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Date of submission: 2nd April, 2013

Submitted by……..
Sabiha Chowdhury

Sanjana Haque

H.M.Alamgir
Muhaiminul Adib
Kazi Md. Meskatul Islam
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Shah Md. Zubaer

ACKNOWLEDGEMENTS

Firstly, we would like to express our deepest gratitude to Md. Aminul Islam, the Plant
Human Resource Manager, Sanofi Aventis Bangladesh Ltd . for his kind acceptance to allow us
to perform the in-plant training in Sanofi Aventis Bangladesh Ltd. to get an insider’s view
and gain practical knowledge about the activities of this renowned pharmaceutical
company.

We would also like to excel our gratitude to Mr. Mahbubul Huque, Director Industrial
Affairs, Mr. A.B.M. Anwar Hussain, Director Industrial Quality and Compliance, Md. Muin
Uddin Mazumder, Plant Manager, who have enriched us with important and valuable
information about different site activities. We also thank Mr. Mostafa Ali Haider, IA Site
Administration, for keeping us informed about the schedule and office decorum. We sincerely
appreciate your co-operation and time, that you have spared for us, in an effort to make prepared
for our professional life.

We are greatly indebted to all the officers for their generous help during our in -plant
training period. Thanks to all of them.

Then we wish to thank all the supervisors, workers and employees associated with Sanofi
Aventis Bangladesh Ltd . for their cordial behavior, cooperation and valuable help
throughout our training period.

Finally, we are grateful to Professor Dr. Saiful Islam (Honorable Dean, Faculty of
Pharmacy) and Professor Selim Reza for their invaluable efforts for arranging and
creating the opportunity to perform the in-plant training in Sanofi Aventis Bangladesh Ltd .
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SCOPE OF THE TRAINING

 To understand the basic concept of manufacturing quality product.

 To help to develop control measures for various functions.
 To test skills in communicating analysis, conclusion and recommendation.
 To understand the In-Plant environment of the Pharmaceutical Industry.

PURPOSE OF THIS REPORT

It gives us an opportunity to see for ourselves how theoretical knowledge being

implemented practically, which in turn will help us understand things better in our professional
field.
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Contents Page
History of sanofi Aventis 05

Organogram of sanofi aventis Plant,Tongi 08

Human Resource Management(HRM) 09

Health Safety Environment 13

Product Development 16
T4 Solid Area 17

Liquid Cream Area 41

Liquid Sterile Areas 48

CPR area 55

Dispensing 75

Industrial Quality & Compliance 78

Microbiology 83

Packaging & Printing Area 91

Engineering 94

Plant Logistic 113

Purchasing 125

Industrial Affairs 126

Product List 129

Conclusion 131
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HISTORY OF AVENTIS

Aventis is one of the world's largest pharmaceutical companies. Formed by a series of

mergers and acquisitions, Aventis is currently operating as Sanofi-Aventis SA, after a 2004
purchase by France's Sanofi Corp. The company is best known for the development of Plavix, a
blood thinner that is among the world's best-selling drugs. Sanofi-Aventis is also known for its
cancer drugs, allergy medications, and for the development of vaccines through its Sanofi-
Pasteur organization.

RHONE-POULENC

Rhone-Poulenc was formed by the merger of two 19th-century French chemical

companies. The Establishment Poulenc-Freres was founded in 1858, and began as an apothecary,
or drugstore. Throughout the 19th century, Poulenc diversified into chemicals, textiles and
photography supplies. The company is also credited with producing many of the drugs and
medical supplies used by the French military during WW I.
In 1895, as Poulenc expanded its operations, a new company called Societe Chimiques des
Usines du Rhone began operating in France. Rhone not only produced many popular fragrances
and perfumes, but also created a medical product called Rhodine, which would eventually
become aspirin.
As chemical and pharmaceutical competition increased, the two companies joined forces in 1928
to stay afloat in a tough economy. The newly merged company was called Société des Usines
Chimiques Rhône-Poulenc

HOECHST

Hoechst was formed in Frankfurt, Germany, in 1863. The company focused primarily on
dyes and chemicals, and it stumbled into drug production only sporadically. In 1883, Hoechst
researchers who were working on new dye technology discovered Antipyrin, an early painkiller.
Over the next two decades, the company is also credited with inventing Novocaine, synthetic
insulation and adrenaline, and a syphilis treatment known as Salvarsan. In spite of these
achievements, Hoechst stayed focused on chemicals, including military production for the
German government. After WW II, Hoechst was left with only basic equipment, as well as a
small textile plant. The company invested heavily in rebuilding Germany after the war, and
profits soared in the chemical and manufacturing industries.
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AVENTIS

Throughout the 20th century, Rhone-Poulenc rapidly expanded its pharmaceutical lines
while reducing focus on chemicals and industry. By the 1990s, the company was the largest drug
manufacturer in Europe, as well as among the largest in the world. At the same time, Hoechst
had gradually shifted its efforts from textiles and chemicals into drug production, and it was
among the world's leading producers of antibiotics, diabetes medication and steroids. In
December 1998, the two companies announced a planned merger, which would take place over
the next three years. As part of the merger, both companies would sell remaining chemical and
industrial interests, and the resulting pharmaceutical company would take the name "Aventis."

SANOFI AVENTIS

In 1999, the Sanofi-Synthelabo company was among the world's leading pharmaceutical
companies. Based in Paris, Sanofi-Synthelabo was known for creating the sleep-aid Ambien, as
well as a hypertension drug called Avapro. Despite its size, Sanofi found itself forced to partner
with larger drug companies to successfully introduce new products in major markets like the
U.S. To eliminate the need for such partnerships, the company made a hostile takeover bid for
Aventis in 2004. After this effort failed, the two companies entered negotiations and signed a
deal for Sanofi to acquire Aventis in May 2004. The new company was valued at more than $65
billion, and it would use the name Sanofi-Aventis.

SANOFI AVENTIS TODAY

The Sanofi Aventis merger helped the two companies gain leverage in the market and to
take advantage of synergies to cut costs and increase development. The newly merged company
also formed a subsidiary known as Aventis Pasteur, which is the world's largest producer of
vaccinations for a large variety of conditions. Since 2007, the company has been surrounded by
speculation of a possible merger with Bristol-Myers Squibb Co. Such a merger would put Sanofi
Aventis's size and scope on par with Pfizer, the world's top pharmaceutical company. A 2007
report in the Times of London described details of talks between the two companies. In 2009, the
European Union gave final approval to Sanofi Aventis's acquisition of Zentiva, a dfrom the
Czech Republic. Sanofi Aventis plans to use this acquisition as a springboard for expansion into
Eastern Europe.
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SITE HISTORY

 1960: Incorporation as a joint venture company Pakistan Pharmaceutical Industry with

May & Baker owning 60% and Pakistan Industrial Development Corporation 40%
shares.

 1962: Production and marketing of Largacil, Flagyl, Stmetil, Phenergan etc.

 1971: Independence of Bangladesh

 1972: Renamed as Bangladesh Pharmaceutical Industry

 1981: Started Animal Health & Nutrition and Agrochemical business

 1986: Renamed as Rhone-Poulenc Bangladesh Limited

 1990: Development of sales of Profenid, Peflacine, Imovane, etc.

 1995:
 Renamed as Rhone-Poulenc Rorer Bangladesh Limited
 Animal Health and Nutrition and Agrochemical Business, reformed as a new
company- Rhone-Poulenc Agrovet Bangladesh Limited.
 Acquisition of Fisons
 1997: GMP upgrade and implementation of GMPs on site

 1998: Started Qualification and Validation activities

 1999: Mereger of Rhone-Poulenc Rorer and Hoechst Marion Roussel to form a new
company Aventis Pharma

 2001: Complete transfer of Fisons and HMR products on site

 2002: Complete technology transfer of Amaryl and Tritace from Scopitto, Ital

 2004:
 Commendable achievement of the site in IACS Audit- ‘Green Site’
 New company – Sanofi Aventis
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ORGANOGRAM of SANOFI AVENTIS PLANT

Industrial Affairs

Industrial Affairs

M. Hoque

Information Solutions Industrial Quality and Compliance

and Business Development
A. Uddin
A. Hussain

Industrial Affairs Control Pharma Plant

S. Ahmed M. Mazumder

Plant Logistics Plant Human Resources

M. Hossain A. Islam

Engineering Health, Safety and Environment

M. Islam K. Alam

Purchasing Maintenance

G. Arif I. Masud
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Industrial Quality and Compliance and Business

Development

A. Hussain

Quality Quality Quality Analytical Microbiology Validation and

Control Assurance Assurance Support/Analytical Training
Regulatory Development TBA
TBA Liaison S. Doha S. Ferdousi
M. Islam
M. Islam

Human Recourse Management (HRM)

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 Human Resources (HR) is the set of individuals who make up the workforce of an
organization and Human Resources Management (HRM)is the management of that
workforce of the organization.

 It is the department concerned with people at work and with their relationship
within as enterprise.

 It is responsible for selecting, recruiting, screening, training, appraising and

rewarding employees while also overseeing organizational leadership and culture,
and ensuring compliance with employment and labor laws.

Industrial Occupational
Relations Health

General
Activities/Ad
Plant Human
ministration/
Resources
Support HR
Services
Activiti
es
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General Services/Administration/Support Services

Trans Site
Licens port secur
Site e Hous
ity
beaut e
ificati keepi
Leave on ng Visito
and
rs and
admi General guest
nistra
tion Service s
Cante
Overt s/Admi en
nistrati mana
ime
geme
on nt
Atten Petty
dance cash
Legal
Laund Affair
ry s
Dresse Pest
s control

 Industrial Relations:
 Negotiation

 Monitoring Union activity

 Monitoring latest political and labor situations

 Relation with Regulatory body ,e.g. Govt. agencies, labor authorities,

Pressure group.

 Occupational Health:
 Physical and mental adaptation of the employee to the working
environment

 Prevention of acute and chronic threats related to work activity

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 Health promotion

 Industrial hygiene: evaluation and control of exposure.

 Occupational health sacrifices:

 Medical surveillance

 Health promotion

 Pre-employment medical checkup

 Yearly medical checkup

 Human Resources:
 Recruitment and Selection

 People development:

 Training

 Orientation of new employees

 Talent identification

 Performance assessment

▫ Management: March

▫ Non-management: by December

 Compensation and Benefits

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HEALTH, SAFETY & ENVIRONMENT

Industrial Safety Management aims at minimizing the chances of risks, injuries and
accidents by implementing risk management techniques and safety management operations,
improving the standard of health of the employees, monitoring the operating systems and
bolstering the safety measures of an industry in general. With the rise of natural disasters in and
around our world, the importance of the safety of human capital, protection of the environment
and conservation of existing assets of an industry is increasing, leading to growing relevance of
skills in Industrial Safety Management.

The key requirements of the HSE department are:

 Maintains the Policies & Qualities

 Following the appropriate Guidelines
 Acts according to the SOP

THE TEAM HSE

Manager HSE is the head of the department & the HSE committee consists of the following
members:

 All functional managers

 Union representatives and
 Company doctors

The committee meets at regular intervals.

HSE PRACTICES
The following are the areas where HSE practices their program:

 Health
Employees should undergo medical checkup by the internal doctors. Health screening program
should be carried out every year, to find out any problem, due to exposure to different
environments. Doctors are given health promotion program training and medical support should
also be provided.
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 Safety

 People - Gowning is carried out and should be area specific

 OEL – Occupational Exposure Limit and based on this exposure, it is divided into 5
categories.
 OEB – Occupational Exposure Band, low exposure limit gives higher band.

Exposure can be reduced by maintaining a control system, for example; what type of ventilator
should be used for the total number of people in a specified area. Employees use masks, to
reduce exposure. N-100 filter masks are used in places, where pharmaceutical production occurs.
Different sectors have different level of protection, depending on the product.

 Emergency Management Plan / Crisis Management Plan

- Fire
- Flood Earthquake
- Sabotage

Emergency is another point which comes under safety. The company should have an emergency
management plan. Fire fighting team should be present, which should be given training.
Everyone in the plant should be given training for emergency evacuation.

 Environment

 Exposure from the work place

 Wastes can be hazardous and non- hazardous

Hazardous waste can be active dust, chemicals, salts, toxics, flammable, etc and wastes can
be solid, liquid or gas. The wastes are given to a particular contractor and they carry out
incineration (burn the waste into dust at high temperature 120◦C) usually done to the hazardous
waste and this is not definitely done inside the plant.

Wastes like packaging materials, blister, glass, plastics, foil, etc. are sent to the recycling
contractor after dephasing. In production areas HBSC systems with filters (HEPA) are present so
that the dusts are collected and they do not come in contact with the external environment.

LOCAL ENGINEERING CONTROL

Employees should wear eye protections and ear plugs, when they work at areas where rotating
objects are present and where machines produce sound. Machines should be maintained and
given necessary protection.
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RISK ASSESSMENT OF HSE

The risk factors are:

 Ergonomics
 Environmental Risks (pollution, noise)
 Fire

Ergonomics is the relation between the employee and the environment in which they work.
Standard environment should be maintained. Therefore a Risk Assessing Team (RAT) is created
by this department and it is divided into 6 groups. They inspect the work process in the wok area
and check how the work is carried out. Analysis is done if the work is not carried on properly
and every after three years external audit takes place.

PROCESS SAFETY
Due to the use of many products there might be risks, like, explosion etc. therefore safe process
should be followed.
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PRODUCT DEVELOPMENT

Product Development (PD)

PD works with both existing and new product. PD personnel follow the respective guideline in
executing their actions on the two types of product.

1. Existing Product

In case of an existing product reformulation is done in which minor changes are conducted on
the product like changing coating material, flavor, shape etc. PD also ensures that, surplus
materials that remain after the production are properly utilized in the following batch so that the
wastage is minimal; this ensures more consumption and less inventories.

2. New Product

In case of a new product, PD undergoes the following procedures:

 New product launching plan after PD consults with the Product Management Department
(PDM).
 PD pharmacist collects all possible information regarding the product through the PDM
or other relevant persons.
 The PD pharmacist will collect the sample along with the method of analysis via
TSD/SDM and all required information and prepare specification.
 Then the PD pharmacist makes trials and evaluate the product as per specification and if
meet the requirements then go for similar another two trials and make a comparative
analysis of the product.
 Then place the sample for stability study as per the stability protocol.
 After three months of stability study, if the product is in satisfactory state in terms of
physical and chemical stability then the next course of stability study is carried out.
 In addition , six months stability data and required documents are sent to the Drug
Regulatory Authority through Regulatory Site Management of sanofi aventis for
licensing and price approval
 After getting approval of recipe, PD goes for commercial procurement or require raw
materials and then go for three pilot batches.
 Then PD go for validation batch for process validation and hands it over to production for
commercial batches.
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T4 SOLID AREA

Solid dosage forms

A solid dosage form is the solid form of a dose of a chemical compound used as a drug or
medication intended for administration or consumption.

Solid dosage forms are referred to as single unit dosage forms which are relatively least
expensive, easy to prepare, most popular and convenient methods for drug delivery. They are
manufactured in non-sterile environment and the technology is well-known after more than 100
years of development.

Solid dosage forms includes: powder, granule, tablet, and capsule.

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Here in Bangladesh, Sanofi is mainly concerned with manufacturing tablets and capsules. The
raw materials for solid dosage forms and pellets for capsules are imported from ICH
(International Conference on Harmonization) or non-ICH countries.

