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QUALITY MANAGEMENT SYSTEM For drug manufacturing in

(FTO Unit-6)

Prepared By:

PGDPM- 1ST Year Institute Of Health Management Research (IIHMR) Jaipur, Rajasthan

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TOPIC A. Preface B. Acknowledgement C. Glossary D. Abbreviations E. Introduction F. GMP Regulations G. Quality management system 1. Quality system 2. Management responsibility 3. Document control 4. Vendor management 5. Product and equipment identification and traceability 6. Manufacturing process control 7. Testing 8. Handling of deviation 9. Handling of incidents 10. Handling of out-of-specification 11. Control of nonconforming product 12. Self inspection 13. Annual product review H. Conclusion I. References 30-31 32 33-35 36-39 40-46 47-49 50-52 53 54 55 56-57 58-59 60-62 63-64 65 PAGE NO. 2 3 4-7 8-9 10-22 23-29

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Summer training is an integral part of PGDPM programme and for this purpose I had undergone summer training in DR. Reddys Lab Ltd, Baddi, which is an integrated company producing a wide range of quality, affordable medicines, trusted by healthcare professionals and patients across geographies. During summer training period I have been involved in informative project. The major project I worked on was to study the Quality management system of Dr. Reddys, Baddi. Project included study of QUALITY manual, SOPs, documents and face to face interview of employees regarding the system. In this report initially there is introduction of Indian pharmaceutical industry and brief profile of Dr. Reddys Lab Ltd focusing on corporate profile, strategy, key products, vision and aspiration. There are thirteen chapters giving insight of quality management system and the quality standards followed by Dr. Reddys, Baddi.

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I would like to show my sincere gratitude to Dr. S.D. Gupta, Director and Dr. (Brig) S.K. Puri Dean Academics for providing us with an opportunity to explore our knowledge and energies and learning the practical aspect of management studies through summer training.

Of the many people who have been enormously helpful in the preparation of this report, I am especially thankful to Professor Abhishek Dadich and Professor R.S.Goyal (mentors) for the help and support in guiding me through to its successful completion.

I would also like to warmly acknowledge Mr. Surinder Pal (HR Head) and Mr. Rahul Puri (Head of Quality assurance department) for their support throughout the process of this report, as well as Mr. Dinesh Jamwal, Mr. Sanjeev Kumar, Mr. Sunil Kumar, Mr. Aman Paul, and Mr. Ritesh Arora who went out of their way and invested time in providing me with necessary additional details about the project. , In addition, a special thanks to my family and all my friends for their consideration and motivation.

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Active Pharmaceutical Ingredient (API) Any substance or mixture of substances intended to be used in the manufacture of a pharmaceutical dosage form and that, when so used, becomes an active ingredient of that pharmaceutical dosage form. Such substances are intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment or prevention of disease or to affect the structure and function of the body

Audit Systematic and independent examination to determine whether quality activities and related results comply with quality policy and if this policy has been implemented effectively.

Batch (or lot) A defined quantity of a material produced in a process or series of processes so that it is expected to be homogeneous within specified limits. In the case of continuous production the batch (or lot) may be defined by a fixed quantity or time.

Batch Number (Or Lot Number) A distinctive combination of numbers and/or letters which uniquely identifies a batch with its labels, batch records and the corresponding certicates of analysis, etc is batch number.

Batch Records All documents associated with the manufacture of a batch of bulk product or end product. They provide a history of each batch of product and of all circumstances pertinent to the quality of the nal product

Deviation A deviation is an activity performed differently and/or modified than that specified in approved document/procedures.

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Good receipt note Official document issued by a port, shed, warehouse to acknowledge receipt of item listed in it under customary or specified terms and conditions.

In-process control Checks performed during production in order to monitor and, if necessary, to adjust the process, including repeating a process step, to ensure that the process performs as expected. The monitoring of the environment or utilities may also be regarded as part of the in-process control.

Inspection Activity such as measuring, examining, testing or gauging one or more characteristics of an entity and comparing the results with specified requirements in order to establish whether conformity is achieved for each characteristic.

Intermediate Partly processed material which must undergo further processing before it becomes a final product is intermediate.

Manufacture All operations from purchase of materials and products, through production, quality control, release and storage, to distribution of drugs and the related controls is known as manufacturing.

Materials A general term used for raw materials, process aids, intermediates, final product and packaging materials.

Nonconformity No fulfillment of specified requirement.

Packaging material Any material used to protect drugs during storage and transport, but excluding labels.

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Procedure Description of the operation(s) to be carried out, the precautions to be taken, and measures to be applied directly or indirectly, related to the manufacture of drug

Process Set of inter-related resources and activities which transform inputs into outputs.

Quality Totality of features and characteristics of a product or service and its ability to satisfy stated or implied needs. That is, meeting agreed requirements in a cost effective manner.

Quality assurance The sum total of the organized arrangements made with the object of ensuring that drug quality requirements are met.

Quality manual Key documents stating the quality policy and briefly describing the quality system of an organization

Quality system Organizational structure, procedures, processes and resources needed to implement quality management.

Raw material Any ingredient intended for use in the production of drug Quality Management System integrating GMP into ISO

Record Documented evidence of activities performed or results achieved.

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Recovery Any treatment of materials by a process intended to make them suitable for further use.

Reprocessing The treatment of any batch or sub-batch of materials by repeating the same process steps from a defined stage of production is reprocessing.

Retest date The date after which samples of the API should be re-examined to ensure that material is still suitable for use.

Supplier Its an organization that provides a product or service to the customer.

Standard Operating Procedure (SOP) Documented instruction to support, correct and keep consistent performance of activities.

Vendor Vendor is a manufacturer, who produces intended material and may supply material either directly or through a trade in its original packaging,

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AQL- Acceptable Quality Check Limit

ANVISA- Agncia Nacional de Vigilncia Sanitria (National Health Surveillance Agency Brazil)

API- Active Pharmaceutical Ingredients

APR- Annual Product Review

BMR- Batch Manufacturing Record

BP- British pharmacopeia

BPR- Batch Production Record

BSE- Bovine Spongiform Encephalopathy

GRN- Good Receipt Note

GMP- Good Manufacturing Record

ICH- International Conference on Harmonization

IP- Indian Pharmacopeia

ISO- International Organization for Standardization

MCC- Medicines Control Council

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MHRA- Medicine and Health Care Products Regulatory Agency

NF- National Formulary

QA- Quality Assurance

QC- Quality Control

QMS- Quality Management System

RH- Relative Humidity

SCM- Supply Chain Management

SOP- Standard Operating Procedures

STP- Standard Technical Procedures

TGA- Therapeutics Goods Administration

TSE- Transmissible Spongiform Encephalopathy

TTG- Technology Transfer Group

USFDA- United States Food and Drug Administration USP- United States Pharmacopeia

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MILESTONES- INDIA STORY The Indian pharmaceutical industry is a success story providing employment for men and ensuring that essential drugs at affordable prices are available to the vast population of this subcontinent. - Richard Gerster Pharmaceuticals has emerged as one of the leading industries in the Indian Inc., with the domestic market showing an unprecedented growth from a mere $0.3 bn turnover in 1980 to about $22 bn by 2009. The country now ranks 3rd in terms of volume of production (10 % of global share) and 14th largest by value (1.5%). At the time of independence in 1947, Indias pharmaceutical market was dominated by Western MNCs that controlled between 80 and 90% of the market primarily through importation. Approximately 99% of all pharmaceutical products under patent in India at the time were held by foreign companies and domestic Indian drug prices were among the highest in the world. The Indian pharmaceutical market remained import-dependent through the 1960s until the government initiated policies stressing self-reliance through local production. At that time, 8 of Indias top 10 pharmaceutical firms, based on sales, were subsidiaries of MNCs. To facilitate an independent supply of pharmaceutical products in the domestic market, the government of India founded 5 state-owned pharmaceutical companies. Today, India is the worlds 3rd largest producer of bulk drugs. Government policy culminated in various actions including: the abolition of product patents on food, chemicals, and drugs; the institution of process patents; the limitation of multinational equity share in India pharmaceutical companies (initially post de-licensing), and the imposition of price controls on certain formulations and bulk drugs. Subsequently, most foreign pharmaceutical manufacturers abandoned the Indian market due to the absence of legal mechanisms to protect their patented products (Product Patents were abolished from the Patents Act, 1970 in 1972 & most striking

