, hand, and shoe covers. This level of gowning requires lower space temperature and relative humidity conditions than a standard occupied space to increase personnel comfort and reduce shedding of contaminants. Uncomfortable operators are also more prone to commit errors. Depending on specific gowning conditions, temperature setpoints generally range between 65 and 70F, and relative humidity setpoints between 40% and 50%, depending on temperature setpoint. Independent of gowning requirements, relative humidity ranges must be care-fully selected. Continuous relative humidity levels below 15% can cause static electricity discharge and health concerns and levels above 60% can be the source of microbial growth and corrosion. Areas may be designated to operate at a range of controlled temperature and relative humidity to provide flexibility.These must be designed for operation at full load conditions at either end of the operating range. Allowable space and system control tolerances must also be identified, as well as the impact of these tolerance requirements on the systems design. Proper outdoor ambient design conditions must be determined in order to select the proper conditioning equipment. Equipment is designed to meet the indoor design criteria based on outdoor conditions and the capacity of the equipment. If outdoor conditions are chosen too conservatively, the equipment will be oversized, costing more than required and possibly requiring more energy for operation. If conditions are not chosen conservatively enough, space or process conditions may not be met under certain circumstances. An assessment must be made as to the possible risks of not making space or process conditions and the effects on productivity.
Air Cleanliness:The level of acceptable airborne contamination within the space must be identified,whether supporting product quality or employee safety.
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Environmental cleanliness is determined by several factors: The quality of air introduced into the space The quantity of air introduced into the space The effectiveness of air distribution through the space The effectiveness of the removal of the air contaminant Removal of the contaminant as close to its source is always the most effective method of contamination controlwhether it is central filtration at an air handling unit before supply to the facility, or dust collection at a point source of contamination within a space. Clean room design takes contamination control to its highest level. Federal Standard 209 historically had been the document governing clean room design. This standard has been replaced by the ISO 14644 and 14698 global clean room standards. Previously, clean room cleanliness was categorized by cleanliness classes, which were qualified by the quantity of 0.5 micron or larger particles per cubic foot of air within a specific area. Particulate control is crucial because particles entering the product may contaminate it physically or through microorganisms associated with the particle. Standard categories of cleanliness were Classes 100000, 10000,1000, 100, 10, and 1. As an example, the FDA Guideline on Sterile Drug Products Produced by Aseptic Processing recommends a minimum of Class 100 when measured not more than 1 foot from the sterile open product work site; that is, no more than 0.5 micron can occupy any cubic foot of air within the space at any time. The ISO standards have been an outgrowth of these classes but have expanded the classifications to ISO 1 through 9 and widened the range of particulate sizes to micron through 5 microns. A rough comparison of the ISO and Federal Standard 209E is as follows:
ISO 1 2 3 4 5 6 7 8 9
Federal Standard 209E ----1 10 100 1000 10000 100000 1000000
Air must also have low microbial levels. The above guidelines also recommend a maximum allowable level of colony-forming unit (CFU) per given volume of air. Particulate filtration can eliminate the majority of microbial contamination. In areas with high background microbial levels (such as facilities surrounded by large amounts of farmland); however, other methods may also be employed such as carbon bed prefiltration.
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Pressurization
Space relative pressurization will be determined primarily by requirements of the product, but also by characteristics of the product that may adversely effect personnel. Space containment and isolation techniques, in general, can protect the product, the operator, or both. Where product contamination control is required, the space relative pressurization must be designed to assure that the movement of exfiltrated air is from the clean to the less clean areas. In some cases, especially when dealing with hazardous products (e.g., high potency compounds), this relative pressurization and resultant air movement is sometimes reversed to contain the hazard and protect personnel. In these cases, product contamination can be controlled by the use of special laminar flow hoods or personal isolation suits, and/or positive and negative pressurization utilizing airlocks. Some operations may require flexibility for either positive or negative pressurization, depending on the application.
Building Intake and Exhaust:Careful attention must be paid to the incoming system air quality. This can be specific to the area in which the facility has been constructed such as an industrial area. An industrial area may have a more corrosive or chemical laden air quality. These issues must be carefully considered when selecting filtration systems so as to minimize the possibility of product contamination. Most often, however, building intake re-entrainment or its own effluent is the greater problem. Careful consideration must be made as to the impacts of building exhaust and relief systems, loading docks and other incidences of vehicle exhaust and electrical generator exhaust. Analysis must be made of the subject buildings impact on itself and other surrounding buildings, and their impact on the subject building. Potential future building activities should also be considered. Rooftop activity safety should also be analyzed and a safety rooftop environment should be provided for routine maintenance activities.
Noise Considerations:Given the overriding concerns for durability and cleanability in process spaces, little can be done to dampen the finished surface acoustic qualities. By definition a cleanable space has smooth, hard finishes with simple geometries that reflect rather than absorb sound. This makes the control of noise contributed by utility systems critical in these spaces. Sound attenuation can be added to supply and exhaust air systems. Dust collection inlets, however, tend to be the greatest contributor to space noise and absolute attention to design parameters can minimize the sound radiated from these inlets. Manufacturing facilities also tend to utilize large process and utility equipment that can radiate noise to the outdoor environment. Local ordinances and community goodwill may require that noise generated by this equipment be minimized. Methods of enclosure and the specification of sound attenuation devices can significantly reduce noise transmitted outside of the facility.
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Cost Considerations:Pharmaceutical manufacturing facilities and processes are extremely costly facilities to design, construct, and operate. When designing a facility and process, careful consideration must be made of the initial construction cost, balanced against life cycle operating costs. Careful analysis must be made of all of the components that comprise a facility or process design. A cost cutting measure taken during the initial capital expenditure can multiply into huge operating costs by years of inefficient operation. Conversely, a complex, cost intensive project can take too long to build and commission, which may affect speed to market and ultimately production and sales.
Heating Systems:Heating of facility and process systems is generally accomplished utilizing steam or hot water as the heat source. There may also be intermediate methods of heat transfer utilizing a secondary steam or heating hot water system. Heating can also be provided by electric means that is easily controlled but is expensive to operate and therefore not in widespread use. Steam used for sterilization of containers or equipment or that comes in direct contact with the product through a process or though humidified room air in an open product space must be clean steam. This steam is produced in a dedicated heat exchanger or boiler supplied with purified feed water that is also free of chemical additives. Piping for clean steam is preferably welded stainless steel.
Cooling Systems:Cooling of facility and process systems is generally accomplished utilizing chilled water, condenser water, or direct refrigerant expansion (DX) as the heat sink. In isolated cases, a water/anti-freeze solution or other heat exchange fluid may be utilized, generally without a phase change. Primary chilled and condenser water is usually generated central cooling system. It is then distributed throughout the facility to points of use that include cooling coils, heat exchangers, and jacketed heat exchange processes. Plant chilled water is generally produced utilizing watercooled or air-cooled chillers. Chilled water supply temperatures are usually in the range of 40 45F and are determined by the requirements of the cooled medium, generally air.
Humidification Systems:In most cases, air supplied to the space or process will require the addition of moisture to maintain relative humidity conditions. Moisture is generally provided utilizing steam injection and in some cases atomized water utilizing compressed air. In the cGMP environment, the added moisture cannot be a source of contamination. Its source is therefore generally purified water that is then atomized or converted to clean steam. These humidifiers are typically constructed of stainless steel.
Dehumidification Systems:In cases of high latent loads from processes or high quantities of outside ventilation air, the building cooling system may not be capable of the higher dehumidification requirements. Several moisture removal methods are available.
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These include low temperature latent cooling used in concert with reheating, solid and liquid desiccant drying systems, and the injection of sterile, dry compressed air into the air stream.
Supply Air Handling Systems

Air systems have the greatest influence over the environment within the space or process that it serves. It assists in determining the temperature, moisture level, and cleanliness of that environment. It also assists in the relative pressurization of the space or process.
Space Supply Air Handling Systems:Supply air systems are divided into four specific components: prime movers, distribution, terminal control equipment and terminal distribution equipment.
Primer Movers:
Prime movers on the supply air system are generally enclosed in an air handling unit comprised of several components. The device that drives the air is a fan.Coils are used to transfer heat into or out of the air stream. Humidification devices are often placed inside of the air handling unit but can also be installed within the ductwork outside of the unit, saving unit casing cost.Air systems tend to be noisy. Contributors are primarily fans, dampers and terminal air control boxes. Sound attenuation is often place in or near the air handling unit to decrease the radiated noise of the fan. Concerns here are the type of attenuator, which could also be a source of particulate and microbial growth.
TYPICAL AIR HANDLING SYSTEM COMPONENTS:-
Distribution:Distribution is generally sheet metal ductwork, although it can be piping or other materials. The greatest consideration is often the material.Galvanized sheet steel is most often used, but is difficult to sanitize. If the material is open to product or product space or must be frequently decontaminated, it is often specified as stainless steel.
Terminal Control Equipment:This includes air volume control boxes, terminal heating and cooling coils, terminal humidification and sound attenuation. Air volume control boxes control the air quantity delivered to the space.Terminal cooling coils provide for space subcooling and or dehumidification. Terminal heating coils provided for reheat of space air to support dehumidification and room temperature control. Accessibility for maintenance is the primary concern for these devices. Terminal humidifiers provide
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additional moisture to the space greater than the system can.
Terminal Distribution Equipment:These includes diffusers, registers and grilles,and terminal filtration. Diffusers, and registers and grilles introduce air into the space. Proper application of the different types of devices is critical to maintain effective distribution. The airflow direction into the space is important.Unidirectional diffusers are often specified instead of the aspirating type to provide, in concert with the exhaust terminal device, a sweeping effect in the room to more effectively remove particulate from the space. Another important consideration is device cleanability within the space. The device cannot be a source of contamination. Terminal filtration is applied most often where space cleanliness is paramount.While this application of filtration can protect the space and product from contaminant within the air system, it can also protect the air system from product or contaminant within the space in case of system failure. Important considerations for the selection and placement of terminal filtration are its location, change out requirements, and accessibility for testing.
Different components of HVAC and their functions:-
Silencer
Flow rate controller
Fan
Filter
Weather louvre
Control damper
Prefilter
+
Humidifier Terminal filter
Cooling coil Heating coil with droplet separator
Production Room
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HVAC & PERSONNEL FACILITIES NITU K. CHANGOIWALA
1. SILENCER
The silencer is not important from a GMP point of view, but from an environmental one, as ventilation units can be very noisy. Be sure that the silencers are manufactured of suitable materials as the linings of standard silencers can contaminate air with particulates. Depending on the local legislation, the installation of silencers can be mandatory. To prevent insects, leaves, dirt and rain from entering. Weather louvre and silencer are a less critical element compared to the components associated with the flow rate control. Automated adjustment of volume of air. For humidification purposes, especially in clean areas, high purity water should be used, to avoid contamination. The cooling unit is important during the hot season. Be aware that stagnating water (condensed water) can bring bacterial growth, which can contaminate the filters, pass through them (depending on their retention properties) and end up contaminating production areas. Dampers to control pressure differentials are important. They can be automated or fixed. As filters get dirty the system pressure losses increase, and if airflow is not regulated, the flow decreases and pressure differentials change. This could cause flow reversal and crosscontamination. Variable speed drives for fan motors are also commonly used to control airflow. In some cases, it is necessary to have very dry air for galenical reasons in certain rooms (production of effervescent tablets and humidity sensitive products in general). To generate dry air, the air supplied to the production is passed over an adsorbent (silica gel, lithium chloride, etc.) where the humidity is removed from the air. The adsorbent is then re-generated, on a continuous or on a batch-wise base.
2. WEATHER LOUVRE
3. FLOW RATE CONTROLLER

4. HUMIDIFIER 5. COOLING UNIT
6. CONTROL DAMPER
7. DEHUMIDIFIER

8. AIR DIFFUSOR (REGISTER)

The air flows into the rooms via so-called registers (diffusors), which are built and installed in such a way that the air is distributed evenly. In many cases, the terminal filter panel and diffusors are incorporated into one unit.
9. DUCTS
To transport air. To eliminate particles of predetermined dimensions and/or microorganisms.
10. FILTERS
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Types of filters used in HVAC

Primary Panel filters, which are used mainly for lower filtration efficiency or as pre-filters Secondary filters, consisting of mini-pleated media or filter bags used for higher filtration efficiency. HEPA or tertiary filters, usually being the final filter in the system, providing the highest filtration efficiency.
FILTER CLASSES
Dust filters Standard Aerosol
Coarse
Dp > 10 m
Fine
10 m > Dp > 1 m
HEPA
Dp < 1 m
ULPA
G1 - G4
EN 779 Standards
F5 - F9
H 11 - 13
U 14- 17
EN 1822 Standard
ULPA- Ultra-Low Penetration Air filter HEPA- High Efficiency Particulate Air filter
Filters are certified by the suppliers (challenge/efficiency test), but are often not properly installed or can be damaged. Leak tests (integrity tests), showing leakage of air through the filter itself or through its frame, therefore, have to be performed. Integrity tests are usually only carried out on the Aerosol filters (HEPA & ULPA). Integrity or penetration testing is performed to detect leaks from the filter media, filter frame and seal.
FILTER POSITION
The filtered air entering a production room can be coming from:

An air-handling unit, equipped with pre-filtration and the main (HEPA) filter, but at some distance from that room (AHU mounted final filter) An air-handling unit, equipped with pre-filtration in the AHU, and an additional filter (HEPA) situated immediately on the air outlet.
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In many cases, there are only filters in the AHU. However, for injectables and sterile forms, it is recommended that they be placed in terminal position, though there is a growing tendency to have terminal filters in all rooms where open products are handled. It is recommended that classes A & B (ISO 4, 5 & 6) have terminal HEPA filters. If there is no filter in terminal position, it should be ascertained that there are no elements between the main filter and the air outlets which could add contamination. No elements such as fans, heating/cooling batteries, should be situated downstream of the final filter.
HEPA FILTER
PRODUCTION ROOM
AHU MOUNTED FINAL FILTER

In case of filter in terminal position HEPA filter in above figure is situated immediately to the air outlet.
REQUIRMENTS TO QUALITY OF AIR:-
BE
SATISFIED
FOR
THE
(ACC. TO GMP)
The air in the manufacturing & processing areas should contain minimal amounts of particulate matter, both viable & non-viable. This requirement may be met by heating & cooling systems that provides air entering these spaces in a nonturbulent flow pattern & in sufficient volume to remove airborne particles from locations where contamination of product may occur. Flow grates, vents, & vacuum dust removal equipment must be considered as part of the system design. Ideally, an effective air conditioning, filtering, & humidification system will be employed in all new construction & renovations.
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Any air conditioning system design should consider the following factors: 1. Means for preventing the entry of airborne contaminants into work area. 2. Enclosed or semiclosed systems, recirculating only particulate-free air from space to space. 3. Sufficient incoming volumes of air with exhaust to sweep particulate contaminants from the air in a working area. 4. A vacuum or special exhaust system in dusty manufacturing or handling rooms to prevent settling of contaminants. 5. Temperature & humidity controls to insure maximum comfort through-out all climatic conditions. 6. Pressure dampers and diffusers to insure constant velocity (nonturbulent) incoming air. 7. Independent control of incoming air into each departmental area so different needs may be met. Control should be maintained over temperature, humidity & velocity. 8. Absolute HEPA filters located in the system immediately before entrance into the space to prevent passage of microbial & microscopic particulate matter. Sterile manufacturing, filling, & handling spaces require special air processing. HEPA filter units with laminar air flow are minimal requirement in those areas where airborne contamination of product may occur. The manufacturer must make a cost-benefit decision as to the extent of this system. In special areas, modular laminar flow units to enclose those operations during which the drug dosage form is exposed to ambient air may be sufficient. Vertical, rather than horizontal, laminar flow reduces the problem of downwind flow of airborne particulate matter over working spaces. It has been reported that an air velocity of approximately 100 ft3/min is necessary to achieve class-100 working conditions for large enclosed areas. The efficiency of the air handling system must be continuously monitored to insure that desired filtration is being achieved. Airborne particle counters or plates placed at critical locations in the manufacturing cycle determine the amount of particles per unit time. Records of these periodic checks should be maintained so that abnormally high readings may be detected & appropriate remedial action taken.
Problems associated with HVAC components: Flow rate controller - Blocked , No control of pressure differentials Control damper Poorly adjusted , Bad pressure differential systems Humidifier - Bad water/Risks of microbial contamination ,steam quality Cooling Unit - No elimination , Risks of microbial contamination of condensed water
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Filters - Incorrect retention , Risks of contamination rate(particles, microorganisms) , Damaged , Filter integrity fails , Badly installed , Risks of contamination (particles, micro-organisms) Ducts - Inappropriate material , Danger of corrosion , Leaking duct work Intake of unfiltered air
Different air types to be considered within the air handling system:

Fresh air (if the plant is of the re-circulation type, it is necessary to replace some of the re-circulating air with fresh air, which is then called make-up air). A proportion of about 15% fresh air is normal, but this proportion can vary, depending on factors such as number of people, National Regulatory Authority requirements, the presence of certain substances in the air, leakage due to pressure control, etc. Supply air to the rooms Exhaust air from the rooms Return air (about 85% is being re-circulated)
Comparison of fresh air with re-circulated air

The filtered air entering a production room can be eliminated 100% (exhaust air) a proportion re-circulated In case of re-circulation, every possible measure of protection must be taken to ensure that the air coming from a production unit and loaded with product particles does not flow to other production units, thereby contaminating them. There are also cases, in which air re-circulation is prohibited, for example if solvents are used or cytotoxic products are manufactured. With control dampers, the proportions of fresh and re-circulated air can be adjusted
Supply air
There are two ways to supply air to a room or a piece of equipment; 1. Turbulent air flow 2. Uni-directional flow, often called laminar flow The air speed in the uni-directional flow is defined by the WHO at: 0.45 m/s for horizontal units, 0.30 m/s for vertical units (most commonly used) Two aspects have to be considered: GMP aspect: uni-directional air (laminar) installations give a better protection, because of the displacement effect rather than the dilution effect.
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Economical aspect: turbulent air installations are cheaper, as less air has to be treated. For certain operations, namely in class A, a laminar flow must be used. Uni-directional (laminar) flow units exist mostly as vertical, but also as horizontal, units. LF workbenches (mainly used in sterility testing) or LF cabins/booths, routinely used in production, for instance on top of a filling machine. In some cases, the units can be integrated into the ceiling of a room and also connected to the central air conditioning system.
Role of HVAC in pharmaceutical industry

HVAC system plays an important role in product protection, personnel protection and environmental protection.
1. PRODUCT PROTECTION Contamination control Contaminants can originate from: Environment (particles, micro-organisms, dust containing other products). Equipment (residues of other products, oil, particles, rust, gaskets, metal) and can be brought into the product by air movements. Contaminants are in fact the presence of anything in the manufactured product which should not be there. Contaminants can be products or substances other than the product manufactured (e.g. products resulting from air pollution), foreign products, particulate matter, micro-organisms, endotoxins, etc.
Cross-contamination protection Cross-contamination can originate from

poorly designed air handling systems and dust extraction systems, poorly operated and maintained air handling systems and dust extraction systems Inadequate procedures for personnel and equipment Insufficiently cleaned equipment Through all stages of processing, products should be protected from cross-contamination.
This can be achieved with the aid of the following methods.

1. Adequate premises: Minimization of possibility of accumulation of dust; premises 2. Good ventilation and dedusting system. 3. Closed production systems: Closed systems, in which product is transferred from one piece of equipment to another one, without being exposed to the atmosphere.
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4. Validated cleaning procedures: Manual cleaning procedures may not be reproducible. 5. Level of Protection concept : A good hygiene, or Level of Protection concept, specifying requirements for environmental conditions; entry procedures for personnel and material is fundamental for keeping crosscontamination under control. 6. Maintaining the correct air pressure differential between rooms helps prevent cross-contamination. 7. Unidirectional Airflow protection
Temperature and humidity: Product temperature requirements:Temperature requirements for the various products being manufactured should be determined and based on this the HVAC temperature control should be set.
Product humidity requirements:Microbial growth:High temperatures and high humidities cause excessive perspiration from operators. This increases risk of microbial contamination.
2. PERSONNEL PROTECTION Protection from dust

Operators health should not be put at risk by being exposed to harmful products. Where possible, dust should be controlled at source and thus prevented from being released into the room.
Unidirectional Airflow protection

Unidirectional airflow protection, either vertical flow or horizontal flow, is an efficient means of protection for both the operator and the product. The source of the dust and the position in which the operator normally stands should be determined before deciding on the direction of unidirectional flow. It should be ensured that the operator is not in the path of an airflow that could lead to contamination of the product. Obstructions in the path of a unidirectional flow air stream may cause even more dust exposure to the operator.
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Air Showers
When operators have been working in a dusty environment, their protective garments could become coated with a film of dust. Operators should change out of their protective garments before going to the canteen. Operators could pass through an air shower, prior to entering the change room, on leaving the production area.
Protective enclosures
When dealing with particularly harmful products, additional steps, such as handling the products in glove boxes or using barrier isolator technology, should be used.
Operator comfort
Temperature conditions should be adjusted to suit the protective clothing that the operators are wearing. Typical comfort condition of 18C should be applicable in a sterile manufacturing area where full protective clothing is worn, whereas 21 to 22C should be comfortable in an OSD facility where the dress code is less onerous.
3. PROTECTION OF THE ENVIRONMENT Exhaust air dust

Exhaust air discharge points on pharmaceutical facilities, such as from fluid bed driers and tablet coating equipment, and exhaust air from dust extraction systems, carry heavy dust loads and should be provided with adequate filtration to prevent contamination. On typical solid dosage plants, where the powders are not highly potent, final filters on a dust exhaust system should be fine dust filters having a filter classification of F9 according to EN779 filter standards. On systems where harmful substances such as penicillin, hormones, toxic powders and enzymes are exhausted, the final filters should be HEPA filters with an H12 classification according to EN1822 filter standards. For exhaust systems where the discharge contaminant is considered particularly hazardous, it may be necessary to install two banks of HEPA filters in series, to provide additional protection should the first filter fail.
Fume removal
Although fume, dust and effluent control relating to the ambient are not GMP issues, but rather environmental issues, they could also become a GMP issue. For example if an exhaust air discharge point was close to the HVAC system fresh air inlet.
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Removal of fumes should be by means of wet scrubbers or dry chemical scrubbers (deep bed scrubbers). Wet scrubbers for fume removal should normally have various chemicals added to the water to increase the adsorption efficiency. Deep bed scrubbers should be designed with activated carbon filters, or chemical adsorption granular media. The chemical media for deep bed scrubbers should be specific to the effluent being treated. The type and quantity of the vapours to be treated should be known, to select the type of filter media as well as the volume of media required.
Effluent discharge
Effluent control should be designed to ensure that system do not become source of possible risk or contamination..
IMPORTANCE OF MONITORING PRESSURE DIFFERENTIATION