Solid manufacturing area of Sanofi Aventis

Solid area is a core department or vital manufacturing area of any pharmaceutical company as
because the majority of drugs are available in the form of solid dosage forms in the market.

At Sanofi Aventis, solid area is located at T4 building and non-antibiotics are manufactured here
in the form of tablets and capsules in a very large scale.
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Environmental Zones:
The manufacturing of solid area is classified under the environmental zone 3.

The non-sterile area of each segment is divided into three zones.

Zone 1: include the gowning area and cleaning area

Zone 2: includes the secondary packaging area

Zone 3: includes the primary packaging area, production area and delivery area.

Important Parameters
The most important parameters of the production area of solid dosage forms are temperature,
humidity and
pressure. Pressure difference
Temperature
≥ 2.5Pa Humidity
22°C ± 3°C
40 - 65%

Pressure : Pressure difference between the production room and corridor must be ≥ 2.5Pa

Solid Area

PRODUCTION ROOMS (-) PRESSURE

Corridor (+) Pressure

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Inside the production rooms (-) pressure must be maintained and in the Corridor, (+) pressure
should be maintained. So that dust cannot pass from the production area to the Corridor to
prevent contamination.

Requirements for the manufacturing process

At Sanofi-Aventis, prior to manufacture of any batch product, some documentations are
followed, such as

 SOP
 BMR
 PO
 LOG BOOK

SOP: Standard Operating Procedure

Standard Operating Procedure (SOP) is a set of written instructions that document a routine or
repetitive activity which is followed by employees in an organization. The development and use
of SOP is an integral part of a successful quality system. It is a Step-by-step instruction of how to
perform operational tasks or activities. It provides information to perform a job properly, and
consistently in order to achieve pre-determined specification and quality end-result. Procedures
are essential for any plant’s effectiveness and efficiency, and they are regulatory requirement in
the pharmaceutical industry.

SOPs detail the regularly recurring work processes that are to be conducted or followed within a
pharmaceutical plant. They document the way activities are to be performed to facilitate
consistent conformance to technical and quality system requirements and to support data quality.
They may describe, for example, fundamental programmatic actions and technical actions such
as analytical processes, and processes for maintaining, calibrating, and using equipment. SOPs
are intended to be specific to the organization or facility whose activities are described and assist
that organization to maintain their quality control and quality assurance processes and ensure
compliance with governmental regulations.

SOPs should be also systematically reviewed on a periodic basis, e.g. every 1-2 years, to ensure
that the policies and procedures remain current and appropriate, or to determine whether the
SOPs are even needed. The review date should be added to each SOP that has been reviewed. If
an SOP describes a process that is no longer followed, it should be withdrawn from the current
file and archived.
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Responsibilities

Pharmaceutical plant should have SOP on preparation, approval, revision and control of standard
operating procedure for better control and management of overall systems. Everyone should
follow the procedure exactly with each and every step in detail. Overall system management
should:
 Ensures that SOPs meet the quality requirements and are user friendly.
 Manages SOP change controls.
 Distributes SOPs.
 Ensures that SOPs are current.
 Ensures that new or changed SOPs are valid only after training has occurred and provides
training about the SOP system.
 Measures system performance and periodically reports results to management
 Continuously improves the system

Safety consideration

 Personnel safety
 Environmental safety

Operation

Operations are performed consistently to maintain quality control of processes and products.

Cleaning procedure

 Equipments
 Production area

BMR: Batch Manufacturing Records

The Batch Manufacturing Record (BMR) is the necessary quality and GMP documentation for
tracing the complete cycle of manufacture of a batch or lot.

A specific quantity of an intermediate or API intended to have uniform character and quality,
within specified limits, and produced according to a single manufacturing order during the same
cycle of manufacture. A batch may also mean a specific quantity of material or API processed in
one process or series of processes so that it could be expected to be homogenous. Batch records
provide step-by-step instructions for production related tasks and activities as well as include
areas on the batch record itself for documenting such tasks. Batch manufacturing records should
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be prepared, maintained and controlled for each batch of product. In general, they should be
retained for a period of approx. 3 years after distribution has been completed.

Contents of BMR

 Name of products, batch size and shelf life

 Manufacturing formula
 Dispensing records
 Manufacturing process:
• Granulation
• Blending
• Compression
• Coating

Process Order (PO)

PO is a key element of order fulfillment associated with the delivery of raw and packaging
material.

Contents of PO

 Product name
 Name and quantity of APIs and Excipients
 Batch or Lot number

SAP ( System application for process)

Creation of master recipe of a product

Process order

BMR +PO

Dispensing area Production area

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At Sanofi Aventis, a master recipe of a product is uploaded into the SAP which is known as
process order. This PO and BMR both are sent to the dispensing area and production area.

Master formula records for each product should be prepared and dated by a responsible
individual and should be independently checked and dated by another responsible individual.
The information contained in the records should be provided in a format and language that will
not be misinterpreted by the operating personnel and the supervisor, to assure that each batch of
a product can be identically reproduced.

Although the content and format may differ from product to product, the master formula record
includes the following information:

 The name of the product, a description of the dosage form and its strength
 The complete list of the ingredients, designated by whole names and codes sufficiently
specific to indicate any special characteristics.
 The quantity by weight or volume of each ingredient, regardless of whether it appears in
the finished product. If variations in the quantity of a particular ingredient are permitted,
as it sometimes necessary in the preparation of a dosage form, an adequate statement
should be provided in the record.
 The standards or specifications of each ingredient used in the product.
 An appropriate statement concerning any calculated excess of an ingredient.
 Appropriate statement of theoretic yield at various stages and the termination of
processing.
 Manufacturing and control instructions, specifications, precautions and special notations
to be followed.
 A detailed description of the closures, containers, labeling, packaging, and other finishing
materials.

Log Book
Logbook is a record book with periodic entries. The purpose of a log book is to document in a
chronological order equipment related events such as validation and qualification work,
calibrations, equipment cleaning, preventive maintenance and repairs and unexpected events /
deviations for manufacturing equipment, apparatus, quality control and IPC analytical equipment
and utilities. Each product has machine log book.
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Contents of machine log book

 Machine name
 Cleaning of machines
 Room number
 Room temperature, humidity and pressure
 Operator’s name
 Batch number product name and date
 Start and end date
 Available hours
 Set up hours
 Machine run times
 Maintenance times
 Daily and weekly check (in case of compounds)

Other considerations of the solid area

 Proper gowning procedure
 Good house keeping
 Sequential work flow
 Proper status labeling

Any production in the pharmaceutical industry is followed strictly and blindly according to
previously developed protocols. So for production, the entire process, precautions, equipment,
conditions to be maintained are mentioned in the Batch Manufacturing Record (BMR). This
BMR is documented by the R&D unit and checked for improvements by the Analytical
development unit.

At Sanofi Aventis, firstly the raw materials (APIs and Excipients) are obtained from the ware
house unit. Then the raw materials are sent to the dispensing area to calculate the exact amounts
required for production of one batch of tablets and deliver accordingly into the production unit
from the dispensing area through the pass box. The raw material, before entering is tested by
Quality Control and checked if it is suitable for production.
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Ware House

Dispensing Area

Production Area

Cross checking must be done in each department to prevent risk. If any deviation is occurred,
then necessary steps should be taken to correct them.

Tablet Manufacturing Method

At Sanofi Aventis, tablets are manufactured at a very large scale by following the two methods

Granulation

-Dry Granulation

-Wet Granulation

-Direct Compression

Tablet Manufacturing Method

Granulation Direct Compression

Dry Granulation Wet Granulation

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Process Route for Tablet Manufacture

Dry Granulation Wet Granulation Direct Compression

Drug Drug Drug

Diluent Mixing Mixing Diluents Blending
Lubricant Diluents Glidant
Disintegr
ant
Pre compression

Binder
solvent Wetting

Sieving

Granulation

Drying

Sieving
Lubri
Disinte- Disintegrant
cant Compression
grant Glidant
Glidant Mixing Lubricant Mixing
Lubrica-
-nt

Compression Mix

Fill Die, Compress Tablet & Eject Tablet

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Granulation :

Granulation is the process in which the powder particles of raw materials are made to form larger
particles in order to facilitate compression for the production of tablet.

For suitable granulation, it is required to have 30-40% powder and 60-70% granules and also 1-
5% moisture in compressing particles.

Importance of Granulation:
The reasons why granulations are often necessary are as follows:
 To prevent segregation of the constituents of the powder mix
 To improve the flow properties of the mix
 To improve the compaction characteristics of the mix
 To reduce toxicity
 To reduce storage space
 To impart physical property

Methods of granulation

Granulation methods are divided into two types:

 Wet granulation methods, which use a liquid in the process and

 Dry granulation methods in which no liquid in used.

In suitable formulation, a number of different excipients will be needed in addition to the drug.
The common types used are diluents, to produce a unit dose weight of suitable size and
disintegrating agents, which is added to aid the break-up of the granule when it reaches a liquid
medium e.g. on ingestion by the patient. Adhesives in the form of a dry powder may also be
added, particularly if dry granulation is employed. These ingredients will be mixed before
granulation.
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Wet granulation method

Wet granulation involves the massing of a mix of dry primary powder particles using a
granulating fluid. The fluid contains a solvent which must be volatile so that it can be removed
by drying and be non-toxic. Typical liquids include water, ethanol and isopropanol either alone
or in combination. The granulation liquid may be used alone or more usually, as a solvent
containing a dissolved adhesive. Which is use to ensure particle adhesion once the granule is dry.
Water is commonly used for economical and ecological reasons. Its disadvantages as a solvent
are that it may adversely affect drug stability, causing hydrolysis of susceptible products and it
needs a longer drying time than do organic solvents. This increases the length of the process and
again may affect stability because of the extended exposure to heat. The primary advantage of
water is that it is no-flammable, which means the expensive safety precautions such as the use of
flameproof equipment not to be taken. Organic solvents are used when water-sensitive drugs are
processed, as an alternative to dry granulation or when a rapid drying time is required.

Adding
Weighing Dry sieving
Lubricant

Mixing Drying Blending

Adding
liquid Wet sieving
binder

Fig: Wet granulation process

Moisture content of granule is one of the important factors in case of Wet Granulation process.
The moisture content of granules should not be more than 1%

For example, during our in plant training period at Sanofi Aventis, we saw the production of
Metronidazole (FLAGYL) which was done by the Wet Granulation process.
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Paste Preparation
At Sanofi Aventis, paste is prepared which is used as liquid binder or granulating fluid in the wet
granulation process according to the following procedure:

At first, Cold and Hot water should be mixed in a

right proportion

Desired amount of liquid binder (10%-20%

starch) should be added and mixed properly

Finally steamed water should be added to

result in paste preparation

Binders used in wet granulation method

 Ethyl cellulose polymers (Ethocel)

 Methyl cellulose ethers (Methocel)
 Polyvinyl pyrrolidone
 Cellulose derivatives (hydroxy propyl methyl cellulose)
 Sucrose
 Gelatin

Dry granulation Method

In the dry method of granulation the primary powder particles are aggregated under high
pressure. There are two main processes. Either a large tablet produce in a heavy-duty tabletting
process or the powder is squeezed between two rollers to produce a sheet of material. In both
process these intermediate products are broken using a suitable milling technique to produce
granular material, which is usually sieved to separate the desired size fractions, the unused fine
material may be reworked to avoid waste. This dry method may be used for drugs that do not
compress well after wet granulation or those which are sensitive to moisture.
 P a g e | 31

APIs, Filler
Mono-sized
& Sieving
Lubricant Granules

Blending
Precompress
Drying Lubricant,
ion Glidant &
Disintegrant

Sieving Granules

Slugging

Roller
Compaction

Fig: Dry granulation process

The difference between Wet Granulation and Dry Granulation process is that, in case of Wet
Granulation we generally use granulating fluid whereas no granulating fluid is added in Dry
Granulation process.
 P a g e | 32

Equipments used in Granulation process:

Mixer Granulator Cone Blender

Miller machine Fluid bed dryer

Fig: Granulation machines

 P a g e | 33

Mixer granulator:

 Seizoner mixer model-250 L

 JAGUAR mixer model: HSMG 600(capacity 600L)

 DIASONA mixer(capacity 250,Germany)

Fluidized Bed Dryer(FBD):

 GANSON FBD(capacity 150L,India)

 SAPPHIRE FBD(capacity 80 L, India)

 ALLIANCE FBD(capacity 120,India)

Milling and sieving machine:

 Rotogram oscillator(16 mesh)

 Apex regulator mill(India)

 Sruti mill

 Fitz mill(Manesty,England)

 Alexander werk mill

Blender:

 CLINECONE Blender 250 L Apex

 CLINECONE Blender 700 l DEV

 P a g e | 34

Direct Compression

Direct Compression is a process by which tablets are compressed directly from powder mixture
of APIs and suitable excipients. No pretreatment of the powder blend by wet and dry
granulation procedure is required. Tablet presses, also called tableting machines, range from
small, inexpensive bench-top models that make one tablet at a time (single-station presses), with
only around a half-ton pressure, to large, computerized, industrial models (multi-station rotary
presses) that can make hundreds of thousands to millions of tablets an hour with much greater
pressure. The tablet press is an essential piece of machinery for any pharmaceutical and
nutraceutical manufacturer. Common manufacturers of tablet presses include Fette, Korsch,
Kikusui, Manesty and Courtoy. Tablet presses must allow the operator to adjust the position of
the lower and upper punches accurately, so that the tablet weight, thickness and density can each
be controlled. This is achieved using a series of cams, rollers, and/or tracks that act on the tablet
tooling (punches). Mechanical systems are also incorporated for die filling, and for ejecting and
removing the tablets from the press after compression. Pharmaceutical tablet presses are required
to be easy to clean and quick to reconfigure with different tooling, because they are usually used
to manufacture many different products.

Manufacturing Steps for Direct Compression

Direct Compression involves the following steps:

 Milling the drugs and excipients

 Mixing the drug and excipients
 Tablet compression
 P a g e | 35

 Machines used in compression

 Korsch XL – 200 (fully automated, 30 stations, 170000 tablets per hour , Germany)

 Manesty BB3B (semi automated, 39 stations, 60000 tablets per hour , England)

 Manesty BB3B (semi automated, 27 stations, 40000 tablets per hour , England)

 Cadmach CMB4 (semi automated, 41 stations, 111000 tablets per hour , India)

 Rotaplus MK – 11 (semi automated, 45 stations, 450000 tablets per hour)

 CADMACH CADPRESS ll A 45 .1

 CADMACH CADPRESS ll A 45 . 2

Fig: Compression machine

 P a g e | 36

In Process Tests
In process tests are done during and after the compression are occurred. The tablets that we
collect from the direct compression process, are tested by doing the following tests. Such as:

 Weight Variation
 Friability
 Hardness
 Dissolution

weight variation Friability

Test

Hardness Dissolution

Capsules Filling
The word capsule is derived from the Latin capsula, meaning a small box. In Pharmacy the word
is used to describe an edible package made from gelatin or other suitable material which is filled
with medicines to produce a unit dosage, mainly for oral use. There are two types of capsules.

 Hard gelatin capsule

 Soft gelatin capsule

The hard capsule consists of two pieces in the form of cylinders closed at one end, the shorter
piece, called the ‘cap’, fits over the open of the longer piece, called the ‘body’.