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feature of the new law was that it did not recognize product patent protection in drugs and food).Following the de-licensing of the pharmaceutical industry in the 90s, industrial licensing for most of the drugs and pharmaceutical products has been done away with. Manufacturers are free to produce any drug duly approved by the Drug Control Authority. Technologically strong and totally self-reliant, the pharmaceutical industry in India has low costs of production, low R&D costs, innovative scientific manpower, strength of national laboratories and an increasing balance of trade. Accordingly, the share of the domestic Indian market held by foreign drug manufacturers declined to less than 20% in 2005. As the MNCs abandoned the Indian market, local firms rushed in to fill the void, and by 1990, India was self-sufficient in the production of formulations and nearly self-sufficient in the production of bulk drugs. The Patents Act, 1970was again revised in 2005 under the marquee of WTOs TRIPS Agreement which required developing countries to provide product patents on pharmaceuticals. To comply with TRIPS agreement, India decided to enforce a product patent regime since 2005, which banned copying and selling of patented drugs launched after 1995. Indian companies countered the new product patent regime since 2005 by setting up global standard facilities and entering into regulated markets. This gave them confidence to take on global generic companies and went ahead to acquire numerous overseas units to enter newer markets The Indian pharmaceutical sector has come a long way, being almost non-existent before to become a prominent provider of healthcare products, meeting almost 95 per cent of the country's pharmaceuticals needs. Currently there are about 250-300 large units that control 70per cent of the market with market leader holding nearly 7 per cent of the market share and about8000 Small Scale Units together which form the core of the pharmaceutical industry in India(including 5 Central Public Sector Units). These units (adding in numbers every year) produce the complete range of pharmaceutical formulations, i.e. medicines ready for consumption by patients and about 350 bulk drugs, i.e. chemicals having therapeutic value and used for production of pharmaceutical formulations. Post the global economic downturn the industry is back on a growth track after the relatively dull years, when exports from the country had dipped(Net pharma exports from India during 2008-09 was around Rs 30,759 crore compared to Rs31,130.70 crore in 2007-08 notably the Export of pharmaceutical products from India increased from Rs26,895 crore in 2006-07 to Rs30,760 crore in 2007-08 and to Rs39,538 crore in 2008-09a CAGR of 21.25%) but now India's net turnover in the pharmaceutical

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industry including exports is Rs 90,000 crore . The Indian domestic formulation market grew at a CAGR of 14.4%in the past five years to reach $8.7 bn in 2009-10, surpassing the global pharmaceutical growth rate of 7.8 % (and approximately US$12 bn in 2010, and showed a strong growth of 21.3% for Mr. D G Shah, Secretary General of Indian Pharmaceutical Alliance (IPA) and a leading industry advisor in a public meeting The Industry today is in the front rank of Indias science-based industries with wide ranging capabilities in the complex field of drug manufacture and technology. It ranks very high in the third world, in terms of technology, quality and range of medicines manufactured. From simple headache pills to sophisticated antibiotics and complex cardiac compounds, almost every type of medicine is now made indigenously. International companies associated with this sector have stimulated, assisted and spearheaded this dynamic development in the past 53 years and helped to put India on the pharmaceutical map of the world. The Indian Pharmaceutical sector is highly fragmented with more than 20,000 registered units with severe price competition and with government price control. It has expanded drastically in the last two decades.

PHARMACEUTICALS EXPORTS, OPPORTUNITIES GALORE The demand for exports, which is further classified formulations and bulk drug exports, is expected to more than triple in the next 5 years and cross 22 billion $ by 2011-12. The export market, estimated to be slightly higher than the domestic formulations market in 2006-07 is likely to grow to twice the size of the domestic formulations market by 2011-12. Overall pharmaceutical demand (including exports), estimated at $ 13 billion in 2006-07, is expected to cross $ 33 billion by 2011-12.

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INDIA SET TO CASH IN THE FORMULATIONS EXPORTS OPPORTUNITY Formulations exports that, in the past, have been largely to semi-regulated markets now witness numerous takers from the US, European and Japanese markets. With a host of patent expiries lined up over the next 5 years and the increasing penetration of Indian players in these markets through market authorizations and acquisitions, formulation exports to regulated markets are expected to soar by 34% (5-year CAGR) and cross the $ 5- billion mark by 2011-12. The phenomenal growth envisaged in the regulated market is therefore expected to overshadow the expected moderate growth of formulation exports to semi- regulated markets.

GENERICS OPPORTUNITY AMPLIFIES SCOPE FOR BULK DRUG EXPORT; INNOVATOR CONFIDENCE STRENGTHENS There is tremendous growth potential in exports of bulk drugs over the next 5 years. We expect bulk drugs exports to account for the largest share of the overall Indian pharmaceutical industry, as we anticipate growth in demand at a CAGR OF 28% to about $ 12.7 billion. Our belief is strengthened by the escalating generics demand (especially in the US and European markets), the growing number of contracts awarded to Indian pharmaceutical players (for manufacturing bulk drugs for patented products), and the growing dominance of India in the number of overall DMF filings. Exports of bulk drugs for off-patent drugs are already on the rise and are expected to outnumber overall bulk drugs exports to semi-regulated markets in the long term.

LIFESTYLE, CHRONIC DISEASES TO ENSURE STEADY GROWTH IN DOMESTIC FORMULATIONS We expect the current momentum in the domestic formulations market to continue over the long term. Demand which is expected to grow moderately to $ 11.4 billion by 2011-12, will be driven by chronic therapeutic segments like anti-diabetic, CNS, CVS, and lifestyle diseases like gastrointestinal ailments. The changing lifestyle in the Indian society is expected to result in a higher incidence of chronic ailments. We expect continuing higher-than-expected demand in the anti-infective segment due to poor sanity conditions across India.

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INDIA STRENGTHS The expected expansion of key regulated generics market (especially in the US and Europe), the emphasis on formulation exports set by key Indian players through the growing share of ANDA approvals (final and tentative), and more importantly the growing ANDA pipeline (filings) are factors expected to drive growth in formulation exports in the long-run. Key strengths such as low-cost manufacturing, strong process chemistry skills, a favorable talent pool at low cost, and an expanding product basket consequent to the growing number of DMF filings are expected to aid growth in bulk drug exports.

SCENARIO FORMULATIONS SEGMENT Formulation demand which makes up about two-thirds of the total pharmaceutical demand can broadly classified into domestic demand and export demand, and is currently dominated by the demand for domestic formulations. However, going forward, we anticipate significant changes in demand mix as the strong growth expected in formulations exports is set to surpass the domestic formulations market, which is set on a steady growth trend in the coming years. Formulation exports continued the success story by registering growth at a CAGR of 23.4% between 2001-02 and 2005-06 (to reach $ 2.4 billion in 2005-06) and a y-o-y growth of around 29% in 2006-07 to an estimated $ 3.15 billion. The key contributor to this healthy growth was the rise in exports to regulated markets, which surged at a compounded rate of 30% between 2001-02 and 2006-07 as compared with a compounded rate of 22% in exports to semi-regulated markets.