1) Pressure differentials must be defined, monitored and alarmed in critical cases. 2) The overpressure of each room is measured against a reference point in the factory (point zero). 3) The pressure differential in sterile areas is set up at 15 Pa between zones of different cleanliness. 4) Sufficient pressure differential required to ensure containment and prevent flow reversal but not so high as to create turbulence. 5) Doors must be opened to higher pressure. 6) Factory layouts must be carefully planned, in order not to have too high a pressure differential between entrance and exit of a sterilizing or depyrogenating tunnel, as the air flow may significantly affect the temperature in a tunnel. 7) Pressure differentials must be constantly monitored. The loss of overpressure in a filling room for injectable may mean the loss of the batches under production and the need for complete sanitation of the facility. It is therefore essential that the systems are designed in such a way that there is no loss of overpressure in case of power loss (overpressure fan should be linked to emergency power grid). 8) The entry into some rooms (containing dangerous products such as hormones, cytotoxics, low RH products or strongly colored products) is protected by airlocks.
VALIDATION AND QUALIFICATION

List of Parameters to be qualified
For a pharmaceutical facility some of the typical HVAC system parameters that should be qualified include: room temperature (if there is an impact on product quality) room humidity (if there is an impact on product quality) supply air quantities for all diffusers
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return air or exhaust air quantities room air change rates room pressures room air flow patterns laminar flow velocities containment system velocities HEPA filter penetration tests room particle counts room clean-up rates microbiological air and surface counts
QUALIFICATION/VALIDATION
a. as built no equipment, no person in room b. at rest only equipment c. in operation both equipment & person Furniture/equipment can have an influence on the air flow and thus the air flushing and people may influence the quantities of microorganisms and particles. Though WHO does not specify different values for both at rest and in operation situations, the need for accurate specifications for planning and operation still exists. However, we also have to remember that, once a ventilation system is installed, it is necessary to see how well it performs in comparison to its planned purpose, which is to provide a quality environment of specified parameters for the product. The whole process is of course supported by adequate documentation. There are different tests for the turbulent and for the uni-directional air flows.
Unidirectional airflow / LAF 2 N/A 2, 3 2 2 2 Turbulent / mixed airflow 1 = As built 2, 3 Optional 2 N/A 3 2 = At rest 3 = Operational Description
Test Differential pressure on filters differential pressure Room Airflow velocity / uniformity Airflow volume / rate Parallelism Air flow pattern
Test Recovery time Room classification (airborne particle) Temperature, humidity
Unidirectional airflow / LAF N/A 2 N/A
Turbulent / mixed airflow 2 2,3 2,3
Description 1 = As built (ideally used to perform IQ) 2 = At rest (ideally used to perform OQ) 3 = Operational (ideally used to
M.PHARM. PART-I (2009-10) PQ) perform
L.M.COLLEGE OF PHARMACY, AHMEDABAD-09
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1.The differential pressure on filters is an indication of the clogging of the

filters with the charging of dust on the filters, the differential pressure will increase. 2.In order to keep the volume of air constant, the fan speed may increase, with the following consequences: Damage to filters, and passage of unfiltered air Particles and micro-organisms will be pushed through the filter units. 3.Airflow patterns are interesting to visualize (smoke tests), as zones without proper flushing can be easily identified 4.It is also important to monitor air flow velocities for each HEPA filter according to a program of established intervals because significant reductions in velocity can increase the possibility of contamination, and changes in velocity can affect the laminarity of the airflow. 5.Airflow patterns should be tested for turbulence, as these can interfere with the flushing action of the air. 6. The recovery time (clean-up time) is also an important parameter to be determined. Once doors have been opened and people have been entering a room, the original conditions have been disturbed and, for a short while, before recovering, the room does not always correspond to the laid down parameters. It is important to know how long this period is. There are no regulations laid down as to how long this clean-up time should be. However, the generally accepted time to clean-up from one cleanroom classification to the next higher classification should be less than 15 minutes. 7.It should also be remembered that a room is to be qualified in operation when it has a certain number of people in it. After qualification, the number of people in that room, as challenged during qualification, cannot be exceeded. 8.Temperature and humidity can also be important (comfort in clean areas, stability of effervescent products Requalification of these parameters should be done at regular intervals, e.g. at least annually.
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The tables below, giving the recommended time periods for
retesting or requalification, are taken from the ISO 14644 standard and are given for reference purposes only. The actual test periods may be more frequent or less frequent, depending on the product and process.
STRATEGIC TESTS (ISO 14644)
Schedule of Tests to Demonstrate Continuing Compliance Test Parameter Clean room Class All classe s Max Time Interval 6 Months Test Procedure
Particle Count Test (Verification of Cleanliness)
Dust particle counts to be carried out & result printouts produced. No. of readings and positions of tests to be in accordance with ISO 14644-1 Annex B Log of pressure differential readings to be produced or critical plants should be logged daily, preferably continuously. A 15 Pa pressure differential between different zones is recommended. In accordance with ISO 14644-3 Annex B5* Air flow readings for supply air and return air grilles to be measured and air change rates to be calculated. In accordance with ISO 14644-3 Annex B13* Air velocities for containment systems and unidirectional flow protection systems to be measured. In accordance with ISO 14644-3 Annex B4*
Air Pressure Difference (To verify non crosscontamination)
All classe s
12 Months
Airflow Volume (To verify air change rates)
All Classes
12 Months
Airflow Velocity (To verify unidirectional flow or containment conditions)
All Classes
12 Months
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RECOMMENDED OPTIONAL STRATEGIC TESTS (ISO 14644)

Schedule of Tests to Demonstrate Continuing Compliance Test Parameter Clean room Max Test Procedure Class Time Interval Filter leakage Tests (To verify filter integrity) All Classes 24 Months Filter penetration tests to be carried out by competent person to demonstrate filter media and filter seal integrity. Only required on HEPA filters. In accordance with ISO 14644-3 Annex B6* Demonstrate that contaminant is maintained within a room by means of: airflow direction smoke tests Room air pressures. In accordance with ISO 14644-3 Annex B4* Test to establish time that a clean room takes to recover from a contaminated condition to the specified clean room condition. Should not take more than 15 min. In accordance with ISO 14644-3 Annex B13* Tests to demonstrate air flows: from clean to dirty areas do not cause crosscontamination uniformly from unidirectional flow units Demonstrated by actual or videoed smoke tests. In accordance with ISO 14644-3 Annex B7*
Containment leakage (To verify non crosscontamination)
All Classes
24 Months
Recovery (To verify clean up time)
All Classes
24 Months
Airflow Visualization (To verify required air flow patterns)
All Classes
24 Months
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MAINTENANCE OF HVAC
The HVAC system should be subjected to planned preventative maintenance. Maintenance should be done in accordance with written procedures and records of maintenance should be kept. HVAC systems for clean room facilities are normally sophisticated and maintenance staff should be adequately trained. HEPA filters should only be changed by specialists or trained personnel. Maintenance of the HVAC system, with regards to component accessibility, should be considered during the design stage of the system. Where possible, items requiring routine maintenance should be located outside of the clean zones. Any maintenance activity should be critically assessed to determine any impact on product contamination. Maintenance activities should normally be scheduled to take place outside of production hours, and any system stoppage should be assessed with a view to possible re-qualification of an area that may be required as a result of an interruption of the service. Prevention of operator contamination should also be addressed at the design stage, e.g. exhaust air filters that could be contaminated with harmful products may require safe-change filter housings.
MANUFACTURERS OF HVAC:MidwestBAS - Supplier of HVAC Equipment & Other Products For Commercial Buildings SEMCO Inc. - Missouri-based Manufacturer of Round Duct, Air Duct and HVAC Systems & Solutions HVAC Plus - Supplier of HVAC Equipment, Controls, Parts & Tools From Leading Manufacturers Kathabar Systems - Global Manufacturer of HVAC equipment. Air Specialties Express - Manufacturer of HVAC Equipment Carnes Company - HVAC Equipment Manufacturer & Supplier Engel Europa International Ltd - Manufacturer Of HVAC Duct Forming Machinery & Other Machines For HVAC Industry
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Smart Temp Australia Pty Ltd - Manufacturer Heating & Cooling Thermostats & Zone Controls Cosaf Environments Ltd - Specializing In Industrial Air Conditioning, Heating & HVAC Design & Installation RAPTOR - Manufacturer of Heat Pump Covers & AC Covers.
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PERSONNEL FACILITIES:(ACCORDING TO GMP)

FACILITIES FOR EATING AND DRINKING: Eating facilities well segregated from all the production areas are mandatory. 1. Eating & drinking permitted only in separate eating facilities: smoking permitted only where an adequate disposal is provided, & apart from production areas. 2. Prominent signs indicating these rules posted at entrances to production areas. 3. Enforcement procedures against violators taken by management. 4. Permanent facilities for breaks & people bringing lunches required; ideally cafeterias serving hot meals to reduce amount of food, a potential contamination source, brought into the plant. 5. Manufacturer should provide facility of canteen; it should be away from operating areas.
FOR PRODUCTION AND MATERIALS PROCESSING AREAS: Drinking, eating, smoking, tobacco chewing & expectoration prohibited. Tissues & closed disposal containers readily available.
LAVATORIES & LOCKERS:1. 2. 3. 4. 5. 6. Adequate in number for the number of personnel employed. Conveniently located to all areas. Hot shower facilities are provided Disinfectant soaps are utilized. Adequate ash & waste receptacles provided. Periodic cleaning of the area during each shift with logging of times & conditions mandatory. 7. Complete cleaning with cleansing & disinfectant agents daily; follow-up inspection by supervisory personnel logged. 8. Eating & drinking not permitted; foods & beverages for meals & breaks stored only in lockers. 9. Lavatory & locker areas separated from all sterile spaces by an air lock.
CLOTHING:Sufficient amount of clean uniforms provided by company to personnel. Regulations stipulating maximum intervals between changes for each function.
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Workers in special clean areas wearing only lint- & dust-free garments to prevent shedding. Where necessary the following articles are provided by the company:1. Hats & head covers for clean areas. 2. Aprons 3. Safety shoes 4. Gloves, disposable in clean areas 5. Safety glasses 6. Masks 7. Protective goggles 8. Disposable boots for clean areas 9. Lint-free coveralls for clean areas
FIRST AID FACILITIES: The manufacturer should provide adequate facilities for first aid and should train some persons from every section in first aid. There should be Medical check up & Facility for Vaccination Manufacturer should make arrangements for medical examination of workers at the time of recruitment and thereafter once in a year, with particular attention being devoted to freedom from infectious conditions. In order to minimize the risk of a serious medical hazard due to crosscontamination, dedicated and self-contained facilities must be available for the production of particular pharmaceutical products, such as highly sensitizing materials (e.g., penicillins) or biological preparations (e.g, live microorganisms). The production of certain other products, such as some antibiotics, hormones, cytotoxic substances, highly active pharmaceutical products, and non-pharmaceutical products, should not be conducted in the same facilities.
GOWNING ROOMS: Gowning areas should be used when exposure to product could put personnel at risk & when necessary to prevent product contamination. Control should be in place to ensure that gowning &degowning are not potential sources of contamination. Should be provided separate for each sex, & With locker facilities Schedule-M prescribes an area of 8 sq. meters for change room. Gowning rooms should be adjacent to the washing area and before entry to the production area. Gowning rooms should be kept clean and should be disinfected at regular intervals.
RESTROOM FACILITIES: Restroom facilities should be physically separated from lab & processing areas by a room, corridor or other intermediate space. Such facilities should be adequately spaced & sufficiently equipped for facility of personnel. All facilities should meet applicable building requirements.
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SAFETY PROGRAMS
Plant safety programs play an important role, since hazardous conditions diminish employee moral and performance. This should consist of: An active continuing safety campaign throughout the plant include:1. Posters displayed prominently & changed often. 2. Safety equipment available free of cost to employee. 3. Safety showers and eye baths in hazardous areas. 4. Lectures, movies 5. Safety bulletin boards listing recent plant accidents & methods of prevention. 6. Safety inspection teams from several departments to audit work areas periodically. All lines correctly & continually identified, including direction of flow:1. drinking-potable water, water 5. work in process for injection 6. steam 2. gas 7. electrical 3. vaccum 8. communication. 4. waste Fire extinguishers for all types of fires in each department. In-plant alarms available & locations marked. Telephones available. Emergency lights & generators available. Emergency teams including fire & first-aid, trained & readily available during all working hours.
TRAINING FACILITES: Management must provide training in accordance with written program for all personnel whose duties taken them into manufacturing area or into control lab & for other personnel as required. Besides basic training on theory & practise of GMP newly recruited person should receive training appropriate to the duties assigned to them. Continuing training should also be given . Approved training programmes should be available. Training records shall be kept. Personnel working in areas where contamination is a hazard those should be given specific training. Consultant & contract staff should be qualified for services they provide. evidence of these should be included in training records
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QUESTIONS :HVAC:PRIOR QUESTIONS:1. Give role of HVAC in pharmaceutical industry. 2. Draw a diagram of HVAC. 3. Give name of different components, their functions & problems associated with their. 4. Parameters controlled by the air handling system. 5. Give different type of air. 6. Importance of monitoring pressure differentiation in production room. 7. Write note on validation and qualification of HVAC. NEW QUESTIONS:1. What is HVAC? 2. Write a note on system design criteria for HVAC? 3. Explain different systems used as a structural components of HVAC? 4. Explain air handling system with detailed diagram? 5. Write a note on different types of filters, position of filters & filter classes with reference to HVAC? 6. Give the importance of maintenance of HVAC? 7. Enlist various companies manufacturing HVAC? 8. Why is cleaning of HVAC essential? 9. How is cleaning of HVAC done? PERSONNEL FACILITIES:What are the personnel facilities required in a pharmaceutical industry as per GMP?
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REFERENCES: GOOD DESIGN PRACTICES FOR GMP PHARMACEUTICAL FACILITIES BY:- ANDREW. A.SIGNORE & TERRY JACOBS VOL-146, PAGE NOS:- 50,90-104,345 GOOD MANUFACTURING PRACTICES PHARMACEUTICALS BY:- JAMES SWARBRICK VOL-2, PAGE NOS:- 20,21,22,23,36,37 www.who.org www.wikipedia.com www.p2pays.org www.foreigntradeexchange.com www.industrialleaders.org
FOR
www.scribd.com
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GMP & its implementation KALPESH
GOOD MANUFACTURING PRACTICE(GMP) AND ITS IMPLEMENTATION
GUIDED BY: Dr. R.K.PARIKH
PREPARED BY: KALPESH G. VYAS M.PHARM -1 YEAR-2009-10 ROLL NO-10
DEPARTMENT OF PHARMACEUTICS AND PHARMACEUTICAL TECHNOLOGY

L.M.COLLEGE OF PHARMACY AHMEDABAD-09
DEPARTMENT OF PHARMACEUTICS AND PHARMACEUTICAL TECHNOLOGY L.M.COLLEGE OF PHARMACY, AHMEDABAD-09 Page 78
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CONTENTS :
DEFINITION UNDER GMP WHY GMP ? IS GMP NECESSARY IF THERE IS QUALITY CONTROL LAB? CAN MANUFACTURER AFFORD TO IMPLEMENT GMP? CFR (CODE OF FEDERAL REGULATION) GMP FOR PREMISES AND MATERIAL REQUIREMENTS OF PLANT AND EQUIPMENT CHANGES IN GMP COMPARISON OF GMPS OF DIFFERENT COUNTRIES. WHO ENFORCES THE GMP? MODEL CERTIFICATE OF GOOD MANUFACTURING PRACTICE STUDY QUESTIONS REFERENCES
DEPARTMENT OF PHARMACEUTICS AND PHARMACEUTICAL TECHNOLOGY L.M.COLLEGE OF PHARMACY, AHMEDABAD-09
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DEFINITION:
Good manufacturing practice is that part of quality assurance which ensures that products are consistently produced and controlled to the quality standards appropriate to their intended use and as required by the marketing authorization GMP is aimed primarily at diminishing the risks inherent in any pharmaceutical production. Such risks are essentially of two types: cross-contamination (in particular of unexpected contaminants) and mix-ups (confusion) caused by, for example, false labels being put on containers.
Under GMP:1. All manufacturing processes are clearly defined, systematically reviewed in the light of experience, and shown to be capable of consistently manufacturing pharmaceutical products of the required quality that comply with their specifications; 2. Qualification and validation are performed; 3. All necessary resources are provided, including: (i) appropriately qualified and trained personnel; (ii) adequate premises and space; (iii) suitable equipment and services; (iv) appropriate materials, containers and labels; (v) approved procedures and instructions; (vi) suitable storage and transport; (vii) adequate personnel, laboratories and equipment for inprocess controls; 4. Instructions and procedures are written in clear and unambiguous language, specifically applicable to the facilities provided; 5. Operators are trained to carry out procedures correctly; 6. Records are made (manually and/or by recording instruments) during manufacture to show that all the steps required by the defined procedures and instructions have in fact been taken and that the quantity and quality of the product are as expected; any significant deviations are fully recorded and investigated; 7. Records covering manufacture and distribution, which enable the complete history of a batch to be traced, are retained in a comprehensible and accessible form; 8. The proper storage and distribution of the products minimizes any risk to their quality; 9. A system is available to recall any batch of product from sale or supply; 10.Complaints about marketed products are examined, the causes of quality defects investigated, and appropriate measures taken in respect of the defective products to prevent recurrence.
1. 2. 3. 4. 5. 6.
WHY GMP ?
Final testing of the product cannot ensure the Quality efficiency and safety. Final testing may always not detect contamination, error, etc. Conformance to the predetermined specification To minimize contamination eg:- microbial contamination To eliminate error. To produce product of consistent quality. Page 80
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7. They are designed to minimize risks involved in pharmaceutical production. These risks are: Unexpected contamination of products. incorrect labels on containers inadequate or excess of active ingredients
Is GMP necessary if there is quality control lab?

Good quality must be built in during the manufacturing process. Testing of finished product is not enough. GMP prevent errors that cannot be eliminated through quality control of finished product. Though quality control laboratory are set up, it covers only the finished product, so WHO established GMP guidelines to cover whole process of production.
Can manufacturer afford to implement GMP?

A poor quality medicine causes health hazards and waste of money not only to government and consumers, but also to manufacturer. GMP is designed to ensure that mistake does not occur. Implementation of GMP is an investment in good quality medicines. It will improve the health of patient as well as benefit the pharmaceutical industry and health professionals.
CFR (Code of Federal Regulation) :

