PHARMACEUTICAL a ManoharA® Rotdar, Q NIRALI PRAKASHANPHARMACEUTICAL QuauTy ASSURNACE ISBN NO. 978-81-85790-59-6 Second Edition December 2007 © Author us 30.00 arte tt of his publication. or part hereot, shoud pot be ead or praia! 1 by Sony ot feos ‘Tela or ener Inmauon straps arcs wiNou We rl pemouon e AUB wt arom ne condition is liable for legal action. % a i Oat te Lod Sabet ara onion hin aleatn: woe of ‘may be jht fo our notice which shall be taken care of in the next edition. Saba ene tb opener ny mops oon of ston wayne ayn may mane, Para i NIRALI FNS iy ‘Abhy Pragati, 1312 Shivaji Nagar, Of, Ras Bahn Nedinowa Center, PUNE - 411005, Te Fi 2551 DISTRIBUTION CENTERS PUNE ‘MUMBAI Pragati Books Pvt Ltd. Pragati Books Pvt. Lid. 119, Budhwar Peth,, wari Mandir Lane 385, S.V.P. Road, Rasdhara Co-op. 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Road, Opp. Hotel Roopali, Tel (020) 2445 2254 / 6609 2463 ‘Shivainagar, Pune 411004, Maharashira ‘Tel: (020) 2568 33721 6602 2728 Tel : (022) 2422 3526 | 6852 5254 Ermail: pocbombay@pragationine.com ‘www pragationiine.com pragatibooks@veninetCONTENTS CHAPTER 1: PERSONNEL 1L1to 122 1.0 Introduction ul 1.1 Qualification, Experience and Training ul 1.2 Responsibilities and Key Personnel 14 13 Personal Hygiene and Clothing Lz 14 Aspects 19 1.5 Consultants 110 Documents and Formats 110 CHAPTER 2: SURROUNDING, BUILDINGS AND FACILITIES 2.1 to 2.15 2.0 Introduction 21 2.1 Principal Areas 22 2.2 Plumbing and Drainage systems 26 2.3 Lighting 26 2.4 Sewage, Refuse and Disposal of Waste 27 2.5 Washing and Toilet Facilities 28 2.6 Sanitation 28 2.7__Maintenance 29 Documents and Formats 2.10 CHAPTER 3: EQUIPMENT 3.1 to 3.14 3.0 Introduction 31 3.1 Design, Size, Location and Construction of Equipment 31 3.2 Equipment Identification 33 3.3. Equipment log 33 3.4 Cleaning and Maintenance of Equipment 34 3.5 Automatic, Mechanical and Electronic Equipment 34 3.6 Planned Preventive Maintenance Programme 34 Documents and Formats 3.5 CHAPTER 4: MATERIALS MANAGEMENT. 4.1 to 4.18 4.0 Introduction 41 4.1 Purchasing 41 4.2 Raw Materials 42 4.3. Packaging Materials 44 4.4 Intermediate and Bulk Products 45 4.5 Finished Products 45 4.6 Rejected and Recovered Materials 454.7 Recalled Products 46 48 Returned goods 46 49 Reagents and Culture Media 47 4.10 Waste Materials tg 4.11 Reference standards 0 4.12 Miscollancous Materials Documents and Formats CHAPTER 5 : QUALITY MANAGEMENT 5.1 to 5.58 5.0 Introduction 51 5.1 Quality Assurance 55 5.2 Components of @.A. 58 5.3 Good Manufacturing Practice 5.10 5.4 Quality Control 5.12 Documents and Formats BT CHAPTER 6 : MANUFACTURING OPERATIONS AND CONTROL __6.1 to 6.34 6.0 _Introduction 61 6.1 Sanitation of Manufacturing Premises 62 6.2 _Mix-ups and Cross Contamination 62 6.3 _ Processing of Intermediates and Bulk products 65 64 Packaging Operations 66 65 LP.Q.C. 67 86 Relonso af Finished Product 68 er _P Doviati ao 68 _Charge-in of Components 69 BG sine atlas P an 6.10 Drug product Inspection 6.11 6.11 Expiration Dating 6.11 6.12 Calculation of Yields 6.11 ais PB sia Ried RAGA Documents and Formats JCB CHAPTER 7: DOCUMENTATION AND RECORDS CS. to 7.6 10 Introduction T1 1.1__ Specifications 15 : z 7.4 Important SOPs and Records 7:10 7.5 Change Control Tm ‘16 Site Master File 12CHAPTER 8 : PHARMACEUTICAL VALIDATION 8.1 to 8.108 8.0 Introduction 81 8.1 Validation of Buildings and Facilities 89 8.2 Validation of Equipment 8.13 83 Process Validation 8.20 84 Cleaning Validation 8.22 8.5 Validation of Analytical Methods 8.28 8.6 Validation of Computer Systems 8.31 8.7 Validation of Specific Dosage Forms 8.36 88 Calibration Master Plan 8.38 89 Validation Master Plan 8.42 Documents and Formats 8.44 CHAPTER ’9 : OUTSOURCING 9.1 to 94 9.0 Introduction 91 9.1 Manufacturing and Packaging Outsourcing 92 92 Analytical Outsourcing 94 93 Other Services Outsourcing 94 CHAPTER 10: POST OPERATIONAL ACTIVITIES 10.1 to 10.8 10.0 Introduction 10.1 10.1 Distribution 10.1 10.2 Recalled Products 10.2 10.3. Returned Products 103 10.4 Complaints and Adverse Effects 10.4 10.5 Drug Product Salvaging 10.6 Documents and Formats 10.6 CHAPTER 11 : SITE AND PLANT SECURITY 11.1 to114 11.0 Introduction t 11.1 Security Personnel 1. 