FOCUS ON REGULATED MARKETS STEPS UP Semi-regulated markets including Africa, Asia, Central Asian Republics (CARs), the Commonwealth of Independent States (CIS) and Latin America had been, until recently, the favored destination for Indian formulation exporters. But with the huge opportunity arising from the regulated generics market (from drugs that would be going off-patent), Indian players are increasingly stepping up exports to these markets. As a result, the proportion of exports to regulated markets has increased from 31% in 2001-02 to 37% in 2006-07.

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The North American market (which takes in more than 50% of the total exports to regulated markets) is estimated to have grown by 33% (compounded) between 2001-02 and 2006-07 as compared with the European market, which grew at a rate of 26%. In fact, formulation exports to the US (growing at over 50% CAGR between 2001-02 and 200607) are estimated to have surpassed exports to Europe in 2006-07. This led to a decline in the proportion of exports to Europe (out of total formulation exports) from 52% in 2001-02 to 42% in 2006-07, whereas the share of US remained at around 43%. Among semi-regulated markets, Africa, Asia, CIS and CAR countries which account for around 86% of total exports to semi-regulated markets grew at a (collective) rate of 22% between 2001-02 and 2006-07. Latin America, which accounts for the remaining 14% of the semi-regulated market, grew at a faster rate of 24% on a smaller base.

INDUSTRY STRUCTURE AND CURRENT SCENARIO Though nearly 20,053 firms are registered for the production of drugs and pharmaceuticals in India, the number of operational units is estimated at around 8000. Of these, close to 1000 units produce bulk drugs, out of which 250 units are in the large sector. These 250 units constitute the core of the industry and are responsible for more than half of the total drug production and exports. The formulations segment has approximately 6,900 small scale units. The combined effect of the Indian Patent Act, DPCO was also the various incentives granted to the small sector, such as exemption from payment of excise duty, has resulted in the highly fragmented structure. Geographically, there is a concentration of manufacturing operations in three states of Maharashtra, Gujarat and Andhra Pradesh. By product-type, the industry can be divided into the bulk drugs and formulations segments. Bulk drugs are active ingredients with medicinal properties that are the basic raw materials for formulations. Formulations are specific dosage forms of a bulk drug or of a combination of different bulk drugs. The final forms in which the drugs are sold are syrups, injections, tablets and capsules.

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REGULATORY ISSUES Two issues that influence the performance of the sector are the price controls and patent regime. The prices of the drugs in the domestic market are controlled by the Drug Price Control Order 1995 and are monitored by the National Pharmaceutical Pricing Authority. The Indian Patent Act, 1970 essentially provides for process patents for drugs and medicines for five-seven years, as against product patents in the regulated markets, like USA and Europe, which are provided for 15-20 years. Export revenues account for almost half the total revenues of the top three Indian pharmaceutical companies, Ranbaxy Laboratories, Dr.Reddys Laboratories and Cipla.

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PRESENT STATUS OF INDIAN PHARMACEUTICAL INDUSTRY Indian pharmaceutical industry is one of the fastest growing segments of Indian manufacturing sector. The pharmaceutical industry has experienced a growth rate of 12% with the annual turnover of the sector crossing US$ 11 billion, in 2005-06. Globally, Indian pharmaceutical industry ranks 4th in terms of volume with a share of 8% in the world pharmaceuticals market. In terms of value, Indian pharmaceuticals industry ranks 14th the annual turnover of the Indian pharmaceutical industry is over US$ 11 billion. Globally it ranks 4th in terms of volume with a share of 8% in the world pharmaceutical market. In terms of value, it ranks 14th. Key therapeutic segments of Indian pharmaceutical industry include anti-infective, gastrointestinal and cardio-vascular. Acute therapies make up about 60% of the market. However, it is expected that with the changing lifestyle and aging population, sales of chronic therapies (i.e. diabetes, cardiovascular) are growing rapidly. The pharmaceutical industry is also showing good performance in terms of exports. It is one of the top export items from India accounting for more than 4% of Indias total exports in 2006-07. Exports, which constitute around 50% of the industrys total production, have grown at a CAGR of 14% in the last decade. Major export markets include highly regulated markets such as USA, Germany, UK and Canada. Europe is the biggest export destination for Indian pharmaceuticals accounting for more than 30% of the total exports, followed by the Americas region (25%)

MAJOR PLAYERS IN THE PHARMACEUTICALS INDUSTRY Competition is mainly from the domestic manufacturers and imports from China because of the low manufacturing cost. With the new patent regulations the industry expects to see a major structural shift with the entry of foreign pharmaceutical manufacturers. There are five government-owned companies of the Indian public sector. These companies are the Indian Drugs and Pharmaceuticals, Hindustan Antibiotics Limited, Bengal Chemicals and Pharmaceuticals Limited, Bengal Immunity Limited and Smith StanStreet Pharmaceuticals Limited. Some of the major Indian private companies are Alembic Chemicals, Aurobindo Pharma, Cadila Healthcare, Cipla, Dr. Reddys, IPCA Laboratories, Lupin Labs, Lyka Labs, Nicholas Piramal, Ranbaxy Labs, Matrix Laboratories, Orchid Chemical and Pharmaceuticals, Sun Pharmaceuticals, Torrent Pharma, TTK Healthcare, Unichem Labs, and Wockhardt.

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BRIEF COMPANY BACKGROUND Dr. Reddy's Laboratories is India's leading pharmaceutical company with presence in over 100 countries. Dr Reddy's manufactures a range of products such as Active Pharmaceutical Ingredients, Generic & Branded Finished Dosages, Specialt y

Pharmaceuticals, and Biopharmaceuticals. Dr. Reddy's Laboratories was founded in 1984 by Dr Anji Reddy. In 1986, Dr. Reddy's went public and entered international markets with exports of Methyldopa. In 1987, Dr. Reddy's obtained its first USFDA approval for Ibuprofen API and started its formulations operations. In 1988, Dr. Reddy's acquired Benzex Laboratories Pvt. Limited to expand its Bulk Actives business. In 1990, Dr. Reddys entered a new territory when it, for the first time in India, exported Norfloxacin and Ciprofloxacin to Europe and Far East. In 1993, Dr. Reddy's Research Foundation was established and the company started its drug discovery programme. In 1994, Dr. Reddy launched a GDR issue of US$ 48 million. In 1995, the company set up a joint venture in Russia. In 1997, Dr. Reddy's became the first Indian pharmaceutical company to out-license an original molecule when it licensed anti-diabetic molecule, DRF2593 (Balaglitazone), to Novo Nordisk. In 1998, Dr. Reddy's licensed anti-diabetic molecule, DRF 2725 (Ragaglitazar), to Novo Nordisk. In 1999, the company acquired American Remedies Limited, a pharmaceutical company based in India. In the year 2000, became the first Asia Pacific pharmaceutical company, outside Japan, to be listed on the New York Stock Exchange. In 2001, Dr. Reddy's Laboratories became India's third largest pharmaceutical company with the merger of Cheminor Drugs Limited, a group company. In 2002, Dr. Reddy's made its first overseas acquisition - BMS Laboratories Limited and Meridian Healthcare in UK. In 2003, Dr. Reddy's launched Ibuprofen, first generic product to be marketed under the "Dr. Reddy's" label in the US. In 2006, Dr. Reddy's achieved revenue of US$1 Billion. In the same year, Dr. Reddy's acquired Betapharm- the fourth-largest generics company in Germany. In 2008, the company has acquired Jet Generici Srl, a company engaged in the sale of generic finished dosages in Italy. The deal has been completed via Dr Reddy's Italian subsidiary. The company proven research capabilities and vertically integrated with a presence across the pharmaceutical value chain and it conducts research in the areas of