It is the Portion of FDA. Divided into 50 titles. Current regulations of GMP appear in part 210 (title 21) of code of federal regulations published by USFDA. 21 Code of Federal Regulations Part 210. Current Good Manufacturing Practice in Manufacturing Processing, packing, or Holding of Drugs. 21 Code of Federal Regulations Part 211. Current Good Manufacturing Practice for Finished Pharmaceuticals.
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GMP FOR PREMISES AND MATERIALS
1. GENERAL REQUIREMENTS: 1.1. Location and surroundings The factory buildings for mfg. of drugs shall be so situated or shall have such measures as: To avoid risk of contamination from external environment. 1.2. Building and premises The building should be designed in such a way that permits mfg. operations in hygienic conditions. 1. Compatible with other mfg. operations. 2. Adequately provided working space. 3. To avoid risk of mix-ups. 4. To avoid contamination. 5. Designed to avoid entry of pests, birds, rodents etc. Interior surface should be smooth and free from crakes 6. The production and dispensing area shall be well lightened, ventilated, and may have proper air handling system. 7. Proper drainage system as specified for various categories of products. 8. The walls and floors of mfg. area shall be free from cracks and open joints to permit easy and effective cleaning. 1.3. Water system 1. There shall be validated system for treatment of water to render it potable. 2. Potable water should be used to perform all the operations except cleaning and washing. 3. The storage tanks shall be cleaned periodically and records maintained by the licensee. 1.4. Disposal of waste 1. The disposal of sewage and effluents shall be in conformity with the requirements of Environment Pollution Control Board. 2. All bio-medical waste shall be destroyed as per the provisions of Bio-Medical Waste Rules, 1996. 3. Record shall be maintained. 4. Provision shall be made for proper storage of waste materials. 2. WARE HOUSING AREA: Adequate areas for proper warehousing of various categories of materials and products. Designed and adapted to ensure good storage conditions. Quarantine area shall be clearly demarcated and restricted to authorized persons. DEPARTMENT OF PHARMACEUTICS AND PHARMACEUTICAL TECHNOLOGY L.M.COLLEGE OF PHARMACY, AHMEDABAD-09 Page 82
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Separate sampling area for active raw materials and excipients. 3. PRODUCTION AREA: Designed to allow the production preferably in uni-flow and with logical sequence of operations. Separate mfg. facilities shall be provided for the mfg. of contamination causing and potent products such as -lactam, sex hormones and cyto-toxic substance. Service lines shall be Well designed and constructed, shall be identified by colours. Direction of flow shall be marked. 4. ANCILLARY AREA: Rest and refreshment rooms shall be separate from other areas. Facility for changing, storing clothes and for washing and toilet purpose shall be easily accessible and adequate. Areas for housing animals shall be isolated and maintained as prescribed in rule 150- C (3) of D & C Rules, 1945. 5. QUALITY CONTROL AREA: Quality control laboratories shall be independent of the production areas.seperate areas shall be provided each for physico-chemical, biological, micribiological or radio isotope analysis. Adequate space shall be provided to avoid mix-ups and cross contamination. The design of the laboratory shall take into account the suitability of construction materials and ventilation. Separate air handling units and radioisotopes testing areas. The laboratory shall be provided with regular supply of water of appropriate quality for cleaning and testing purposes. 6. PERSONNEL : The manufacture and testing shall be conducted under direct supervision of qualified technical staff. Personnel for QA & QC shall be qualified and experienced. No. of personnel employed shall be adequate and in direct proportion to the workload. Personnel in production and QC lab. shall receive training appropriate to the duties & responsibility assigned to them. 7. HEALTH CLOTHING AND SANITATION OF WORKERS: The personnel handling beta-lactam antibiotics shall be tested for penicillin sensitivity before employment and those handling sex hormones, cytotoxic substances and other potent drugs shall be periodically examined for adverse effect.
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Prior to employment, all personnel shall undergo medical examination including eye examination, and shall be free from tuberculosis, skin and other communicable or contagious diseases. Clothing:Protection of operator and product, highly potent products or product those of particular risk. Need for special protective clothing. Personnel should not move between areas producing different products. Garments need to be cleaned. Health examinations: On recruitment for direct operators, repeated on regular basis. Training: Check Induction training for new operators includes basic personal hygiene training. Written procedures - to wash hands before entering a manufacturing area. Illness: Staff with illness or open lesions should not handle starting materials, intermediates or finished products. Adverse conditions: Operators trained to recognize risks Willingness to report illness to the area supervisor 8. MANUFACTURING OPERATIONS AND CONTROLS: All manufacturing operations shall be performed by trained personnel under direct supervision of approved technical staff approved by the licensing Authority. All the materials & containers used in mfg. process shall be conspicuously labeled with Name of product 1. Batch number and batch size 2. Stages of manufacture Products not prepared under aseptic condition are required to be free from pathogens like, Salmonella, Escherichia coli, Pyocyanea, etc. The licensee shall prevent mix-up and cross-contaminations of drug materials and drug product by proper air handling system, pressure differential, segregation, and status labeling and cleaning. Proper records and SOPs thereof shall be maintained. Time limitations on production. When appropriate, time limits for the completion of each phase of production shall be established to assure the quality of the drug product. Deviation from established time limits may be acceptable if such deviation does not compromise the quality of the drug product. Such deviation shall be justified and documented. DEPARTMENT OF PHARMACEUTICS AND PHARMACEUTICAL TECHNOLOGY L.M.COLLEGE OF PHARMACY, AHMEDABAD-09
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9. SANITATION IN MANUFACTURING PREMISES: Manufacturing premises shall be Cleaned and maintained according to validated cleaning procedures. Manufacturing areas shall not be use as storage. A Routine sanitation program shall be drawn up and observed. manufacturing premises shall be maintained clean & in orderly manner, free from accumulated waste,dust,debris,etc eating,chewing,smoking or any unhygienic practices shall not be permitted in the manufacturing area OBJECTIVES OF SANITATION : Removal of dust & dirt & other waste materials Minimize the risk of cross contamination between different products in the same area Reduce the number of microorganisms Control pests so that these do not affect the quality of materials ,to be used in manufacture of drugs Sanitation in manufacturing area is more important than other areas because risk of contamination is more in these areas, protection from outside environment is too necessary by, Avoiding multiple entry /exit positions, Providing air-lock at each entry point. Install insectocutors at effective positions like main entrances, entrances to manufacturing areas including packaging section, inside manufacturing areas, Keep surrounding of the building clean. Maintenance of lawn will keep incidence of dust low. Carry out pest control periodically. Sanitation programme for each area should be prepared in writing. These cleaning instructions or SOP should include: Frequency of cleaning of floors,walls,ceiling,doors,electrical fittings, etc Method of cleaning including details of cleaning equipments, cleaning & disinfecting agents. 10. RAW MATERIAS: The licensee Keep an inventory of all raw materials to be used at any stage of production of drugs and maintain records as per Schedule U. All materials shall store under appropriate storage condition & follow first in/first expiryfirst out rule. Raw material from each batch checked for quality & appropriately labels the storage area. DEPARTMENT OF PHARMACEUTICS AND PHARMACEUTICAL TECHNOLOGY L.M.COLLEGE OF PHARMACY, AHMEDABAD-09 Page 85
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There shall be adequate separate area for materials under test, approved , and rejected .It allow dry, clean and orderly placement of stored materials and products, wherever necessary, under controlled temp. and humidity. Only raw materials which have been released by the quality control department and which are within their shelf- life shall be used .It shall be ensured that shelf life of formulation product shall not exceed with that of active raw material used. It shall be ensured that all the containers of raw materials are placed on the raised platforms/racks and not placed directly on the floor. 11. EQUIPMENTS: Equipment shall be located, designed, constructed, adapted and maintained to suit the operations to be carried out. The layout and design of the equipment shall aim to minimize the risk of errors and permit effective cleaning and maintenance in order to avoid crosscontamination, build up of dust or dirt and in general any adverse effect on the quality of product. Balance and other measuring equipment of an appropriate range, accuracy and precision shall be available in the raw material stores, production and in process control operation and these shall be calibrated and checked on a scheduled basis in accordance with SOP and record maintained. To avoid accidental contamination, wherever possible, nontoxic / edible grade lubricant shall be used and the equipment shall be maintained in a way that lubricants dont Contaminate the products being produced. Defective equipment shall be removed from production and quality control areas or appropriately labeled. 12. DOCUMENTATION AND RECORDS: Its aim is to define the specification for all materials, method of mfg. and control, to ensure that all personnel concerned with manufacture know the information necessary to decide whether or not to release a batch of a drug for sale and to provide an audit trail that shall permit investigation of the history of any suspected defective batch. Documents shall be approved, signed and dated by appropriate and authorized persons. The records shall be made or completed at the time of each operation in such a way that all significant activities concerning the mfg. of pharmaceutical product are traceable. Records and associate d SOP shall be retained for at least one year after the expiry date of the finished product. 13. LABELS AND OTHER PRINTED MATERIALS: Necessary for identification of the drugs and their use. Printed in bright colours and legible manner. DEPARTMENT OF PHARMACEUTICS AND PHARMACEUTICAL TECHNOLOGY L.M.COLLEGE OF PHARMACY, AHMEDABAD-09 Page 86
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All containers and equipment shall bear appropriate labels. Different color coded labels can be used. Printed packaging materials & leaflets shall be stored separately to avoid mixup. Packaging, labeling and release shall be done after approval of QC department Record of receipt and use of all material shall be maintained. 14. QUALITY ASSURANCE: To understand key issues in quality assurance/quality control. To understand specific requirements on organization, procedures, processes and resources. To develop actions to resolve current problems. Requirements for QA Systems 1. Ensure products are developed correctly. 2. Identify managerial responsibilities. 3. Provide SOPs for production and control. 4. Organize supply and use of correct starting materials. 5. Define controls for all stages of manufacture and packaging. 6. Ensure finished product correctly processed and checked before release 7. Ensure products are released after review by authorized person 8. Provide storage and distribution 9. Organize self-inspection. 15. SELF INSPECTION AND QUALITY AUDIT: The purpose of self-inspection is to evaluate the manufacturers compliance with GMP in all aspects of production and quality control. The self-inspection programme should be designed to detect any shortcomings in the implementation of GMP and to recommend the necessary corrective actions. Self-inspections should be performed routinely, and may be, in addition, performed on special occasions, e.g. in the case of product recalls or repeated rejections, or when an inspection by the health authorities is announced. The team responsible for self-inspection should consist of personnel who can evaluate the implementation of GMP objectively. All recommendations for corrective action should be implemented. The procedure for self-inspection should be documented, and there should be an effective follow-up programme. Items for self-inspection (a) personnel; (b) premises including personnel facilities; (c) maintenance of buildings and equipment; (d) storage of starting materials and finished products; (e) equipment; (f) production and in-process controls; DEPARTMENT OF PHARMACEUTICS AND PHARMACEUTICAL TECHNOLOGY L.M.COLLEGE OF PHARMACY, AHMEDABAD-09
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(g) quality control; (h) documentation; (i) sanitation and hygiene; (j) validation and revalidation programmes; (k) calibration of instruments or measurement systems; (l) recall procedures; (m) complaints management; (n) labels control; (o) results of previous self-inspections and any corrective steps taken. Self-inspection team Management should appoint a self-inspection team consisting of experts in their respective fields and familiar with GMP. The members of the team may be appointed from inside or outside the company. Frequency of self-inspection The frequency at which self-inspections are conducted may depend on company requirements but should preferably be at least once a year. The frequency should be stated in the procedure. Self-inspection report A report should be made at the completion of a self-inspection. The report should include: (a) self-inspection results; (b) evaluation and conclusions; (c) recommended corrective actions. Follow-up action There should be an effective follow-up programme. The company management should evaluate both the self-inspection report and the corrective actions as necessary. Quality Audit A quality audit consists of examination and assessment of all or part of a quality system with the specific purpose of improving it. A quality audit is usually conducted by outside or independent specialist or a team designed by a management for this purpose. Basically three types: 1. Internal audit: Done by QA department 2. External audit: Done by FDA consultants 3. Regulatory audit. Additionally there is personal audit in which the personnel does the selfchecking to see whether he/she is following the quality standards or not. 16. QUALITY CONTROL SYSTEM: Quality control shall be concerned with 1. sampling 2. specification
3. 4.
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It is not confined to laboratory operations but shall be involved in all decisions concerning the quality of the product. All the batches released after certification of QC department. Maintain reference/retained sample from each batch. The area of the quality control laboratory may be divided into chemical, instrumentation, microbiological and biological testing. Adequate area having the required storage conditions shall be provided for keeping references samples. The quality control department shall evaluate, maintain and storage reference samples. There shall be authorized and dated specifications for all materials, products, reagents. The quality control department shall conduct stability studies of the products to ensure and assign their shelf life at the prescribed conditions of storage .All records of such studies shall be maintained. The in charge of quality Assurance shall investigate all product complaints thereof shall be maintained All instruments shall be calibrated and testing procedures validated before these are adopted for routine testing. Periodical calibration of instrument and validation of procedures shall be carried out. Pharmacopoeias, reference standard, reference spectra, other references materials and technical books, as required, shall be available in the quality control laboratory of the licensee. 17. SPECIFICATIONS: For raw material & packaging material. For product containers & closures. For in-process & bulk products. For finished product. For preparation of containers & closures. 18. MASTER FORMULA RECORDS: Includes:1. Name of product with reference code. 2. Patent & proprietary name with generic name. 3. Description of dosage form. 4. Name, quantity & reference no. Of all starting materials. 5. A statement of expected final yield & the principal equipment to be used. 6. Detailed SOP with the time taken for each step. 7. Requirements for storage conditions of the products, containers, labeling 8. Packaging detail and specimen labels. 9. Any special precautions.
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19. PACKAGING RECORDS: There shall be Authorized packaging instructions for each product, pack size & type that includes a. Name of product with other description. b. Volume of product in final container. c. Complete list of all the packaging materials with quantities size & type. d. Description of packaging operations. e. Detail of in process control 20. BATCH PROCESSING RECORDS: There shall be Batch processing Record for each product. It shall be based on the parts of the currently approved master formula. Before any processing begins, check shall be performed and recorded to ensure that the equipment and work station are clear of previous products, documents or materials not required for the planned process are removed and that equip0ment is clean and suitable for use. During processing, the following information shall be recorded at the time each action is taken and the record shall be dated and signed by the person responsible for the processing operations: 1. Name of the product 2. No. of the batch being manufactured 3. Date and time of commencement 4. Initials of the operator of the different significant steps of production and where appropriate, of the person who checked each of these operations. 5. Batch no. 6. Equipments used. 7. Records of the IPQC. 8. Amount of then product obtained at different and critical stages of manufacture. 9. Special problems. 21. STANDARD REGARDING. OPERATING PROCEDURES (SOP), AND RECORDS,
1 Receipt of material Includes Written SOP for receipt of raw, primary & printed packaging materials. Written SOP for the internal labeling, quarantine & storage of various materials. SOPs for related instrument & equipments.
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2. Sampling Includes SOP for method of sampling. SOP for equipments to be used. Precautions to avoid contamination. Instruction for qty. & pooling of sample. Specific precautions for sampling of sterile or hazardous materials 3. Batch numbering SOPs Describing the detail of batch numbering set up for each batch of intermediate, bulk or finished product. Applied to a processing stage & to the respective packaging stage. Include date of allocation, product identity & batch size. 4. Testing: There shall be written procedures for testing materials and products at different stages of manufacture, describing the methods and equipment to b e used, the tests performed shall be recorded. 22. REFERENCE SAMPLES: Each lot of every active ingredient, in a quantity sufficient to carry out all the tests, except sterility and pyrogens/Bacterial Endotoxin test shall be retained for a period of 3 months after the date of expiry of the last batch produced from that active ingredient. Samples of finished formulations shall be stored in the same or simulated containers in which the drug has been actually marketed. 23. REPROCESSING AND RECORDING: Where processing is necessary, written procedures shall be established and approved by the Quality assurance Department that shall specify the condition and limitations of repeating chemical reactions. Such reprocessing shall be validated. If the product batch has to be reprocessed the procedure shall be authorized and recorded. 24. DISTRIBUTION RECORDS: Prior to distribution or dispatch of given batch of a drug, it shall be ensured that the batch has been duly tested, approved and released by the quality control personnel. Pre-dispatch inspection shall be performed on each consignment on a random basis to ensure that only the correct goods are dispatched.
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Records for distribution shall be maintained in a such manner that finished batch of a drug can be traced to the retail level to facilitate prompt and complete recall of the batch, if and when necessary. 25. VALIDATION AND PROCESS VALIDATION: Essential part of GMP and shall be conducted as per the predefined protocols. A written report summarizing recorded result and conclusions shall be prepared, documented and maintained. Shall be undergo periodic validation to ensure that they remain capable of achieving the intended results. Critical process shall be validated, prospectively or retrospectively. When any new master formula or method of preparation is adopted, steps shall be taken to demonstrate its suitability for routine processing. Significant changes to the mfg. Processes, including any change in equipment or materials that may affect product quality and/or the reproducibility of the process, shall be validated. 26. PRODUCT RECALLS: A prompt and effective recall system of defective products shall be devised for timely information of all concerned stockists, wholesalers, suppliers, up to the retail level within the shortest period. The distribution records shall be readily made available to the persons designated for recalls. The effectiveness of the arrangements for recalls shall be evaluated from time to time. The recalled products shall be stored separately in a secured segregated area pending final decision on them. 27. COMPLAINTS AND ADVERSE REACTIONS: All complaints thereof concerning product quality shall be carefully reviewed and recorded according to written procedures. Each complaint shall be investigated /evaluated by the designated personnel of the company and records of investigation and remedial action taken thereof shall be maintained. Reports of serious adverse drug reactions resulting from the use of a drug along with comments and documents shall be forthwith reported to the concerned Licensing Authority. There shall be written procedures describing the action to be taken, recall to be made of the defective product.
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28. SITE MASTER FILE: The licensee shall prepare a succinct document in the form, of Site Master File Containing specific and factual GMP about the production and /or control of pharmaceutical manufacturing preparations carried out at the licensed premises. It shall contain the following: 1 General information:(a) Brief information of the firm; (b) Pharmaceutical manufacturing activities as permitted by the licensing authority; (c) Other manufacturing activities, if any, carried out on the premises; (d) Type of product licensed for manufacture with flow charts mentioning procedure and process flow; (e) Number of employees engaged in the production, quality control, storage and distribution; (f) Use of outside scientific, analytical or other technical assistance in relation to manufacture and analysis; (g) Short description of the Quality Management System of the firm; and (h) Products details registered with foreign countries. 2 Personnel :(a) Organizational chart showing the arrangement for quality assurance including production and quality control; (b) Qualification, experience and responsibilities of key personnel; (c) Outline for arrangements for basic and in-service training and how the records are maintained; (d) Health requirements for personnel engaged in production; and (e) Personal hygiene requirements, including clothing. 3 Premises: (a) Simple plan or description of manufacturing areas drawn to scale; (b) Nature of construction and fixtures/fittings; (c) Brief description of ventilation systems. More details should be given for critical areas with potential risk of airborne contamination (schematic drawing of systems). Classification of the rooms used for the manufacture of sterile products should be mentioned; (d) Special areas for the handling of the highly toxic, hazardous and sensitizing materials; (e) Brief description of water system (schematic drawings of systems), including sanitation; and (f) Description of planned preventive maintenance programs for premises and of the recording system.
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4 Equipment:(a) Brief description of major equipment used in production and Quality Control Laboratories (a list of equipment required); (b) Description of planned preventive maintenance programs for equipment and of the recording system; and (c) Qualification and calibration including the recording systems. 5 Sanitation: (a) availability of written specifications and procedures for cleaning manufacturing areas and equipment. 6 Documentation:(a) arrangements for the preparation, revision and distribution of; necessary documentation for the manufacture; (b) any other documentation related to product quality that is not mentioned elsewhere (e.g. microbiological controls about air and water). 7 Production :(a) brief description of production operations using, wherever possible, flow sheets and charts specifying important parameters; (b) arrangements for the handling of starting materials, packaging materials, bulk and finished products, including sampling, quarantine, release and storage; (c) arrangements for the handling of rejected materials and products; and (d) brief description of general policy for process validation. 8 Quality Control :(a) description of the quality control system and of the activities of the Quality Control Department. Procedures for the release of the finished products. 9 Loan licence manufacture and licensee:(a) description of the way in which compliance of Good Manufacturing Practices by the loan licensee shall be assessed. 10 Distribution, complaints and product recall :(a) arrangements and recording system for distribution; and (b) Arrangements for handling of complaints and product recalls. 11 Self inspection :(a) short description of the self inspection system indicating outside, independent and experienced external export was involved in evaluating the manufacturers compliance with Good manufacturing Practices in all aspects of production 12 Export of drugs: (a) Products exported to different countries; and (b) Complaints and product recall, if any.
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REQUIREMENTS OF PLANT AND EQUIPMENT

Area requirements 1. External preparations 2. Oral liquid preparations 3. Tablets Coating section 4. Powders 5. Capsules 6. Surgical dressings 7. Ophthalmic preparations 8. Pessaries & suppositories 9. Inhalers & vitrellae 10. Repacking of drug & pharmaceutical chemicals 11. Parenteral preparations 150 sq. m 100 sq. m(SVP) 150 sq. m (LVP) 150 sq. m 100 sq. m (LVP Packaging) Basic installation 30 sq. m 30 sq. m 80 sq. m 30 sq. m 30 sq. m 25 sq. m 30 sq. m 25 sq. m 20 sq. m 20 sq. m 30 sq. m Ancillary Area 10 sq. m 10 sq. m 20 sq. m 10 sq. m 10 sq. m 10 sq. m -
11.1 In glass containers
11.2 In plastic containers
250 sq. m
CHANGES IN GMP
GMPs change formally and informally. GMPs are currently undergoing significant changes. Example of formal change: The U.S. medical devices GMPs have been completely rewritten, making them more compatible with the ISO-9001 quality document. In fact device GMPs were renamed - FDA now calls them the Quality System Regulation (QSR). DEPARTMENT OF PHARMACEUTICS AND PHARMACEUTICAL TECHNOLOGY L.M.COLLEGE OF PHARMACY, AHMEDABAD-09
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What is QSR? cGMP requirements are set forth in this quality system regulation. The requirements in this part govern the methods used in, and the facilities and controls used for, the design, manufacture, packaging, labeling, storage, installation, and servicing of all finished devices intended for human use. The requirements in this part are intended to ensure that finished devices will be safe and effective and otherwise in compliance with the Federal Food, Drug, and Cosmetic Act. This part establishes basic requirements applicable to manufacturers of finished medical devices. This regulation does not apply to manufacturers of components or parts of finished devices, but such manufacturers are encouraged to use appropriate provisions of this regulation as guidance. Manufacturers of human blood and blood components are not subject to this part. Example of Informal change: Expectations that inspectors have evolved over time. In the U.S., these changes are communicated by seminars and papers presented by FDA personnel and through agency Guides and Guidelines. One other way industry personnel can keep track of changes in expectations is by watching the FDA-483s (inspectional observations) and Warning Letters issued to firms by the agency.
COMPARISON OF GMPS OF DIFFERENT COUNTRIES

At a high level, GMPs of various nations are very similar most require things like, Equipment and facilities being properly designed, maintained, and cleaned. Standard Operating Procedures (SOPs) be written and approved. An independent Quality unit (like Quality Control and/or Quality Assurance). Well trained personnel and management. The WHO version of GMP is used by pharmaceutical regulators and the pharmaceutical industry in over one hundred countries worldwide, primarily in the developing world. The European Union's GMP (EU-GMP) enforces more compliance requirements than the WHO GMP, as does the Food and Drug Administration's version in the US. Similar GMPs are used in other countries, with Australia, Canada, Japan, Singapore and others having highly developed/sophisticated GMP requirements. In the United Kingdom, the Medicines Act (1968) covers most aspects of GMP in what is commonly referred to as "The Orange Guide", because of the color of its cover, is officially known as The Rules and Guidance for Pharmaceutical Manufacturers and Distributors.
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Enforcement of GMP in Different countries:

GMPs are enforced in the United States by the FDA; within the European Union, GMP inspections are performed by National Regulatory Agencies (e.g., GMP inspections are performed in the United Kingdom by the Medicines and Healthcare products Regulatory Agency (MHRA); in Australia by the Therapeutical Goods Administration (TGA); in India and Pakistan by the Ministry of Health
MODEL CERTIFICATE OF GOOD MANUFACTURING PRACTICES
A model certificate of Good Manufacturing Practices (GMP) for a manufacturing site is suggested (see below). It is suggested that the certificate should remain valid for a period of 2 years from the date of issue, but not exceeding 3 years after the inspection was carried out. It is recommended that, where possible, GMP certificates should have, e.g. security seals, watermarks or holograms, to help prevent counterfeiting, tampering and other fraudulent activities. MODEL CERTIFICATE OF GOOD MANUFACTURING PRACTICE This one-page certificate conforms to the format recommended by the World Health Organization (general instructions and explanatory notes attached). Certificate No: ______________________________________________ On the basis of the inspection carried out on ____ [date] ____ we certify that the site indicated on this certificate complies with Good Manufacturing Practices for the dosage forms, categories and activities listed below. 1. Name and address of site: ____________________________________________________________ 2. Manufacturers licence number: ____________________________________________________________ 3. Table 1: Dosage form(s) Category(ies) Activity(ies) The responsibility for the quality of the individual batches of the pharmaceutical products manufactured through this process lies with the manufacturer. This certificate remains valid until ____ [date] ____ It becomes invalid if the activities and/or categories certified here with are changed or if the site is no longer considered to be in compliance with GMP. Address of certifying authority: ____________________________________________________________ Name and function of responsible person: ____________________________________________________________ Email: __________ Telephone no.: __________ Fax no.: __________ Signature: Stamp and date: ____________________________________________________________
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QUESTIONS
1. Write a note on comparison of GMPs of different countries. (Uni. 2007) 2. Discuss the self inspection & Quality audit proposed by FDA regarding maintenance of pharma. Mfg. unit (Uni. 2006) 3. Give prototype sample of site master file and discuss each component of it in detail. (Uni.2006)
REFERENCES:
1. Good manufacturing practices for pharmaceutical products. In: WHO Expert Committee on Specifications for Pharmaceutical Preparations. Thirty-second report. Geneva, World Health Organization, 1992, Annex 1 (WHO Technical Report Series, No. 823). 2. Quality assurance of pharmaceuticals. A compendium of guidelines and related materials. Vol. 2. Good manufacturing practices and inspection. Geneva, World Health Organization, 1999. 3. Good manufacturing practices for sterile pharmaceutical products. In: WHO Expert Committee on Specifications for Pharmaceutical Preparations. Thirtysixth report. Geneva, World Health Organization, 2002, Annex 6 (WHO Technical Report Series, No. 902). 4. International basic safety standards for protection against ionizing radiation and for the safety of radiation sources: a safety standard. Vienna, International Atomic Energy Authority, 1996 (Safety Series, No. 115). 5. Regulations for the safe transport of radioactive material. Vienna, International Atomic Energy Authority, 1996 (IAEA Safety Requirements Safety Standards Series, No. TS-R-1, Revised). 6. Good manufacturing practices and inspection, Volume 2, 1999. World Health Organization, Geneva and subsequent updates. 7. Good manufacturing practices for pharmaceutical. A plan for total quality control by willing. 8. The Gazette of India .Sch M. 9. The Theory and practice of industrial pharmacy by Lachman. Pg:- 804 10. www.fda.gov 11. www.gmp.com
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PAPER-910201
CHAPTER-6
cGMP & PAT BY: SAURABH
PHARMACEUTICAL cGMP & PROCESS ANALYTICAL TECHNOLOGY
GUIDED BY: DR.R.K.PARIKH
PRESENTED BY: SAURABH M.PHARM- I 2009-10 ROLL NO.- 03
DEPT. OF PHARMACEUTICS & PHARMACEUTICAL TECHNOLOGY M.PHARM PART-1 L.M.COLLEGE OF PHARMACY, AHD-09 PAGE: 99
PAPER-910201
CHAPTER-6
CONTENT
PHARMACEUTICAL CGMP FOR 21ST CENTURY (A RISK BASED APPROACH) INTRODUCTION RISK BASED REVIEW
RISK MANAGEMENT MODEL FLEXIBLE GMP
GUIDELINE FOR INDUSTRY: PAT INTRODUCTION
PAT TOOLS
CHEMOMETRICS
REAL TIME RELEASE
APPLICATION OF PAT TO TABLET MANUFACTURING
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Pharmaceutical cGMP for 21st century: A Risk Based Approach INTRODUCTION:There exists an ample opportunity to improve the efficiency of pharmaceutical manufacturing and quality assurance through the innovative applications of novel product and process developments, process controls and modern analytical tools. However companies catering to regulated markets are hesitant to adopt new technologies and innovations. One of the reasons sighted by industry for this is regulatory uncertainty. In order to overcome this barrier to use of innovations in the manufacture and testing of drugs ,on august 21,2002 the FDA announced a new initiative called Pharmaceutical cGMP for 21st century: A Risk Based Approach. This is a two year programme. Goals of risk based cGMP:- The goals include Focus cGMP on potential risk areas Ensure regulatory work does not impede innovations. Enhance consistency in GMP inspections Encourage industry to use latest scientific advances in manufacturing. Focus the FDAs requirements squarely on potential public health risks. Ensure the FDAs establishment / enforcement of pharmaceutical product quality standards does not impede innovation / introduction of new technologies in the pharmaceutical industry. Enhance consistency and predictability of FDAs approach to assuring production quality and safety among FDA Centers and field components
What is risk?
Probability that the desired outcome will not be achieved. or Someone or something that creates or suggests a hazard. Also Risk can be defined as the combination of the probability of occurrence of harm and the severity of that harm (ISO/IEC Guide 51) and proposed to be adopted by ICH Q9. Three defined risk types: Patient Business Regulatory
What is Risk-based Approach?