At Sanofi Aventis, only hard gelatin capsules are manufactured at a large scale in the solid area.
 P a g e | 37

Capsule Filling Process

 AT first, capsules are inserted and separated
 Then cap of the capsules are segmented by upward movement
 Body of the capsules are segmented by forward movement
 After that pellets or powders are filled within the capsules shell
 Faulty capsules are ejected
 Segment moving is occurred
 Then downward/backward movement of cap/body segment is done
 After that cap and body of the capsules are closed
 Finally filled capsules are discharged
 Segment cleaning is done after completing filling process

The figure in the last page, the capsule filling machine is divided into three parts, such as:

 Capsule Filling machine

 Capsule polisher
 Dust collection

At first, encapsulation is done in the capsule filling machine and then the encapsulated capsules
are polished by the capsule polisher and ejected properly. During the encapsulation process
occurs, dusts are collected by the dust collector.

Tablet Coating
Tablet coating is the application of a coating material to the exterior of a tablet with the interior
of conferring benefits and properties the dosage form over the uncoated variety. In its widest
sense the technology is also applicable to multi particulate systems intended for modified-release
applications. To a much lesser extent coatings may also be applied to hard-shell and soft elastic
capsules.
 P a g e | 38

Types of Tablet Coating

Three main types are in use:

 Film coating
 Sugar coating
 Press coating

Film and Press coating

At Sanofi Aventis, tablets are coated by both film and press coating process. Film coating is the
major technique. Virtually all new coated products introduced on to the market are film coated.
For example, Tritace, is coated by film coating process and Metronidazole ( FLAGYL) is coated
by following press coating process over here.

Sugar Coating

At Sanofi Aventis, Sugar coating process was done before, but now a days, this process is not
done due to increase blood pressure in diabetes patients.

Coating Materials
 Polymers
 Plasticizers
 Solvents
 Colorants

Reasons for tablet coating

 Ingredients may need protection from the environment, particularly light and moisture
 Coating is done to mask the bitter or unpleasant taste of tablets
 Colored coatings also mask any batch differences in the appearance of raw materials and
hence patients concern over tablets of differing appearance
 Coating may be optimized with respect to coloration and gloss to aid in their sales appeal
or to reinforce a marketing brand identification
 P a g e | 39

 Colored coating aid in the rapid identification of product by the manufacturer, the
dispensing pharmacist and patients
 Coating confers an added mechanical strength to the tablet core. Cross contamination is
also reduced in the manufacturing plant.
 Functional film coating are used to impart enteric or controlled-release properties to the
coated tablet.

Coating process
Film coating involves the deposition, usually by a spray method, of a thin film of polymer
surrounding the tablet core. It is possible to use conventional panning equipment, but more
usually specialized equipment is employed to take advantage of the fast coating time and high
degree of automation possible.

The coating liquid (solution or suspension) contains a polymer in a suitable liquid medium
together with other ingredients such as pigments and plasticizers.

This solution is sprayed on to a rotating, mixed tablet bed or fluid bed. The drying conditions
permit the removal of the solvent so as to leave a thin deposition of coating material around each
tablet core.
 P a g e | 40

Equipments of the solid area

Sr. no Machine Location Model no Capacity

1 SSSJ Manufacturing Vessel SM 01 T. Guisti & 50L

Sons, UK
2 SS Storage Vessel SM 01 400L

3 Fitzmil SM 03 Manesty 225-

Machine, UK 680kg/hr
4 Apex Clynocone Blender SM 03 Apex 250L
Construction,
UK
5 Dev Clynocone Blender SM 04 Dev Industries, 700L
India
6 Sapphire Fluid Bed Dryer SM 05 Sapphire 100kg
Machines,
India
7 Saizoner Mixer Granulator SM 05 Tapasya 250L
Engineering,
India
8 Jaguar Mixer Granulator SM 06 General 600L
Industries,
India
9 Alliance Fluid Bed Dryer SM 06 Alliance 200kg
Engineering,
India
10 Tablet Capsule Inspection SM 07 Kwang Dah
M/C Engg. Taiwan
11 Cadmach CMB4 Tablet SM 09 Cadmach Max. 2940
Compression M/C Machinery, tab/min
India
 P a g e | 41

12 Korsch Tablet Compression SM 10 Korsch AG, Mx.

M/C Germany 1,26,000
tab/min
13 Manesty Tablet SM 16 Manesty Max. 3300
Compression M/C machines, UK tab/min
14 Manesty Tablet SM 17 Manesty 260-520
Compression M/C Macnines, UK tab/min
15 Manesty Tablet SM 18 Manesty 760-2200
Compression M/C Machines, UK tab/min
16 Markem Capsule SM 19 Markem
Inspection M/C Macnine, UK
17 Se-Jong Capsule Filling M/C SM 19 Se-Jong Max.
Machinery, 25,200
korea cap/min
18 Rotapress MKII Tablet SM 20 Manesty Max. 3780
Compression M/C Machines, UK tab/min
19 Se-Jong Coating M/C SM 21 Se-Jong Max.
Mchinery, 300kg/load
korea
20 Accelacota Coating M/C SM 22 Manesty 150kg/load
Machines, UK
21 Hearus Oven SM 26 Hearus,
Germnany
22 Avery Balance Avery, UK 150kg

23 Avery Balance Avery, UK 30kg

24 Avery Balance Avery, UK 17kg

25 Mettler Balance Mettler, 310kg

Switzerland
 P a g e | 42

LIQUID & CREAM AREA

At sanofi-aventis the liquid and cream area is situated at the T4 building. Liquid, cream,
ointment and suppositories are manufactured here.

LIQUID
Liquid preparation includes solution, emulsion, suspension and syrup:
 P a g e | 43

 Solution
Solution is a homogenous liquid preparation containing two or more components where the
active ingredients are dissolved in a suitable vehicle. The component that determines the phase
of the solution is termed as solvent and usually constitutes the large proportion of the system.
The other components are termed as solutes. Solutions may be classified according to the
physical states of the solutes, i.e. gas, solid or liquid. At Sanofi Aventis solutions in the form of
liquid are only manufactured.

 Emulsion
Emulsion is a heterogeneous preparation consisting two immiscible liquid phases, one of
which is dispersed throughout the other in the form of fine droplets. A third component,
emulsifying agent (sodium lauryl sulphate, acacia etc.) is necessary to stabilize the emulsion.

Pharmaceutical emulsions usually consist of water and oil. Two main types can exist:

 Oil in water (o/w)

 Water in oil (w/o)

Depending upon whether the continuous phase is aqueous or oily. Other types are water in oil
in water (w/o/w) and oil in water in oil (o/w/o) and are termed as multiple phases.

 SUSPENSION
Suspension is defined as a coarse dispersion containing finely divided insoluble material
suspended in a liquid medium. It is a two-phase system consisting of an undissloved or
immiscible material dispersed in a vehicle (solid, liquid, or gas). Suspensions contain aqueous
dispersion phase however in some cases they may be an oily or organic phase. The suspensions
have dispersed particles above the colloidal size that is mean particle diameter above 1µm.

 SYRUP
Syrup is a concentrated solution of a sugar, such as sucrose, in water or other aqueous liquid,
sometimes with a medicinal agent added; usually used as a flavored vehicle for drugs. It is
commonly expanded to include any liquid dosage form (e.g., oral suspension) in a sweet and
viscid vehicle.
 P a g e | 44

CREAM
Creams are semisolid emulsions for external application and usually contain one or more
medical ingredients. Oil in water (o/w-vanishing cream) emulsions are most useful as water
washable bases and water in oil (w/o-cold cream) emulsions are emollient and cleansing. Patients
often prefer a w/o cream to an ointment because the cream spreads more rapidly and is less
greasy.

OINTMENT
Ointments are greasy semisolid preparations often anhydrous and containing dissolved or
dispersed medicaments. The medicaments are dispersed in bases such as hydrocarbon bases, fat
and fixed-oil bases, absorption bases, emulsifying bases and water-soluble bases.

SUPPOSITORIES
Suppositories are mediated solid dosage form,
rectal route, vagina and to a lesser extent, the
usually employ vehicles (suppository bases) that
vaginal suppositories sometimes called pessaries,
disintegrate in the body fluids.
mainly for the administration of drugs via the
urethra. The rectal and urethral suppositories
melt at the body temperature, whereas the
are also made as compressed tablets that

PHARMACEUTICAL WATER

Two grades of water are used in the liquid and cream manufactur ing area:

(a) Purified water: This water is directly used in the formulation.

(b) Processed water: This water is used for the preliminary cleaning of the machine.

MANUFACTURING AREA

 Liquid & Cream Manufacture

At Sanofi Aventis liquid and cream unit, storage and manufacturing vessels are present in the
capacity of 500L. Pressure is maintained above 25Pa. As ethanol is used as a solvent, which
produces sparks, the vessels are connected with wires which work as earthing and provide safety.
 P a g e | 45

Product passes though Meta filter when it passes from the manufacturing vessel to the storage
vessel. Hyflo Supercel filter is used for chemical filtration and is not used in production area. It
is a polymer grid, which later on turns brown.

 Syrup filling and sealing

Concentrated aqueous solution of syrup is automatically filled in the bottles which are
previously washed and then sealed automatically. After sealing the bottles are inspected visually
under light.

 Suppository
Suppositories are manufactured manually. After filling they are kept in the refrigerator for
solidification for 24 hours. Then sealing is done and the initial temperature is 140◦C and the final
temperature is 175◦C.

ORGANIC SOLVENT
A certain number of organic solvents are used in an acceptable range in dosage form, so that
they do not cause any harmful effect to the CNS. These are used as disinfectant for cleaning
walls and floors.

Manufacturing & packaging of liquid, cream and suppository are done in separate units. The
environment of this area is maintained according to GMP. Room classification is not required in
this area as microbial contamination.

AIR CIRCULATION
Air is supplied from the vent present at the ceiling and air is sucked via the vent present at
the side of the room. 1% of that air goes into the environment and the rest is filtered via HEPA
filter and enters the room again.

Retin A, is a product of Sanofi Aventis, where nitrogen gas is used to remove oxygen.
Nitrogen gas is flushed over the mixing vessel, where Retin A is being produced.

Another product of Sanofi Aventis is Pevison, where the slurry is prepared in colloid
preparation and the mixing size is 0.5-1.5 µ. They produce Brownian motion.

- Hygrometer: dry 24◦C, wet 18◦C, difference 56%

 P a g e | 46

- Temperature range: 19◦C - 25◦C

- Humidity: 55% - 65%

Humidity controller, electronic smoke detector is present.

CLEANING PROCESS
 Floor: 2.5% detol is used for 1 week. 17.5% savlon is used for successive week to
prevent the resistance of the microorganism.
 Walls: Purified water
 Glass Windows: Wiper and glass cleaners

For product change over

 Liquid manufacturing vessel: 1% Na lauryl sulfate is used.

 Cream and suppository manufacturing vessel: 2.5% Na lauryl sulfate is used.

Types of product:

Some mentionable products of this section are-

 Ascabial (Emulsion)

 Phanergan (Elixir)

 Flagyl (Suspension)

 Bitrim (Suspension)

 Pholcodine (Syrup)

 Inflame (Syrup)

 Fisat (Syrup)

 Motilon (Drop)

 Macrocin (Gel)

Pevison(Cream)
 P a g e | 47

EQUIPMENTS USED

Equipment Made in Capacity

Master bottle washing machine India 120 bottle/min

E Chung rotary bottle washing Taiwan 160 bottle/min

machine

Automat bottle filling machine India 160 bottle/min

King cap sealing machine UK 160 bottle/min

King labeling machine UK 120 bottle/min

Imaje Ink Jet printer France 5.4 m/sec

Automat carton sealing machine India 1500 carton/hr

Strunk bottle filling machine Germany

Myth cap sealing machine Bangladesh 1500 bottle/hour

Gravfill filling machine

Jih Cheng labeling machine Taiwan 60-120 bottle/min

I.S cap sealing machine UK 1680 bottle/min

Premier colloid mill

Kalix cream filling machine France 2500 tube/hr

Owen Refrigerator

Sartorius Balance Germany 2100 gm

Sartorius Balance Germany 600 gm

Ohas balance Germany 150kg

Ohas balance Germany 15kg

Ohas balance Germany 350kg

 P a g e | 48

Manufacturing Process in Short:

Dispensing material Melting suppository Stirring for some

mesh % (48.91 kg) 70oC
time
with steam for 0.5 hr

Transfer the Check for agglomerates Diclophene Sodium

material through between two glasses (1.08 kg)
100 s mesh sieve

Submit to Q.C for Transfer the bulk to

Check by 50 L filling vessel at
supervision approval
temp 37o-40oC

Coating Filling dose 2-3 gm Submit to QC

Limit 2.07-2.53 gm

Sealing Finished product

 P a g e | 49

LIQUID STERILE AREA

At the liquid sterile area sterile products in the form of injections are manufactured. The
maximum size of the products is about 100 ml and large volume of parenterals products are not
manufactured in this area.

Two types of water plants are required in this area:

(a) Purified water plant

(b) Water for injection plant

Water for injection is used during the manufacturing process

 P a g e | 50

Purified water treatment plant

It is a multicolumn distilled water plant
which works on the principle of inter stage
heat exchange and enable to produce large
scale pyrogen free sterile distillate. The
distilling column operates at different
pressure and temperature.

Machines in use

 Scion Hipol De-ionizer plant-

Capacity: 2000 litre
Conductivity: <1.3 μ Siemens/cm
pH: 5-7
Components: Conductivity display, Recorder, Storage display, Rope filter, Carbon filter,
Recycle tank, Mixed base column, Cartridge filter, UV sterilizer, Storage tank

 Pharmalab Machine-
Capacity: 700 litre storage
Conductivity: <1.3 μ Siemens/cm
Origin: India
Components: Conductivity display, Boiler steam temperature, Distillate Steam
temperature,
Cooling water out temperature display, Filter, Steam line, Storage tank
 P a g e | 51

Basic steps of water treatment plant:

Water from Storage tank Cation column Anion column

well

Purified water Distillation

W.F.I(water for injection) Filtration

Chemical reaction in cation & anion column:

Cation column : this column contains Na,Ca,Mg etc ions. This reaction occurs in this column
and produce HCL.

R- H+ + X+CL- R-X+ +H+CL- ,X=Na,Ca

Anion column:

H+CL- + R+OH- R- X+ + H2O

MANUFACTURING AREA

 Personnel entry

In Sanofi Aventis, before entering this area, proper gowning should be done:
 Gown
 Head cover
 Mask
 Shoe Cover
 Gloves should be worn.
 P a g e | 52

 Material entry
Materials are sent from the warehouse and before entering this area, they are cleaned. After
cleaning the materials, are sent into the area, via a pass door. The pass door is an interlocking
system and then the materials are received and sent into the dispensing room.

 Dispensing
The materials are then weighed at the dispensing area and sent to the manufacturing area.

 Manufacturing area
In the manufacturing area, manufacturing vessels are present of capacity, 100L and 200L.
Water for injection is stored in a large vessel, before it enters the manufacturing vessel via tubes.
The manufacturing vessels have thermostat to control the temperature. After filling the water for
injection in the manufacturing vessel, a tube is fitted to the vessel, through which nitrogen gas
enters the vessel. Nitrogen gas is used to prevent oxidation. Then the ingredients are mixed with
the water for injection in the vessel, and mixing is done for a particular time as stated in the
BMR (Batch Manufacturing Record). After mixing, the product is passed through a cartridge
filter, with pore size of 0.2µ and the product is collected in small vessels, which are then taken
into the filling area. Bubbling Test is done to check the filter’s pore size.