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diabetes, obesity, cardiovascular diseases, anti-infective and inflammation. To help people lead healthier lives by delivering affordable and accessible medication to all parts of the world and discovering, developing and commercializing innovative medicines that satisfy unmet medical needs are the two parallel objectives of Dr. Reddy's Laboratories Limited, and it is sustain path of the company to survive. The appreciation and recognition is a role to boost, as part the company has received plenty of awards and applications already, continued that, the company got Pharma Excellence Awards 2006-07 under the category of Sustained Growth by The Indian Express, Dun & Bradstreet American Express in Corporate Awards 2007, Best Corporate Social Responsibility Initiative 2007 by BSE - India and Amity Leadership Award for Best Practices in HR in Pharmaceutical Sector. Today, Dr. Reddy's Laboratories is leading pharmaceutical company in India in terms of turnover and profitability

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QUALITY MANAGEMENT SYSTEM A set of co-ordinated activities to direct and control an organization in order to continuously improve the effectiveness and efficiency of its performance is quality management system These activities interact and are affected by being in the system, so the isolation and study of each one in detail will not necessarily lead to an understanding of the system as a whole. The main thrust of a Quality Management System is in dening the processes, which will result in the production of quality products and services, rather than in detecting defective products or services after they have been produced.

BENEFITS OF A QUALITY MANAGEMENT SYSTEM A fully documented Quality management system will ensure that two important requirements are met: The customers requirements condence in the ability of the organization to deliver the desired product and service consistently meeting their needs and expectations. The organizations requirements both internally and externally, and at an optimum cost with efficient use of the available resources materials, human, technology and information. These requirements can only be truly met if objective evidence is provided, in the form of information and data, to support the system activities, from the ultimate supplier to the ultimate customer. A Quality management system enables an organization to achieve the goals and objectives set out in its policy and strategy. It provides consistency and satisfaction in terms of methods, materials, equipment, etc, and interacts with all activities of the organization, beginning with the identication of customer requirements and ending with their satisfaction, at every transaction interface. Management systems are needed in all areas of activity, whether large or small businesses, manufacturing, service or public sector. A good Quality management system will: Set direction and meet customers expectations Improve process control

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Reduce wastage Lower costs Increase market share Facilitate training Involve staff Raise morale

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y y y To understand the working of the organization. To understand the quality management system. To understand the quality management system of Dr. Reddys, FTO Unit -6.


This report describes the QMS in Dr. Reddys (FTO Unit-6) which is based on Good Manufacturing Practice (GMP) regulations. Dr. Reddys QMS involve all staff whose activities influence quality, have a clear and unambiguous continuous improvement focus, and incorporate relevant, realistic performance measures with emphasis on reducing failure costs, and satisfying (internal and external) customer needs. The quality manual occupies the highest level in the document hierarchy. It overviews and acts as a directory to the QMS, capturing the unique character of the company. This document, have been addressed in thirteen distinct chapters the recognition of the importance of issues concerning hygiene; facilities and utilities in Dr. Reddys. Each chapter is structured in such a way which summarizes the appropriate Dr. Reddys QMS principle and philosophy as a preface to the main text which integrates relevant GMP requirements and QMS principles.

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F. GMP Regulations for Pharmaceuticals

The quality of pharmaceuticals has been a concern of the World Health Organization (WHO) since its inception. The setting of global standards is requested in Article 2 of the WHO Constitution, which cites as one of the Organizations functions that it should develop, establish and promote international standards with respect to food, biological, pharmaceutical and similar products. WHO Expert Committee for Pharmaceutical Preparations, created The International Pharmacopoeia, which made numerous recommendations relevant to quality assurance and control in pharmaceuticals. For the first time, Volume 2 of International Pharmacopoeia published by the WHO 1999, reproduces guidelines related to good manufacturing practices (GMP) and to the inspection of pharmaceutical manufacturers and drug distribution channels.

GMP Good Manufacturing Practices (GMP) are the part of quality assurance that ensures that drugs are consistently produced and controlled in such a way to meet the quality standards appropriate to their intended use, as required by the marketing authorization. There are standards set in GMP for:

1. QUALITY MANUAL The GMP regulation says that quality manuals should be dened and document its policy and objectives for, and commitment to, quality in a quality manual. It should ensure that this policy is understood, implemented and maintained at all levels in the organization. The information contained in the quality manual and procedures should include at least: (a) A quality policy statement; (b) A description of the organization including details of any governing board, its constitution, terms of reference and rules of procedure (c) The names, qualications, experience and terms of reference of the senior staff and both internal and external (d) Details of training arrangements for inspection personnel

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(e) An organizational chart showing the responsibility and reporting structure of the inspectorate and the allocation of functions (f) Details of the documented procedures for recommendations to the authorization holder for the issue, suspension or revocation of marketing authorizations. (g) Details of internal quality audits (h) Details of testing of samples (i) The control of non-conforming products

2. QUALITY POLICY y The quality policy should emphasis the importance of planning to avoid quality failures. The need for continuous improvement should be emphasized by use of specific performance measures. y Management should ensure that the quality policy is fully understood and implemented by all members of staff. y Management should clearly demonstrate their continuing support for the quality policy (e.g. by regular quality briefings)

3. ORGANIZATION AND MANAGEMENT y There should be an adequate organizational structure defined with the aid of an organizational chart. The responsibility, authority and interrelationships of all personnel should be clearly defined. y A designated person should be appointed who should have defined authority and responsibility for ensuring that a quality management system is implemented and maintained. y Managerial and technical personnel must have the authority and resources needed to carry out their duties and to set up and maintain a quality management system, as well as to identify and correct deviations from the quality management system. y The responsibilities placed on any one individual should not be so extensive as to present any risk to product quality.

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There should be arrangements in place to ensure that management and personnel are not subject to commercial, political, financial and other pressures or conflicts of interest that may have an adverse effect on the quality of service provided.

Individual responsibilities should be clearly defined and understood by the individuals concerned and recorded as written job descriptions. Certain activities may require special attention such as the supervision of performance of activities, in accordance with local legislation.

Safety procedures relating to all relevant aspects including, for example, the safety of personnel and property, environmental protection and product integrity, should be in place.


Document issue
y The procedure should include the design, identification, review, approval and distribution of documents. Obsolete documents should be under control and archived. y All quality related documents should be designed by persons with practical knowledge of the process described. y Documents should be reviewed, coded, signed and approved by competent and authorized persons. The status of the documents should be indicated (issue date and version/revision) and verifiable by reference to the master document or a master list. y The procedure should insure that current documents are correctly distributed and available when and where needed. y When entries need to be made in documents, sufficient space should be available for the entry. The type of entry, date, units used and the person making the entry should be indicated and identifiable. y The procedure for controlling documentation should insure that obsolete documents are promptly removed. A list identifying the current version of all the documents should be readily available.

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Original versions of obsolete documents should be retained for legal / historical / knowledge preservation purposes. Obsolete documents should be clearly identified to prevent unintended use.