Risk-based Approach Within an established quality system and for a particular manufacturing process, one would expect an inverse relationship between the level of process understanding and the risk of producing a poor quality product. The approach is based on science and engineering principal for assessing and mitigating risks related to poor product and process quality. Initiative Risk Based Approach 21 Aug. 2002 Final Risk Based Approach Sept. 2004
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What does it mean?

The approach will be applied to the review, compliance, and inspectional components of FDA regulation. Focus the attention of the FDA on the areas of highest-risk in the manufacturing process. Call for global reassessment of how the agency conducts product quality regulation. The FDA plans to direct its resources to the parts of the manufacturing process that pose the greatest risk. This is a major cultural change for both FDA and Industry.
Objectives:
To encourage the early adoption of new technological advances by the pharmaceutical industry To facilitate industry application of modern quality management techniques, including implementation of quality systems approaches, to all aspects of pharmaceutical production and quality assurance To encourage implementation of risk-based approaches that focus both industry and Agency attention on critical areas To ensure that regulatory review and inspection policies are based on state-of-the-art pharmaceutical science To enhance the consistency and coordination of FDA's drug quality regulatory programs, in part, by integrating enhanced quality systems approaches into the Agency's business processes and regulatory policies concerning review and inspection activities
Risk-based regulatory approaches recognize:

The level of scientific understanding of how formulation and manufacturing process factors affect product quality and performance The capability of process control strategies to prevent or mitigate the risk of producing a poor quality product
Risk Based Review:

Review - Minimizes intolerable risk to patient safety Process: Identify risk scenarios Assess likelihood of fault condition Assess severity of impact Assign risk grade Assess probability of detecting fault condition Determine mitigation strategy
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Quality Risk Classification (Based on SUPAC and GAMP-4)
LEVEL 3
LEVEL 2 LEVEL 1
Areas where industry could apply risk-based approach:

o Qualification of raw materials and components Reduced sampling BSE/TSE Risk Assessment of Animal Derived Raw Materials o Validation of methods, utilities, equipment and processes Critical systems first o Commitments from change controls, audits and investigations Complete high-risk first rather than date-due first
RISK MANAGEMENT MODEL

Steps:Risk perception Risk assessment Risk management Risk management is the translation of what was learned in the risk assessment into actions that minimize the risk associated with an event to an acceptable level Specifically, risk management is an iterative process of: 1) Assessing a products benefit-risk balance, 2) Developing and implementing tools to minimize its risks while preserving its benefits, 3) Evaluating tool effectiveness and reassessing the benefit-risk balance, and 4) Making adjustments, as appropriate, to the risk minimization tools to further improve the benefit-risk balance.
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FDAS
RISK MANAGEMENT MODEL CHALLENGES TO IMPLEMENTATION OF RISK BASED SYSTEM:This includes Cultural change Trust Risk assessment Management training Communication Perceived risk-dev report
IMPLEMENTATION OF RISK BASED APPROACH:The implementation of risk based approach is planned in three steps, namely immediate, intermediate, and long term steps. a) Immediate steps:- This includes Holding scientific workshops with key stakeholders Enhancing expertise in pharmaceutical technologies. (e.g.pharmaceutical engineering and industrial pharmacy) by additional training and hiring and by leveraging external expertise. Encouraging innovation within the existing framework of statutory provisions and regulations by allowing certain changes in the manufacturing process without prior review or approval.(e.g. Comparability protocols) Evaluating the optimal mechanisms to effectively and efficiently communicate deficiencies to industry, including content, consistency, disclosure and education. Including product specialists, as needed as a part of inspection teams. Having centers provide a scientific and technical review of all drug cGMP warning letters. Developing a technical dispute resolution process. Improving the operations of team biologics. b) Intermediate steps: Use emerging science and data analysis to enhance compliance programs to target the highest risk areas. DEPT. OF PHARMACEUTICS & PHARMACEUTICAL TECHNOLOGY M.PHARM PART-1 L.M.COLLEGE OF PHARMACY, AHD-09 PAGE: 104
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Evaluating the feasibility of establishing dedicated cadres of pharmaceutical inspectors. c) Long term steps: Enhanced training of agency staff on new scientific approaches and innovative pharmaceutical manufacturing technology. Develop and publish policies and procedures reflecting a science based, risk management approach. Educate industry on new regulatory approaches encouraging innovation.
Q. Are humans in India treated differently, medically on the basis of their ability to afford medicines? Ans:- The answer to this question lies in the answer to following questions., Does
everybody in this world eat only in five star hotels? Do they go hungry if five star quality is not available or affordable? Do not they consume food through the same mouth in which they consume medicines? Thus one can not ignore the fact that there is existence of multilayered GMP in India also in the world. The fact is known to everyone from the regulators, owners, manufacturing and quality professionals to the prescribers and to a limited extent to the consumers.
CONCLUSION :- There is a legal view, commercial view, Humanitarian view and

a scientific view to every aspect. So each line of thinking should be given a thought but basing on our affordability there is existence of flexibility. We agree that GMP is necessary and we should be among the best in the world. We should take into consideration the size, diversity, of country and the availability of resources especially money, manpower & machinery. After talking a lot about GMP, when actually it comes to the respective workplace the GMP goes as inexplicably for a toss as a Becham goal kick sailing over the bar. This has led to release of phrases like considered acceptable, released under special circumstances etc.The paying customer or consumer is nowhere in the picture where GMP or lack of it affects him and his near and dear ones directly.GMP is now a ticket to a few more percentage earning. Thus GMP is about practice, not about an object.
INTRODUCTION:Many years ago, Alexander Hamilton Said, Experience teaches that men are often so much governed by what they are accustomed to see and practice, that the simplest and most obvious improvements, in the most ordinary occupations, are adopted with hesitation, reluctance, and by slow gradations. Men would resist changes so long as even bare support could be ensured by an adherence to ancient courses, and perhaps even longer same is the case in implementation of PAT, So It will take time but it can be predicted that PAT initiatives by FDA will be a success in near future. Guidance PAT Sept. 2004
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WHAT IS PROCESS ANALYTICAL TECHNOLOGY (PAT) ?

Process analytical technologies involve the use of raw material properties, manufacturing parameters, process monitoring, and chemo metric techniques to produce finished product of acceptable quality. The central point of PAT is to generate product quality information in real time. A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance. It a process to ensure acceptable end product quality at the completion of the processing. PAT can be defined as the optimal application of process analytical chemistry (PAC) tools, feedback process control strategies, information management tools and/or product process optimization strategies to the manufacture of pharmaceuticals. The Agency(FDA) considers PAT to be a system for designing, analyzing, and controlling manufacturing through timely measurements (i.e., during processing) of critical quality and performance attributes of raw and in-process materials and processes, with the goal of ensuring final product quality. It is designed to modernize quality control by shifting companies toward continuous product analysis using sophisticated instruments at every stage of the manufacturing process. But Pat is not concerned about how to collect data or what kind of instrument should be used but rather what data should be collected, what is done with the data and what conclusions are drawn from them thus a complete and through understanding of the manufacturing process is important. PAT focuses on the principles of building quality into the product and process as well as continuous process improvements. It will enable the drug companies to improve efficiency and make safer product. It will allow them to gain a better understanding of their own process. It will help to minimize the potential for drug shortage and product recalls . PAT provides an opportunity to move from the current testing to document quality paradigm to a Continuous Quality Assurance paradigm that can improve our ability to ensure quality was built-in or was by design - ultimate realization of the true spirit of cGMP! Quality cannot be tested into product; it should be built-in or should be by design The guidance is applicable to all manufacturers of drug substances, drug products, and specified biologics (including intermediate and drug product components) over the life cycle of the products The term manufacturers includes human drug, veterinary drug, and specified biologic sponsors and applicants
BENEFITS AND CHALLENGES OF PAT IMPLEMENTATION: AN INDUSTRY PROSPECTIVE

Positive perceived benefits of PAT include: Decrease in cycle times Lower costs Increased efficiency and batch to batch consistency. Process finger printing (signature) that would be useful for validation, scale-up, and confirming acceptable handling of changes. Increased process understanding and a decrease in variability, rejects, and lot failures. DEPT. OF PHARMACEUTICS & PHARMACEUTICAL TECHNOLOGY M.PHARM PART-1 L.M.COLLEGE OF PHARMACY, AHD-09 PAGE: 106
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Possible continuous processing and the ability to adjust process on the basis of real time monitoring data. Higher yields, less rejection to no rejection No Lab interference with product quality Less validation expenses Easier transfer of master manufacturing Sops, documentation and data. Global manufacturing capacity utilization Easier regulatory adherence and compliance. Actual challenges include: Product approval delays by inclusion of PAT methodologies into relatively traditional drug development and validation activities. Lack of a written PAT guidance document from FDA. An increase in amount of data being generated, Increased pressures to meet aggressive filing timelines, added costs to make changes, Lack of senior management support and resource constraints.
PAT INITIATIVES
it includes : Implement quality by design-building Quality into manufacturing process rather than testing after the process, To improve pharmaceutical product quality, Promote real-time quality monitoring, Increases efficiency in pharmaceutical manufacturing , Reduce manufacturing cycle time, laboratory testing burden and costs, Established links between process variable and product performance.
COMPONENTS OF PAT FRAMEWORK:It includes (1) A set of scientific principles and tools supporting innovation (2) A strategy for regulatory implementation that will accommodate innovation.
Quality is built into pharmaceutical products through a comprehensive understanding of:

The intended therapeutic objectives; patient population; route of administration; and pharmacological, toxicological, and pharmacokinetic characteristics of a drug The chemical, physical, and biopharmaceutic characteristics of a drug Design of a product and selection of product components and packaging based on drug attributes listed above The design of manufacturing processes using principles of engineering, material science, and quality assurance to ensure acceptable and reproducible product quality and performance throughout a product's shelf life
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Gains in quality, safety and/or efficiency will vary depending on the process and the product, and are likely to come from:
Reducing production cycle times by using on-, in-, and/or at-line measurements and controls Preventing rejects, scrap, and re-processing Real time release (Real time release is the ability to evaluate and ensure the acceptable quality of in-process and/or final product based on process data. ) Increasing automation to improve operator safety and reduce human errors Improving energy and material use and increasing capacity Facilitating continuous processing to improve efficiency and manage variability
PAT TOOLS:It includes 1) Multivariate tools for design, data acquisition and analysis 2) Process analyzers 3) Process control tools 4) Continuous improvement and knowledge management tools These tools enable the identification and evaluation of product and process variables that may be critical to product quality and performance. The tools may also identify potential failure modes and mechanisms and quantify their effects on product quality.
1) Multivariate Tools for Design, Data Acquisition and Analysis

Pharmaceutical products and processes are complex multi-factorial systems. (From a physical, chemical, or biological perspective ) Traditional one-factor-at-a-time experiments do not address interactions among product and process variables The use of multivariate mathematical approaches, such as statistical design of experiments, response surface methodologies, process simulation, and pattern recognition tools, in conjunction with knowledge management systems help to support and justify flexible regulatory paths for innovation and post approval changes.
2) Process Analyzers
Process analysis has advanced significantly during the past several decades due to an increasing appreciation for the value of collecting process data. Process analyzers typically generate large volumes of data. Available tools have evolved from those that predominantly take univariate process measurements, such as pH, temperature, and pressure, to those that DEPT. OF PHARMACEUTICS & PHARMACEUTICAL TECHNOLOGY M.PHARM PART-1 L.M.COLLEGE OF PHARMACY, AHD-09 PAGE: 108
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measure biological, chemical, and physical attributes. Indeed some process analyzers provide nondestructive measurements that contain information related to biological, physical, and chemical attributes of the materials being processed. Process analysis measurements done: At-line: Measurement where the sample is removed, isolated from, and analyzed in close proximity to the process stream. On-line: Measurement where the sample is diverted from the manufacturing process, and may be returned to the process stream. In-line: Measurement where the sample is not removed from the process stream and can be invasive or noninvasive. Here probes are placed in constant contact with the product. Design and construction of the process equipment, the analyzer, and their interfaces are critical to ensure that collected data are relevant and representative of process and product attributes. Robust design, reliability, and ease of operation are important considerations. Installation of process analyzers on existing process equipment in production should be done after risk analysis to ensure this installation does not adversely affect process or product quality.
PAT: Measurement
Laboratory
Production Diverted Area Sample Inserted Probe No Product Contact
Off-Line
At-Line
On-Line
In-Line
t0
Non Invasive
t0
t+
t++
Real-time release
t++
3) Process Control Tools

It is important to emphasize that a strong link between product design and process development is essential to ensure effective control of all critical quality attributes. DEPT. OF PHARMACEUTICS & PHARMACEUTICAL TECHNOLOGY M.PHARM PART-1 L.M.COLLEGE OF PHARMACY, AHD-09 PAGE: 109
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Process monitoring and control strategies are intended to monitor the state of a process and actively manipulate it to maintain a desired state. Design and optimization of drug formulations and manufacturing processes include step like, Identify and measure critical material and process attributes relating to product quality Design a process measurement system to allow real time or near real time (e.g., on-, in-, or at-line) monitoring of all critical attributes Design process controls that provide adjustments to ensure control of all critical attributes Develop mathematical relationships between product quality attributes and measurements of critical material and process attributes Within the PAT framework, a process end point is not a fixed time; rather it is the achievement of the desired material attribute. This, however, does not mean that process time is not considered. A range of acceptable process times (process window) is likely to be achieved during the manufacturing phase and should be evaluated, and considerations for addressing significant deviations from acceptable process times should be developed. Rigorous statistical principles should be used for defining acceptance criteria for end point attributes that consider measurement and sampling strategies.
4) Continuous Improvement and Knowledge Management

Continuous learning through data collection and analysis over the life cycle of a product is important. These data can contribute to justifying proposals for postapproval changes. Improve the usefulness of available relevant product and process knowledge during regulatory decision making
Most benefit when it consists of scientific understanding of the relevant multifactorial relationships (e.g., between formulation, process, and quality attributes)
THE FOUR LEVELS OF PAT

PAT can be seen as operating on four levels. First level: The first, and most appreciated, is the application of on-line or at-line instrumentation for the immediate analysis of the end-product of a step in the pharmaceutical production, e.g., granulation, drying, mixing, tabletting, and coating. Here multivariate analytical data are translated back to concentrations, pH, temperatures, etc., before interpretations, alarms, etc. DEPT. OF PHARMACEUTICS & PHARMACEUTICAL TECHNOLOGY M.PHARM PART-1 L.M.COLLEGE OF PHARMACY, AHD-09 PAGE: 110
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Second level: PAT at the second level is less bound to the conventional data interpretation, and defines acceptable profiles, signatures of data, corresponding to acceptable product, without necessarily returning to concentrations of known compounds or other known properties. Here one can alternatively use classification to determine whether the sample in question is OK (pass) or not. Third level: The third level of PAT constitutes the use of the same on-line spectroscopic and other multidimensional sensor arrays to follow the manufacturing process in real time, and at each time-point determine whether the process is doing OK or not. The approach and tools are basically the same as PAT level 2, but applied "continuously" throughout all time points and phases of the pharmaceutical manufacturing processes, to make sure that these processes are all the time "in spec", as well as the trajectories are within specification for "good process". Fourth level: The fourth level, finally, concerns the monitoring of the whole process, from synthesis of active ingredient, characterization of excipients and other raw materials, granulation, mixing, etc., until tabletting, coating, and packaging. Sequential multivariate modeling is needed.
CHEMOMETRICS
previously, manufacturing processes have been treated in a univariate manner, with single parameters tracked by control charts. However, the reality is that physicochemical processes are multivariate with subtle interactions of variables. Chemometrics is the intersection of chemistry and the mathematics of large matrices of data. Chemometrics is complex and requires the use of computers and software to perform the necessary computations. These techniques reduce large amounts of data into a few recognizable components without any loss of data. Two chemometric techniques that have been found to be useful are Principal Component Analysis (PCA) and Partial Least Squares Regression (PLS). These techniques are recognized for their ability to eliminate noise, identify latent variables, and extrapolate missing data. a) PCA It is a technique of creating data models of previously produced and tested batches to verify similarity to newly created batches.
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One advantage this technique has over the commonly used f2 metric is that batches are now compared to a substantial compilation of batches included in a validated model. Trends could potentially be identified earlier than with an f2 comparison. This could help improvement of process consistency after scale up and post approval changes. Another advantage of PCA is that it can handle the large amount of data produced by dissolution fiber optic (Dis-FO) techniques without the need to reduce data points. b) PLS It is used to correlate data, such as finished product dissolution results, to raw material, process parameters, and in-line readings. Variables which affect the dissolution rate can be better understood and monitored. The effect of scale ups and post approval changes can be quantified. Critical parameters can be controlled, thereby creating high quality drug product, less level/stage 2 testing, and minimal product failure. When out of specification results do occur, drug products can be better investigated through the use of PLS to determine which underlying variables contributed to the failing drug product.
REAL TIME RELEASE:

Real time release is the ability to evaluate and ensure the acceptable quality of in-process and/or final product based on process data. Typically, the PAT component of real time release includes a valid combination of assessed material attributes and process controls. Material attributes can be assessed using direct and/or indirect process analytical methods. The combined process measurements and other test data gathered during the manufacturing process can serve as the basis for real time release of the final product and would demonstrate that each batch conforms to established regulatory quality attributes. Real Time Release to be comparable to alternative analytical procedures for final product release. In real time release, material attributes as well as process parameters are measured and controlled. The Agency's approval should be obtained prior to implementing real time release for products that are the subject of market applications or licenses. Process understanding, control strategies, plus on-, in-, or at-line measurement of critical attributes that relate to product quality provides a scientific risk-based approach to justify how real time quality assurance is at least equivalent to, or better than, laboratory-based testing on collected samples.
Possible Fields of PAT Applications:

1. Monitoring the Water Content of Lyophilised Vials by near IR
o The water content of the lyo cake is very important according to the stability of the product DEPT. OF PHARMACEUTICS & PHARMACEUTICAL TECHNOLOGY M.PHARM PART-1 L.M.COLLEGE OF PHARMACY, AHD-09 PAGE: 112
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2. Monitoring a Powder Blending Process by near IR

o A homogeneous blend is a prerequisite for a good content uniformity
3. Chemical Imaging by NIR:

Detection of empty capsule in a blister Current Regulatory Situation -Identification (ID) testing of every container of raw material delivery Received Traditional Approach -Raw Materials remain in quarantine (max up to 3 days) until Laboratory have completed ID testing PAT Approach -To use NIR to Identify all containers of Raw Materials Very quick -Gives both Chemical and Physical information. -Conducted rapidly at-line by warehouse operators.
4. Raw and Packaging Materials
5. Cleaning Validation / Verification:

Current Regulatory Situation - Cleaning validation must be performed to validate the consistent removal of product, microbiological matter and cleaning agents, to an acceptable level, from production equipment. Traditional Approach -Product has to be extracted from the swab -Long sample preparation -Destructive testing -Limited ability to test for all ingredients PAT Approach - Developed a method based on direct scanning of swabs by NIR - Method uses alcohol as solvent Increases number of ingredients that can be tested Rapid sample preparation -Method does not require the extraction step from swab into test solution (large source of error and time) -Decreased turn-around time due to greatly reduced sample preparation and analysis time (~60% reduction)
Methods for PAT Applications

NIR IR Raman Light Induced Fluorescence Chemical imaging Reflectance UV & fiber optics Fast HPLC NMR Dielectric determinations
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APPLICATION OF PAT TO TABLET MANUFACTURING:By application of PAT to tablet manufacturing, the manufacturing process can be continuously monitored and adjustments are made to ensure that the finished product would meet the desired specifications. Measurements from these techniques have already been used successfully to give predictive values for dissolution, content uniformity, assay, moisture content and hardness. using PAT the processes would be under such high control that the dissolution results could be accurately predicted well before the product is being analysed.The techniques used include NIR(near infrared) raman,mid IR, Acoustic emission signals and other imaging techniques. Dissolution scientists face is to become familiar with this next generation of pharmaceutical testing and its potential applications in pharmaceutical testing.
Example: Current Tablet Production