 Filling and Sterilization

Ampoules are filled in aseptic area and the bulk injections are filled in the sterile area.
Containers for filling injections are washed in Rotary machine. Washing of containers are done
in another room. The containers are first washed with normal water and then purified water and
finally with distilled water. The containers are then passed through a pass door to the filling area.
Before filling, the containers are washed with distilled water, then filling is done, and the finally
sealed, which is done automatically. Before the ampoules are filled, they are washed individually
in an autoclave machine at 230◦C for 150mins, and this process is called Depyrogenation. In
Sanofi Aventis, a separate room is present for aseptic filling of ampoules.

The ampoules after autoclaving are passed through a pass door into the aseptic area. The
filters are also autoclaved and then they enter the aseptic area. The product is passed to the
aseptic area via a small pipe, so that only the sterile product enters the area. While filling the
ampoules, nitrogen gas is passed into the empty ampoules and is also passed after filling. The
ampoules upper part is heated, so that it becomes soft and then the product is automatically filled
 P a g e | 53

by an injection process by the machine and finally the upper part is then sealed. After filling the
ampoules, are sent to the inspection area, via a pass door. The ampoules are inspected both
manually and automatically.

Above every filling machine, HEPA filters are present, H14, and that particular area is Class A.

 Sterile area has a (+) pressure, which is maintained manually.

 Non-sterile area has a (-) pressure.
 Inspection

Ampoules which are of 50ml are inspected manually, and ampoules which are above 50ml,
are inspected by using a machine. Optically the ampoules are inspected by holding them in front
of a white and black screen. If there is any fiber, or glass piece, then it is rejected. All the
machines present in this area are autoclaved after using it to manufacture a batch of specific
product.

TESTING THE INTIGRITY OF LAF

A cleaning room is present, where all equipments and vessels are cleaned before autoclaving.
To test pressure of an area, DOP (diopthyle phthalate) is used. Before entering the aseptic area,
separate gowning is done.

Sterile Manufacturing:
Machines-

HOONG-A Blister packing machine (liquid sterile)

1. Dimension – 5200*1000*1900 mm2

2. Power source – 380KV
3. Total power – 7 KVA
4. Phase – 3 phase
5. Frequency – 50 hertz
6. Weight – 2000 kg
7. Operating speed – 20 rpm
8. Cover foils material – Al with width 146 mm approx
 P a g e | 54

Rota Ampoule filling and sealing machine

1. Conveter belt – 1 unit

2. Chain belt – 1 unit
3. Maximum rpm – 200
4. Utilization – 12000 per hour
5. Maximum production rate – 10800 per hour
6. Limit O2 Production – less than 1.5%

Auto clave room

Capacity – 2300oC temperature for 2 ml

Inlet pressure – 7 kg/cm2

Outlet – 2.8 Kpa

Extra addition – clean steam generator

Sanomij Autoclave

 Air leakage test is done in a sterilized chamber

 Bowie and dick test is done by heat penetration
 Hot water program – 121oC for 10-30 mm – to produce sterilizer
 Ampoule water program – 121oC for 10-30 mm – to produce sterilizer
 Steam water program – 134oC for 10-30 mm – machine filter parts
 Capacity – 4600oC for 2 ml
 P a g e | 55

Aseptic section flow diagram

Raw material Processing Solution preparation

autoclave filling filter

Inspection Store Quality control

Ware House Packing Re-Store

Cartoon Terminal
 P a g e | 56

CPR section

CPR is elaborated as Cephalosporin, Penicillin and Rifampicin .But now a days an anti-
epileptic drug, epilim is manufactured instead of rifampicin.

At Sanofi Aventis the antibiotic production area (CPR) is located in a separate building
because antibiotics act directly on the human immune system they should be totally
contamination free. At Sanofi Aventis the CPR bulding is divided into three segments numbered
separately as
 P a g e | 57

Zone 1: include the gowning area and cleaning area

Zone 2: includes the secondary packaging area

Zone 3: includes the primary packaging area, production area and delivery area.

Sterile area is one of the important areas in an antibiotic production area. The sterile area
is classified into different classes as

Class A: filling areas under LAF (Laminar Air Flow)

Class B: the room where filling occurs, i.e, class A is surrounded by class B and tertiary
gowning area

Class C: corridors

Class D: secondary gowning area

Class E: materials delivery system

The most important parameters of an antibiotic production area are temperature,

humidity and pressure.

Temperature: 22°C ± 3°C, for tablets temperature should maintained at 25°C and for
injections temperature should be maintained at 22°C.

Humidity: not more than 50%, for tablets it should be not more than 30% and for
injections it should be not more than 25%.

Pressure: should be equal to or greater than 25Pa.

The pressure differential between the corridors and the production rooms should be greater
than or equal to 2.5 Pa for both sterile and non sterile area.
 P a g e | 58

Features of this section are:

 Separate warehouse is maintained for the raw materials

 Separate storing region for finished products

 Proper uniform is maintained to enter the section

 Raw materials kept at special condition at warehouse

a) Laminar airflow (for controlling dust and other micro particles)

b) At a controlled temperature 12-25oC

 Barcode readers for identification of medicines yet to be introduced in our country, but

are in use in various countries

 SPL -32 grade for lubricating oil is used for lubrication

 Liquid paraffin is also used in some cases

 Syrup filling machine will be in continuous service in near future

 Blister machines will be installed replacing the stream machines

 There is an IPC (in process control) officer for monitoring everything.

 OEE (overall efficiency report) is submitted monthly

 P a g e | 59

T21, PENICILLIN AREA

Fig: The layout of penicillin area at Sanofi Aventis

Where, PA: production area

PP: primary packaging area

SP: secondary packaging area

1°G: primary gowning area

2°G: secondary gowning area

 P a g e | 60

SA: sterile area

DD: double door, air lock system

DA: dispensing area

STA: storage area

API: active pharmaceutical ingredients

LAF: laminar air flow

Water plants: two water plants are present at the penicillin area, one for water for
injection and one for purified water.

Equipments Penicillin Area

NAME MODEL NO. LOCATION CAPACITY

Apex Granulator Apex Construction, UK 120 Lb/min
Oscillating Granulator Manesty Machine, UK/MKIII 30-70
Oscillation/min
Fitzmil Manesty Machines, UK/D P 46 225-680 Kg/hr
Manesty B3B Tablet Manesty Machine, UK/B3B P 32 1000 Tab/min
Compression
Machine(23)
Manesty B3B Tablet Manesty Machine, UK/B3B P 32 260-520 Tab/min
Compression
Machine(16)
Manesty D3A Tablet Manesty Machine, UK/D3A P 33 260-520 Tab/min
Compression Machine
Zanasi AZ 20 Capsule Zanasi Nigris S.P.A. Italy/Az P 24 20 000 Capsules/hr
Filling Machine 20
P+am Capsule Filling PAM Machinery, India/AF P 25 90 000 Capsules/hr
Machine 90T
N.R. Cota Coating N/\.R. Industries, P 57 70-100 Kg/Load
Machine Thailand/39B
Noack Blister Packing Eth Noack, Germany/DPN P 37 40 St/min
Machine 760
HoongA Blister HoongA Corporation, P 39 30 St/min
Packing Machine Korea/Minister-V
Ganson Strip Packing Ganson Machine, India/GAV- P 41 40 St/min
 P a g e | 61

Machine D
Hemson Strip Packing Hemson Pvt. Ltd, India/GAB P 39 50 St/min
Machine 72
Hauser Auger Filler Hauser Machinery, P 17 30 Vial/min
Canada/AF 90 TB
Arenco Auger Filler Arenco Alite Ltd. P 43 40 Bottles/min
Sweden/400A
Gentinge Autoclave Gentinge b.v. Sweden/GE P 18 564 L
2617 ERC-2
Double Door Hot Air Jaw Chung Machinery, P 18 Working Volume-
Depyrogenation Oven Taiwan/HSR-70 728 L
E.Chung Rotary E.Chung Machinery, P 13 Max. 160
Washing Machine Taiwan/RUR. L02 Bottles/min
Strunk Vial Washing Manesty Machines, UK/MP P 18
Machine 60S
Strunk Vial Washing Manesty Machines, UK/MP P 18
Machine 60S
Manesty Fluid Bed Mark Industries, P 21 60 Kg
Dryer Bangladesh/BD-EO
Bottle Dryer (32 Mark Industries, P 13 32 Racks
Rack) Bangladesh/BD-EO
Bottle Dryer (28 Jih Cheng Machinery, P 13 28 Racks
Rack) Taiwan/JC-LL
Jih Cheng Labeling Manesty Machines, UK/300 P 44 60-120 Bottles/min
Machine
Manesty 300 Mixer Karl Kolb, Germany/SA 300 P 21 60 Kg/Load
Drum Hoop Mixer Foster Yates & Thom, 300 L
UK/Size No.-4
Roto Cube Mixer Dev Industries, India/Cap P 26 150 Kg/Load
1000L
Clin Cone Blender Mark Industries, Bangladesh P 35 1000 L
(1000 L)
Mark Cap Sealing Mark Industries, Bangladesh P 43 1500 Bottles/hr
Machine
Master Cap Sealing Master Machinery, India P 43 1500 Bottles/hr
Machine
Lippke Blister Tester Paul Lippke, Germany/VC P 75 998 mbar
1380
Ink Jet Printer Qty. 3 Imaje S.A. France/Jaime 1000 P 39 & P 44 5.4 M/Sec
Nos S8
 P a g e | 62

T22, CEPHALOSPORIN AREA

Fig: The layout of cephalosporin at Sanofi Aventis

The layout of cephalosporin at Sanofi Aventis is shown below:

Where, PA: production area

1°G: primary gowning area

2°G: secondary gowning area

St.A: storage area

SA: sterile area

PP: primary packaging area

SP: secondary production area

 P a g e | 63

FP: finished product storage

DA: dispensing area

DD: double door, air lock system

LAF; laminar air flow

Equipments Cephalosporin Area

NAME MODEL NO. LOCATION CAPACITY

Manesty Oscillating Manesty Machines, C 21
Granulator England/MK-111
Capsule Filler Zanasi Zanasi, Italy AZ-40 F C 23 4000/hr
AZ-40
Klockner Otto Hansel Klockner, Germany/CP-5 C 32 25 Stk/min
Gmbh
Granson Strip Packing Gansons Ltd. India/G-4V/D C 20 40 Stk/ min
Manchine
Hauser Auger Filler Hauser Machinery, C 30 35 Bottles
Canada/AF-90
IMA Powder Micro IMA S.p.a. Italy/MD-150 C 18
Dosing Machine
Hauser Dual Auger Hauser Machinery, Canada C 30 35 Bottles
Filler
Gentinge High Gentinge b.v. Sweden/GEC C 15 564 L
Pressure Sterilizer 2617 ERC-2
Double Door Hot Air Jaw Chung Machinery, C 15
Depyrogenation Oven Taiwan/HSR-70
E Chung Rotary E. Chung Machinery, C 14
Bottle Washing Taiwan/ECRW 18B
Machine
E Chung Rotary Vial E. Chung Machinery, C 15
Washing Machine Taiwan/ECRW 18B
Mark Bottle Dryer Mark Industries, Bangladesh C 14
SS Hot Air Bottle Mark Industries, C 14 3500 Bottles
Dryer Bangladesh/BD-44
Lippke Blister Tester Paul Lippke, Germany/VC C 32 998 mbar
 P a g e | 64

1380
Automatic Labeling Jih Cheng Machinery, C 31 & C 32 60-120 Bottles
Machine Taiwan/JC LL
Drum Hoop Mixer Karl Kolb, Germany/SA 300 C 21 300 L
Airtech Clean Booth,
Utopia- Aire
Laminar Air Flow
Laminar Air Flow,
Oliphant pty
I.S. Cap Sealing Metal Closers Ltd. UK/IV LM03 1680 Bottles
Machine
Mark Cap sealing Mark Industries, Bangladesh 1500 Bottles
Machine
Pneumatic Transfer Vac-U Max, India/V412UEP C 30
System
RO Purified Water
System
Water For Injection
System
Balance (310 g), Mettler, Switzerland 310 gm
Mettler
Balance (300 g), Sartorius, Germany 300 Kg
Sartorius
Balance (210 g), Sartorius, Germany 210 Kg
Sartorius
Balance (8100 g), Mettler, Switzerland 8100 gm
Mettler
Balance (310 g), 310 gm
OHUS
Balance (150 g), Sartorius, Germany 150 Kg
Sartorius
Ink Jet Printer Qty. 3 Imaje S.A. France/Jaime 1000 5.4 M/Sec
Nos S4
 P a g e | 65

 Penicillin production : process flow diagram

Dispensing Mixing active Blending In process

raw material ingredients control

Blister Visual Quality check Capsule filling

packing inspection & by LQC
polishing

Cartoon packing Warehouse shipment

Store
 P a g e | 66

 Dry powder for setup : process flow diagram

Purchasing of sugar Blending

Quality check by Granulation

I.Q.C

Filling of dry powder Sealing of bottle cap

Storage Packaging
 P a g e | 67

 Water treatment plant :

two water plants one for water for injection and the other for purified water.

Penicillin and cephalosporin both have separate ware house of their own so that cross
contamination do not occurs.

Purified
pump
water

Heating by
preheated condenser

column
condenser

Store in distilled Distilled

water water water
tank

Use for vial

washing
 P a g e | 68

 Major production steps of vial filling

Raw Production
material
dispensing

Storage Filling
for 14
days

Blistering Packing

Transportation Storage
 P a g e | 69

 Product 500 mg capsul

Dispensing Blending

Setup of Cleaning
machine

Filling Encapsulation
granules

Quality check
Finished product
by I.Q.C
 P a g e | 70

 Granulation Shop

Raw material Mixing of Granulation

dispensing different

Compression Sieving & Drying in fluid

Blending bed dryer

Coating operation Inspection Temporary

Storage

Inspection Striping Storage

 P a g e | 71

 Syrup Filling Shop

Feeding raw
Bringing material into
empty bottle
and inspection

Provide & cap Filling empty

on bottle for
filling

Cleaning the Feed the bottle

bottle using to sealing by
cloth sealing

Packing
Labelling

Quality check,
storage
 P a g e | 72

Products of penicillin and cephalosporin

Product List of Penicillin

Dosage form Name of product

Tablet Fimoxyclav 375 mg,625 mg, 1 gm

Fimoxyl 250 mg & 500 mg
Oracyn-K 250 mg & 500 mg
Capsule Fimoxyl 250 mg & 500 mg
Ficlox 500 mg

Syrup/drop Fimoxyl Paed. Drop 15 ml

Ficlox Paed. Drop 15 ml
Fimoxyl Syrup 100 ml
Oracyn-K Syrup 50 ml

Fimoxyclav 0.6 ml & 1.2 ml

Injection
Carbanem 500 mg
 P a g e | 73

Product List of Cephalosporin

Dosage form Name of product

Tablet Kuracef 200 mg & 400 mg

Sefurox 125, 250 & 500 mg

Sarelox 100 mg & 200 mg

Capsule Sefrad 250 mg & 500 m

Powder for Kuracef 30 ml & 50 ml

suspension
Sefrad 100 ml

Srelox 50 ml

Sefrad 15 ml
Paediatric Drop Sarelox

Carbanem 500 mg IV & 1 gm IV

Injection Winnipime 500 mg, 1gm & 2 gm
IV
 P a g e | 74

TOLL PRODUCTS

Dosage Name of product

form

NOVARTIS Megion 250 mg, 500 mg & 1 gm IM

Megion 250 mg, 500 mg & 1 gm IV

BEXIMCO Arixon 250 mg, 500 mg, 1gm & 2 gm

IM
Arixon 500 mg, 1 gm & 2 gm IV

Intracef 250 mg & 500 mg vial

Epilim Chrono Tablet 200 mg, 300 mg , 500 mg

 P a g e | 75

Sterile area of penicillin and cephalosporin area

Penicillin and cephalosporin have separate sterile areas. The sterile area is classified in to
classes as stated before. Secondary gowning should be done before entering the sterile area and
tertiary gowning should be done before entering the aseptic area to prevent any risk of
contamination. Sterilization is an important process that occurs in the sterile area, only primary
sterilization is done here as the injectable products are packed in vials.