11.2 Entry to Site 112 11.3 Entry to Plant Buildings 112 114 Internal Security 113 11.5 Current Issues 113 CHAPTER 12: SAFETY AND ENVIRONMENTAL PROTECTION 12.1 to 12.2 12.0 Introduction 12.1 12.1 Safety 12.1 12.2 Environmental Protection and Procedures 12.1 CHAPTER 18 : STERILE PHARMACEUTICAL PRODUCTS 18.1 to 13.60 18.0 Introduction 13.1 13.1 Personnel 13.313.2_Building and Premises 13.9 13.3_HVAC system. 13.10 13.4 Water and Steam System 13.11 13.5 Equipment 13.13 13.6 Processes 13.15 27 Starilizati 13.19 13.8 Quality Control 13.22 13.9 Sanitation 13.23. 13.10 Finishing of Sterile Products 13.24 13.11 Documentation #2... NB Documents and Formats 13.26 ABBREVIATIONS LIST A1-A2 GLOSSARY G1-G8 REFERENCES R1-RS INDEX 11-16 oooChapter 1... PERSONNEL 1,0 INTRODUCTION Managements basic job is the effective utilization of people, which they have, to achieve from the organisational objectives. It is through the combined efforts of personnel that technological, financial, physical and other resources are utilized. Without human efforts, no organisation can achieve their objectives. Therefore, motivation of people is of utmost importance everywhere. Pharmaceutical manufacturers, manufacture quality medicines using various resources, in this, human resource is the most important. The quality of medicine depends upon the quality of people who produce them. The regulatory guidelines talks about many things, about people. Some of these are as follows : (i) People must be qualified, experienced and trained. (ii) They must be sufficient in number. (iii) Their job responsibilities must be well explained to them and monitored. (iv) They must follow hygienic practices and finally, (v) They must be highly motivated. All the above points will be discussed in this chapter. Document required Nil 1.1 QUALIFICATION, EXPERIENCE AND TRAINING Once I had an opportunity to speak to Dr. M. Venkashwaralu, the Dy. Drug controller of India, Mumbai, about why organisations fail in regulatory inspections ? He laughed and said, "Potdar, people feel that good buildings, costly equipment and a few cleverly designed formats is the key to success in regulatory inspections, but they forget the most important factor of success, and that is the people. The people behind every thing is the only one important factor in any success story. And I can tell you, assuredly, that any organisation who has well qualified, experienced, trained and motivated people, will never fail any regulatory inspections, I only wish that, organisations realise this thing and work on it". I still remember his words. They were just engraved in my mind forever. All regulatory requirements talk about the importance of right people, who are appropriately qualified, experienced and trained. Let us go little more in this and see what it is. The W.H.O. guidelines on G.M-P. opens the chapter on "Personnel", saying - The establishment and maintenance of a satisfactory system of quality assurance and the correct 11Pharmaceutical Quality Assurance 12 Personnel manufacture and control of pharmaceutical products and active ingredients rely upon people. For this reason there must be sufficient qualified personnel to carry out all the tasks for, which the manufacturer is responsible. Individual responsibilities should be dearly understood by the individual concerned and recorded as written descriptions. It further adds that, all personnel should be aware of the principles of GMP that affect them. The M.C.C. South Africa further emphasises on following things, it states that, there should be sufficient personnel at all levels with the ability, training, experience and where necessary, the professional / technical qualifications and managerial skills appropriate to the tasks assigned to them. If we distill the above comments of the W.H.O. and M.C.C, we get the following points coming out from the distillate. (People must have appropriate technical/professional qualifications, (ii) They must be trained. (ii) They must have sufficient relevant experience. (iv) They must have ability to perform the given task at given level. (v) They must have appropriate managerial skills, Let us now try to look into the above five points : () Appropriate Technical / Professional Qualifications : W.H.O. guidelines on GMP give some guidelines on the qualifications e.g. it states that, the education should include study of an appropriate combination of (a) Chemistry (analytical and organic) or biochemistry, (b) Chemical engineering, (c) Microbiology, (d) Pharmaceutical science and technology, (e) Pharmacology and toxicology, (f) Physiology, (g) Other related sciences ete. I personally think this guideline is quite elaborate, hence we can think of people with following qualifications for relevant areas of operation viz., (a) Pharma production : B. Pharm, M. Pharm, Ph.D, B. Sc. (Tech), M. Se, (Tech), Ph. D. (Tech) () Q.A/Q. 0. : B.Pharm, M. Pharm, Ph.D, B. Se. (Tech), M. Se. (Tech), Ph. D. (Tech) B. Sc., M. Sc, Ph. D. (in analytical chemistry, organic chemistry, biochemistry, pharmaceutical chemistry, microbiology etc.) (©) Other areas : P.G. Diploma in Packaging Technology. Relevant area qualifications like B.E/M.E. in Mech. Electrical electronics, chemical ete. for engineering work. Qualified people in materials management for stores and purchase function ete. (4) Managerial : Appropriate technical qualifications must be backed with formal managerial qualifications such as M.B.A/P.G.D.B.A in appropriate specialisation.a You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.a You have either reached a page that is unavailable for viewing or reached your viewing limit for this book.Pharmaceutical Quality Assurance 15 Personnel Ideally a job description must contain knowledge about : (Organisational position giving reporting relationships i.c. clearly mentioning, who reports to him and he will report to whom ? Gi) Individual assignments. (ii) Job summary — what the job entails. (iv) Working conditions, hazards of the job. (v) Duties, responsibilities and accountability. The regulatory authorities expect all important positions must have written, authorised and accepted job descriptions. (2) Key Personnel : ‘Most regulatory guidelines define the key personnel and job descriptions of some of the key personnel. Key personnel can be defined as those positions in the organisation, which have a direct impact on the working of the organisation and quality of the products produced. Different regulatory guidelines have different positions mentioned as Key-personnel. Following is a brief matrix on the same. Sr.No. Positions India | UK | Aust. | WHO| SA | USA 01 | Head of Production - ¥ Y v “ 02 | Head of QC. = v v Y v ss 03 | Head of Q.A. a si ms zs v 2 04 | Head of Sales and Distribution | — - - - - 05 _ | Authorised person = - - “ - - 06 | Managing Director = = - - v - So totally there are six different key-personnel identified in regulatory literature but only two of these positions have been described in detail ic. head of production and hend of Q. C. However other regulatory literature randomly mentions the importance of these positions without calling them key personnel. Now let us see the Job profiles of the two key-personnel described in the literature. It is expected that all the key personnel should have appropriate qualifications and sufficient, suitable experience to carry out their responsibilities, The South African guide lines specifically lay down a requirement that the Managing Director of the Pharmaceutical Company should be a pharmacist residing in South Africa and registered with the Pharmacy Couneil. (A) The Head of Quality Control He generally has the following responsibilities : (a) To approve or reject starting materials, packaging materials and intermediate, bulk and finished products.Pharmaceutical Qualty Assurance 16 Personnel (b) To evaluate batch records. (©) Toensure that all necessary testing is carried out. (d) To approve sampling instructions, specifications, test methods, and other quality control procedure. (e) To approve and monitor analysis carried out under contract. () To check the maintenance of the department, premises and equipments. (g) To ensure that the appropriate validations, including those of analytical procedures and calibrations of control equipment are done. (h) To ensure that the required initial and continuing training of quality control