Raw Material Dispensing Blending Compression
Identification Tests (Chemical Only)
No Tests (Time Based) Test Product Quality for Release (Active Only)
Process at Risk
End-Product Focused Testing to Document Quality
PAT Tablet Production
Raw material Functionality & Dispensing
Predictive Models
Blending
Compression
Functional Tests (Chemical and Physical)
Control Blending (Particle Size & Disintegrant Distribution)
Validate Process Control
Mitigate the Process Risk
Process Focused
REFERENCE: 1. http://www.fda.gov/cvm/guidance/published.html 2. Shah Vinod , cGMP for 21st Century; Pharma Times, Volume 36,Jan 2004: 29-32. 3. Process analytical technology: application to the pharmaceutical industry, by Peter Scott, Quality assurance analytical services, AstraZeneca, Westborough, MA DEPT. OF PHARMACEUTICS & PHARMACEUTICAL TECHNOLOGY M.PHARM PART-1 L.M.COLLEGE OF PHARMACY, AHD-09 PAGE: 114
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4. The four levels of PAT and associated risks and benefits in pharmaceutical production. By- Svante Wold,Umea Univ,Umea, Sweden 5. Pharma,s Process analytical technology, By-Corinne A.Marasco, Chemical& Engineering news, Washington 6. Process analytical technology-Concepts And Principles By- Mark L. Balboni,Senior compliance consultant, PAREXEL International 7. Risk Based cGMP-A New initiative by USFDA, By Dr. Premnath Shenoy, Pharma Times, Vol-36, February 2004,23-24 8. P.M Manker, Flexible GMP : Some current, some not so current, Pharma Times,Vol-38,April 2006,21-22
QUESTIONS:
1. What is Risk based approach? How it will be helpful to improve product quality? 2. What is PAT? What impacts it make over pharmaceutical industries? 3. Described in brief (1) PAT tools i. (2) Risk Based Review ii. (3) Real Time Release iii. (4) Chemometrics iv. (5) Risk management Model Define PAT? Add a note on its four levels? Do you think PAT will benefit the pharmaceutical industry to a large extent? Justify Write in detail application of PAT to tablet Manufacturing? Define PAT? Add a note on its benefits And challenges to its implementation?
4. 5. 6. 7.
QUESTIONS ASKED IN EXAM:

1. Explain PAT & Risk based approach- Discuss about Real time release (Sept- 2005) 2. What is risk based approach & PAT? Discuss application of PAT in tablet manufacturing (Sept- 2006) 3. Write a note on comparison of GMPs of different countries. What is flexible GMP & PAT? (2007)
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WORLD CLASS & FLEXIBLE GMP BY: SHWETA IYER
WORLD CLASS MANUFACTURING & FLEXIBLE GMP
SEMINAR ON
GUIDED BY: Dr. R.K.PARIKH
PREPARED BY: SHWETA IYER M.PHARM SEM-I ROLL NO.08 2009-2010
DEPARTMENT OF PHARMACEUTICS & PHARMACEUTICAL TECHNOLOGY L.M. COLLEGE OF PHARMACY, AHMEDABAD-09
M.PHARM SEM I L.M.COLLEGE OF PHARMACY, AHMEDABAD-09 PAGE:116
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WORLD CLASS MANUFACTURING:

WCM is a cross-functional process for designing, producing, and delivering goods that delight customers and lead to exceptional organizational performance. It combines skills and resources from various functions to focus on opportunities and threats in the environment. To meet quality standards for world class manufacturing, 5S Quality Program is implemented by many companies. 5S, abbreviated from the Japanese words Seiri, Seiton, Seison, Seiketsu, and Shitsuke, are simple but effective methods to organize the workplace. The 5S, translated into English are: Housekeeping, Workplace organization, Cleanup, Keep cleanliness, and Discipline.
There are 3 principles behind World Class Manufacturing:

The first is what is known as Just in Time or Lean Manufacturing, the step by step elimination of waste. Waste in this sense is defined as any activity that adds cost but not value to the end product such as excess production, stock, idle work in progress, unnecessary movement and scrap. The second is total quality, a culture of intolerance to defects both in the processes and also information such as bills of material and stock records. Total quality is often these days called Six Sigma which uses total quality and lean manufacturing techniques to attempt to reduce rejects. The final principle is the principle of total preventative maintenance where, whenever practical, a preventative maintenance programme means that unplanned stoppages due to equipment failure are minimised.
ACTION AGENDA FOR MANUFACTURING EXCELLENCE: 1. Get to know the customer 2. Cut wip inventories 3. Cut flow times 4. Cut setup & changeover times 5. Cut flow distance and space 6. Reduce number of suppliers 7. Improve supplier performance 8. Reduce parts proliferation 9. Design for manufacturability 10. Cross-train workers and managers 11. Post production, quality, and problem data 12. Give line people first crack at solving problems 13. Maintain & improve existing equipment & human capital 14. Use simple, cheap, movable equipment 15. Automate incrementally
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How is World Class Manufacturing Achieved?

There are a large number of "tools" which can be used to realize these objectives with regard to Production control, inventory and work-organization. Some of these are to do with factory layout; others affect production scheduling, machine changeover, quality assurance and work organization. There is no universal toolkit that all firms need to adopt in all circumstances. Which tool is relevant depends upon the particular Critical Success Factors in the market in which the firm is operating. In making the transition to World Class Manufacturing, the firm needs to address three primary challenges, namely to: Develop the awareness of the need to make the transition to World Class Manufacturing Develop the ability to search for relevant tools and to apply them effectively Monitor progress so that an improvement programme can be systematically utilised. Typical Critical Success Factors, which operate in open markets, are listed in the table below, which also identifies which tools are relevant to make an effective response to these market challenges. Moreover, improvement depends on knowing how the firm is doing, and thus it is also important to determine how progress might be measured.
Process for Implementing World Class Manufacturing:

1. Set business goals and understand customer expectations, 2. Define essential manufacturing competencies, 3. Create metrics for these competencies, 4. Benchmark performance, 5. Determine target levels for each metric, 6. Develop plans and programs to achieve the targets, 7. Organize and manage the implementation process, and 8. Evaluate performance & revise the systems.
SKINNERS PROCESS STEPS FOR MANUFACTURING STRATEGY FOR WORLD CLASS MANUFACTURING: 1. Competitive analysis 2. Company audit/inventory 3. Company strategy formulation 4. Implied manufacturing objectives 5. Cost structures and economic constraints 6. Technology analysis 7. Manufacturing evaluation and options 8. Decide manufacturing policies 9. Requirements/targets for mfg organization 10. Design systems/procedures 11. Control systems 12. Set operations parameters
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13. Monitor performance 14. Continuous improvement on strategy 15. Continuous improvement on operations and policies Implementing World Class Manufacturing: Tools to Measure and Record Progress
Critical Success Factor 1. Cost control World Class Manufacturing tool Just-in-time logistics, quality at source and supply chain management tools Measurement Indicators Inventory holdings Absence of defects and rework Cost of incoming materials Customer return rates Internal reject, rework and scrap rates Supplier quality performance Time from customer order to delivery Delivery frequency and reliability to customers Delivery frequency and reliability of suppliers Machine changeover times Batch and lot sizes Inventory levels Throughput time through factory Machine utilization levels Numeracy and literacy levels Labour/management turnover levels Absenteeism rates Training expenditure and types of training Employee development Suggestion schemes/continuous improvement R&D expenditure Proportion of sales from new products
2. Quality
3. External flexibility
Statistical Process Control, fool-proofing to prevent errors, Pareto analysis of types and causes of production defects Just-in-time logistics, quality at source and supply chain management tools
4. Internal flexibility
Cellular layouts, single unit flow, production pulling, kanban signaling system, single-minute exchange of dies for rapid machine changeover, supply chain management Multi-tasking, multiskilling, quality circles, kaizen groups, training, incentive schemes.
5. Capacity to change (Human resource development)
6. Innovation capacity
Concurrent engineering, new product development techniques
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CONCLUSION: To achieve WORLD CLASS MANUFACURING, companies should attempt to be best in the field at each of the competitive priorities (quality, price, delivery speed, delivery reliability, flexibility and innovation). Organisations should therefore aim to maximise performance in these areas in order to maximise competitiveness. However, as resources are unlikely to allow improvement in all areas, organisations should concentrate on maintaining performance in 'qualifying' factors and improving 'competitive edge' factors. The priorities will change over time and must therefore be reviewed.
FLEXIBLE GMP:
WHAT IS FLEXIBLE GMP? It is the existence of different strata of quality standards in India to suit each category of people of our society. It named so as there is flexibility in available quality standards and also there is free hand in choosing any of the quality standard and target any class of people. JUSTIFICATION FOR THE EXISTENCE OF FLEXIBLE GMP: If we analyze the people of India, we will find there is a social stratum comprising of extra rich, the rich, the upper middle class, the lower middle class and economically backward class. Thus there is need for availability of medicines to suit each pocket. So there is a need of exploring and utilizing different quality standards starting from minimum quality standards (schedule M) to highest quality standard (USFDA), so that each stratum of people have a comfortable access and affordability to medicines. Thus the existence of flexible GMP is justified.
EXTRA RICH
US FDA
THE RICH UPPER MIDDLE CLASS LOWER MIDDLE CLASS ECONOMICALLY BACKWARD CLASS
TGA (AUS) MHRA (U.K) MCC GMP (S.A) WHO GMP SCHEDULE-M (MININUM STANDARD)
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To clear above view, lets take an example: Typical drug manufacturing system is equivalent to food outlets(which vary from road side fast food joints to 5 star hotels).The same food is produced and served at varying levels of cleanliness, ambience and quality for a varying price to suit different classes of people. The client would choose his category of eatery according to affordability. Similarly Indian drug manufacturing industry churns out same drug at varying costs from factories varying from minimum acceptable to highest world standards. This has led to the existence of flexible GMP and its existence is justified. Q.Why people in India are treated differently, medically, on the basis of their ability to afford medicines? Ans:- The answer to this question lies in the answer to following questions., Does everybody in this world eat only in five star hotels? Do they go hungry if five star qualities are not available or affordable? Do not they consume food through the same mouth in which they consume medicines? Thus one cannot ignore the fact that there is existence of multilayered GMP in India & also in the world. The fact is known to everyone from the regulators, owners, manufacturing and quality professionals to the prescribers and to a limited extent to the consumers. CONCLUSION: - There is a legal view, commercial view, Humanitarian view and a scientific view to every aspect. So each line of thinking should be given a thought but on the basis of our affordability there is existence of flexibility. We agree that GMP is necessary and we should be among the best in the world. We should take into consideration the size, diversity, of country and the availability of resources especially money, manpower & machinery. After talking a lot about GMP, when actually it comes to the respective workplace the GMP goes as inexplicably for a toss .This has led to release of phrases like considered acceptable, released under special circumstances etc. The paying customer or consumer is nowhere in the picture where GMP or lack of it affects him and his near and dear ones directly.GMP is now a ticket to a few more percentage earning. Thus GMP is about practice, not about an object.
REFERENCES:
www.bpic.co.uk/faq/world_class_manufacturing.htm www.emeraldinsight.com Manufacturing Strategy Concepts -Massachusetts Institute of Technology Sloan School of Management www.nitc.ac.in/nitc/bulletin/files/opt_7865_657067492.pdf P.M Manker, Flexible GMP: Some current, some not so current, Pharma Times, Vol-38,April 2006,21-22.
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Production Planning & Control BY: HIMAXI
PRODUCTION PLANNING AND PRODUCTION CONTROL
Guided by: Dr.R.K.Parikh
Prepared by: Himaxi Rajput M.Pharm I(2009-2010) Roll no. 9
Department Of Pharmaceutics and Pharmaceutical Technology L.M. College Of Pharmacy, Ahmedabad 09.
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POOL OF CONTENT 1) Production 2) Production management 3) Production planning organization chart of a PPMC Department Objectives, Importance, Functions Levels of production planning Steps of production planning 4) Production control
[1]Production
It is the foundation on which every organization is built. Production is an intentional act of producing something in an organized manner. It is a fabrication of a physical object through the use of man, material and equipment. The main objectives of production are: 1. Optimum use of resources at optimum cost 2. Manufacture of desired quality and quantity of goods and services in the most efficient and economical way Therefore efficient management of the production function is of utmost importance in order to achieve this objective.
[2]Production management
It is the process of effective planning and regulating the operations of that section of an enterprise which is responsible for the actual transformation of materials into finished product. Production management deals with decision making related to production process so that the resulting goods and services are produced in accordance with the quantitative specifications and demand schedule with minimum cost. Form the above definitions it is clear that production planning and its control are the main characteristics of production management. Functions of production management: 1. Design and development of production process 2. Production planning and control 3. Implementation of the plan and related activities to produce the desired output 4. Administration and coordination of the activities of various components and departments responsible for producing the necessary goods and services M.PHARM SEM I L.M.COLLEGE OF PHARMACY, AHMEDABAD-09 PAGE:123
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[3]Production planning
It is the function of management which decides about the resources the firm will require for its future manufacturing operations and allocating these resources to produce the desired output in required amount at lowest cost. PP is necessary for directing and controlling the methods used for production and deals with the setting up of production facilities viz. building, machine, equipment etc. in available space. It involves the predetermination of manufacturing requirements such as materials, money; order priority, production process etc. for efficient production of desired goods and services. A representative organization chart of a PPMC Department
PLANT MANAGER
FACTORY PRODUCTION
PRODUCTION PLANNING AND MATERIAL CONTROL
PLANT MAINTENANCE
MATERIAL CONTROL
ESTIMATING AND ROUTING
ORDER WRITE-UP
DISPATCHING AND FOLLOW UP
TOOL CONTROL
SCHEDULING AND CONTROL
Objectives 1. 2. 3. 4. 5. Define production management, production function and its component Explain the design of production system and manufacturing process List out the factors influencing the choice of production process To establish targets and checking these against performance To establish routes and schedules for work that will ensure the optimum utilization of materials, workers, and machines 6. To coordinate labour, machine and equipment in the most effective and economic manner 7. To ensure smooth flow of material by eliminating all types of bottlenecks. 8. To utilize the underemployed resources 9. To provide the means for ensuring the operation of the plant in accordance with these plans 10. To manufacture the desired output of right quality and quantity at right time. M.PHARM SEM I L.M.COLLEGE OF PHARMACY, AHMEDABAD-09 PAGE:124
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Importance It reduces the cost of production by minimizing the wastage of material and economic utilization of resources. It leads to lower investment by efficient and balanced utilization of sources. It promotes employee morale by avoiding all sorts of bottlenecks. It enhances customer satisfaction and confidence. Scope To liaison with purchase department for efficient and effective procurement of inputs. To liaison with marketing dept, to determine the nature and magnitude of output. To plan the layout of operations indicating in detail the places/points in the system where various production activities/operations are to be performed. Establishment of time schedule for various stages/levels of production by setting up necessary standards. To ensure continuous inspection over the quality of goods manufactured. Instituting necessary controls to complete the work according to schedule. Functions Forecasting to predict customer demand on various products over a given horizon. Aggregate Planning to determine overall resource needed. Materials Requirement Planning to determine all required components and timing. Inventory Management to decide production or purchase quantities and timing. Scheduling to determine shop-floor schedule of various components. Levels of Production Planning It can be done at three levels which are: 1) FACTORY PLANNING Here the sequence of work tasks is planned in terms of building, machines and equipment required for manufacturing the desired good sand services. The relationship of workplaces in terms of departments is also planned at this stage. This stage also deals with plant location and layout. 2) PROCESS PLANNING There are many operations involved in factory planning for transforming the inputs into some desired end product. In process planning, these operations are located and the sequence of these operations in production process is determined. Plans are also made for the layout of work centers in each process. 3) OPERATION PLANNING It is concerned with planning the details of the methods required to perform each operation viz. selection of work centers, designing of tools required for various operations. Then the sequences of work elements involved in each operation are planned.
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Specification about each transfer, work centers, nature of tools required and time necessary for completion of each operation are prescribed.
Steps of Production Planning