The temperature, humidity and pressure should be maintained in the sterile area similar to
that of the non sterile area. Few exceptions are that the pressure should be greater than or equal
to 15 Pa during the filling of syrup and greater than or equal to 45 Pa while filling injection
under the laminar air flow. Whereas, outside the laminar air flow the pressure should be greater
than or equal to 30 Pa.
 P a g e | 76

Dispensing
In sanofi-aventis, the dispensing booth is just beside the Central warehouse and it is
completely built and designed in the European standard, and is the most sensitive and every
parameter (temperature, pressure, & humidity) are maintained very carefully. There is a double
door system, and the doors are 3 meters apart from each other. If one door is opened, the other
remains close, that is both of the doors don’t open simultaneously. If one door remains open, the
other won’t open. This is done to prevent cross contamination. Positive pressure is maintained in
the space between the two doors. When the door leading to the warehouse closes, a flow of air
gives a pressure to that door and that pressure is released when the door opens.

 Range of fast acting roller doors

 Internal and external use
 Cleanroom application
 Smooth rapid action
 Energy saving
 Counter-balance system
 Vision panels
 Choice of standard RAL Colors
 Interlocking options

There are total four rooms in the Sanofi-Aventis dispensing unit.

 Storage of the Loose materials for dispensing to the production

 Two rooms for the loose materials to weigh
 Two office rooms

There is a main office room within the dispensing unit, where there are many hygrometers,
hung on the wall. All of them are there to inspect and control the pressure of all the rooms,
present, at once. Each of the hygrometer is connected with another hygrometer in another
room. Every room contains a very tiny nozzle, which is situated inside the ceiling, and that is
required to detect the pressure of each of the room, which is displayed in the hygrometer.

The real work of the Dispensing unit is to weigh certain amount of raw materials, API, to the
production, in polythene bags. A container contains a maximum proportion of API and
production doesn’t always require the whole amount in the container. When they want a little
amount, the container is sent to the dispensing unit, and there the API is weighed carefully, under
the super vision of the Sanofi-Aventis qualified Pharmacist, and that required amount, which is
called the loose materials, is then dispensed for production. The room, which contains two
weighing machines, is the most sensitive room in this unit since materials are exposed to the
 P a g e | 77

environment here. Therefore, the weighing machines are situated under laminar airflow, so that
contamination doesn’t occur. The small weighing machine is used to dispense very minute
amount of API, and there is a large weighing machine which is required for weighing large
amount of API.

The Balance in the Dispensing unit is validated every day, in the morning by the Bubble Point.

Material handling requires four precautions during Dispensing:

 OEB (Operational Exposure Band) 1 & 2- Materials are less sensitive and less
problematic and doesn’t require excessive gowning but mask should be worn.
 OEB (Operational Exposure Band) 3 & 4- Materials are highly sensitive and proper
gowning is required, mask with low porosity, which is the fliter mask should be used.

Cool Chain
Products of Sanofi-Aventis like, Lantus,Taxotere, Clexene and the products of Sanofi
Pasteur like the vaccines, Verorab, Numo 25, or any other raw materials etc needed to be stored
in temperate 2-8◦C inside the Cool Chain. Basically cool chain is the series of routes where these
sensitive products are stored in the temperature 2-8◦C. These products are imported directly from
France and Germany by air. In the plane this cool chain temperature is maintained, and from the
airport it is taken to the warehouse cool chain via a truck, covered van, which is also temperature
controlled by a generator.

When the products start their journey, a data logger is also carried with them. A data logger
is a small device which shows and records the temperature. The data from the data logger is
collected and the details are downloaded and a graph is shown. The graph will either show the
temperature deviation, or can show stable temperature which occurred all throughout the
product’s journey. The result of the graph is then sent to QC, for inspection. The result is also
sent to the head quarter of Sanofi-Aventis in France. The fate of the product is controlled by a
third party or a vendor. Then it reaches the warehouse, and after all the parameter inspection of
the product, it is then stored inside the cool chain of the plant. The temperature of cool chain is
maintained twice a day:

 Morning: 10-11 a.m.

 Afternoon: 2-3 p.m.

To maintain the temperature outside the cool chain, that is when distributed into different
depots and also in the patient’s hand, coolant box is used.
 P a g e | 78

Chemists who have refrigerator, only to those the vaccines are supplied. If the ice in the cool
chain is over during transportation, then:

 Ice can be brought and kept in Polythene bags

 Good relation with customers, and can store the product in their store
 In remote areas, where ice is not present, the product is buried inside the soil.

When a product’s fate cannot be maintained in a proper temperature, it is then sent to the
production for stability testing. Risk Assessment guidelines are followed in Sanofi-Aventis,
which comprises of all the possible situations, that is risk factors, which can deteriorate a
product.
 P a g e | 79

INDUSTRIAL QUALITY & COMPLIANCE

sanofi aventis believes “No Small Product, No Small Country”. The quality of all the products
of sanofi aventis is same all over the world irrespective of the country and plant from which they
are produced. This notion is ensured as the same guideline ‘Global Quality Directives’ (GQD) is
followed in all the plants of Sanofi Aventis all over the world. This GQD is composed by
selecting the strictest procedures from the eight guidelines cited below:
 P a g e | 80

United States Food & Drug Administration (USFDA)

Medicine & Health Regulatory Authority (MHRA)
European Union GMP (EUGMP)
Association of French Pharmaceutical Regulatory Agency (AFSSAP)
Therapeutic Goods Administration (TGA)
Safety ensuring for Food & Drug Agency (SFDA)
Medicine Control Authority (MCA)
National Agency for Sanitary Surveillance (ANVISA)

The Industrial Quality and Compliance (IQC) entail the following departments:
 Quality Assurance
 Quality Control
 Microbiology
 Analytical Support & Analytical Development
 Regulatory Site Management
 Validation & Training

QUALITY ASSURANCE

This is the department for which Sanofi Aventis can claim that they produce the highest
quality product. The QA personnel with are the inspectors of the plant with supreme authority to
scrutinize all the activities regarding the product quality. The QA team consists of ten personnel
altogether.

Before start-up of a production the QA checks on:

 Environmental and microbiological control and sanitation of the production unit
 Batch Manufacturing Record
 Raw Materials
 Manufacturing Equipments

At start-up of a production the QA personnel establish regular check points and controls to
monitor the quality of the product as it is produced upon the completion of the manufacture. It
begins with raw material and component testing and also includes in-process, packaging,
labeling and finished product testing as well as batch auditing and stability monitoring.
 P a g e | 81

Analytical reports of the starting material, manufacturing, packaging, analytical, microbiology

are sent to the QA after a batch has been completed which they compare with the GQD to see
whether the reports are compliant or not. The quality personnel have to be strict during the time
of approving and rejecting a batch. If any of the report is non-compliant with the guideline QA
personnel have all the power to reject the batch because if after the release of the batch, there
comes any complain regarding the quality of the product, the QA personnel has to take the full
responsibility for that.

QUALITY CONTROL

This is the department which masters their analytical ability to qualify the raw material as
it is transformed into its finished product taking into account of some pertinent factors. The
quality control analyze on closures, in-process materials, packaging material, labeling, and drug
products, and the authority to review production records to assure that no errors have occurred
or, if errors have occurred, that they have been fully investigated. So it is evident that there is a
close link between QC and warehouse, production and packaging unit. The responsibilities that
cover all the activities of this department are as follows:

Ware
house

Quality
Control

Packaging Production

In the warehouse the raw materials that come from the various approved sources are
initially kept in the quarantine zone with the quarantine tag on the container. The raw materials
are then tested by the quality control personnel whether they conform to the specifications or not.
If the results comply then the containers are tagged with approved label over the quarantine tag
and stored in the approved zone. The raw materials are then ready for production.
 P a g e | 82

In production, the raw materials or the incoming stocks are checked for quality. The
quality control tests are especially chemical and physical. Tests are carried to check appearance,
solubility, loss on drying, residue on ignition, assay, identity, UV absorption and many others
according to the specification on the monograph of the product. Several in-process quality
control tests are carried out according to the type of preparation. In Sanofi Aventis Bangladesh
plant, there are different types of preparation that are being produced, which includes solid,
liquid, semisolid and parenterals. In accordance to the types of preparation their respective in-
process quality control tests are carried according to the specification.

After that comes the turn of the finished product. The QC analysts check on the finished
products. Finished product controls are distinctively analytical in nature and embodied in the
specifications known as the drug standards:

 Standard for Identity: Distinctive qualitative chemical methods used to confirm the
actual presence of the compound.

 Standards of Quality: Physical methods used to measure accurately the characteristic

properties of the drug.

 Standards of Purity: Designed to estimate the levels of all known significant impurities
and contaminants in the drug under evaluation.

 Standards of Potency: Assays that determine the quantity of active ingredient in the
drug

The quality control team also checks on the primary packaging material as it remains in
direct contact with the product. So the packaging materials definitely have to comply with the
specific guidelines in the GQD in accordance to the type of preparation they are in comprising.
 P a g e | 83

Analytical instruments
Analytical instruments present in the QC laboratory with their brand names:

Analytical Instrument Brand Name

Liquid Particle Copunter Hiac Royco
Thermostabilizer Thermostabil G
Vacuum Pump Gallenkamp
UV/Vis Spectrophotometer Shimadzu
IR Spectrophotometer Jasco
Non Organic Solvent Titration Metrolum
Moisture Balance Sartorious
Vacuum Pump Specac
HPLC Shimadzu
HPLC Alliance
Centrifuger Gallenkamp
Electromanetic Sieve Shaker Electrolab
Compound Microscope Binocular Will Weltzlar
Viscometer Brookield
Karlfisher Titrator Mattler Toledo
Friability Tester Erweka
Dissolution Testor Erweka
Dissolved Oxygen Meter HACH
pH Meter Seketa
Hardness Tester Erweka
Hardness Tester Logan
Friabilator Automatic Electrolab
Automatic Refractometer Index Instruments
Distilltion/Digestion Unit Buchi
Gas Chromatography Thermo Scientific
Total Organic Carbon Analysis Shimadzu
Digital Polarimeter Bellington + Stanley LTD.
Gas Purifier Shimadzu
Ultrasonic Bath Decon
 P a g e | 84

MICROBIOLOGY

This is the department which works as an alarm of any micro-organism development on

man, machine, environment and hence on the product. Although the department is a part of IQC
but the building is separated from that of the main IQC building and comparatively smaller.
 P a g e | 85

The room classification is well maintained within this department. The sterile room is
classified as Class A under the laminar air flow which is surrounded by Class B. The rooms
which encompass the incubators, sterilizers, chemical and biological agents are placed in rooms
which are classified as Class C.

Some of the significant tests that carried in this department are as follows:

 Environmental Study: Settle plates of suitable media are exposed for a fixed period on
which colonies are counted after incubation or known volume of air is passed over the
agar surface. Personal manufacturing equipments contamination can be detected by
swab or contact plates.

 Bioburden: It is the quantitative estimation of the viable micro-organism in or on

product, device and the raw material before sterilization. This test is crucial in
sterilization validation and it determines the sterilization dose and as well as routine
tracks of the bioburden level.

 Endotoxin Test: This test is crucial in terms of parenteral products. Presence of

endotoxin or pyrogen can be detrimental for the patients. So by using LAL reagent,
lipopolysaccharide can be easily detected.

 Bioassay: This test is done as an indication of the potency of the antibiotics that are
produced in the in the plant.

 Sterility Test: Three successive sterility tests are conducted on the filling machines of
the asceptic preparation for process validation. If the results are close and conform with
the specification then the batch can be started.

DISINFECTION EFFICACY TEST OF DISINFECTANTS AND

ANTISEPTICS

The disinfectants/antiseptics are tested at the use-dilutions or use-condition prescribed on the

product label to determine their efficacy.

STERILITY TEST OF STERILISED PHARMACEUTICAL PRODUCTS

All pharmaceutical products meant for parenteral use and any device used in conjunction with
the administration is tested for sterility.
 P a g e | 86

TEST FOR EFFECTIVENESS OF ANTIMICROBIAL PRESERVATIVES

Antimicrobial preservatives are substances added to dosage forms to protect them from
microbial contamination. They are used primarily in multiple-dose containers to inhibit the
growth of micro-organisms that may be introduced inadvertently during or subsequent to the
manufacturing process or during consecutive use from the same container.

TESTS FOR MICROBIAL LIMITS FOR NON-STERILE

PHARMACEUTICAL PRODUCTS

Tests for Microbial Limits are designed for the determination of the level of bioburden and the
absence of specific pathogens in pharmaceutical raw materials and finished products, which are
not compulsorily sterile. The bioburden limit expressed as total aerobic microbial count and
absence of specific pathogens are stipulated in some of the USP/BP monographs of the non-
sterile pharmaceutical products.

MICROBIOLOGICAL IDENTIFICATIONS TESTS

The tests apply to isolated colonies from monitoring culture plates (settle plates, contact plates,
air sampler strips and swabs) from microbiological monitoring of manufacture environment.

EQUIPMENTS

Machine Brand Name Country Feature

Autoclave Priorclave UK Routine Sterilization
of article media
Natsteel Germany Decontamination
Gatinge Germany Decontamination
Dry Heat Sterilizer Gallenkamp England Depyogenation
 P a g e | 87

Analytical Support & Analytical Development

The three most important responsibilities of this department are

 Stability Study
 Analytical Method Development
 Analytical Method Transfer

Stability study is conducted on;

o Marketed Product
o New Product
o Product Under Changed Control

MARKETED PRODUCTS

It is already decided the number of batches that are going to be launched in the following
year. If the batches of a product are more than fifty than two batches are selected for stability
study and if less than fifty than one batch is selected for stability study. The stability study
schedule is followed as par the instructions of SOP.

SCHEDULE TEST FREQUENCY

Shelf Life/Months Test Frequency

18 0-9-18
24 0-12-24
36 0-12-24-36
48 0-12-36-48
60 0-12-24-36-60

Stability study is an indicating method for impurities, if the impurity level exceeds the prescribed
range within three years; it indicates the product has failed the stability study. Stability chamber
is also an alarming system, if the humidity and the temperature exceed the range prescribed than
it gives alarm. Then action will be taken as per SOP.

NEW PRODUCTS

Before launching a product, stability study is carried for three batches in stability
chamber in three different conditions as follows:
 P a g e | 88

Parameter Accelerated 2nd Condition 3rd Condition

Condition
Temperature/ °C 40±2 30±2 25±2
Humidity/% 75±5 75±5 60±5
Duration/Months 6 24 24
Test Frequency 0-6-12 0-3-6-9-12-18-24 0-3-6-9-12-18-24

If the product is stable for six months then shelf life given is two years. If the product is
not stable in the accelerated condition then the following two conditions are applied on the
product.
International Committee for Harmonization does the zone division and it has declared
Bangladesh as zone 4B as it is a hot and high humid place so the duration of the accelerated is
lengthened.