Document changes
y Changes to documents should be reviewed and approved by the same functions that performed the original review and approval, unless specifically designated otherwise. y The designated functions should have access to pertinent background information upon which to base their review and approval. y Where appropriate, the nature of the change(s) should be identified in the revised document or attachments. However, it is advantageous to incorporate a brief summary of previous changes in the current version of the document. y Relevant changes in documents previously submitted to regulatory authorities and/or customers should also be notify


Materials and equipment identification

y Raw materials, auxiliaries, packaging materials, intermediates and API should be assigned a unique code which allows the traceability of materials. Where appropriate, this code should be included on the label of each container upon receipt or isolation. y Each item of equipment influencing product quality should be clearly identified

Batch (or lot) identification

Any batch (or lot), received or produced should be assigned a unique code to allow for the traceability of all materials and equipment used in its manufacture.

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y There should be a written procedure describing the system for labeling materials and equipment. y Each container should be identified by an appropriate label, showing at least the product identification and the assigned batch code, or any other easily understandable combination of both. Other data, such as weight, storage conditions, and safety or transport instructions can also be included on the label. y Containers for external distribution may require additional labels. These should be adequately controlled and contain relevant information to meet user requirements as well as compliance with applicable safety and transport regulations. y Quality critical equipment should be clearly and uniquely identified, together with an indication of status (e.g. clean; waiting cleaning; in use; out of order). When in use the content of each item of equipment should be identifiable. y Material, product, equipment and status information should be recorded to facilitate subsequent traceability

6. TESTING y Specifications and methods should be established for the inspection and testing of raw materials, intermediates, API, final product and packaging materials. They may also be required for process aids, e.g. filters, gaskets or other items which are used in production and could have a critical impact on product quality. y Written, validated, approved and dated test procedures should be available for checking if the specifications are met. They should be clearly understandable and sufficiently detailed to enable a trained operator to follow them. y In case of Out of Specification (OOS) results, re-analysis should be in accordance with a written procedure

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In-process testing and inspection

The product should be tested and the intermediate lots should be held in quarantine until the inspection and testing has been completed or the relevant reports have been received and verified In-process test procedures should be validated where the result is critical to the quality of the product. Test results should be recorded in writing and these records should become part of the batch record.

Final inspection and testing

All final inspection and testing should be performed as described in the quality plan (i.e. written procedures; methods and specifications; etc.) to ensure the completeness of the evidence that the final product meets specified requirements.

7. CONTROL OF NONCONFORMING PRODUCT y A non conforming product should be recorded, clearly identified as nonconforming and physically segregated (unless an alternative, equally effective procedure is available) to prevent unintended use until its disposition (i.e. rework, reprocess, release on conditional status, disposal) can be agreed. y Relevant staff should be notified and an investigation performed to determine the extent and cause of the nonconformity and to agree appropriate action. y Responsibility for reviewing information relevant to, and authority to, decide the disposition of nonconforming product should be clearly documented. y y y Subsequent use of nonconforming material should be approved by the Quality Function. The likely effect upon related batches of product should be assessed. Any decision to reprocess returned nonconforming product should take into consideration the fact that the product has been outside the control of the manufacturing company. y y Reprocessing and rework should be documented and included in the batch records. A new batch number should be assigned following rework.

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The nature of the nonconformity together with details of the associated investigation and justification for disposition of the nonconforming product should be recorded.

If reprocessing and/or reworking become a regular occurrence, the adequacy of the original manufacturing process should be investigated.

8. INTERNAL QUALITY AUDITS(SELF-AUDITING) y Internal quality audits, incorporating GMP requirements, provide a regular and systematic way of obtaining objective evidence about how the QMS is functioning. y Internal quality audits should be scheduled as part of an ongoing QMS internal audit programme covering the scope of the quality system documented in the quality manual. The frequency with which different parts are audited should be determined on the basis of importance to overall QMS performance i.e. activities with known weaknesses should be audited more frequently. y Internal quality audits should be planned, performed, recorded and followed up by suitably trained staffs that are independent of the area being audited. Internal quality auditors should be experienced in QMS and GMP in order to perform audits which benefit the organisation. y Internal quality system audit findings should be discussed with responsible management. Agreed, time-limited remedial actions should be recorded and followed up to completion and sign-off. y y The follow-up activities should verify the effectiveness of the corrective action taken. Output of the internal quality audit programme should be summarized and periodically submitted to senior management as an integral part of the management review process. Taking the base of these few GMP regulations this document has been prepared showing the set of the SOPs prepared by the DR.REDDYS to ensure the quality of the processes to be carried out for the appropriate setup for the drug manufacturing.

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The Quality system - in the form of organizational structure, procedures, processes and resources needed to implement the quality policy - should be described in a quality manual. The need for quality planning is an important feature of the QMS. It requires that adequate consideration is given to an activity before implementation, thereby reducing the risk and cost of failure. These quality policies are listed in companys quality manual containing the following: y Quality policyAims at sustaining the operating system and procedures and further improve them to achieve higher standards of system and quality compliance.

Organization and responsibilitiesAims at showing the department and personnel involved for ensuring quality management system relating to product, process and quality system.

Specifications and Standard Technical Procedures Emphasizing on need of specification and analytical methods for ensuring the quality of raw material, packaging material, intermediates and finished product for further who all are involved in approval of these.

Standard Operating Procedures Emphasizing on need of SOPs, who all are involved in forming these and who all are further involved in controlling these SOPs.

Batch record Shows the role of BMR and BPR and for what purpose these are used.

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Documentation Aims at showing how documentation is done along with the procedures followed for maintenance of new and old documents.

Vendor development This put some light on the process for approving the vendors for providing raw material to the company.

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Quality policy
Dr. Reddys is committed to provide customers products, meeting or exceeding expectation consistently in terms of specification, delivery, technical support, regulatory compliance and competitiveness. Constantly improve procedures, technology and infrastructure and continuously better the quality of product produced.

Organization and Responsibilities

 TTG and Junior Manufacturing Executive- batch documentation preparation  Senior Executive and Junior manager(Production)- batch manufacturing and packaging  Senior Executive and Junior manager(QA)- supervision  Senior Manager and Junior manager (QC)- analysis  QC Head- report approval\  Packaging development head- packaging  QA Head- Final dispatch  SCM head- monitor SCM aspects

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There should be a written procedure for the systematic control of all quality related documents such as quality manual, cross-functional procedures, organization charts, standard operating procedures (SOPs), and formats for repetitive processes. This also applies to any document received from external sources (i.e. regulatory authorities or customers)

y Documentation assurance personnel are responsible for control, issuance, retrieval and storage of document. y Head of QA or his designee is responsible for implementation/compliance of this procedure.

a. Master document Include all master document used in manufacturing, packaging and testing including: y y y y y y y y y y y y y Product manual BMR, BPR Specifications (raw material, in-process, finished product) Packaging material specification and test procedures Manufacturing work orders STP and analytical methods Process validation protocol Datasheet and standard packaging specification SOP Storage condition for raw/packaging material Approved vendor list for raw/packaging material Site master file Process validation report All master documents are in letter size paper and signed in blue.