A. Routing Routing means determination of path or route over which each piece is to travel in being transformed from raw material into finished products.-Kimball and Kimball Under this, the operations, their path and sequence are established. To perform these operations the proper class of machines and personnel required are also worked out. The main aim of routing is to determine the best and cheapest sequence of operations and to ensure that this sequence is strictly followed. IT INVOLVES FOLLOWING ACTIVITIES 1) 2) 3) 4) 5) 6) 7) An analysis of the article to determine what to make and what to buy To determine the quality and type of material Determining the manufacturing operations and their sequences A determination of lot sizes Determination of scrap factors An analysis of cost of article Organization of product control forms
B. Scheduling The determination of time that is required to perform each operation and also the time required to perform entire series as routed is Scheduling. -Kimball and Kimball. It means working out of time that should be required to perform each operation and also the time necessary to perform the entire series as routed, making allowances for all factors concerned. It mainly concerns with amount of work to be done and the time when each element of work will start. Features of Scheduling Description of When and Where of each operation in a production process is to be executed. Establishment of timetable at which to begin and complete each event or operation comprising any procedure. Objectives of scheduling The main objective of scheduling is to arrange the work of the production in such a way that: Items are delivered on due date Prevent unbalanced allocation of time among various department The production cost is minimum M.PHARM SEM I L.M.COLLEGE OF PHARMACY, AHMEDABAD-09 PAGE:126
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Types of scheduling Operation schedule It determines the total time require d to do a piece of work with a given machine or process. It indicates the time required to perform as well as other details of types of materials, machines, labour etc. required for each and every operation. It takes into account following factors. 1) Physical plant facilities of the type required to process the material being scheduled. 2) Personnel who possess the desired skills and experience to operate the equipment and perform the type of work involved. 3) Necessary materials and purchased parts. Master schedule It is a list showing how many of each item to make in each period of time in future. The nature of master schedule depends on whether the manufacture is to order to stock. The development of master schedule for manufacture to stock begins with a sales forecast. Sequential scheduling It is difficult to define a sequence for multi product plant which passes through a number of departments. If sequence is varied in each department the number of sequences increases will increase and there is no known technique to identify the optimum sequence. If duration of each operation is known, then optimum sequence can be find by two rules:1. For minimum time lost, each operation should be shorter than any predecessor in a program. 2. For minimum individual lead time, each operation should be shorter than any predecessor in a programme. Tools of scheduling /PP 1. 2. 3. 4. 5. 6. GANTT CHARTS Network analysis/ technique(CPM & PERT) WORK BREAKDOWN STRUCTURE MOTION STUDY (METHOD STUDY) TIME STUDY (WORK MEASUREMENT) JUST IN TIME (JIT)
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1) GANTT CHART
A Gantt chart is a horizontal bar chart developed as a production control tool in 1917 by Henry L. Gantt, an American engineer and social scientist. Frequently used in project management, a Gantt chart provides a graphical illustration of a schedule that helps to plan, coordinate, and track specific tasks in a project The bar chart is a means of displaying simple activities or events Plotted against time A project is broken down into separate tasks. Estimates are made of how much time each requires as well as total time required to complete the entire project. A Gantt chart is constructed with a horizontal axis representing the total time span of the project, broken down into increments (for example, days, weeks, or months) and a vertical axis representing the tasks that make up the project Horizontal bars of varying lengths represent the sequences, timing, and time span for each task. As the project progresses, secondary bars, arrowheads, or darkened bars may be added to indicate completed tasks, or the portions of tasks that have been completed. A vertical line is used to represent the report date. Gantt charts may be simple versions created on graph paper or more complex automated versions created using project management applications such as Microsoft Project or Excel Advantages 1. Simple to understand and easy to change 2. Simplest and least complex means of portraying progress or the lack of it 3. Can easily be expanded to identify specific elements that may be either behind or ahead of schedule
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4. Automated Gantt charts store more information about tasks, such as the individuals assigned to specific tasks, and notes about the procedures. Limitation 1. Bar charts do not show the interdependencies of the activities and hence do not represent a network of the activities. You cannot tell how one task falling behind schedule affects other tasks. 2. The relationship between activities is crucial for controlling program costs. Without this relationship bar charts have little predictive value. 3. Do not clearly indicate DETAILS REGARDING THE PROGRESS of activities. 2) Network analysis/ technique Deficiency of GANNT technique can be eliminated to a large extent by showing the interdependence of various activities by means of connecting arrows called network technique It is the general name given to certain specific techniques which can be used for the planning, management and control of projects. CPM was developed by Du pont and the emphasis was on the trade off between the cost of the project and its overall completion time. PERT was developed by the US Navy for the planning and control of the Polaris missile program and the emphasis was on completing the program in the shortest possible times In CPM ACTIVITIES are shown as network of precedence relationships using activity- on- node network construction It is used for the jobs of repetitive in nature where the activity time estimates can be predicted with considerable certainty due to the existence of past experience. In PERT activities are shown as network of precedence of relationships using activity-on- arrow network construction. It is used for non repetitive jobs (R&D), where the time and cost estimates tend to be quite uncertain.
Terminology of network analysis Activity: a time consuming effort that is required to perform a part of the work. It is bound to two events: Predecessors event and Successors event. Arrows An arrow leads form tail to head directionally indicate activity Event: a point in the time where one or more activities start and /or finish. Nodes a node is represented by a circle indicate event Time Estimate (Expected Time): completion time is assumed to be uncertain and unknown therefore project completion time is estimated. Three time estimates are made for each activityOptimistic Time (a), Pessimistic Time (b), Normal Time or Most Likely Time (m)
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Expected Time (Te): a + 4m + b 6 Network diagram: It is pictorial presentation of events and Interconnecting activities, which define series or parallel sequence of activities. Critical Path: It is longest path in a network (it is the sequence of activities that requires the maximum time for completion.) It is denoted by darker or double lines to distinguish Earliest Start Time (EST): This is the earliest time when an activity can start up. Earliest Finish Time (EFT): This is the earliest time when an activity can finish. EFT = EST + Time taken by the activity. Latest Start Time (LST): It is the latest time at which an activity should be started if the project is to be completed. Latest Finish Time (LFT): It is the latest time at which an activity should be completed, if the project is to be completed at a fixed time. LST = LFT Te Slack Time: Slack time can be defined as the amount of time a task can be delayed without causing another task to be delayed or impacting the completion date of your project. Slack may be positive or negative. Positive slack represents idle time. Negative slack occurs when project requires more resources. Float: Delay in completion of an event is called float. The following is an example of CPM network diagram
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The following figure shows an example PERT chart:
The first number above each node represents the time to complete that task and the second number represents the slack time for that task. The critical path is A-E-F-G and the minimum completion time is 70 (10 + 25 + 25 + 10). Steps in the PERT process 1. 2. 3. 4. 5. 6. Identify the specific activities and milestones Determine the proper sequence of the activities Construct a network diagram Estimate the time required for each activity Determine the critical path Update the PERT chart as the project progresses.
Benefits of PERT EXPECTED project completion time Probability of completion before a specified date The critical path activities that directly impact the completion time The activities have slack time and that can lend resources to critical path activities Activity start and end dates.
Limitations The activity time estimates are somewhat subjective and depend on judgment. In cases if the person or group performing the activity estimates the time there may be bias in the estimate. 3) WORK BREAKDOWN STRUCTURE A complex project is made manageable first breaking it down into individual components in a hierarchical structure, known as the work breakdown structure, or the WBS. M.PHARM SEM I L.M.COLLEGE OF PHARMACY, AHMEDABAD-09 PAGE:131
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Generally, WBS uses a tree diagram/structure diagram to show the resolution of overall requirements into increasing levels of detail. WBS allows a team to accomplish its general requirements by partitioning a large task into smaller components and focusing on work that can be more easily accomplished Importance of WBS It is the single most important element because it provides a common framework from which: 1. 2. 3. 4. 5. 6. 7. 8. The total program can be described as summation of subdivided elements. Planning can be performed Costs and budgets can be established Time, performance and cost can be tracked Objectives can be linked to company resources in logical manner Schedules and status reporting procedures can be established Network construction and control planning can be initiated The responsibility assignments for each element can be established
When to use it: In the quality planning process, WBS begins with a generalized goal and then identifies progressively finer levels of actions needed to accomplish the goal. In the quality improvement process, the tool is especially useful for creating an implementation plan to remedy identified process problems. For WBS to accurately reflect the project, however, it is essential that the team using it have detailed understanding of the tasks required.
How to use it:1. Identify the primary requirement or objective: This should be a clear item, based on customer requirements, to which the entire team agrees. Write this requirement at the top of the chart.
2. Subdivide the requirement statement into major secondary categories: These branches should represent requirements, products, or activities that directly lead to the primary objective or that are directly required to fulfill the overall requirement. The team should continually ask, What is required to meet this condition?, What happens next?, and What needs to be addressed? Write the secondary categories below the primary requirement statement.
3. Break each major heading into greater detail: As you move from top to bottom in the WBS, products and activities should become more and more specific. Stop the breakdown when each task is tiny enough to be easily completed and evaluated for accuracy. M.PHARM SEM I L.M.COLLEGE OF PHARMACY, AHMEDABAD-09 PAGE:132
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4. Review the WBS for logic and completeness: Make sure that each subheading and path has a direct cause-and-effect relationship with the one before. Examine the paths to ensure that no obvious products or actions have been left out. Also ensure that the development of listed products or completion of listed actions will indeed lead to the anticipated results.
SCHEMATIC REPRESENTATION
FINAL ASSEMBLY
SUB ASSEMBLY
SUB ASSEMBLY
COMPONENT
COMPONENT
ELEMENT
ELEMENT
RAW MATERIAL
RAW MATERIAL
4) MOTION STUDY (METHOD STUDY) Motion study is a technique, which analyzes each operation, of a given piece of work, very closely in order to eliminate unnecessary operations and to approach the quickest and earliest methods of performing each necessary operation. PROCEDURE OF MOTION STUDY Motion Study can be performed in the following steps: Step 1: Break up the operation and make a detailed list of all steps in the present operation. Step 2: Question each detail of job: Purpose? Place? Sequence? Person? Means? Step 3: After considering the above questions, a new and better method is developed. Step 4: Installing the new method. Step 5: Maintaining new method. M.PHARM SEM I L.M.COLLEGE OF PHARMACY, AHMEDABAD-09 PAGE:133
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5) TIME STUDY (WORK MEASUREMENT) Time study is defined as the art of observing and recording the time required to do each detailed element of an industrial operation. Time study is done on a printed time-study record. After noting all these readings, average time is calculated. Standard time = Average time Where, Standard time: It is the time, which is taken by normal worker for a specific task. Rating Factor: This is expressed as percentage of the efficiency of representative operator (generally taken as 110% - 120%). Allowances: Interference allowances: When worker is attending more than one machine. Process allowances: This is an allowance provided to compensate the enforced idleness during a process. (It includes: no work, power failure, faulty material, faulty tools and equipments). Contingency allowances: Delays, which cannot be measured correctly. Special allowances: It includes: start up, cleaning, shut down, change-over time, equipment change, etc. 6) Just-In-Time Concept: Just In Time (JIT) is a production and inventory control system in which materials are purchased and units are produced only as needed to meet actual customer demand. Its objective is to eliminate product inventories from the supply chain and inventories are reduced to the minimum and in some cases are zero. As much a managerial philosophy as an inventory system, JIT encompasses all activities required to make a final product from design engineering onwards to the last manufacturing operation. JIT systems are fundamental to time based competition and rely on waste reduction, process simplification, setup time and batch size reduction, parallel (instead of sequential) processing. It was developed and perfected by Taiichi Ohno of Toyota Corporation during 1960s and 70s to meet fast changing consumer demands with minimum delays It has the most profound effects, however, on the operations of manufacturing companies which maintain three class of inventories-raw material, Work in process, and finished goods. Traditionally, manufacturing companies have maintained large amounts of all three types of inventories to act as buffers so that operations can proceed smoothly even if there are unanticipated disruptions. M.PHARM SEM I L.M.COLLEGE OF PHARMACY, AHMEDABAD-09 PAGE:134 Rating Factor / other allowances.
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While these inventories provide buffers against unforeseen events, they have a cost. In addition to the money tied up in the inventories, presence of inventories encourages inefficient and sloppy work, results in too many defects, and dramatically increase the amount of time required to complete a product. Advantages of Just in Time Manufacturing System: 1. Funds that were tied up in inventories can be used elsewhere. 2. Areas previously used, to store inventories can be used for other more productive uses. 3. Throughput time is reduced, resulting in greater potential output and quicker response to customers. 4. Defect rates are reduced, resulting in less waste and greater customer satisfaction. 5. The flows of goods from warehouse to shelves are improved. 6. Employees who possess multiple skills are utilized more efficiently. 7. Better consistency of scheduling and consistency of employee work hours. 8. Increased emphasis on supplier relationships. 9. Supplies continue around the clock keeping workers productive and businesses focused on turnover Disadvantages of Just in Time Manufacturing System: 1. There can arise unexpected delivery hang-ups that cause a loss in sales C. Loading It is the study of the relationship between load and capacity at the places where work is done. Loading and scheduling are designed to assist in the efficient and systematic planning of work. It provides complete and correct information about the number of machines available and their operating characteristics, such as, speed, capability etc. This information can be used to calculate the difference between workload and actual capacity and then to determine whether customers order can be completed on due date or not.
[4]PRODUCTION CONTROL
It is one of the important functions of the enterprise. It ensures the desired output of specified quantity at the prescribed time in the most economical way to meet an approved sales program. Production provides the foundation on which most of the other industrial controls are based. Production control is some scientific procedure to regulate an orderly flow of the material and co ordinate various production operations to accomplish the objective of producing desired item in right quantity of desired quality, at the required time by the best and cheapest method i.e. to attain highest efficiency in production.
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Techniques of production control 1) Programming Production programming regulates the supply of the finished product in desired amount at due date in accordance with the production plan. In production programming three decisions are taken i.e. a) Nature of the product to be manufactured. b) The total quantities to be produced c) When to produce The main objectives of programming are a) Reliable delivery to the customers b) Even loading of plant c) Even loading of labor in total man hours per week d) Efficient use of capital 2) Ordering It breaks down the requirements for products to be completed at specific times into orders for materials and processed parts and attempts to do so in such a way that they are available when needed. The information such as requirement, quantity and order quantity is required for each other. 3) Dispatching It is routine of setting production activities in motion through the release of the order and instruction in accordance with the previously planned times and sequences embodied in rote sheets and schedule charts The decision of assigning various jobs to different machines is known as dispatching. The functions of dispatching are a) To check the immediate availability of materials. b) To ensure that all production and inspection aids are available for use c) To obtain the appropriate drawing specification or material list. 4) Progressing or follow up Follow up or expediting is checking production activities systematically so that production may be carried out according to plan. It is the measurement of output against plan, analysis of performance for shortfalls and following up the line management to apply corrective action for excessive shortfall. Follow up is the most important step of production control. It can be done at three stages, for materials, work in progress and stage during assembly and execution. Progressing is the function by which one can give an early warning when actual production deviates from planned production and thus makes it possible to take corrective action. M.PHARM SEM I L.M.COLLEGE OF PHARMACY, AHMEDABAD-09 PAGE:136
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5) Inventory control It ensures protection against fluctuations in demand, better use of men, machines and materials and protection against fluctuation in output. The main of inventory control is to observe the stock investments and to ensure that it lies within limits which the organization can afford. Production control tries to serve the interests of both producer and consumer. Its operation ensures the quality and quantity of the product. Consumer is able to get the desired product Similarly production control tries to minimize the chances of the product being rejected by the consumer and avoid or minimize waste and scrap. In this way it saves the producer from losses.
References
Pharmaceutical industrial management by R.M.Mehta Project Management: A Systems Approach to Planning, Scheduling, and Controlling By Harold Kerzner Entrepreneurship Development By S Anil Kumar Factory management &business organization by A.S. Deshpande Project management practice 1 work breakdown structure (rev E, june 2003) Introduction to production control by D.Tiranti & Walker Production and Inventory Control BY DR. LOTFI .K.GAFFAR http://www.businessdictionary.com www.NetMBA.com
Questions
1) Discuss JIT Just in time for PPMC. (July 05) 2) Define PPMC, organization, objective & functioning of it, what is scheduling, tool for it? (July 05, 07&uni 05, 06, 07) 3) Relationship between PP & MC. (July 05, 07 uni 05, 07) 4) How can you contribute to production planning and material control as a person of Pharmatechnology to run your industry economically viable? (July 04, 08) 5) What is inventory control? Discuss the role of PPMC Manager in effective running of Pharma Unit. (uni 04)
PAPER 910201
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MATERIAL CONTROL Himanshu
SEMINAR ON MATERIAL
control
PREPARED BY: MANAVADRIYA HIMANSHU M.PHARM: I ROLL NO: 02 YEAR-2009-10 GUIDED BY: Dr R.K PARIKH
DEPARTMENT OF PHARMACEUTICS AND PHARMACEUTICAL TECHNOLOGY L. M. COLLEGE OF PHARMACY, AHMEDABAD- 09

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INDEX
Sr NO. 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. CONTENTS INTRODUTION AREA OF CONCENTRATION CONTROL ( In General) MATERIAL MANAGEMENT or MATERIAL CONTROL MATERIAL REQUIREMENT PLANNING (MRP) MASTER PRODUCTION SCHEDULE (MPS) BILL OF MATERIALS (BOM) FILE PRIMARY MRP REPORTS SECONDARY MRP REPORT SUMMARY OF MATERIAL MANAGEMENT REFERENCES
M.PHARM-I (2009-10) L.M. COLLEGE OF PHARMACY, AHEMEDABAD-9
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[1] INTRODUCTION:
MANAGEMENT
The classic definition of management is the art and science of planning, organizing, directing and controlling human effort and resources for the general good within the organizational framework and economic environment of the firm. Materials management is the branch of logistics that deals with the tangible components of a supply chain. Specifically, this covers the acquisition of spare parts and replacements, quality control of purchasing and ordering such parts, and the standards involved in ordering, shipping, and warehousing the said parts.
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[2] AREA OF CONCENTRATION:

2.1 Goals
The goal of materials management is to consolidate and efficiently handle core services. It creates truck deliveries and service vehicle routes that reduce conflicts for vehicles and pedestrians. Delivery sites and loading docks are more effective and reduce redundancy. Cost is reduced when it comes to solid and hazardous waste removal, storage, and recycling. Utility infrastructure and service equipment relocation can improve aesthetics.[1]
2.2 Quality Assurance

A large component of materials management is ensuring that parts and materials used in the supply chain meet minimum requirements by performing quality assurance (QA). While most of the writing and discussion about materials management is on acquisition and standards, much of the day to day work conducted in materials management deals with QA issues. Parts and material are tested, both before purchase orders are placed and during use, to ensure there are no short or long term issues that would disrupt the supply chain. [2] This aspect of material management is most important heavily automated industries, since failure rates due to faulty parts can slow or even stop production lines, throwing off timetables for production goals.
2.3 Standards
The other major component of materials management is standards compliance. There are standards that are followed in supply chain management that are critical to a supply chain's function. For example, a supply chain that uses just-in-time or lean replenishment requires absolute perfection in the shipping of parts and material from purchasing agent to warehouse to place of destination. Systems reliant on vendormanaged inventories must have up-to-date computerized inventories and robust ordering systems for outlying vendors to place orders on. Materials management typically insures that the warehousing and shipping of such components as are needed follows the standards required to avoid problems. This component of materials management is the fastest changing part, due to recent innovations in SCM and in logistics in general, including outsourced management of warehousing, mobile computing, and real-time logistical inventories.
2.4 Promoting Sustainability

Many business and institutional campuses have cluttered, noisy, and oftentimes inefficient service environments. Delivery trucks compete with pedestrians, loading docks are in plain sight, trash dumpsters sprout up, and lobbies, hallways, and stairwells are cluttered with unplanned storage. With forethought and creativity, these systems can reduce energy use and carbon emissions, minimize traffic congestion, streamline operational flows, and enhance esthetics.
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2.5 Improving circulation infrastructure

Redundancy can be reduced and effectiveness is increased when service points are clustered to reduce the amount of redundancy. An effective materials management program can also resolve island approaches to shipping, receiving, and vehicle movement. Solutions can include creating a new central loading location, as well consolidating service areas and docks from separate buildings into one. Developing better campus circulation infrastructure also means re-evaluating truck delivery and service vehicle routes. Vehicle type, size, and schedules are studied to make these more compatible with surrounding neighborhoods. This will reduce truck traffic, creating a safer environment for pedestrians and a more attractive environment for other uses.
2.6 Materials Management Week

Each year, an entire week is dedicated to celebrating resource and materials management professionals for their outstanding contributions to healthcare and the overall success of the supply chain. Sponsored by the Association for Healthcare Resource & Materials Management (AHRMM), National Healthcare Resource & Materials Management Week (MM Week) provides an opportunity to recognize the integral role materials management professionals play in delivering high-quality patient care throughout the health care industry. In 2009 Material Management Week is October 4-10 October.
2.7 Benefits
An effective materials management plan builds from and enhances an institutional master plan by filling in the gaps and producing an environmentally responsible and efficient outcome. An institutional campus, office, or housing complex can expect a myriad of benefits from an effective materials management plan. For starters, there are long-term cost savings, as consolidating, reconfiguring, and better managing a campus core infrastructure reduces annual operating costs. An institutional campus, office, or housing complex will also get the highest and best use out of campus real estate. An effective materials management plan also means a more holistic approach to managing vehicle use and emissions, solid waste, hazardous waste, recycling, and utility services. As a result, this means a greener, more sustainable environment and a manifestation of the many demands today for institutions to become more environmentally friendly. In fact, thanks to such environmental advantages, creative materials management plans may qualify for LEED Innovation in Design credits. And finally, an effective materials management plan can improve aesthetics. Removing unsafe and unsightly conditions, placing core services out of sight, and creating a more pedestrian-friendly environment will improve the visual and physical sense of place for those who live and work there.[1]
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2.8 Dredged Material Management

Three management alternatives may be considered for dredged material: open-water disposal, confined (diked) disposal, and beneficial use. Open-water disposal is the placement of dredged material in rivers, lakes, estuaries, or oceans via pipeline or release from hopper dredges or barges. Confined disposal is placement of dredged material within diked nearshore or upland confined disposal facilities via pipeline or other means.[3] Potential environmental impacts resulting from dredged material disposal may be physical, chemical, or biological in nature. Because many of the waterways are located in industrial and urban areas, sediments often contain contaminants from these sources. Unless properly managed, dredging and disposal of contaminated sediment can adversely affect water quality and aquatic or terrestrial organisms. Sound planning, design, and management of projects are essential if dredged material disposal is to be accomplished with appropriate environmental protection and in an efficient manner.
2.9 Beneficial Use

Ten broad categories of beneficial uses have been identified, based on the functional use of the dredged material or site. They are: Habitat restoration/enhancement (wetland, upland, island, and aquatic sites including use by waterfowl and other birds). Beach nourishment. Aquaculture. Parks and recreation (commercial and noncommercial). Agriculture, forestry, and horticulture. Strip mine reclamation and landfill cover for solid waste management. Shoreline stabilization and erosion control (fills, artificial reefs, submerged berms, etc.). Construction and industrial use (including port development, airports, urban, and residential). Material transfer (fill, dikes, levees, parking lots, and roads). Multiple purpose
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[3] CONTROL (In General)

Planning ranks first in the sequence of managerial functions, while controlling is the last among them. Yet, controlling is as important as planning.
Fundamentally, it is any process that guides activity towards some predetermined goal. The essence of the concept is in determining, whether the activity is achieving the desired results.
3.1 CHARACTERISTICS OF CONTROL

An end function of the management A Continuous activity It is exercised at all levels Dynamic process Constructive activity Control is forward-looking Control s people-oriented. Related to planning Control can be informal also Internal activity
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3.2 CLASSIFICATION OF CONTROL

Classified in various ways: 3.2.1 On the basis of standards. 3.2.2 On the basis of different uses 3.2.3 On the basis of activities
3.2.1 On the basis of standards

A) Physical i) Quantitative B) Financial i) Expenses ii) Qualitative
ii) Revenue
3.2.2 On the basis of different uses

A. B. C. D. E. F. G. Controls used to standardize performance Controls used to safeguard Companys assets Controls used to standardize quality Controls used for delegation of authority Controls used to measure performance. Controls used to motivate workers Controls to synchronize all the activities
3.2.3 On the basis of activities

A. B. C. D. Control over policies Control over procedure Control over organization Control over personnel E. Control over inventory F. Control over quality G. Control of all-over performance, etc.
3.3 CONTROLLING STEPS

The basic control process embraces three steps in all situations. They are as follows: 1. Establishment of standards 2. Measurement of performance 3. Taking corrective steps. In short, controlling consists of a) determining what should be done or what is expected, b) finding out what is being done, c) comparing results with expectations and d) applying corrective measures if results deviate from the expectations.
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The steps establishing control procedure may be represented diagrammatically as follows:
3.4 CONTROLLING AREAS

The area of control is very wide, as the management has to control all the operational activities of pharmaceutical industry. Control over organization structure Control over policies Control over procedure Control over personnel Control over production Control over production process Control over sales Control over finance Control of Over-all performance
3.5 TECHNIQUES USED FOR CONTROL

3.5.1 Ratio analysis 3.5.2 Break-even analysis 3.5.3 Budgetary Control 3.5.4 Zero-Based Budgeting or ZBB 3.5.5 PERT (Programme Evaluation and Review Technique) 3.5.6 CPM (Critical Path Method)
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3.5.1 Ratio Analysis

Accounting ratio is an important tool in the hands of the management for control purposes. The relation between two items of financial statements like profit and loss account and balance sheet gives a good account of profitability, liquidity, capital structure and shortterm as well as long term solvency of the business. For example: Profit Ratio = Profit Sales x 100
3.5.2 Break-even analysis

Management of every firm or industry is interested in knowing the level of sales at which the cost and revenue will be equal. This helps the management in determining the amount of sales to be achieved for the desired level of profit. Break-even analysis is useful for this purpose. For the purpose of break-even analysis, all expenses are divided into two parts: Fixed costs and Variable costs Those expenses which do not vary in proportion to output i.e. which remain fixed whether the output increases or decreases, are called Fixed Expenses or Fixed Costs E.g. managers salary, rent, rates, etc. Those expenses which vary with output i.e. which increases when the output increases and decrease when the output is reduced, are called the Variable Expenses or Variable Costs E.g. Raw materials, direct wages, etc. Now, following terms will give a clear idea of Break-even analysis. Contribution = Sales Variable Costs Profit = Contribution Fixed Costs Break even Point (BEP): Contribution = Fixed Costs
3.5.3 Budgetary Control

A budget is a forecast of future activities. A budget is a comprehensive over-all plan in which management, on the basis of estimated sales volume and receipts, establishes cost and expenses allowances for
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future operations, in this way effectively integrating and directing activities towards carefully determined goals.
3.5.4 Zero-Based Budgeting

In this technique of control, in contrast to traditional budgeting system, previous years financial accounts are not taken into consideration. Thus, ZBB does not take any previous allocation as the base. It rather subjects all expenditure current as well as new to fresh scrutiny.
3.5.5 PERT and 3.5.6 CPM

Both the methods are systems of determining the minimum time within which a programme or a project can be completed systematically.
3.6 LIMITATIONS OF CONTROL

Difficulties of determining standards Objective standards not possible Difficult to locate responsible factor Expensive Locating control points Impact of External forces
[4] MATERIAL MANAGEMET or MATERIAL CONTROL

Material management is one of the recent additions to the growing glossary of management. It is a concept aimed at company-wide, total integrated approach towards the management of materials. In recent years, material management has gained increasing recognition as a management function embracing all aspects of industrial handling, storage warehousing, stock control and transport. The Material Management is classified into three basic activities 4.1 Purchasing 4.2 Stores-keeping 4.3 Inventory Control
4.1 PURCHASING
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Purchasing, is indeed, an art. Erroneous buying raises the cost of materials, stores, equipment and finished product. It relates to the procurement or purchase of raw materials, intermediate products, components and supplies in case of manufacturing concern. Hence, it is essential that the activity of buying should be just as efficiently and effectively performed as any other operation in the organization In the words of Gantt, Two-thirds of all the gain possible through the most efficient management could be realized by having all the material ready when you want it, where you want it, and in the condition you want it.
4.1.1 Functions of the Purchasing department

Locating and selecting sources of supply for materials or services required. Interviewing suppliers, representatives, arranging conferences and plan visitations. Requesting for quotations and conducting negotiations. Procuring materials and services when required Verifying quality and quantity received. Approving invoices and handling rejections and adjustments. Maintaining records necessary for proper operation of its function. Keeping informed on business trends, assembling and analyzing pertinent data on markets, supply, demands, price trends, etc. Disposing of scrap and surplus.
4.2.2 Purchasing responsibility

The purchasing function should be under a single head, whether it can be centralized without substantial sacrifice in efficiency due to restriction of the local initiative. The purchasing agent should be a big man, capable of consideration and prompt decision having balance judgment and clear foresight.
4.3.3 Methods of Purchasing

Purchasing by requirement: Purchasing by requirement means that no purchase is made until the need arises. Purchase for a specified future period: Purchase for a specified future period is standard practice for buying goods regularly used, but not in great quantity, and on which price variations are negligible. Market Purchasing: Market Purchasing is defined as purchasing according to conditions of the market, to take advantage of price fluctuations.
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Speculative Purchasing: It consists in buying when the market is low, more than can be possibly used in manufacturing with the idea of reselling much of the material at a considerable price. Contract Purchasing: All purchasing by contract, but the term contract purchasing is applied to the special type of contract which calls for differed delivery over a period of time. Group Purchasing of small items: There are number of small items, so trivial in value that the cost of placing an order often exceeds the value of good purchased. So those items are purchased in large amounts in advance. Scheduled Purchasing: Essentially, this plan consists of giving suppliers approximate estimates of purchase requirements over a period of time, thus enabling them to anticipate the receipt of orders and be prepared to fulfill them when they arrive.
4.3.4 Summary of Purchasing

According to Chatterjee, Head of Procurement and Transportation, Calcutta, the broad objectives of a purchaser are attained by what are commonly known as the 5-R Principles. Right Quality Right Quantity Right Price Right Delivery Right Supplier
4.2 STORES-KEEPING
Knowles and Thomson depict the stores department as, the connecting link between the planning and production department, and the shops. Parts and materials move through it as money moves into and out of the commercial department of a bank.
Planning
Production Department
Shops
STORES-KEEPING
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PILOT PLANT & SCALE UP
By: Jignasha & Vijay
PILOT PLANT SCALE UP TECHNIQUES
GUIDED BY:Dr.R. K. Parikh
PREPARED BY:Vijay makwana Roll no:-1 Jignasha R. Bhuria Roll no:-5 M. Pharm Sem-1 YEAR:-2009-2010
DEPARTMENT OF PHARMACEUTICS AND PHARMACEUTICAL TECHNOLOGY, 2009-2010
M.PHARM. SEM-I (2009-10) L.M.COLLEGE OF PHARMACY, AHMEDABAD-9
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CONTENTS:
INTRODUCTION ON PILOT PLANT AND SCALE UP o PILOT PLANT DESIGN o PILOT PLANT OPERATION GENERAL CONSIDERATIONS ABOUT PILOT PLANT REQUIREMENTS STEPS OF SCALE UP SCALE UP FOR SOLID DOSAGE FORM (TABLET) SCALE UP FOR PARENTERAL PRODUCT SCALE UP CONSIDERATIONS FOR LIQUID ORALS SCALE UP FOR SEMISOLID DOSAGE FORMS SCALE UP FOR BIOTECHNOLOGY-DERIVED PRODUCTS THEORY OF SIMILARITY HOW TO SCALE UP SCIENTIFICALLY? SCALE UP OF LIQUID & SEMISOLID MANUFACTURING PROCESS SCALE UP OF POWDER BLENDING OPERATION IMPROVING THE LIKELYHOOD OF SCALABILITY CONCLUSION REFERENCES AND QUESTION BANK
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[1] INTRODUCTION
What is Pilot plant : Defined as a part of the pharmaceutical industry where a lab scale formula is transformed into a viable product by the development of liable practical procedure for manufacture. R&D Production
Pilot Plant
Why conduct Pilot Plant Studies?