personnel is carried out and adopted according to need. () To establish, verify and implement all quality control procedure. (B) The Head of Production He generally has the following responsibilities : (a) To ensure that products are produced and stored according to the appropriate documentation in order to obtain the required quality. (b) To approve the instructions relating to production operations, including in process controls, and to ensure their strict implementations. (©) To ensure that. production records are evaluated and signed by a designated person before they are made available to the quality control department. (d) To check the maintenance of the department, premises and equipment, (@) To ensure that appropriate process validations and calibrations of control equipment are performed and recorded and the reports are made available. () To ensure that the initial and continuing training of production personnel is carried out and adapted according to need. (C) Joint Responsibilities of Q.C. and Production Heads Following are some of the joint responsibilities of the heads of production and quality control. (a) To authorise written procedures and other documents including amendments, (b) To monitor and control the manufacturing environment. (© Plant hygiene. (@) Process validations and calibrations of analytical apparatus. (e) Training, including the applications and principles of quality assurance. () The approval and monitoring of supplies of materials. (g) The approval and monitoring of contract manufacturers. (h) The designing and monitoring storage conditions for materials and products. (i) The retention of records @_ The monitoring of compliances with GMP requirements (k) The inspection, investigation and taking of samples, in order to monitor factors that may affect product quality.Pharmaceutical Quality Assurance 17 Personne! In connection with key-personnel, following few remarks in regulatory literature must be kept in mind. () The firm must have an organisation chart. (ii) People in key positions should have specific tasks recorded in written job descriptions and adequate authority to carry out their responsibilities. (iii) The duties of key personnel may be delegated to designated deputies of a satisfactory qualification level. (iv) There should be no gaps or unexplained overlaps in the responsibilities of those personnel concerned with application of GMP. (y) The responsibilities placed on any one individual should not be so extensive as to present any risk to quality. (vi) The person responsible for production and the person responsible for quality assurance should be different persons of equal level of authority, neither of whom should be responsible to other but both have a responsibility for achieving requisite quality. (vii) Key personnel show be provided with adequate supporting staff. Documents Required (i) Job descriptions of Key-personnel plus other positions. eg. Head of @. C. Head of . A. Head of Production. Head of Sales and Distribution Authorised Person. Managing Director. 1.3 PERSONAL HYGIENE AND CLOTHING ‘We have opened the chapter on personnel by emphasising the importance of people in the manufacturing of pharmaceuticals. We said earlier that people engaged in the manufacturing of drugs and pharmaceuticals should be qualified, experienced and trained, we now add the fourth dimension i.e. the persons engaged in manufacturing of drugs and pharmaceuticals must also be healthy and not only healthy, but they themselves have good hygienic and sanitational habits and also propogate the same to others. Because maintaining a high level of hygienic conditions in manufacturing environment is a must. With these things in mind, the regulatory guidelines provide following guidance to the manufacturer. () High standare: of personal cleanliness should be observed by all those concerned with production processes. Additional specific and stringent requirements must be kept in mind for people employed in sterile ~ products manufacturing. Gi) Habit of hand washing must be inculcated in all the employees. (ii) Organisation should develop detailed hygiene programmes for their employees and such programs must be implemented.