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b. Receipt of documents Approved copy of master document is submitted to documentation assurance along with distribution slip by initiator. Distribution slip contains: y y y y y y y Document title Document number Department Plant Number of copies required Effective date Reason for request

c. Control of document User department raise document distribution slip, get it approved by QA and send to documentation assurance department. Documentation assurance department stamp the effective date of respective document. Original copy is retained as master copy by document assurance department. Photocopies are distributed to the departments on the bases of request made.

d. Issuance of document Photocopy of master document is circulated as per distributed slip. QA mention the number of copies distributed. Distributed slip is filled along with master copy. All master copies in use are for revision is issued as controlled copies. The photocopy of master document issued for considered as uncontrolled document. Documentation assurance department put signature and date with blue ink on stamp issued by on first page.

e. Retrieval of documents When updated versions of controlled copies are available then old ones are retrieved. Proper record of document issue, control, retrieval and destruction of superseded copy

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of all documents is maintained by documentation assurance department. The retrieved copies received by QA/user department are then destroyed.

f. Supersede document In case of any amendments in master document, its updated and the older version of document get superseded. Documentation assurance department put red ink stamp on the superseded document.

g. Obsolete document Obsolete document is one which is not in use now. Initiator department raises change control with justification which gets approved by QA. This change control forwarded to documentation assurance department which further make it obsolete. Documentation assurance department put red ink stamp of obsolete copy on master copy along with sign and date.

h. Storage of documents Storage is such to prevent loss or damage of document by fire, water, environment, insects, rodent, theft, etc. Access to storage area is controlled and restricted

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Vendor is a manufacturer, who produces intended material and may supply material either directly or through a trade in its original packaging, Process of selecting a vendor is called vendor management. Vendor management includes: 1. Identification and Qualification 2. Disqualification 3. Requalification

Identification and Qualification

Identification and qualification of vendors are done for: y y y API Exipients Packaging material

a. API AND EXIPIENTS (for commercial use ) Supply chain management sends tentative specification to vendor and arrange for sample for technical evaluation. Three lots from the vendor are checked by R&D and analytical reports are formed as per specifications. If the lot is satisfactory then onsite inspection is done. In onsite inspection vendor audit questionnaire is considered as checklist. Vendor audit questionnaire include: y General information About the manufacturer including the certificates of WHO-GMP, MCC, MHRA, TGA, ANVISA, USFDA, ISO 9000 etc.

Building and facilities Facilities and cleaning are to be taken care off.

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Component and material control Checklist includes checking of standards maintained for storing and examining the material available for production.

Production Facilities and cleaning of the area, equipment etc is to be checked according to the standards. E.g. guidelines are followed as per Environment protection agency/ Bureau of international standards.

Quality assurance There is a check for any QA system available and required standards to be maintained. E.g. material available in QC is as per pharmacopeia grade (IP/BP/USP/NF/ICH requirement)

TSE/BSE certification Include checking that material is derived from animal or plant origin. Checking that animal origin ingredient is produced by the country which is BSE free in accordance of FU, TGA listed country.

Food /pharma grade certification Check that material supplied to be used as food grade/ pharma grade of material and attached declaration

Additional information Record any information giving details of quality management system of vendor.

Based on satisfactory evaluation of document, QA approve the vendor and same is entered in SAP. Supply of material is supported by certificate of analysis

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Primary packaging

Printed packaging

Supply chain management sends tentative specification to vendor and arrange for sample for technical evaluation. R&D reviews the sample as per approved specification and test methods by packaging development. If the sample are acceptable packaging development advice SCM for procurement of packaging material for trail/suitability studies/vendor capability study which is evaluated by packaging development, SCM, QA. Certification of vendor based on satisfactory onsite inspection including the vendor audit questionnaire. Vendor audit questionnaire include: y General information About the manufacturer including the certificates of WHO-GMP, MCC, MHRA, TGA, ANVISA, USFDA, ISO 9000 etc.

Building and facilities Facilities and cleaning are to be taken care off.

Component and material control Checklist includes checking of standards maintained for storing and examining the material available for production.

Production Facilities and cleaning of the area, equipment etc is to be checked according to the standards. E.g. guidelines are followed as per Environment protection agency/ Bureau of international standards.

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Quality assurance There is a check for any QA system available and required standards to be maintained. E.g. material available in QC is as per pharmacopeia grade (IP/BP/USP/NF/ICH requirement)

TSE/BSE certification Include checking that material is derived from animal or plant origin. Checking that animal origin ingredient is produced by the country which is BSE free in accordance of FU, TGA listed country.

Food /pharma grade certification Check that material supplied to be used as food grade/ pharma grade of material and attached declaration.

For type of material used (aluminum foils/tubes/glass/bottles/films/bags etc) Check for type, facilities, outsourcing etc.

Disqualification of vendor
Disqualification of vendor is done on the basis of: y y y Supply of contaminated material which cause adverse impact on product quality. If three consecutive supply of the material fails to meet its requirement in year. Inability of vendor to comply with gaps identified during the audits.

Requalification of the vendor

A disqualified vendor is again requalified once the senior management at the vendor side provides adequate assurance providing writing with control and commitment. SCM initiate a change control for requalification of vendor. Upon satisfactory review of commitment made vendor is re-audited and qualified as detailed in respective SOP.

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It should be possible to identify and trace any material from receipt through production and delivery to the customer. All quality critical equipment should also be identified and its use is traceable.

Materials and equipment identification

Raw materials, auxiliaries, packaging materials, intermediates and API should be assigned a unique code which allows the traceability of materials. Where appropriate, this code should be included on the label of each container upon receipt or isolation. Each item of equipment influencing product quality should be clearly identified.

Responsibilities  Technology transfer group assign the code  Head of user department to execute the coding system  Head of QA ensure implementation/ compliance of this procedure.

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i. Coding of area Each area is coded and area code consists of five characters. First two alphabets denotes department. DEPARTMENT Warehouse Production Quality assurance Quality control Engineering Technology transfer group Regulatory affairs Housekeeping General (administration, safety) CODE WH PR QA QC EN TT RA HK GN

Last three numerical denoting serial numbers starting from 001 for each department. E.g. first room of warehouse would be coded as WH001. If there is need to update its updated by TTG/QA.

ii. Coding of equipment/ instrument/ system Coding of equipment/ instrument/ system contain seven characters. First two characters are department code number followed by hyphen and last three numbers starting from 001 for each department. E.g. first equipment of production is coded as PR-E001. Accessories of equipment bear same equipment code as that of main equipment.

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BATCH IDENTIFICATION DefinitionBatch is defined as quantity of starting material, packaging material, intermediates or finished product that is intended to be homogenous in character and quality and which has been produced during a defined cycle of manufacture.


Dosage form

Parental/semi solid form

Exhibit batch

i. For dosage form


 First alpha character of batch no. indicate the location code which start from A and continue till Z.  Second numerical character indicate the last digit of the year from 0-9. The repeated after every 10 year. e.g. for year 2010 it is 0.  Next five numerical character indicate the serial no. of respective batch which star from 00001 and continue till 31st december of the same calender year.

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ii. For parental and semi solid dosage form


 First alpha character of batch no. indicate the location code starinf from A and continue upto Z.  Second numerical character indicate the last digit of year 0-9. The no, is repeated after 10 year. e.g. for year 2010 it is 0.  Next three numerical character indicate the serial no. of the respective batch ehich starts from 001 and continue till 31st december of the same calender year.

iii. For exibit batch



 First alpha numerical character E of batch no. indicate the exhibit batch.  Second alpha character indicate the location code starting from A-Z.  Third and fourth numerical character indicate the year. e.g. for 2010 its 10.  Next three numerical character indicate the serial no. of respective batch which start from 001 and continue serialy till 31st December of the same calender year.

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Different label are used in different areas like receipt, handling, storage, manufacturing and packaging. Current index of label are prepared by QA personnels. There are different types of labels: a) Reserved samples  These are generated by QA/QC  Prepared for samples which are not for sale. b) Under test labels  These are generated by warehouse personnels  Information on this label is derived from SAP  This indicate that GRN- good receipt note has been prepared and material are awaiting for sampling.

c) Sampled  These are generated by QC  These are fixed after completion of sampling of raw material/packed material.  Its affixed on container from which sample is taken. Sampled GRN no. Container no. Sign Date

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d) Approved label  If the material is approved as per specification then QC incharge put label label of approved.  Its information is derived from SAP  This label is put on the under test label. Approved GRN no./AR no. Approved date Sign Retesting date Date

e) Rejected label  If the material is rejected as per specification then QC incharge put label label of rejected.  Its information is derived from SAP  This label is put on the under test label. Rejected GRN no./AR no. Rejected date Sign Rejecting reason Date

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f) Dispensed material label Its generated by WH when material is dispensed.