A pilot plant allows investigation of a product and process on an intermediate scale before large amounts of money are committed to full-scale production It is usually not possible to predict the effects of a many-fold increase in scale It is not possible to design a large complex food processing plant from laboratory data alone with any degree of success
A pilot plant can be used for

Evaluating the results of laboratory studies and making product and process corrections and improvements Producing small quantities of product for sensory, chemical, microbiological evaluations, limited market testing or furnishing samples to potential customers, shelf-live and storage stability studies Determining possible salable by-products or waste stream requiring treatment before discharge Providing data that can be used in making a decision on whether or not to proceed to a fullscale production process; and in the case of a positive decision, designing and constructing a full-size plant or modifying an existing plant
Considerations in pilot plant development

Kind and size depends on goals; evaluating product and process; producing samples of product for evaluation; market testing or furnishing to potential customers Location: near R&D facility? At an existing plant? Close liaison between R&D and pilot plant staff is essential Labor requirements and costs: engineering staff, skilled operations and maintenance staffpilot plant costs may exceed those of usual plant production costs. The pilot plant may be used for training personnel for a full- scale plant
Objective of scale up
Find mistakes on small scale and make profit on large scale. To produce physically and chemically stable therapeutic dosage forms. Review of the processing equipment. Guidelines for productions and process control. Evaluation and validation. To identify the critical features of the process.
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To provide master manufacturing formula. Pilot plant studies include the close examination of the formula to determine :
Its ability to withstand batch scale . Process modification . Compatibility of the equipment with the formulation . Cost factor . Availability of raw materials meeting the specifications required to produce the product . Market requirement . Physical space required and the layout of the related functions .
Thus , during the scale up efforts in the pilot plant :

Production and process controls are evaluated , validated and finalized . Product reprocessing procedures are developed and validated . Appropriate records and reports are issued to support cGMP .
In short , all critical features of a process must be identified so that as the process is scaled up , it can be adequately monitored to provide assurance that the process is under control and that the product produced at each level of the scale up maintains the specified attributes originally intended .
PILOT PLANT DESIGN

A pilot plant design should support three key strategic objectives :
Formulation and process development . Clinical supply manufacture . Technology evaluation , scale up and transfer .
Attributes playing a key role in achieving the above objectives are :

cGMP Compliance . A flexible highly trained staff . Equipment to support multiple dosage form development . Equipment at multiple scales based on similar operating principles to those in production . The pilot plant design should be according to cGMP norms . The layout should be according to the need for flexibility (portable equipment installed , use of multipurpose rooms) , restricted access , personnel flow and material flow. The facility and equipment should be able to capture critical process information . Intermediate sized and Full scale production equipment should be available in order to evaluate the effects of scale up of research formulations . Adequate space required to carry out each function smoothly (eg., cleaning of pilot plant equipments) . The final design should result in a facility that support the key strategic objectives and should have low maintenance and operating costs . Although the pilot plant design must simulate the manufacturing environment in which the new product will ultimately be produced , there are many differences in operation because of the specific objectives of the two types of facilities i.e. the pilot plant facilitates product development activities , whereas the manufacturing plant routinely fabricates products for the market place .
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PILOT PLANT OPERATION

Operational Aspects of Pilot Plant includes : Validation Training Engineering Support Maintenance Calibration Material Control Inventory Orders Labeling Process and Manufacturing Activities Quality Assurance and Quality Control
VALIDATION : A validation master plan should be develop that addresses-The design specifications
Installation qualification Operational qualification Performance qualification of all major utility systems , process equipment , and computer control systems . A fully validated pilot plant should ensure compliance with cGMP and should meet current FDA standards . TRAINING : Training in four major area required Compliance with quality standards such as cGMP Safety and environmental responsibilities Compliance with SOPs Technical skills and knowledge ENGINEERING SUPPORT : It is required for Design , construction , commissioning and validation of the pilot plant facility Co-ordination , scheduling and direction of ongoing operations
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By: Jignasha & Vijay MAINTENANCE : It is required to Meet cGMP norms To ensure data integrity and equipment reliability during the development process. The maintenance program should be documented and written procedures established.
CALIBRATION : Calibration of critical instruments/equipments is required forCompliance with cGMP Maintaining the integrity of data generated during the development process Calibration should be performed by well trained and expert staff . MATERIAL CONTROL : More flexible and efficient computer based system is required for material control in pilot plant . INVENTORY : Inventory should be maintained in a Computer Based InventoryOrdering-Dispensing System . ORDERS : All orders must be placed through the computer system . For placement of the order , First In First Out (FIFO) criteria is followed . LABELING : Labels should comply with GMP-GLP requirements . Computer system must be used for labeling . PROCESS AND MANUFACTURING ACTIVITIES : It includes Formulation and Process Development Studies Clinical supply manufacture Technology evaluation , scale up and transfer Precise documentation of each trials have to be made . QUALITY ASSURANCE & QUALITY CONTROL : QA Activities Auditing pilot plant Auditing and approval of component suppliers Reviewing , approving and maintaining batch records for clinical supplies Sampling and release of raw materials and components required for clinical supplies Release of clinical supplies Maintaining and distributing facility and operating procedures (SOPs) Review and approval of validation and engineering documentation . QC Activities Release testing of finished products Physical , chemical , and microbiological testing of finished clinical products, components and raw materials Testing for validation and revalidation programs
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By: Jignasha & Vijay QC in-process testing during activities development , scale up , and technology transfer
[2] GENERAL CONSIDERATIONS

PERSONNEL REQUIREMENTS : Personnel should have Scientists with experience in pilot plant operations as well as in actual production area are the most preferable As they have to understand the intent of the formulator as well as understand the perspective of the production personnel. The group should have some personnel with engineering knowledge as well as scale up also involves engineering principles SPACE REQUIREMENTS :
Separate provisions for API and excipients further segregated into approved and unapproved areas according to GMP . Storage area for in process materials , finished bulk products , retained samples , experimental production batches , packaging materials (segregated into approved and unapproved areas) . Controlled environment space allocated for storage of stability samples REVIEW OF THE FORMULA : A thorough review of the each aspect of formulation is important. The purpose of each ingredient and its contribution to the final product manufactured on the small-scale laboratory equipment should be understood. Then the effect of scale-up using equipment that may subject the product to stresses of different types and degrees can more readily be predicted, or recognized. RAW MATERIALS : One purpose/responsibility of the pilot-plant is the approval & validation of the active ingredient & excipients raw materials. Why?
Raw materials used in the small scale production cannot necessarily be the representative for the large scale production
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By: Jignasha & Vijay RELEVANT PROCESSING EQUIPMENT : The most economical and the simplest & efficient equipment which are capable of producing product within the proposed specifications are used. The size of the equipment should be such that the experimental trials run should be relevant to the production sized batches. If the equipment is too small the process developed will not scale up, Whereas if equipment is too big then the wastage of the expensive active ingredients. PRODUCTION RATES : It can be determined by the immediate future market requirements. Equipment and the process should be chosen on the basis of production of a batch at a frequency that takes into consideration : 1. Product loss in the equipment during manufacture . 2. The time required to clean the equipment between batches . 3. The number of batches that will need to be tested for release . PROCESS EVALUATION :
It is the basis of process validation Documentation of process is to be done . Process is validated only if there are no changes in the formula , quality of the ingredients , or the equipment configuration . Revalidation needs to be done to ensure that changes have not take place . PREPARATION OF MASTER MANUFACTURING PROCEDURES: It includesThe chemical weigh sheet. It should clearly identify the chemicals required in a batch and present the quantities and the order in which they will be used . The sampling directions In-process and finished product specifications Manufacturing directions should be in a language understandable by the operator termed as SOPs . Batch Record Directions should include specifications for addition rates , mixing times , mixing speeds , heating and cooling rates , temperature . Proper documentation should be carried out.
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Product stability and uniformity:The primary objective of the pilot plant is the physical as well as chemical stability of the products. Hence each pilot batch representing the final formulation and manufacturing procedure should be studied for stability. Stability studies should be carried out in finished packages as well
GMP CONSIDERATIONS : GMP items that should be a part of scale up are Equipment qualification Process validation Regularly schedule preventative maintenance Regularly process review & revalidation Relevant written standard operating procedures The use of competent technically qualified personnel Adequate provision for training of personnel A well-defined technology transfer system Validated cleaning procedures. An orderly arrangement of equipment so as to ease material flow & prevent crosscontamination
TRANSFER OF ANALYTICAL METHODS TO QUALITY ASSURANCE : Analytical methods developed in research must be transferred to QA department . Transfer process includes 1. 2. 3. 4. Review the process to make sure that proper analytical instrument is available . Personnel should be trained to perform the test . Reliability of the test should be checked . At last assay procedure should be reviewed before transfer .
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[3] SCALE UP TECHNIQUES

Scale-up:- The art for designing of prototype using the data obtained from
the pilot plant model.
STEPS IN SCALE UP
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[4] Pilot Plant design for Tablets

The primary responsibility of the pilot plant staff is to ensure that the newly formulated tablets developed by product development personnel will prove to be efficiently, economically, and consistently reproducible on a production scale. The design and construction of the pharmaceutical pilot plant for tablet development should incorporate features necessary to facilitate maintenance and cleanliness. If possible, it should be located on the ground floor to expedite the delivery and shipment of supplies. Extraneous and microbiological contamination must be guarded against by incorporating the following features in the pilot plant design: Fluorescent lighting fixtures should be the ceiling flush type. The various operating areas should have floor drains to simplify cleaning. The area should be air-conditioned and humidity controlled. High -density concrete floors should be installed. The walls in the processing and packaging areas should be enamel cement finish on concrete. Equipment in the pharmaceutical pilot plant should be similar to that used by production division- manufacture of tablets.
1)Material handling system

In the laboratory, materials are simply scooped or poured by hand, but in intermediate- or large-scale operations, handling of this materials often become necessary. If a system is used to transfer materials for more than one product steps must be taken to prevent cross contamination. Any material handling system must deliver the accurate amount of the ingredient to the destination. The type of system selected also depends on the characteristics of the materials. More sophisticated methods of handling materials such as vacuum loading systems, metering pumps, screw feed system.
2) Dry Blending
Powders to be used for encapsulation or to be granulated must be well blended to ensure good drug distribution. Inadequate blending at this stage could result in discrete portion of the batch being either high or low in potency. Steps should also be taken to ensure that all the ingredients are free of lumps and agglomerates. For these reasons, screening and/or milling of the ingredients usually makes the process more reliable and reproducible.
The equipment used for blending are:

V- blender Double cone blender Ribbon blender Slant cone blender
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Bin blender Orbiting screw blenders vertical and horizontal high intensity mixers.
SCALE UP CONSIDERATIONS Time of blending . Blender loading. Size of blender.
3) Granulation
The most common reasons given to justify granulating are:
1. 2. 3. 4. To impart good flow properties to the material, To increase the apparent density of the powders, To change the particle size distribution, Uniform dispersion of active ingredient. Traditionally, wet granulation has been carried out using,
Sigma blade mixer, Heavy-duty planetary mixer. Wet granulation can also be prepared using tumble blenders equipped with highspeed chopper blades. More recently, the use of multifunctional processors that are capable of performing all functions required to prepare a finished granulation, such as dry blending, wet granulation, drying, sizing and lubrication in a continuous process in a single equipment.
Fluidized Bed Granulations :

1. 2. 3. 4. 5. 6. 7. 8. 9. Process Inlet Air Temperature Atomization Air Pressure Air Volume Liquid Spray Rate Nozzle Position and Number of Spray Heads Product and Exhaust Air Temperature Filter Porosity Cleaning Frequency Bowl Capacity
4) Binders:
Used in tablet formulations to make powders more compressible and to produce tablets that are more resistant to breakage during handling. In some instances the binding agent imparts viscosity to the granulating solution so that transfer of fluid becomes difficult. This problem can be overcome by adding some or all binding agents in the dry powder prior to granulation. Some granulation, when prepared in production sized equipment, take on a doughlike consistency and may have to be subdivided to a more granular and porous mass to facilitate drying.
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By: Jignasha & Vijay This can be accomplished by passing the wet mass through an oscillating type granulator with a suitably large screen or a hammer mill with either a suitably large screen or no screen at all.
5) Drying
The most common conventional method of drying a granulation continues to be the circulating hot air oven, which is heated by either steam or electricity. The important factor to consider as part of scale-up of an oven drying operation are airflow, air temperature, and the depth of the granulation on the trays. If the granulation bed is too deep or too dense, the drying process will be inefficient, and if soluble dyes are involved, migration of the dye to the surface of the granules. Drying times at specified temperatures and airflow rates must be established for each product, and for each particular oven load. Fluidized bed dryers are an attractive alternative to the circulating hot air ovens. The important factor considered as part of scale up fluidized bed dryer are optimum loads, rate of airflow, inlet air temperature and humidity. Tray Dryer-- Parameters to be considered for scale up are : 1. 2. 3. 4. Air flow Air temperature Depth of the granulation on the trays Monitoring of the drying process by the use of moisture and temperature probes 5. Drying times at specified temperatures and air flow rates for each product
Fluidized Bed Dryer : Parameters to be considered for scale up are :

1. 2. 3. 4. Optimum Load Air Flow Rate Inlet Air Temperature Humidity of the Incoming Air
6) Reduction of Particle size

Compression factors that may be affected by the particle size distribution are flowability, compressibility, uniformity of tablet weight, content uniformity, tablet hardness, and tablet color uniformity. First step in this process is to determine the particle size distribution of granulation using a series of stacked sieves of decreasing mesh openings. Particle size reduction of the dried granulation of production size batches can be carried out by passing all the material through an oscillating granulator, a hammer mill, a mechanical sieving device, or in some cases, a screening device. As part of the scale-up of a milling or sieving operation, the lubricants and glidants, which in the laboratory are usually added directly to the final blend, are usually added to the dried granulation during the sizing operation. This is done because some of these additives, especially magnesium stearate, tend to agglomerate when added in large quantities to the granulation in a blender.
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7) Blending
Type of blending equipment often differs from that using in laboratory. In any blending operation, both segregation and mixing occur simultaneously are a function of particle size, shape, hardness, and density, and of the dynamics of the mixing action. Particle abrasion is more likely to occur when high-shear mixers with spiral screws or blades are used. When a low dose active ingredient is to be blended it may be sandwiched between two portions of directly compressible excipients to avoid loss to the surface of the blender.
In scale up of blending , following parameters should be considered 1. 2. 3. 4. 5. Blender loads , Blender size , Mixing speeds , Mixing times , Bulk density of the raw material (must be considered in selecting blender and in determining optimum blender load) 6. Characteristics of the material
8) Specialized Granulation procedures: Slugging (Dry Granulation)

A dry powder blend that cannot be directly compressed because of poor flow or compression properties. This is done on a tablet press designed for slugging, which operates at pressures of about 15 tons, compared with a normal tablet press, which operates at pressure of 4 tons or less. Slugs range in diameter from 1 inch, for the more easily slugged material, to inch in diameter for materials that are more difficult to compress and require more pressure per unit area to yield satisfactory compacts. If an excessive amount of fine powder is generated during the milling operation the material must be screened & fines recycled through the slugging operation.
Dry Compaction
Granulation by dry compaction can also be achieved by passing powders between two rollers that compact the material at pressure of up to 10 tons per linear inch. Materials of very low density require roller compaction to achieve a bulk density sufficient to allow encapsulation or compression. One of the best examples of this process is the densification of aluminum hydroxide. Pilot plant personnel should determine whether the final drug blend or the active ingredient could be more efficiently processed in this manner than by conventional processing in order to produce a granulation with the required tabletting or encapsulation properties.
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Compression
The ultimate test of a tablet formulation and granulation process is whether the granulation can be compressed on a high-speed tablet press. During compression, the tablet press performs the following functions: 1. Filling of empty die cavity with granulation. 2. Precompression of granulation (optional). 3. Compression of granules. Ejection of the tablet from the die cavity and take-off of compressed tablet. When evaluating the compression characteristics of a particular formulation, prolonged trial runs at press speeds equal to that to be used in normal production should be tried. Only then are potential problems such as sticking to the punch surface, tablet hardness, capping, and weight variation detected. High-speed tablet compression depends on the ability of the press to interact with granulation. Following are the parameters to be considered while choosing speed of press. 1. Granulation feed rate. 2. Delivery system should not change the particle size distribution. 3. System should not cause segregation of coarse and fine particles, nor it should induce static charges. The die feed system must be able to fill the die cavities adequately in the short period of time that the die is passing under the feed frame. The smaller the tablet , the more difficult it is to get a uniform fill a high press speeds. For high-speed machines, induced die feed systems is necessary. These are available with a variety of feed paddles and with variable speed capabilities. So that optimum feed for every granulation can be obtained. After the die cavities are filled ,the excess is removed by the feed frame to the center of the die table. Compression of the granulation usually occurs as a single event as the heads of the punches pass over the lower and under the upper pressure rollers. This cause the punches to the penetrate the die to a preset depth, compacting the granulation to the thickness of the gap set between the punches. The rapidity and dwell time in between this press event occurs is determined by the speed at which the press is rotating and by the size of compression rollers. Larger the compressions roller, the more gradually compression force is applied and released. Slowing down the press speed or using larger compression rollers can often reduce capping in a formulation. The final event is ejection of compressed tablets from die cavity. During compression, the granulation is compacted to form tablet, bonds within compressible material must be formed which results in sticking. High level of lubricant or over blending can result in a soft tablet, decrease in wettability of the powder and an extension of the dissolution time.
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By: Jignasha & Vijay Binding to die walls can also be overcome by designing the die to be 0.001 to 0.005 inch wider at the upper portion than at the center in order to relieve pressure during ejection.
Tablet Coating
Sugar coating is carried out in conventional coating pans, has undergone many changes because of new developments in coating technology and changes in safety and environmental regulations. The conventional sugar coating pan has given way to perforated pans or fluidizedbed coating columns. The development of new polymeric materials has resulted in a change from aqueous sugar coating and more recently, to aqueous film coating. The tablets must be sufficiently hard to withstand the tumbling to which they are subjected in either the coating pan or the coating column. Some tablet core materials are naturally hydrophobic, and in these cases, film coating with an aqueous system may require special formulation of the tablet core and/or the coating solution. A film coating solution may have been found to work well with a particular tablet in small lab coating pan but may be totally unacceptable on a production scale. This is because of increased pressure & abrasion to which tablets are subjected when batch size is large & different in temperature and humidity to which tablets are exposed while coating and drying process.
[5] Scale-up for parenterals

Injectables
The majority of the parenteral solutions are solutions requiring a variety of tankage, piping and ancillary equipment for liquid mixing, filteration, transfer and related activities. The majority of the equipments are composed of 300 series austenitic stainless steel, with tantalum or glass lined vessels employed for preparation of formulations sensitive to iron and other metal ions. The vessels can be equipped with external jackets for heating and/or cooling and various types of agitators, depending upon the mixing requirements of the individual formulation.
Working area of a parenteral pilot plant

Incoming goods are stored in special areas for Quarantine, Released and Rejected status. A cold room is available for storage of temperature-sensitive products. Entrance into the warehouse and production areas is restricted to authorized personnel. Sampling and weighing of the raw material is performed in a dedicated sampling area and a central weighing suite, respectively.
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By: Jignasha & Vijay The route for final products is separated from the incoming goods; storage of final products is done in designated areas in the warehouse while they are awaiting shipment. Several clothing and cleaning procedures in the controlled transport zone and production area ensure full quality compliance. In addition, a technical area is located in between the production zone and the area for formulation development. Here, the water for injection equipment is located, as well as the technical installation of the lyophilizer.
Facility Design
To provide the control of microbial, pyrogen and particles controls over the production environment are essential.
Warehousing:
All samples should be aseptically taken, which mandates unidirectional airflow and full operator gowning. These measures reduce the potential for contamination ingress into materials that are yet to receive any processing at any site.
Preparation Area:
The materials utilized for the production of the sterile products move toward the preparation area through a series of progressively cleaner environments.
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Compounding area:
The manufacture of parenterals is carried out in class 10,000 (Grade C) controlled environments in which class 100 unidirectional flow hoods are utilized to provide greater environmental control during material addition. These areas are designed to minimize the microbial, pyrogen, and particulate contamination to the formulation prior to sterilization.
Aseptic filling rooms:

The filling of the formulations is performed in a Class 100 environment. Capping and Crimp sealing areas: The air supply in the capping line should be of Class 100 Corridors: They serve to interconnect the various rooms. Fill rooms, air locks and gowning rooms are assessed from the corridor. Aseptic storage rooms. Air-locks and pass-throughs: Air locks serve as a transition points between one environment and another. They are fitted with the UltraViolet lights, spray systems, or other devices that may be effectively utilized for decontamination of materials.
Formulation aspects
Solvent:
The most widely used solvent used for parenteral production is water for injection. WFI is prepared by by distillation or reverse osmosis. Sterile water for injection is used as a vehicle for reconstitution of sterile solid products before administration and is terminally sterilized by autoclaving
Solubilizers:
They are used to enhance and maintain the aqueous solubility of poorly watersoluble drugs.
Solubilizing agents used in sterile products include:

1. co-solvents: glycerine, ethanol, sorbitol, etc. 2. Surface active agents: polysorbate 80, polysorbate 20, lecithin. 3. Complexing agents: cyclodextrins etc
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By: Jignasha & Vijay They act by reducing the dielectric constant properties of the solvent system, thereby reducing the electrical, conductance capabilities of the solvent and thus increase the solubility.
Antimicrobial preservative agents: Buffers:

They are used to maintain the pH level of a solution in the range that provides either maximum stability of the drug against hydrolytic degradation or maximum or optimal solubility of the drug in solution.
Antioxidants:
Antioxidants function by reacting prefentially with molecular oxygen and minimizing or terminating the free the free radical auto-oxidation reaction. Examples phenol (0.065-0.5%), m-cresol (0.16-0.3%) etc.
[6] Scale up for Liquid orals

The physical form of a drug product that is pourable displays Newtonian or pseudoplastic flow behaviour and conforms to its container at room temperature. Liquid dosage forms may be dispersed systems or solutions. In dispersed systems there are two or more phases, where one phase is distributed in another. A solution refers two or more substances mixed homogeneously.
Steps of liquid manufacturing process

1. 2. 3. 4. Planning of material requirements: Liquid preparation: Filling and Packing: Quality assurance:
Critical aspects of liquid manufacturing

Physical Plant: Heating, ventilation and air controlling system: the effect of long processing times at suboptimal temperatures should be considered in terms of consequences on the physical or chemical stability of ingredients as well as product.
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SOLUTION :
Parameters to be considered are 1. Tank size ( diameter ) 2. Impeller type 3. Impeller diameter 4. Rotational speed of the impeller 5. Number of impellers 6. Number of baffles 7. Mixing capability of impeller 8. Clearance between Impeller Blades and wall of the mixing tank 9. Height of the filled volume in the tank 10. Filteration equipment (should not remove active or adjuvant ingredients) 11. Transfer system 12. Passivation of SS (prereacting the SS with acetic acid or nitric acid solution to remove the surface alkalinity of the SS)
SUSPENSION :
Parameters to be considered are 1. Addition and dispersion of suspending agents (Lab scale sprinkling method & Production scale vibrating feed system) 2. Hydration/Wetting of suspending agent 3. Time and temperature required for hydration of suspending agent 4. Mixing speeds (High speed leads to air entrapment) 5. Selection of the equipment according to batch size 6. Versator (to avoid air entrapment) 7. Mesh size (the one which is chosen must be capable of removing the unwanted foreign particulates but should not filter out any of the active ingredients . Such a sieve can only be selected based on production batch size trials.)
EMULSION :
Parameters to be considered are 1. 2. 3. 4. 5. 6. 7. 8. Temperature Mixing equipment Homogenizing equipment Inprocess or final product filters Screens , pumps and filling equipment Phase volumes Phase viscosities Phase densities
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Formulation aspects of oral liquids

Solutions:
Protecting the API Maintaining the appearance Taste/smell masking Buffers, antioxidants, preservatives Colorings, stabilizers, co-solvents, antimicrobial preservatives
Sweetners, flavorings.
Suspensions:
Purpose
Facilitating the connection between API and vehicle Protecting the API Maintaining the suspension appearance Masking the unpleasant taste/smell
Agent
-wetting agents Salt formation ingredients - Buffering-systems, polymers, antioxidants Colorings, suspending agent, flocculating agent. Sweeteners, flavorings
Emulsions:
Purpose
Particle Size Protecting the API Maintaining the appearance Taste/smell masking
Agent
Solid particles, Droplet particles Buffering-systems, antioxidants, polymers Colorings, Emulsifying agents, Penetration enhancers, gelling agents Sweetners, flavorings
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[7] SCALE UP FOR SEMISOLID PRODUCTS

The following parameters are to be considered during the scale up of semisolid products : 1. Mixing equipment (should effectively move semisolid mass from outside walls to the center and from bottom to top of the kettle) 2. Motors (used to drive mixing system and must be sized to handle the product at its most viscous stage.) 3. Mixing speed 4. Component homogenization 5. Heating and cooling process 6. Addition of active ingredients 7. Product transfer 8. Working temperature range (critical to the quality of the final product) 9. Shear during handling and transfer from manufacturing to holding tank to filling lines 10. Transfer pumps (must be able to move viscous material without applying excessive shear and without incorporating air) 11. While choosing the size and type of pump , a. Product viscosity b. Pumping rate c. Product compactibility with the pump surface d. Pumping pressure required should be considered .
[8] SCALE UP FOR BIOTECHNOLOGY-DERIVED PRODUCTS

The design and scale up of biological processes is very challenging (due to complexity of biological systems and the physical and biochemical characteristics of the protein products) . The following parameters are to be considered for scale up of biotechnological products -
BIOREACTOR OPERATION : Usually stirred tank bioreactor is used

Mixing efficiency given by
1. Impeller rate 2. Aeration rate 3. Hydrostatic pressure 4. Agitation rate 5. Mixing time
FILTERATION OPERATION : The key process parameters for filteration scale up are 1. Transmembrane pressure 2. Volume
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By: Jignasha & Vijay 3. 4. 5. 6. Operating time Temperature Flux rate Protein concentration 7. Solution viscosity 8. Retentate flow rate 9. Permeate flux
The fluid dynamic variables used in the scale up work are

1. The length of the fibers (L , per stage) 2. The fiber diameter (D) 3. The number of fibres per catridge (n) 4. The density of the culture ( ) 5. The viscosity of the culture ( ) From these variables , scale up parameters such as wall shear rate and its effect on flux are derived .
CENTRIFUGATION : At laboratory scale batch centrifuge is used .

At production scale continuous centrifuge is used . Low shear centrifuge used to minimize the shear sensitivity of animal cells .
CHROMATOGRAPHY : Key parameters for chromatography scale up are1. 2. 3. 4. 5. Gel capacity Linear velocity Buffer volume Bed height Temperature 6. 7. 8. 9. Cleanability Gel lifetime pH of the elution buffer conductivity of the elution buffer
VIRAL CLEARANCE : Viral inactivation and/or removal steps are critical part of
the process design for biotechnology products derived from mammalian cell culture system
[9] PRINCIPLES OF SIMILARITY

Equipments selected for pilot plant studies should preferably be similar in all respects to those actually used in commercial production . If similarity exists then it helps in effective process translation as well as in production of good quality product . In actuality , approximations of similarity are often necessary due to departures from ideality (e.g., differences in surface roughness , variations in temperature gradients , changes in mechanism) . Stress should be given on four types of similarity : A. Geometric Similarity : Similarity with respect to shape , height , thickness , breadth etc., Small scale model equipments and large scale equipments must be in the scale ratio of 1:2 , 1:5 , 1:20 etc. B. Mechanical Similarity : Mechanical similarity (the application of force to a stationary or moving system) can be described in terms of Static , Kinematic or Dynamic similarity . Static Similarity - It is the deformation under constant stress of one body or structure to that of another . It exists when geometric similarity is maintained .
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By: Jignasha & Vijay Kinematic Similarity -- Geometrically similar moving systems will exhibit kinematic similarity when corresponding particle takes geometrical similar path in the corresponding time interval . Dynamic Similarity -- Forces (gravitational , centrifugal , pressure) which accelerate or retard the motion of materials . Geometrically similar moving systems are dynamically similar when the ratio of all forces is equal . It is useful in the prediction of pressure drops , power consumption. C. Thermal Similarity : It is concerned with flow of heat (by radiation , conduction , convection , or the bulk transfer of material) . Geometrically similar systems are thermally similar when temperature difference bears constant ratio and in moving systems it must have kinematic similarity . D. Chemical Similarity : It is the similarity concerned with the variation in chemical composition from point to point as a function of time . It is related to the existence of comparable concentration gradients . It is dependent upon both thermal and kinemtatic similarity .
The relationship of key groups , key activities and development milestones typically experienced during the transfer of formulation and process technology from the pilot plant to the production facility is shown below :
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DEVELOPMENT MILESTONES
Key Groups
Pharmaceutical Formulation
Key Activities
Marketing Formulation Defined
Identify critical process
Pharmaceutical Formulation Pharmaceutical Technology Development
Process Development
and packaging parameters Pilot scale stability batch manufacture
Development Report
Pharmaceutical Formulation Pharmaceutical Technology Development Manufacturing , Validation QA/QC Site selection
Scale-up/Stability/Clinical Supply Batches
Initial large scale process qualification studies
Scale-up report
Pharmaceutical Formulation Pharmaceutical Technology Development Manufacturing , Validation QA/QC
NDA Submission
Additional large scale process qualification
studies Product transfer document issued

Product acceptance by manufacturing Validation protocol written Preapproval inspection by FDA Manufacturing site
Manufacturing , Validation QA/QC Pharmaceutical Technology Development
Manufacture Validation Batches
preparation Validation report

Manufacturing QA/QC Pharmaceutical Technology Development
NDA Approval
FDA Approval to market product
Production start up
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CHAPTER-1,6,7 &8
[10] HOW TO SCALE-UP SCIENTIFICALLY ?

A rational approach to scale-up is Dimensional Analysis which is a proven method of developing functional relationships that describe any given process in a dimensionless form to facilitate modeling and scale-up or scale-down . Dimensionless Analysis is a method for producing dimensionless numbers and deriving functional relationships among them that completely characterize the process . It was first systematically applied to fluid flow 90 years ago by Lord Rayleigh on the basis of the principle of similitude referred to by Newton in one of his early works . Dimensionless Numbers : Basic Dimensional Quantities : Length (L), Mass (M), Time (T) . Dimensional Numbers have no dimensions . Such numbers are frequently used to describe the ratios of various physical quantities . Newton (Ne) = P/( n3 d5) Froude (Fr) = n2d/g Reynolds (Re) = d2n / in which P is power consumption (ML2/T3) is specific density of particles (M/L3) n is the impeller speed (T-1) d is the impeller diameter (L) g is the gravitational constant (L/T2) is the dynamic viscosity (M/LT) Ne is a measure of the power required to overcome friction in fluid flow in a stirred reactor. In mixer granulation applications, this number can be calculated from the power consumption of the impeller . Fr is described for powder blending and was suggested as a criterion for dynamic similarity as well as scale-up parameter in wet granulation . Re relates the inertial force to the viscous force, is used to describe mixing processes .
[11] SCALE-UP OF LIQUID AND SEMISOLID MANUFACTURING PROCESSES

In mixing and semisolid manufacturing, mixing is an important unit operation . Flow regimes in pharmaceutical system undergoing mixing process may range from laminar to turbulent to transitional flow . The flow regime in the vicinity of an impeller is often turbulent while the flow regime elsewhere in the system can be laminar or transitional .
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By: Jignasha & Vijay For turbulent flow regime, power is Diameter of impeller ) . For laminar flow regime, power is N3D2 ( = density ; N = rotational speed ; D =
N2 (
= viscosity )
Scale-up of solutions : Three methods can be applied . 1. Power Law Approach :N2 = N1 ( 1 n is power law exponent N1 & N2 are rotational speed of impeller R is geometric scaling factor such as : D1T1 or D2T2 (D = impeller diameter and T is mixing tank diameter) ; Z1T1 or Z2T2 (Z = height of liquid in the mixing tank) 2. Dimensionless Numbers :Reynolds Number (the ratio of inertial to viscous forces in a flow) Re = (D2 N ) R )n
Froude Number (the ratio of inertial stress to the gravitational force per unit area in a liquid) Fr = (DN2 g)
It is a means of correlating process characteristics at various production scales . D = Diameter of impeller ; N = Rotational speed of impeller ; = Viscosity ; = density ; g = acceleration gravity
3. Scale of agitation approach :Applicable only if system show Newtonian flow and Geometric similarity . The rheological behaviour of shear-thinning (pseudoplastic) systems may be described by the ostawald-de Waele equation between the shear rate extremes corresponding to the zero shear viscosity, 0 and to the infinite shear viscosity, T=K In which T is the shear stress , constants .
a
is the rate of shear and K and a are
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CHAPTER-1,6,7 &8
The ratio of : 0 corresponding to the ratio of T:T 0 would then be used to facilitate scaling .
[12] SCALE-UP OF POWDER BLENDING OPERATIONS

Regarding scale-up requirements, blending processes can be classified into two fundamentally different groups i.e. for Free flowing and cohesive materials . Their blending requirements vary . Free Flowing Materials :- They are powders and granulations in which interparticle cohesive forces are small enough for particles to move individually . Both inter and intra shell mixing processes can be described by similar equation such as :
2
= Ae-kN where
is mixture variance N is number of revolutions A is unspecified constant K is rate constant .
2
The Froude Number : Fr = [
R/g] where
is rotation rate R is vessel radius g is acceleration from gravity is suggested for tumbling blender scale-up .
Cohesive Powders :- The effect of cohesion on powder flow and scale-up in particular for blending operations is a problem . A cohesive powder can be defined as a material in which the adhesive forces between particles exceed the particle weight by at least an order of magnitude . 1. The cohesive effects are much stronger in smaller vessels and tend to disappear in large vessels . This is because as the blender scale increases gravitational and convective force increase, thereby overwhelming cohesive force . 2. As the blender size increases, the chunk to blender size ratio shrinks. Both arguments can be mathematically dimensionless cohesion number c
c
expressed
in
terms
of
= / gR = ( / g)/R = S/R
in which
= effective cohesive stress (under actual conditions) = powder density under flow conditions g = acceleration of gravity
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R = Vessel Volume S = / g is the chunk size which can be defined as the internal length scale of flow driven by material properties . As R increases , c decreases Mixing rate for radially ( top-bottom ) segregated loading , is independent and constant regardless of mixture cohesion and mixer size . Mixing rate for axially (left-right) segregated loading , the scale-up factors is depended on cohesion , indicating that scale-up is a mixture dependent problem ( but this is at small scale ) . The conclusion from these result is that laboratory scale experiments for cohesive powders are of questionable validity for predicting full-scale behaviour . Behaviour at small scales is likely to be strongly affected by cohesive effects that are of much less intensity in the large scale . The most common scale-up criterion for the application of shear via impellers and I bars is to match the linear speed of the moving element .
[13] IMPROVING THE LIKELYHOOD OF SCALABILITY

Identifying the physical and chemical phenomena involved in pharmaceutical manufacturing process . Understanding whether and how these phenomena are affected by a change in scale (i.e. Are they dependent on volume , area or length ?) Identifying the predominant or controlling process mechanism . Identifying the critical process variables that affect scalability . Identifying or determining the physicochemical properties (eg: density , particle size , viscosity) of the formulation components and the products relevant to scalability . Using dimensional analysis to reduce the number of variables required to characterize a process as the manufacturing scale changes . Using software that enables the estimation of equipment performance and material characteristics .
[14] CONCLUSION
In order to scale up and transfer a process successfully from laboratory scale to pilot scale and multiple commercial manufacturing scales, a thorough understanding of the integration of scale factors , facility design , equipment design and process performance is necessary .
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[15]REFERENCES
The Theory and Practice of Industrial Pharmacy : Leon Lachman , Herbert A Lieberman , Joseph L Kanig : Section IV : Chapter 23 : Pilot Plant Scale-Up Techniques : Page No . 681 710 . Encylopedia of Pharmaceutical Technology : James Swarbrick , James C Boylan : Volume 12 : Pilot Plant Design : Page No . 171 186 . Pilot Plant Operation : Page No . 187 208 . Drugs and The Pharmaceutical Sciences : Pharmaceutical Process Scale-Up : Marcel Dekker series : Michael Levin : Volume 118 Parenteral Drug Scale-Up : Page No. 43 56 . Scale-Up Considerations for Biotechnology-Derived Products : Page No. 95 114 Powder Handling : Page No. 133 150 . Scale-Up of Film Coating : Page No. 259 310 . Scaling Up Manufacturing Processes : A Technology Primer : Supplement To Pharmaceutical Technology 2005 .
POSSIBLE QUESTIONS
1. What is the difference between pilot scale and scale up ? [ 1 mark ] 2. Outline the Pilot Plant Operation and give brief note on each . [ 5 marks ] 3. Which parameters should be considered during the scale up of Tablet Coating ? [2 marks ] 4. Give a brief note on Scale-Up of Biotechnology-Derived Products and Parenteral Solutions . [ 5 marks ] 5. What are the steps involved in transfer of a formulation right from F&D to Production facility ? [ 7.5 marks ] 6. Write a brief note on Dimensional Analysis . [ 2 marks ] 7. various approaches used for scale-up of solutions . [ 5 marks ] 8. Give a brief note on scale-up of blending operation . [ 5 marks ] 9. How will you improve the scalability ? [ 2 marks ] 10. Newton , Reynolds number and Froude number with its applications . [ 3 marks ] 11. Define Scale up techniques in pharmaceutical formulation.Discuss similarities with a view to observe and solve scaling up problems,by giving suitable illustrations.[2004] 12. Write a note on similarity. 13. Write note on pilot plant design and operation.[2005] 14. What are the general consideration for scale up operation and specifically oral liquid dosage form scientifically.
PAGE: 194

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INDUSTRIAL PHARMACY PAPER 910201

M. PHARM PART I (2009-10)

CHAPTER NO. - 1, 6, 7 & 8.

DEPT.OF PHARMACEUTICS & PCEUTICALTECHNOLOGY L. M. COLLEGE OF PHARMACY, ABAD- 09

SEMINAR ON INDUSTRIAL PHARMACY (PAPER-910201) CHAPTER NO.: 1, 6, 7 & 8

9,10 Pilot Plant & Scale-Up techniques

SIGNATURE OF GUIDE:- _______________

PCEUTICAL FACTORY LOCATION BY : SANJAY C. MODI

DEPT. OF PHARMACEUTICS AND TECHNOLOGY L.M.COLLEGE OF PHARMACY AHMEDABAD-09.

PCEUTICAL FACTORY LOCATION BY : SANJAY C. MODI

M.PHARM. PART-I (2009-10) L.M.COLLEGE OF PHARMACY, AHMEDABAD-09

PCEUTICAL FACTORY LOCATION BY : SANJAY C. MODI

IMPORTANCE OF PLANT LOCATION:

FACTORS RESPONSIBLE FOR THE PLANT LOCATION CHOICES:

PCEUTICAL FACTORY LOCATION BY : SANJAY C. MODI

PCEUTICAL FACTORY LOCATION BY : SANJAY C. MODI

Geography Neighbours Factory location Pollution Economic factors

M.PHARM. PART-I (2009-10) L.M.COLLEGE OF PHARMACY, AHMEDABAD-09

PCEUTICAL FACTORY LOCATION BY : SANJAY C. MODI

ADVANTAGES OF A GOOD LAYOUT:

M.PHARM. PART-I (2009-10) L.M.COLLEGE OF PHARMACY, AHMEDABAD-09

PCEUTICAL FACTORY LOCATION BY : SANJAY C. MODI

FEATURES OF A GOOD LAYOUT:

M.PHARM. PART-I (2009-10) L.M.COLLEGE OF PHARMACY, AHMEDABAD-09

PCEUTICAL FACTORY LOCATION BY : SANJAY C. MODI

SAMPLE LAYOUT OF A PRODUCTION DEPARTMENT

SAMPLE LAYOUT OF F&D DEPARTMENT

M.PHARM. PART-I (2009-10) L.M.COLLEGE OF PHARMACY, AHMEDABAD-09

PCEUTICAL FACTORY LOCATION BY : SANJAY C. MODI

SALIENT FEATURES OF PLANNING:

PCEUTICAL FACTORY LOCATION BY : SANJAY C. MODI

STEPS INVOLVED IN PLANNING:

PCEUTICAL FACTORY LOCATION BY : SANJAY C. MODI

M.PHARM. PART-I (2009-10) L.M.COLLEGE OF PHARMACY, AHMEDABAD-09

PCEUTICAL FACTORY LOCATION BY : SANJAY C. MODI

M.PHARM. PART-I (2009-10) L.M.COLLEGE OF PHARMACY, AHMEDABAD-09

UTILITY SERVICES BY: KRUPA

UTILITY SERVICES AND SERVICE FACILITIES

GUIDED BY: Dr. R.K.Parikh

Department Of Pharmaceutics L.M.College Of Pharmacy,Ahmedabad

UTILITY SERVICES BY: KRUPA

Grey Orange Green Insulated White

Raw water Distilled Water Cooling water Steam Air

M.PHARM PART-I (2009-10) L.M.COLLEGE OF PHARMACY, AHMEDABAD-09

UTILITY SERVICES BY: KRUPA

Sanitary waste system

Laboratory waste system:

Process Waste System

Hazardous Material Waste and Retention

M.PHARM PART-I (2009-10) L.M.COLLEGE OF PHARMACY, AHMEDABAD-09

UTILITY SERVICES BY: KRUPA

Storm Drainage System

M.PHARM PART-I (2009-10) L.M.COLLEGE OF PHARMACY, AHMEDABAD-09

UTILITY SERVICES BY: KRUPA

Natural Gas and Propane

5.SANITATION IN THE MANUFACTURING PREMISES

Objectives of sanitation are:

M.PHARM PART-I (2009-10) L.M.COLLEGE OF PHARMACY, AHMEDABAD-09

UTILITY SERVICES BY: KRUPA

CLEANING AGENTS AND DISINFECTANTS

Name of cleaning agent Teepol

UTILITY SERVICES BY: KRUPA