Product under Changed Control

In this case the minor aspects of the product might be changed as packaging, coating,
excipients etc. If the product is not from a critical batch then products from one batch is tested
for stability study but if the product is from a critical batch then products from three batches are
tested for stability study. Schedule Test Frequency is followed as that of the New Products.

Analytical Method Development & Validation

For pharmacopoeial products the analytical methods are already developed unlike the non
pharmacopoeial or compendial products for which the analytical method has to be developed.

Guidelines for method development and validation for new noncompendial test methods
are provided by the FDA draft document along with USP referring to ICH guidelines for
analytical guidance.

Method validation is the process of ensuring that an analytical method is acceptable for its
intended use. The required validation parameters, also termed analytical performance
characteristics, depend upon the type of analytical method.
 P a g e | 89

Pharmaceutical analytical methods are categorized into five general types:

 identification tests
 potency assays
 impurity tests: quantitative
 impurity tests: limit
 specific tests

The first four tests are universal tests, but the specific tests such as particle-size analysis and
X-ray diffraction are used to control specific properties of the active pharmaceutical ingredient
(API) or the drug product. Validation requirements depend upon the type of test method,
including:

 specificity: ability to measure desired analyte in a complex mixture

 accuracy: agreement between measured and real value
 linearity: proportionality of measured value to concentration
 precision: agreement between a series of measurements
 range: concentration interval where method is precise, accurate, and linear
 detection limit: lowest amount of analyte that can be detected
 quantitation limit: lowest amount of analyte that can be measured
 robustness: reproducibility under normal but variable laboratory conditions.

Progress in methods development has been largely a result of improvements in analytical

instrumentation. This is especially true for chromatographs and detectors. Isocratic and gradient
reverse-phase HPLC have evolved as the primary techniques for the analysis of nonvolatile APIs
and impurities.

Analytical Method Transfer

If the local plant wants to launch a corporate product then a feasibility test is done. The
corporate sends a protocol along with the sample of a batch of the product to conduct some tests
on the samples. Two local analysts executes the tests and record their results and sends it back to
the corporate through and then two corporate analysts conduct the same set of tests on the
samples. They compare the their results with that of the local results, if the results are close or
within the range then the corporate allows the local plant to produce the product.
 P a g e | 90

Validation

The customary sample size in end product testing does not provide sufficient statistical
validity for high product quality; it alone cannot verify that the various factors in the system
intended to assure the quality within or between the batches of product are functioning as they
were designed to function. So FDA and industry introduced the concept of Qualification of
generally equipments and Validation of various processes pertaining to production as a means of
achieving the desired quality the producer emphasize on incessantly. So qualification is related to
equipments generally and is used to determine whether the equipments operates as it is designed
to in a reproducible manner and on the other hand validation of a process is the demonstration
that controlling the critical steps of process results in products of repeatable attributes (e.g.
content uniformity) or causes a reproducible event (e.g. sterilization). A validated process is a
systematic, documented program that provides high degree of assurance that a specific process
will consistently produce a product meeting its pre-determined specification and quality
attributes. The proof of validation is obtained through collection and evaluation of data,
preferably, beginning from the process development phase and continuing through into the
production phase. Validation necessarily includes process qualification (the qualification of
equipment, material, system, material, building, personnel), but it also includes control of the
entire processes for repeated batches or runs.

So when new equipment is introduced into the plant, it undergoes the following
qualification;

 Design Qualification: It is checked whether the equipment’s design from the vendor
meets all the specification of the user.

 Installation Qualification: It is checked whether all the parts of the machine are in the
correct position of the device.

 Operation Qualification: It is checked whether the motor of machine is properly working

 Performance qualification: It is checked if the machine is functioning in the correct way,

for example in case of a liquid filling machine, it is seen whether the bottles are labeled
correctly in the appropriate position.
 P a g e | 91

Training

In Sanofi Aventis training is given on the followings:

 Basic Good Manufacturing Practice (GMP): Each every person who work in the plant, or
any guest or trainee who visit the plant are informed about the basic GMP which explains
them the rules and regulation that they have to follow while staying for the period in the
plant.
 On the job: Whenever QA personnel feel that on the job training is required for any
department related to product, they organize such training to improve the efficiency of
their and keep them updated regarding their job.
 Induction: Training is given on core Standard Operating Procedure (SOP) to all the
departments present in the plant.

REGULATORY SITE MANAGEMENT (RMS)

RSM is the authority which keeps the multinational Sanofi Aventis in harmony with the Drug
Administration (DA) of Bangladesh. In order to place a new product in the market a formulation
should be sent to the DA for approval. All the necessary documents from the product
development (PD) department is sent to sent to DA for approval before the production of the
product is to be started. The following are the lists for which approval is required:

• Formula

• Product

• Brand Name

• Price

• Pack Size

• Packaging Material

LICENSING OF A NEW PRODUCT

License number for every product is different. DA has categorized products into two groups
in terms of license number:

• Biological-39

• Non- biological-176
 P a g e | 92

PACKAGING & PRINTING AREA

There are two areas, where, packaging takes place:

 T4 Building: Blister Packaging

 T10 Building: Strip and Blister Packaging

Packaging materials are of two types:

 Primary Packaging materials

 Secondary Packaging materials

Primary Packaging materials uses:

• PVC
• Aluminum Foil
• Clear and Amber glass
• Plastic spoon and syringe
 P a g e | 93

Secondary Packaging materials use:

• Printed Cartoon
• Outer
• Liner
• Labels
• Leaflet
• Printed Tape

Packaging Forms
• Depending on factors like, color, light sensitivity etc. of the product, the packing material
is determined.

1. Blister pack: Tablet, Capsule, Ampoule & Vial

2. Strip pack: Tablet & Capsule

3. Amber glass bottle & Vial: Liquid & Injection

4. Clear glass Ampoule & Vial: Injectables

5. Aluminum collapsible tubes: Cream & Ointment

Equipments:
Blister machine: 6

1 Horn Noack Blister Packer (Germany) - 3

2 E. TH Noack Blister Packing Machine (Germany) - 1
3 Kllockner Hansel Blister (Germany) - 1
4 Hoonga Blister Packer -1
 P a g e | 94

Packaging Procedure
1
3 4
2

Blister forming in the Printer prints Sealing blister,

PVC film, using heat & Tablet filling
Aluminum Aluminum printed
pressure
Print Batch &
Exp. Date
5
12

Perforation
6
12 The cartoons are
sent to warehouse after
QA approval Cutting into
individual blister
Filling the 7 pack
11
printed cartoons 10
9
into outers

Visual & Leak

Filling no. of strips
Opening printed cartoons Test for (15-
into cartoons 30mins)

Fig: Packaging Procedure

PRINTING
Printing is done in another building, where only the:

• Batch no.
• Expiry Date
• Manufacturing Date
• MRP of each product is printed on the label, outer label, aluminum foil (strip), paper
cartoons and blister strips.
 P a g e | 95

ENGINEERING

Engineering is the discipline, art, profession of acquiring and applying scientific,

mathematical, economical, social and practical knowledge to design and build structure,
machines, devices, systems, materials and processes that safely realize a solution to the needs of
society.

The creative application of scientific principles to design or develop structures, machines,

apparatus, or manufacturing processes, or works utilizing them singly or in combination; or to
construct or operate the same with full cognizance of their design; or to forecast their behavior
under specific operating conditions; all as respects an intended function, economics of operation
and safety to life and property.

Engineering Departments
(a) Engineering maintenance

(b) Engineering project

Engineering project
Project engineers are responsible for any new renovation or new project or to change the
facility of an area. For an example the room temperature is 25˚c and relative humidity is 65%.
Here engineering project works to change the environment, such as changing temperature,
pressure etc.

The role of the project engineer can often be described as that of a liaison between the
project manager and the technical disciplines involved in a project. The project engineer is also
often the primary technical point of contact for the customer.

A Project Engineer's responsibilities include schedule preparation and resource

forecasting for engineering and other technical activities relating to the project. They may also be
in charge of performance management of vendors. They assure the accuracy of financial
forecasts, which tie-in to project schedules. They ensure projects are completed according to
 P a g e | 96

project plans. Project Engineers manage project team resources and training and develop
extensive project management experience and expertise. When project teams are structured so
that multiple specialty disciplines report to the Project Engineer, then two important
responsibilities of the Project Engineer are inter-discipline coordination and overall quality
control of the work.

Engineering maintenance
After finishing engineering project, engineering maintenance works to maintain the
facilities. Maintenance Engineering is the discipline and profession of applying engineering
concepts to the optimization of equipment, procedures, and departmental budgets to achieve
better maintainability, reliability, and availability of equipment.

Maintenance, and hence maintenance engineering, is increasing important due to rising

amounts of equipment, systems, machineries and infrastructures. Since the Industrial Revolution
devices, equipment, machinery and structures have grown increasingly complex, requiring a host
of personnel, vocations and related systems needed to maintain them.

Engineering maintenance has two parts:

1. Break down maintenance

2. Preventive maintenance

Break down maintenance or corrective maintenance

It finds out the cause of fall down the machine and solve the problem. Corrective
maintenance is probably the most commonly used approach, but it is easy to see its limitations.
When equipment fails, it often leads to downtime in production. In most cases this is costly
business. Also, if the equipment needs to be replaced, the cost of replacing it alone can be
substantial. It is also important to consider health, safety and environment (HSE) issues related to
malfunctioning equipment.

Corrective maintenance can be defined as the maintenance which is required when an

item has failed or worn out, to bring it back to working order. Corrective maintenance is carried
out on all items where the consequences of failure or wearing out are not significant and the cost
of this maintenance is not greater than preventive maintenance.
 P a g e | 97

Preventive maintenance
It is an active process where routinely check up the machines until it inactives. Preventive
maintenance is maintenance performed in an attempt to avoid failures, unnecessary production
loss and HSE violation. As equipment cannot be maintained at all times, some way is needed to
decide when it is proper to perform maintenance. Normally, this is done by deciding some
inspection/maintenance intervals, and sticking to this interval more or less affected by what we
find during these activities. The result of this is that most of the maintenance performed is
unnecessary;[citation needed] it even adds substantial wear to the equipment. Also, we have no
guarantee that the equipment will continue to work even if we are maintaining it according to the
maintenance plan. The effectiveness of a preventive maintenance schedule depends on the RCM
analysis which it was based on, and the ground rules used for cost-affectivity.

The effectiveness of a preventive maintenance schedule depends on the RCM analysis

which it was based on, and the ground rules used for cost-affectivity. Here there are four types of
instruments to check.

These instruments are:

 Class 1 instruments

The quality of the instrument which if fails then the quality of the product will also fail. This
instrument is checked up routinely after three to six months.

 Class 2 instruments

It is the standard or reference instrument. It is checked up routinely after one year.

 Class 3 instruments

The quality of the instrument which if fails then the quality of the product will not fail but the
instrument is kept stop. It is routinely checked up after one month.

 Class 4 instruments

This is new instrument. After first time calibration this instrument is not calibrated until it cause
any problem.
 P a g e | 98

CLASSIFICATION OF AREA
1. Boiler area/ Steam:

In boiler room there is a boiler machine named Fire Tube Boiler. Its capacity is (3+2) Tons.

It consists of two chambers.

(a) Water chamber

(b) Fire chamber

In the fire chamber methane gas is used to produce fire. Then with the help of heat water
pass through it and steam is produced.

 Boiler:
A boiler is a closed vessel in which water or other fluid is heated. The heated or
vaporized fluid exits the boiler for use in various processes or heating applications.

 Fire tube boiler:

A fire-tube boiler is a type of boiler in which hot gases from a fire pass through one
or more tubes running through a sealed container of water. The heat of the gases is
transferred through the walls of the tubes by thermal conduction, heating the water
and ultimately creating steam .
The fire-tube boiler developed as the third of the four major historical types of
boilers: low-pressure tank boilers, flued boilers with one or two large flues, fire -tube
boilers with many small tubes, and high-pressure water-tube boilers. Their
advantage over flued boilers with a single large flue is that the many small tubes
offer far greater heating surface area for the same overall boiler volume. The general
construction is as a tank of water penetrated by tubes that carry the hot flue gase s
from the fire. The tank is usually cylindrical for the most part—being the strongest
 P a g e | 99

practical shape for a pressurized container—and this cylindrical tank may be either
horizontal or vertical.

 Detail information of Boiler:

Boiler 1 Boiler 2
Type Fire tube boiler Fire tube boiler
Manufacturer Power master England DENNIS BALDWIN &
SONS LTD
PARKWOOD BOILER
WORK
England

fuel Natural gas Natural gas

capacity 6900 lb steam/hr 1.5 ton steam/hr (4000
lb/hr)
Working pressure 10 bar 110 psi
Super heater Absent Absent
Preheater Absent Absent
Operating hour 8.00 AM-17.00 PM 8.00 AM-17.00 PM

Use of steam:
The main use of steam is in heating purpose
2. Compressed air area:

In compressed air room there is a machine used to compressed air called Sullair. Some
vials, doors, autoclave are opened under pressure and this pressure is supplied by this
area.

Here there is a machine used name Sull Air Compressor.

Its capacity is 13.4 CUM/Min.

 P a g e | 100

3. Power generation:

It is used for power supply. Here three types of power source are available. These are,

1. Power Development Board.

2. Gas generation.

3. Diesel generation.

Its total capacity is 3.75MW.

4. Water:

This factory has self water source. Two deep tubewell is available in this factory.

Here there is a machine used for water pump.

Water plant system:

It supplies purified water in different production area.

Input water→→ process→→ output water.

System may be designed on the basis of input but

the output must be same for all water plant system.

It requires for PWDS,

 Water conductivity =1.3µs.

 Temperature =25˚c.
 TOC =500ppb/L.
 Heavy nitrate =.2mg/L.
 Bacterial burden =<100CFU
 Endotoxin = Not defined.
Its total capacity is(2000+375+425+425+425)L/Hr

 Water treatment plant:

 P a g e | 101

I. Drinking water/prosess water

II. Purified water (PW) /demineralized water

III. Water for injection (WFI)

 Main differential characteristics :

Those types of water are difference mainly in mentioned characterisics-

a. Hardness

b. Bacterial count

c. PH

d. Conductivity

In case of WFI:

All these are same but here the endotoxin limit must below .25EU/ml.

Its capacity is (300+300+300)L/Hr

Block diagram of stilmas PWDS,

Input water→ centrifugal separation→ self cleaning→ service tank→ softening resin→
multi bed filter→ softening water tank→ cartridges' filter→ 1st RO→ 2nd RO→ electron
deionizer→ purified water tank → different production area.

 Water treatment plant at sanofi aventis limited:

We have observed the water treatment plant at T4 building. The main functions are
attached with the report.

Location: Sanofi aventis limited

STILMAS WATER TREATMENT PLANT (ITALY)

We have studied this water treatment plant and various equipment. Its capacity=2600
litre/hr
 P a g e | 102

 Basic steps of water treatment plant:

Water from well Storage tank Cation column

Anion column

Purified water Distillation

W.F.I Filtration

(water for injection)

 Chemical reaction in cation & anion column:

Cation column : this column contains Na,Ca,Mg etc ions. This reaction occurs in this
column and produce HCL.