Dispensed material label Material Code AR no./GRN no. Batch no. Tare weight Gross weight Net weight Weighed by Date Checked by Date

g) Container status label Generated by production personnel indicating the status of the product at various stages of manufacturing. This designate the batch status.

Container status label Product Batch no. Status Stage Tare weight Sign Batch size Container no. Next stage Gross weight Date

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Production, installation and servicing processes that affect quality should be identified,planned, documented and performed under control.

i. Documentation Written procedures exist for all activities related to product quality. y Written manufacturing instruction is available (e.g. master formula, master production record) including details of: - raw materials - reactions - process steps - in-process controls - intermediates - drying - filling and packaging This list may not be considered as complete.

Batch records is available for each batch of each product and include details of: - the name of the material to be produced and the batch number or equivalent - the dates between which the batch was made - identification and signature of operators - the names, batch numbers and quantities of raw materials to be used - the equipment used - process steps and conditions, including permitted ranges and special precautions together with the actual process conditions used - the results of in-process tests - the yield obtained - a record of all deviations from the process instructions and all unusual occurrences

This list may not be considered as complete.

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Written instructions for the packaging operations involving the pure or finished product is available and contain detail of: -specifications for the labels and for those packaging components that have direct contact with the product - a list of other packaging materials - any appropriate special precaut

Written instructions for cleaning, calibration and maintenance of equipment is available.


Prevention of product contamination Measures to avoid contamination is designed into the manufacturing process, because the control of potential contaminants in the product itself is extremely difficult. Care is taken to prevent contamination. This is considered for all stages, but it is essential after the final purification stage. Appropriate measures include: - the use and location of equipment should be designed to minimise contamination - the avoidance of contamination due to the use of inadequately cleaned or maintained equipment, corrosion or bearing leakage - the use of adequately purified solvents - the prevention of contamination by materials or utilities that have direct contact with the product. Special care needs is taken during processing steps involving such as isolation, drying and milling. Precautions include: - isolation, drying, milling and homogenisation performed in closed systems or controlled environments - special care taken to avoid contamination of other equipment, other products, or the environment - if local dust extraction alone is used, a subsequent clean up is performed to minimise contamination or cross contamination

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Filling and packaging operations are performed in facilities which prevent cross contamination either of the material being handled or of other materials by that material.


Specific requirements The process is controlled in compliance with quality plans, manufacturing instructions and Good Manufacturing Practice principles. Suitable monitoring and control parameters is chosen to ensure that the process performing as intended by the process design. Monitoring of appropriate in-process controls and parameters are performed to give the necessary level of confidence in the quality of the finished product


Criteria of workmanship There are documentation available that describes in clear detail the standard of workmanship required.

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Take measures to check the quality, performance, or reliability of (something), esp. before putting it into widespread use or practice. These include sampling and in-process checks during manufacturing of drugs to ensure the quality.

Responsibilities y y y y Production personnel- to initiate the request for analysis QA personnel- to collect the sample and handover to concerned Production personnel- to withdraw the sample from equipment for in process check Head- QA or his designee for compliance of this procedure.

Procedure Production personnel raise and forward the intimation for sampling and analysis through request to QA in format. Upon receipt of request for sampling and analysis, QA personnel check and ensure availability of clean/ fresh suitable sampling aids (e.g. cleaned sampling rods, spatula, scoop, fresh poly bags, black poly bags, butter poly bag, butter paper, glass bottle) QA person affix sample for analysis label on sample bag/container. Proper gowning procedure is followed during sampling. Before sampling QA person verify the label for product name, batch number and status.

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A sample quantity is withdrawn as: 1. Sampling of intermediate products Before sampling check the intermediate product for visual defects like, color variation, lump formation. If any discrepancy is observed inform production and QA in charge. For tablets, capsule withdrawn samples from all containers in a bag, mix and collect composite sample in a fresh self sealing bag.

2. Sampling of finished product Finished product of tablets/capsules is sampled online during the batch

compression/filling. Transfer drawn sample to representative sample container. After completion of compression/filling of batch QA officer draw the sufficient quantity of pooled samples equivalent to one complete analysis.

IN PROCESS CHECK Responsibilities

Executives QA for conducting in process checks Plant QA in charge- to ensure implementation and compliance of this procedure

 Ensure whether RH and temperature in compression/capsule are within the limits as mentioned in BMR.  Ensure that differential air pressure is within limit and is recorded.  Ensure that in process test equipment are calibrated.

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Perform in process checks for tablets as outlined below: y Collect composite sample from left hand side discharge port and right hand side discharge prior to check the following parameter:

Group weight Individual weight Thickness Hardness Disintegration time Friability

20 20 06 06 06 10

Collect capsule and perform in process checks : Average weight Individual weight Locking weight 20 20 06

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A deviation is an activity performed differently and/or modified than that specified in approved document/procedures. Any deviation in any approved SOP and BPR is to be made by QA in charge. Deviation is justified and supported by scientific data of nature and is used for validation or is permitted with extraordinary testing and evaluation to assess quality. Such deviations are issued only on exceptional basis. All deviation is handled as per procedure defined for handling of deviation. When deviation relating to manufacturing activity is major, then the lot or sub lot of material is segregated, secured and labeled as appropriate and deviation report is prepared. Deviation report is reviewed by concerned production manager and plant QA in charge who may advise, reject, and rework/acceptance.

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Any unplanned/uncontrolled event in form of non-compliance from designated system/procedure at any stage of manufacturing, packaging, testing, holding and storage of drug product due to system failure or equipment breakdown/manual error is termed as incident.


Quality impact

Quality non-impacting

1. Quality impact Initiators raise report and forward to QA. Concerned HOD carries out detailed investigation immediately after the occurrence of the incident. After taking corrective and preventive actions incident report is disposed by plant QA in charge.

2. Quality non-impacting In this case the initiator raises the report and forwards it to the department HOD. The concerned HOD mentions the corrective and preventive action to avoid the recurrence of incident. After taking corrective and preventive actions the incident report is disposed by concerned department head.

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All suspect results that falls out of pre determined limits or acceptance criteria established in specification are defined as out-of-specification results.

Handling of out-of-specification results

Any out-of-specification result is investigated and documented. Investigation report include following assessment:  Error in sampling  Error in manufacturing  Handling and storage of sample  Error in analysis Investigation is completed within three days of identification of out-of-specification result. Investigation report outlines the corrective actions necessary for corrective batch and to prevent similar reoccurrence. Investigation is extended to other batch and product possibly affected due to process related error or operator error or malfunctioning of equipment.

Investigation is carried out as in SOP: Procedure Analyst brings attention of superior of any out-of-specifications results. Sample is taken out for analyses. Before sending sample to analyses, the adjustments of manufacturing process (pH, viscosity etc) are checked. Sample to be checked for: y y y Lab investigation Microbiology test Investigation at QA

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y y y Production officer- report any discrepancy in product appearance QA officer- performs the physical inspection and prepares the report. QA head- ensures the compliance.