R- H+ + X+CL- R-X+ +H+CL- ,X=Na,Ca

Anion column:

H+CL- + R+OH- R- X+ + H2O

 P a g e | 103

ETP system:
Effluent Treatment Plant is used to purify waste water of a factory.

This plant consists of:

(a) Balance Tank

(b) Biological Tank

(c) Settling Tank

Parameters that are controlled by plant are:

(a)COD (Chemical Oxygen Demand)

(b) BOD (Biochemical Oxygen Demand)

(c) TDS (Total Dissolved Solid)

(d) PH

Process of ETP system:

Waste water→ Balancing tank (where sedimentation of water occurs and

cause coagulation, flocculation balancing)→ Biological tank(Here there
is a rotating disk, where rotation of water occurs)→ Settling tank(Here
water is settled and if any odors contain then it is removed by the
activated charcoal)→ Environment.
 P a g e | 104

 HVAC:
HVAC (Heating, Ventilation, and Air Conditioning) refers to technology of indoor or
automotive environmental comfort. HVAC system design is a major sub discipline 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 (such as the designation of HACR -rated circuit
breakers).

HVAC is important in the design of medium to large industrial and office buildings such as
skyscrapers and in marine environments such as aquariums, where safe and healthy
building conditions are regulated with temperature and humidity, as well as "fresh air"
from outdoors.

In modern buildings the design, installation, and control systems of these functions are
integrated into one or more HVAC systems. For very small buildings, contractors normally
"size" and select HVAC systems and equipment. For larger buildings, building services
designers and engineers, such as mechanical, architectural or building services engin eers
analyze, design, and specify the HVAC systems, and specialty mechanical contractors build
and commission them. Building permits and code-compliance inspections of the
installations are normally required for all sizes of buildings.

The starting point in carrying out a heat estimate both for cooling and heating will depend
on the ambient and inside conditions specified. However before taking up the heat load
calculation, it is necessary to work out the fresh air requirement for each area in details, as
pressurization is an important requirement.
 P a g e | 105

 Heating:
There are many 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 lo cation such as a
furnace room in a home or a mechanical room in a large building. The use of water as the
heat transfer medium is known as hydronics. 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.

In boiler fed or radiant heating systems, all but the simplest systems have a pump to
circulate the water and ensure an equal supply of heat to all the radiators. The heated
water can also be fed through another (secondary) heat exchanger inside a storage cylinder
to provide hot running water.

Forced air systems send heated air through ductwork. During warm weather the same
ductwork can be used for air conditioning. The forced air can also be filtered or put through
air cleaners.

Heating can also be provided from electric, or resistance heating using a filament that
becomes hot when electric current is caused to pass through it. This type of heat can be
found in electric baseboard heaters, portable electric heaters, and as backup or
supplemental heating for heat pump (or reverse heating) system.

The heating elements (radiators or vents) should be located in the coldest part of the room,
typically next to the windows to minimize condensation and offset the convective air
current formed in the room due to the air next to the window becoming negatively buoyant
due to the cold glass.
 P a g e | 106

 Ventilation:
Ventilating is the process of "changing" or replacing air in any space to control temperature
or remove moisture, odors, smoke, heat, dust, airborne bacteria, carbon dioxide, and to
replenish oxygen. Ventilation includes both the exchange of air to the outside as well as
circulation of air within the building. It is one of the most important factors for maintaining
acceptable indoor air quality in buildings. Methods for ventilating a building may be
divided into mechanical/forced and natural types.Ventilation is used to remove unpleasant
smells and excessive moisture, introduce outside air, to keep interior building air
circulating, and to prevent stagnation of the interior air.

 Mechanical or Forced Ventilation:

"Mechanical" or "forced" ventilation is provided by an air handler and used to control
indoor air quality. Excess humidity, odors, and contaminants can often be controlled via
dilution or replacement with outside air. However, in humid climates much energy is
required to remove excess moisture from ventilation air.

Kitchens and bathrooms typically have mechanical exhaust to control odors and sometimes
humidity. Factors in the design of such systems include the flow rate (which is a function of
the fan speed and exhaust vent size) and noise level. If ducting for the fans traverse
unheated space (e.g., an attic), the ducting should be insulated as well to prevent
condensation on the ducting. Direct drive fans are available for many applications, and can
reduce maintenance needs.

Ceiling fans and table/floor fans circulate air within a room for the purpose of reducing the
perceived temperature because of evaporation of perspiration on the skin of the occupants.
Because hot air rises, ceiling fans may be used to keep a room warmer in the winter by
circulating the warm stratified air from the ceiling to the floor. Ceiling fans do not provide
ventilation as defined as the introduction of outside air.
 P a g e | 107

 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 radiation, convection, and by heat pump systems through a
process called the refrigeration cycle. Refrigeration conduction mediums such as water, air,
ice, and chemicals are referred to as refrigerants

An air conditioning system, or a standalone air conditioner, provides cooling, ventilation,

and humidity control for all or part of a house or building.

The refrigeration cycle consists of four essential elements to create a cooling effect. The
system refrigerant starts its cycle in a gaseous state. The compressor pumps the refrigerant
gas up to a high pressure and temperature. From there it enters a heat exchanger
(sometimes called a "condensing coil" or condenser) where it loses energy (heat) to the
outside. In the process the refrigerant condenses into a liquid. The liquid refrigerant is
returned indoors to another heat exchanger ("evaporating coil" or evaporator). A metering
device allows the liquid to flow in at a low pressure at the proper rate. As the liquid
refrigerant evaporates it aborbs energy (heat) from the inside air, returns to the
compressor, and the cycle repeats. In the process, heat is absorbed from indoors, and
transferred outdoors, resulting in cooling of the building.

Dehumidification in an air conditioning system is provided by the evaporator. Since the

evaporator operates at a temperature below dew point, moisture in the air condenses on
the evaporator coil tubes. This moisture is collected at the bottom of the evaporator in a
condensate pan and is removed by piping it to a central drain or onto the ground outside. A
dehumidifier is an air-conditioner-like device that controls the humidity of a room or
building. It is often employed in basements which have a higher relative humidity because
of their lower temperature (and propensity for damp floors and walls). In food retailing
establishments, large open chiller cabinets are highly effective at dehumidifying the
internal air. Conversely, a humidifier increases the humidity of a building.
 P a g e | 108

It is important to keep in mind that because an air conditioner moves heat between the
indoor coil and the outdoor coil, both must be kept just as clean. This means that, in
addition to replacing the air filter at the evaporator coil, it is also necessary to regularly
clean the condenser coil. Failure to keep the condenser clean will eventually r esult in harm
to the compressor, because the condenser coil is responsible for discharging both the
indoor heat (as picked up by the evaporator) plus the heat generated by the electric motor
driving the compressor.

 Air conditioning system of sanofi aventis ltd, tongi:-

 P a g e | 109

 Duct System:
Ducts are used in heating, ventilation, and air conditioning (HVAC) to deliver and remove
air. These needed airflows include, for example, supply air, return air, and exhaust air.
Ducts also deliver, most commonly as part of the supply air, ventilation air. As such, air
ducts are one method of ensuring acceptable indoor air quality as well as thermal comfort.

A duct system is often called ductwork. Planning ,sizing, optimizing, detailing, and finding
the pressure losses through a duct system is called duct design.

Air-conditioned buildings often have sealed windows, because open windows would
disrupt the attempts of the HVAC system to maintain constant indoor air conditions,
resulting in the compressor being over-worked.

 Chiller:
A chiller is a machine that removes heat from a liquid via a vapor-compression or
absorption refrigeration cycle. This liquid can then be circulated through a heat exchanger
to cool air or equipment as required.

In air conditioning systems, chilled water is typically distributed to heat exchangers, or

coils, in air handling units, or other type of terminal devices which cool the air in its
respective space(s), and then the chilled water is re-circulated back to the chiller to be
cooled again. These cooling coils transfer sensible heat and latent heat from the air to the
chilled water, thus cooling and usually dehumidifying the air stream.

Chillers are two types:

1. Air cooled
2. Water cooled

Air cooled: air cooled chillers are usually outside and consist of condenser coil cooled by
fan driven air.Water cooled: these types of chillers are usually inside a building and heat
from these chillers is carried by recirculating water tho outdoor cooling towers.
 P a g e | 110

 Humidity control:
Refrigeration air conditioning equipment usually reduces the absolute humidity of the air
processed by the system. The relatively cold (below the dewpoint) evaporator coil
condenses water vapor from the processed air (much like an ice-cold drink will condense
water on the outside of a glass), sending the water to a drain and removing water vapor
from the cooled space and lowering the relative humidity in the room. Since humans
perspire to provide natural cooling by the evaporation of perspiration from the skin, drier
air (up to a point) improves the comfort provided. The comfort air conditioner is designed
to create a 40% to 60% relative humidity in the occupied space. In food retailing
establishments, large open chiller cabinets act as highly effective air dehumidifying units.

A specific type of air conditioner that is used only for dehumidifying is called a
dehumidifier. A dehumidifier is different from a regular air conditioner in that both the
evaporator and condenser coils are placed in the same air path, and the entire unit is
placed in the environment that is intended to be conditioned (in this case dehumidified),
rather than requiring the condenser coil to be outdoors. Having the condenser coil in the
same air path as the evaporator coil produces warm, dehumidified air. The evaporator
(cold) coil is placed first in the air path, dehumidifying the air exactly as a regular air
conditioner does. The air next passes over the condenser coil re -warming the now
dehumidified air. Having the condenser coil in the main air path rather than in a se parate,
outdoor air path (as in a regular air conditioner) results in two consequences —the output
air is warm rather than cold, and the unit is able to be placed anywhere in the environment
to be conditioned, without a need to have the condenser outdoors.

Unlike a regular air conditioner, a dehumidifier will actually heat a room just as an electric
heater that draws the same amount of power as the dehumidifier. A regular air conditioner
transfers energy out of the room by means of the condenser coil, which is outside the room
(outdoors). This is a thermodynamic system where the room serves as the system and
energy is transferred out of the system.
 P a g e | 111

Dehumidifiers are commonly used in cold, damp climates to prevent mold growth indoors,
especially in basements. They are also sometimes used in hot, humid climates for comfort
because they reduce the humidity which causes discomfort (just as a regular air
conditioner, but without cooling the room). They are also used to protect sensitive
equipment from the adverse effects of excessive humidity in tropical countries.

 Health issues:
Air-conditioning system can promote the growth and spread of microorganisms, such as
Legionella pneumophila, the infectious agent responsible for Legionnaires' disease, or
thermophilic actinomycetes, however this is only prevalent in water cooling towers. As
long as the cooling tower is kept clean (usually by means of a chlorine treatment) these
health hazards can be avoided. Conversely, air conditioning, including filtration,
humidification, cooling, disinfection, etc., can be used to provide a clean, safe,
hypoallergenic atmosphere in hospital operating rooms and other environments where an
appropriate atmosphere is critical to patient safety and well-being. Air conditioning can
have a negative effect on skin, drying it out and a positive effect on sufferers of allergies
and asthma. Air conditioning can also cause dehydration.

 Energy used:

In a thermodynamically closed system, any energy input into the system that is being
maintained at a set temperature (which is a standard mode of operation for modern air
conditioners) requires that the energy removal rate from the air conditioner increase. This
increase has the effect that for each unit of energy input into the system this requires the
air conditioner to remove that energy. In order to do that the air conditioner must increase
its consumption by the inverse of its efficiency times the input of energy. As an example,
presume that inside the closed system a 100 watt light bulb is activated, and the air
conditioner has an efficiency of 200%. The air conditioner's energy consumption will
 P a g e | 112

increase by 50 W to compensate for this, thus making the 100 W light bulb use a total of
150 W of energy.

It is typical for air conditioners to operate at "efficiencies" of significantly greater than

100%.However it may be noted that the input energy is of higher thermodynamic quality
than the output which is basically thermal energy.

 Filter:
Different types of filter are used the main types are:

1. Prefilter
2. Fine filter
3. HEPA ( high efficiency particulate air )

Filter efficiency and integrity are checked by DOP test.

 Sub station and capacity:

Substation Capacity
1 1250
2 500
3 2000

 Own generation:
This company generates power by using generators.
Generator Fuel
Gas generator Natural gas ( supplier Titas gas)
Diesel generator Diesel
 P a g e | 113

 Diesel generator:
Diesel generaator Capacity (KV) Capacity of gas Capacity (KW)
generator

1 500 1 1030
2
3 800 2 1030
4 125

 Function of switches:

 H.T(high tension) switch gear: It will disconnect automatically if any danger

e.g. high voltage or something,prevent tipping make performing maintenance
action easy etc.
 L.T. ( low tension ) switch gear: building wise distribution can be easily
done by this switch.
 Transformer : It is step down transformer. It steps down 11000 kv to 400 kv
 P a g e | 114

PLANT LOGESTICS

Marketing
Research Unit
4. Purchase Department
takes information from
1. Marketing Department gathers data
SAP and decides on RM
from marketing research department to
& PM
determine demand.
.

Marketing Market Supply Planning

Department Manugestic SAP
Chain Department
(Head Office)
3. Marketing
Department
Purchase
2. Marketing
Department gathers data from
marketing
Department
gathers data from
marketing research research
department to department to
5. Purchase Department instructs
determine demand. determine
commercial department to purchase
demand.
RM in the form of Block List

8. Raw
Commercial
Materials sent Department
to warehouse
for storage 7. RM sent to
Narcotics Control
Raw Material if it is a
6. Commercial Department opens
LC and imports required Raw
Warehouse psychotropic
agent
Material

Plant Logistics is a part of the Supply Chain and constituted of three departments:

 Planning

 Commercial

 Warehouse

The respective managers of the above mentioned departments report to the Plant Logistic
manager. After receiving the net demand from the market supply chain, planning does the
production plant for the incoming month and side by side checking the existing material stock
during production plan and hand to the production for execution.
 P a g e | 115

Planning

Basic Task of Planning in sanofi-aventis Bangladesh:

 Check Net demand from MSC, through SAP(MPS) or Excel Sheet(S&OP)

 Planning for FG production & Material (local & Import: Excel Sheet and/or MRP)
 Confirm delivery of the Finished Product from warehouse to the distribution center
 Corporate reporting
 SAP(MM Module)
 GMID

Execution:

1. Determines production :
 No of batches
 When to manufacture
 Weekly production follow up(Scheduling in Production through
discussion with Planning , Purchase, Production, QC &Engg)
 Regular follow up with production, IQC, Warehouse regarding
delivery of FG to support market need
 OOS analysis with MSC & accordingly take action plan
 Month end review based on transfer status regarding product delivery
status

2. Feedback to MSC for any deviation for Product demand & supply, warehouse
capacity, any constraint for Production or material availability: (MPS meeting)
 Review of production plan
 Product delivery risk analysis & solution
 Special issues, constraint, etc. discussion
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 Material availability discussion

3. Material Planning:
 When to buy materials
 When to place requisition
 Weekly open PO & PR monitoring with purchase & commercial
 Material availability risk analysis & feedback to production
Expiry analysis of material

Follow up:

 Production for FG delivery & production schedule

 Purchase & commercial for material availability on time
 Warehouse for FG delivery & material related issues
 QC for expiry issues & urgent test result
 QA for FG delivery
 PD for new product delivery on time & any changes for existing product (formula
change, material replacement)

Material In Production Material Out

Main Factors:

 Safety Stock for both Materials & Products(for uncertain order, forecast fluctuation,
excess sale)
 Shelf life of Materials & Products
 Mode of Transport & Lead Time
 Sea
 Air
 Local
 Uncertain constrain for Materials at supplier end & Production capacity or other
issues
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Commercial
Commercial Department mainly takes care of the import of materials from different
approved vendor in different countries and it does imports in both Industrial and
Commercial basis. sanofi-aventis sources vendor from two countries, India and China. This
department is responsible to find out suitable sources of vendor for sanofi-aventis.

Commercial (Imports & Customs) Functions and Key Responsibilities:

 Organize prior approval of RM, PM, FG from Drugs/Narcotics Authority for Import
and Production/ Sales and Drugs Certification for those after Shipment for Customs
Clearance based on consignment.
 Organize Imports of all RM and PM etc for Production, finished drugs, Diagnostic
Reagents, Non-COGS Items, Plant and Machineries etc in time subject to
Demand/requisition raised following the Internal approval and the local Import
Policy order and other Regulatory rules and regulations.
 Organize insurance Cover Notes for all imports(per LC) and Marine Insurance
Policies for all shipments/consignments (per shipments).
 Monitor Pre-shipment Inspection jobs for the consinments to be shipped/ shipped
against LCs and collect Clean Report of Findings (CRF) for the respective shipments
for Bank & Customs Clearance.
 Organize Bank endorsements and Customs clearing forwarding jobs for all ports/
customer stations
 Organize and verify all imports duty/bills payable through Finance (C/O) for
customs clearance of all materials and supplies in time upon arrival
 Organize renewal of all Business Licenses for three legal entities(around 32Nos.)
related to Commercial jobs like Industrial Imports, Commercial Imports, Exports,
Indenting RC and Narcotics Control etc.
 Coordinate with Business Units, Regulatory and Medical Affairs, Finance (C/O),
Industrial Affairs(I/A) and various local Govt. Regulatory Authorities and Customers
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in connection with Drugs Approval, Funds , Imports and Customs clearance etc in
order to ensure smooth supply of imported materials and supplies.
 Ensure best team effort/performance to get the commercial jobs done in time from
various Regulatory Authorities required inside and outside/ suppliers site.

L/C Opening Chart

3
L/C Bank Notifying Bank
(Importers Bank) (Paying Agent)
6

2 7 6 5 4

1
L/C Opener L/C Beneficiary
(Importer) (Exporter)

1. The exporter and importer sign a bill of sale contract.

2. The importer applies to his bank, the issuing bank, to open a letter of credit.
3. The issuing bank sends the advice of the credit to the advising bank.
4. The exporter is advised of the credit.
5. Following shipment of the goods, the exporter presents the documents to the
advising bank (the paying agent).
6. After checking the documents and confirming that they agree with the letter of
credit terms, payment is made to the exporter. At the same time, the advising bank
sends the documents to the issuing bank and requests reimbursement for the letter
of credit amount plus the advising bank’s fees and expenses.
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7. The issuing bank sends the documents to the importer and debits his account fo r the
letter of credit amount plus the fees and expenses of the banks involved

Local Regulatory Authorities Required

Almost all the Regulatory Authorities & officers related to Commercial jobs are located at
Dhaka Regulatory Authorities and Offices for attaining regular jobs related to Imports and
Customs:
 Directorate of Drugs Administration (two different Govt. offices and required two
way Correspondences)
 Directorate of Narcotic Control (four different Narcotics Control offices)
 Insurance Companies (three Ins. Companies for these legal entities – two times
corres. for every L/C and ship)
 Finance Divisions (Head Office) for jobs like LC authorization, Bank Endorsement,
Import duty etc.
 Banks(three designated Banks, every day 2-3 times visit is required for obtaining
Bank’s jobs done)
 PSI Companies (four Pre-shipment Inspection Companies- contacted for inspection
and for CRF)
 Suppliers/Indenters (for L/C advise, shipment follow up, shipping details and
shipping documents)
 Various shipping lines/ Air Lines(for shipments/goods tracking at different ports/
and or in transit)
 C&F Agents (seven Agents for four different Customs stations Dhaka, ICD, Benapole
and Chittagong)
 Commissioner of Customs(four different Customs stations Dhaka, ICD, Benapole and
Chittagong)
 Local Transports/ carriers(Chittagong Sea port and Benapole Land port
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Regulatory Authorities and Offices for attaining Jobs related to Imports and Customs
etc:

 NBR (National Board of revenue)

 CCI & E Office(Chief Controller of Imports and Exports)
 BOI(Board of Investment)
 Bangladesh Bank(Central Bank) and Standard Chartered Bank, American
Express Bank
 Various Chambers and Forums related to Pharmaceutical Business/sectors
etc.
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Warehouse

Depending on the previous market sales of a specific product, which are collected by the
Marketing Research Unit, its API (Active Pharmaceuticals Ingredient), excipients etc are
brought to the warehouse just one month before its production. The time for a definite raw
material to go for the production is planned by the Planning Department and then is sent to
the Procurement Department for purchasing and then to the Production Department and
lastly the final product is brought back to the warehouse for storage, which ultimately is
then sent to different Sanofi – Aventis depots for distribution.

The materials received, can be inside big containers, like hardboard or hard plastic drums
or bags, are cleaned and then it enters the warehouse. Here, firstly the physical
parameters of the containers are checked, which includes:

 Label Check

 Batch No.

 Manufacturing Date

 Expiry Date

 Supplier’s Name

 Physical attributes of the container (any damage or seal is intact or not etc )

Quarantine Zone :

As soon as the physical parameters are inspected by the wareho use qualified personnel,
the containers are tagged Quarantine, and are kept in the Quarantine zone in the
warehouse. For the QC to approve the materials, samples from the containers are taken by
them. The containers are opened in the Sampling Booth, under laminar airflow and no
containers are opened in the warehouse. Until unless QC (Quality Control) doesn’t approve
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it, the container will bear this Quarantine tag but as soon as QC inspects and approves the
container.

MSDS (Material Safety Data Sheet):

The warehouse maintains a MSDS (Material Safety Data Sheet), which mentions all the
information required for the safety of man and material.

Sanofi Aventis has two Warehouses in their plant :

In T4 building : Non – Antibiotic products

In CPR building : Antibiotic products

The T4 warehouse is in the T4 building & it is the Central warehouse in Sanofi Aventis.
Most of all the raw materials, excipients, promotional samples, products & rejected
products. It contains 5 individual warehouse & they are as follows ---

Warehouse 1 Finished Products

Finished products,
promotional samples &
Warehouse 2
rejected products,

Packaging materials
Warehouse 3 (Antibiotics and non
antibiotics)

Raw materials of
Warehouse 4
Sanofi Aventis

Warehouse 5 Raw materials of FBL

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Sanofi – Aventis does some toll manufacturing for a few Pharmaceutical companies in
Bangladesh.

Novartis: Finished Product, Volterine suppository

Beximco: Finished, WFI
Nuvista: Visceralgin and some semi – finished product

According to the type of materials, they were seen to be stored in two categories

Location Wise Temperature Sensitivity

According to the sensitivity of the materials, they were seen to be divided into three
categories

Highly sensitive
material, Cool Chain Cool Room, below
(2-8oC) where Ambient Temperature
25oC
vaccines the are
stored.
Another Warehouse is in the CPR (Cephalosporin Penicillin Riphampicin) building.
Riphampicin is stored in the Central Warehouse.

Warehouse 6 : Pencillin

Warehouse 7: Cephalosporin

Temperature monitoring:

 Temperature is monitored twice a day (1000 – 1100 and 1400 – 1500 )

 Ware house officer check the temperature as weekly basis

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List of materials store at different temperature :

At ambient temperature :

 Inflammable materials:
Apricot flavor
Etheol
Methanol refined
Isopropyl alcohol
Industrial methyl sport
 Other normal products

At foster cold store :

 Tetavax

 Act HIV

 Euvax

 And other vaccine

At cool store :

 Amoxacycillin Trihydrate

 Cefuroxime axetil for dry syrup and tablet

 Penecillin V potassium

 Tretincoin ph

 Actonel tablet
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Distribution of temperature controlled product :

 For distribution of temperature controlled product some contents are packed into
the cartoon with the product to ensure required temperature and humidity

Name of the coolant Composition of No of box required Active time hours

box coolant
Plastic cold box Log gel 25 15
Emball 150(blue)
Chilltherm TM21 Log gel 25 12
box Emball 150(blue)
Verorab box Log gel / Emball 45 8
150(blue)
Cool pack MC - 3
Cosmos boxes 24 Log gel /lemball 8 4
litre 150(blue)
Cosmos box small Log gel / emball 150 5 15
Cool pack MC-3 3
Chiltherm Cool box Log gel/emball 150 5 20
Cool pack MC-3 1
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PURCHASING

The divisions of the Purchasing Department are:

 Industrial Affairs

 Pharma of Purchasing

 Sanofi Pasteur

Industrial Affairs Pharma of Purchasing Sanofi Pasteur

Purchasing is a support function and joined together with Industrial purchasing and formed
one department, which created an advantage of synchronizing for synergizing behavior. The core
activity of this department is sourcing and negotiating with approved and existing vendors to
reduce the price of raw materials. If one vendor is not available, alternate source is kept in line
for back-up if sometimes monosourcing does not work.

There are two types of Materials:

 COGS (Cost Of Goods Sold): Raw materials and Packaging materials

 Non-COGS (Non- Cost of Goods Sold): Equipments, Furniture, Promotional

Materials, etc.

For Pharmaceutical industries, the main purchasing is of COGS materials. The sourcing is
carried out by the Purchasing Department.

The main source of purchasing of raw materials is Europe and also to some extent India and
China. Sourcing is also done by the Purchasing Department, for example through web tools and
from some other co-coordinators in India and Singapore. The vendor is then audited by sanofi
aventis’ auditors for process, documentation, and their site and if they are approved, they are
enlisted in sanofi aventis’ approved list. The sourcing sample is validated by QC, after approval,
the sample goes under machine trials.

Capex: Capital Expenditure (Machineries)

Opex: Daily Operational Expenditure
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INDUSTRIAL AFFAIRS AND CONTROLLING

Financial Controlling

Major Activities
o Support IA management in strategic planning and cost management activities

o Review and preparation of standard cost budget

o Financial performance review with IA management to achieve target financial and

operating results

o Ensure internal control in IA operation area

o Corporate financial management reporting

o Support new product development

Standard Cost Budget

 Step 1: Production volume budget review with Plant Logistics

 Step 2: Batch size, Bill Of Material, Routing review with Production

 Step 3: Purchase assumptions review with Purchasing

 Step 4: Factory expenses review with departments:

- Salary budget review with HR

- Utility and Maintenance budget review with Engineering

- Quality expenses review with IQC

- Administrative expenses review with Site Management

 Step 5: Preparation of Standard Cost Card

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Financial Performance Review

 Industrial Affairs Profit and Loss with IAMC members

 Purchase Price Variance with Purchasing

 Factory Expenses with IAMC members

 Yield Variance with Production

 Labor Efficiency Variance with Production

 Capital Expenditure with IAMC members

 Short Expired Inventory with Plant Logistics

 Headcount with IAMC members

Internal Control
 Review Financial Policy and Procedures and Ensure Compliance

o Purchase Policy

o Fixed Asset Policy

o Disposal of Fixed Assets

o Petty Cash Policy

 Physical checking of

o Inventory

o Fixed Asset

 Authorization and Financial Approval of

o Purchase Requisition

o Expenses Authorization for project/ event

o Supplier Invoices

o Petty Cash Vouchers

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Reporting

 Monthly Reporting:

o Headcount (EFgR) Day 3

o Inventory (IMP) Day 5

o Profit and Loss (TdB, CEgR) Day 6

o Monthly Site Analysis Day 8

o Forecast toll sales Day 10

 Quarterly Reporting:

o Capital Expenses Day 9

 Forecasts (T2, T3, T4):

o P&L Day 12

o Headcount Day12

o Toll Sales Day 12

o Capital Expenses Day 13

Support New Product Development

 Cost analysis for New Product

o Coordinate with development team to finalize the BOM and Routing

o Coordinate with Purchasing to fix the source

o Prepare Standard Cost Card for New Product

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PRODUCTS LIST

PRODUCT NAME DOSAGE FORM STRENGTH

AMARYL Tablet 1 mg, 2 mg & 3 mg
AVOMINE Tablet
AVIL Tablet 22.7 mg
Injection 2 ml
Syrup 100 ml/ bottle
ASINAR Tablet
BETANOL Tablet 25 mg, 50 mg & 100 mg
BUTAPAN Tablet 10 mg & 20 mg
Injection
CARBANEM Injection 500 mg & 1 g
EPILIM CHRONO Tablet 200 mg, 300 mg & 500 mg
Syrup 100 ml/ bottle
FIMOXYCLAV Tablet 375 mg, 625 mg & 1g
Suspension 100 ml & 500 ml/ bottle
Injection 600 mg & 1200 mg
FLAGYL Tablet 200 mg & 400 mg
Suspension 60 ml/bottle
Injection 100 ml/ bottle
FIMOXYL Capsule 250 mg & 500 mg
Paed. Drops 15 ml/ bottle
Dry Syrup 100 ml/ bottle
Injection 250 mg & 500 mg
Tablet 250 mg & 500 mg
FICLON Injection
Capsule 100 mg
Suppository 50 mg
INFLAM Tablet 200 mg & 400 mg
Suspension 100 ml/ bottle
PHENERGAN Tablet 10 mg
Elixir 125 ml/ bottle
PROFENID Capsule 100 mg & 200 mg
Tablet 50 mg & 100 mg
Injection
Gel 30 g tube
PEVARYL Cream 10 g tube
PEVISONE Cream 10 g & 20 g tube
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ROVAMYCINE Tablet 3 MIU

RIFAZID Tablet 150 mg, 300 mg & 450 mg
STEMETIL Tablet 5 mg
Injection 1 ml
SALBUTAL Tablet 2 mg & 4 mg
Syrup 100 ml/ bottle
TELFAST Tablet 120 mg & 180 mg
SEFRAD Capsule 250 mg & 500 mg
Paed. Drop 15 ml/ bottle
Dry Syrup 100 ml/bottle
Injection 250 mg, 500 mg & 1 g
XEROSEC Capsule 10 mg, 20 mg & 40 mg

IMPORTED DOSAGE FROM STRENGTH

PRODUCT NAME

CLEXANE Injection 2000 IU, 4000 IU, 6000 IU &

8000 IU
LANTUS Solostar
TILADE Inhaler 112 inhalations

NAME OF VACCINES DOSAGE FORM STRENGTH

AVAXIM 80 & 160 Injection 0.5 ml PFS
FAVIRAB Injection 5 ml vial
MENINGOCOCCAL A+C Injection
PENTAXIM Injection
PNEUMO 23 Injection 0.5 ml PFS
TETAVAX Injection 5 ml ampoule
VERORAB Injection

NAME OF
ONCOLOGY DOSAGE FORM STRENGTH
PRODUCTS
ENDOXAN Tablet 50 mg
Injection 200 mg, 500 mg & 1 g
GRANOCYTE Injection
HOLOXAN Injection 1 g, 2g
TAXOTERE Injection 20 mg
UROMITEXAN Injection 400 mg
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CONCLUSION

Sanofi Aventis, the number one Pharmaceutical Company in Europe, ensures to produce quality
medicine, with all its strictly controlled and maintained quality control, engineering and storage
system and also protects the environment by treating waste products. Based on strict company
principals, Sanofi Aventis progresses very fast in the field of Pharmaceuticals.