Any deviation observed by the production personnel with respect to physical appearance is immediately referred to officer QA or during process checks/sampling, if any defects noted by officer QA go for AQL (acceptable quality check limit). QA officer compares the defect observed with defect outlined in the List of possible defects: y y y y y y y y y y y Incorrect product Presence of more than one product Incorrect colour Incorrect shape Incorrect size Incorrect coding details Incorrect labeling Fading or change of colour at time of release Embedded surface spots of contamination Presence of foreign matter Undesired marks, hairs, spot, appearing on primarily on container on outside/inside surface. y y Absence of cotton/desiccant in container Tablet with missing embossing

QA officer collect require quantity of tablets from each container as specified in below tablets in order to inspect 1000 pooled units for AQL checks. QA officer check and determine the acceptability of portioned sample based on percentage of defects.

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The observed defects are entered in individual formats for product inspection for physical defects of core tablets, filled capsules and during packaging respectively. The AQL for type of defects is as follow: y y y Critical defects- 0% Major defects- 1% Minor defects- 3% In case physical defects are observed and after evaluation the percentage are found to be more than specified as AQL the batch/lot is 100% inspected. After 100% inspection the batch/lot is rechecked for physical defects. QA officer affix HOD status label on all containers for inspection. In case the incidence of recurrence of particular defects is frequent for consecutive batches, QA officer notify the same to QA Head for detailed investigation. Product inspections for physical defects are filled in batch production record of respective batch.

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It should be possible to readily identify, at all stages from design through manufacture to delivery to the customer, if a product has pass or fail status, or if it is waiting to be tested. This also include self inspections for ensuring that quality work is maintained throughout.

A planned and systematic examination and check of system, procedure or operation by internal auditor in order to monitor compliance the effectiveness of established standards and to allow for improvement and corrective measures where required.

Internal audit teams carry out periodic audits in all operational departments. Departments: y y y y y y y y y y y Warehouse QC lab QA Production Engineering and service Human resource Housekeeping Packaging and development Distribution SCM Regulatory affairs These all are inspected in shifts.

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Additional self inspection may be carried out in special circumstances but not limited to: y y y Production recall Repeated product failures Serious market complaints

Plant QA in charge constitutes the internal audit team from cross functional areas comprising of two members out of which one member is from QA department. For given departmental inspection cross-functional team exclude the representative from auditee department. Representative from other than QA audit the QA department. Head of

department/authorized nominee of respective department audit his/her department.

Auditors verify the compliance with written procedure and completeness of documents in respective department/area and categorize the observation as critical, major, and minor in self inspection report. Auditors conduct the inspection but not limited to items specified in checklist as: y y y y y y All equipments bear equipment identification no. and are status label. Instruments/equipments bear calibrated tag, wherever applicable. Entries made in calibration record are complete and same as entered on calibrated tag. Any calibration performed before schedule date is recorded. Annual calibration schedule is available. Certificate which certifying calibration of standards weights and other calibration standards are available. y The categorization of critical, major, minor observation is based on the following guidelines I. Critical observation Any observation causing significant effect on strength, identify, purify and safety of product and may have an adverse physiological response to the consumer.

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II. Major observation Any observation which has produced a product that does not comply with its marketing authorization a major deviation from the manufacturing license or GMP approval come under major observation. III. Minor observation Any observation that has no direct influence on product quality is minor.

After completion of audit the auditor conduct exit meeting with concerned HOD. All self inspection finding of the respective department is reported and submitted in the form of self inspection report. Upon receipt of self inspection report the auditee prepare agreed action plan in cooperation with plant QA in charge or designee and define time lines for corrective and preventive measures within 15 working days. The head of audited department is responsible for corrective and preventive actions for observations made during self inspection. Auditee submits the action plan to plant QA in charge in same inspection report. The plant QA in charge follow up with concerned HOD to correct the deficiencies within the time line unless otherwise justified. After completion of necessary corrective actions, plant QA in charge close the audit by preparing statement of self inspection. Once every quarter the observation along with action plan is shared with the higher management indicating the status of compliance.

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An organized and comprehensive review of all production, analytical, stability, complaints, changes, deviation, recall, retention, sample and customer data associated with pharmaceutical product so as to monitor the drug product quality and improve where necessary.

y QC executives- collect and organize all QC data associated with Annual Product Review y Production executive- collect and organize all production data inclusive of process parameter associated with Annual Product Review y y Regulatory affairs- for providing data on marketing authorization Plant QA in charge- prepare the summary report and ensure the compliance of corrective action arising out of recommendation of APR y Head QA- responsible for implementation.

APR is done from calendar year i.e. 1st January to 31st December. It can also be done for date of product approval by regulatory authorities. Summary of report is made available within 60 days of scheduled date. For APR the starting material, primary material used in product especially those from new sources is taken. Reviews of critical parameters of products e.g. assay, related substances, moisture content is done. Finished product and in-process analytical data of relevant critical parameters as mentioned below: y y y Water content Dissolution Hardness

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y y y y y

Assay Disintegration time Impurities Residual solvent Microbial test

Following data is collected and reviewed: y y y y y y y y y y Critical process parameter Market complaints and related investigation All rejected batch All significant deviation Review of all changes carried out to process Any product recall and related information Returned good and salvaged goods Control sample review of product Batch taken for processing Different pack size of product offered

Result obtained is compared with standard value to determine the variation that could indicate shift in tendencies if any.

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H. Conclusion
Over the last few years the global pharmaceutical market has undergone significant change, forcing pharmaceutical companies, more than ever before, to focus on customer needs and upon their own internal efficiency in order to achieve the ultimate goal that is quality life. Pharmaceutical industry has traditionally focused upon the application of Good Manufacturing Practice (GMP) and it has been considered the potential benefits to be gained by implementing them in Quality Management System (QMS). With this in mind Dr. Reddys one of the leading pharmaceutical companies in country integrated current GMP requirements into its QMS framework. To achieve this, company has set a model for quality assurance in design, development, production, installation and servicing. For the purpose of guidance document, the QMS of Dr. Reddys have been addressed in this report. Setting the GMP principles as a benchmark various aspects of quality management system of the company are designed e.g. Quality manual set by the company covers the company policy showing commitment to the quality standards. There is an appropriate organizational structure defined in the company with the responsibility, authority and interrelationships of all personnel, as defined in the international standards. The SOPs for documentation in the company includes the design, identification, review, approval and distribution of documents. Dr. Reddys procedures for identification, disqualification and requalification of vendors are also following the foot markers of GMP regulations. Products and equipments identification standards for the assigning the unique alphanumeric code and proper labeling to each and thing present in the production area are taken from the set standards. Testing standards including sample collection, validation, QA personnel in process checks and documentation are properly carried out so that minimum deviation could occur from the GMP standards. Handling of deviations, out-ofspecifications and incidents whether quality impacting or non-impacting is done with corrective and preventive actions as set by the international standards. GMP principles set for designing the SOP of non conforming products taking AQL approach in use for detection and then appropriate action on the same are dedicatedly followed. Internal quality audits, incorporating GMP requirements are also providing a regular and systematic way of

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obtaining objective evidence about how the QMS is functioning. The process of annual product review for maintenance of QC standards and collection of the data is controlled in compliance with quality plans of Good Manufacturing Practice principles. In this document safety, health and environment are not specifically addressed. However, it is widely acknowledged that implementation of a robust QMS will provide a sound basis for the future development of Dr. Reddys such Integrated Management System.

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1. Kop, S., Good Distribution Practices (GDP) For Pharmaceutical Products, Working document QAS/04.068/Rev.2, , [20 October 2005]

2. WHO, Quality assurance of pharmaceuticals, A compendium of guidelines and related material, Volume 2, 2nd updated edition, harmVol2.pdf , [16 December 06]

3. Department








4. Jaiswal,






Reddy s

lab ,


5. APIC active pharmaceutical ingredient committee, Quality Management System For Active pharmaceutical Ingredients manufactures ,, [ December 1997] 6. Dr. Reddy s Lab, standard operating procedures