THE GMP HANDBOOK g o o d m a n u fac t u r i n g p r ac t i c e quality systems for the pharmaceutical industry Ke y2 C om pl ia nc e AB by Anna Lundén ANNEXES Key2Compliance AB
Annexes - Content Annexes - Content A Requirements for procedures and records in 4 each respective GMP The symbols at the margins in the chapters of the handbook refer to the specific minimum requirement from the three different GMP texts. These requirements are shown here with referrals to their respective paragraph in the separate GMPs. B Referral to the requirements for verification of a 17 second individual (or equivalent systems) In the different GMP texts there are specific referrals to different forms of verifications or double checks of a second individual that is presented in this annex. C Reference matrix ISO 9001 and GMP-texts 18 In this matrix, the starting point is ISO 9001 and for each section there are references to corresponding requirements in the different GMPs. This matrix can be used as a supporting tool when a comprehensive quality system shall be designed with the ISO principles as a basis. 3
The GMP Handbook quality systems for the pharmaceutical industry Annexes Annex A. Requirements for procedures and records in each respective GMP The symbols at the margins in the chapters refer to the specific minimum requirement from the three different GMP texts. These requirements are shown here with referrals to their respective paragraph in the separate GMPs. EU GMP Guide Part I Requirements Procedures Records Description Identification Managerial/individual responsibilities 1.04, 1.05, 1.07 Chap 2 Principle 2.03 Processing/packaging procedures 1.04, 4.17, 4.18 Release procedure and QP certification 1.04, 4.27 1.04, 1.09, 2.06 Self-Inspection 1.01, 4.29, 9.01 4.29, 9.03 Quality Manual 1.07 Sampling, inspection and testing of starting 1.09, 4.22, 4.25, 1.09, 4.22, 4.26, materials, intermediate, bulk, and finished product 4.26, 6.07, 6.11, 5.38, 6.07, 6.11, 6.12, 6.15, 6.18 6.16, 6.17, 6.18 Environmental/media monitoring 1.9, 4.29 3.19, 4.29, 5.43, 6.07 Product Quality Review 1.10 (according to 4.29) 1.10, 4.29 Ongoing review of corrective and preventive actions 1.04, 1.11 1.04, 1.11 Risk management (procedure not mentioned 1.12 1.12 but may be requested) Organisation chart 2.02 Evaluation of production records of Production 2.07 department Training 2.11, 4.29 2.11, 4.29 6.13 4
2016 Key2Compliance AB Annex A EU GMP Guide Part I (cont.) Requirements Procedures Records Description Identification Personnel hygiene, health, and clothing 2.15, 2.16, 4.29 4.29 Information about consultants 2.23 Premises - cleaning, disinfection and identification Equipment - use, cleaning and identification 3.36, 4.29, 4.30, 5.21 Calibration, maintenance, and checking 3.41, 4.29, 6.07 3.41, 4.29, 4.31, 6.07 3.02, 4.29, 5.21 4.29, 5.21 3.21, 5.12, 5.13 4.29, 4.31, 5.21 3.42, 3.44, 5.12, 5.13 Sanitising of water systems 3.43 Site Master file Chap 4 Principle Computerized systems 4.01 Alterations in documents 4.09 Justification for retirement of records 4.12 Specifications for starting and packaging 4.13, 4.14, 6.07 materials Specifications for finished products 4.13, 4.16, 6.07 Specifications for intermediate and bulk products 4.15, 6.07 Packaging instructions 4.19 Batch processing records 4.20 1.08, 4.20 Batch packaging records 4.21 4.21 Internal labeling 4.24 Distribution records 1.08, 4.28, 8.23 5
The GMP Handbook quality systems for the pharmaceutical industry Annexes EU GMP Guide Part II Requirements Procedures Records Description Identification Rational for point of beginning 1.2 System for quality management 2.11 Persons authorised to release 2.14 Notification to management 2.18 Risk management (procedure not mentioned 2.21 2.21 but may be requested) Responsibilities of quality unit 2.32 Responsibility for production 2.40 Internal audits/self inspection 2.50 2.51 Product quality review 2.60, 2.61 Personnel responsibilities 3.11 Training 3.12 Records on consultants 3.31 Utility systems 4.20 Water quality specifications 4.32 Validation and qualification 4.33, 4.41, 5.40, 4.33, 4.41, 5.40, 5.41, 8.45, 12.10, 5.41, 5.42, 8.45, 12.20, 12.30, 12.22, 12.23, 12.80, 18.51 12.30, 12.80, 12.83, 18.51 Inactivation and cleaning 4.41 Prevention of cross-contamination 4.42 8
2016 Key2Compliance AB Annex A EU GMP Guide Part II (cont.) Requirements Procedures Records Description Identification Sewage and refuse 4.60 Sanitation and cleaning of buildings and facilities 4.71 Use of rodenticides etc. 4.72 Drawings for equipment and installations 5.16 4.23, 7.23 Equipment maintenance 5.20 6.20, 6.21 Cleaning and release of equipment 5.21, 5.25, 19.30 6.20, 6.21 5.26, 8.16 Calibration of equipment 5.30, 19.30 5.32, 6.61 5.33 Changes to data 5.43 Operation and maintenance of computerized systems 5.44 5.46, 5.48 Changes to computerized systems 5.47 5.47 Document control 6.10 2.15 Retention of documents 6.12 Specifications and acceptance criteria 6.17, 7.12, 9.11, 11.13 6.30, 7.13 Equipment cleaning and use record 6.20 Master production records 6.40, 6.41 Handling, storage, test and use of material 6.41, 7.10 6.30 7.23, 7.24 Batch production record 6.50 6.50, 6.52 6.51 Documentation and investigation around deviations 6.53, 11.15 2.16, 5.46, 8.15, and failures 8.20 Batch and control record review 6.70 6.30, 6.60 9
The GMP Handbook quality systems for the pharmaceutical industry Annexes US 21 CFR 211 Key2Compliance Requirements Procedures Records Identification Responsibilities of QCU 211.22(d) Consultants 211.34 Cleaning and sanitation of buildings and facilities 211.56(b) Use of redenticides etc 211.56(c) Cleaning, sanitation, maintenance and inspection of equipment Calibration of equipment 211.68(a), 211.160(b) (4) 211.67(b) 211.67(c ), 211.182 Data back-up 211.68(b) Computer program validation 211.68(b) 211.68(b) Receipt, identification, sampling etc of components, containers and closures 211.80(a), 211.84(c), 211.160(a) 211.68(a), 211.182, 211.194(d) Component specifications 211.84(d)(2) 211.184(b) Containers and closures specifications 211.84(d)(3) & (5), 211.94(d) 211.184(a)&(b) 211.80(d), 211.84(c ), 211.89 Validation of suppliers test results 211.84(d) 211.84(d) Validation of depyrogenation processes 211.94 211.94 Production and process procedures 211.100(a) 211.100(b) Deviation from written procedures 211.100(b) Charge-in of components 211.101 211.101(b) Theoretical and actual yield 211.103 211.103 AB 12
2016 Key2Compliance AB Annex A US 21 CFR 211 (cont.) Requirements Procedures Records Identification Equipment identification 211.105 In-process controls and validation 211.110(a) 211.110(a) In-process specifications 211.110(b) Specifications, standards, sampling plans and testing 211.110(c ), 211.160(a), 211.194(a) 211.160(b) procedures 211.160(a)&(b), 211.165, 211.186(b) Rejected in-process material 211.110(d) Time limits 211.111 211.111 Contamination control 211.113(a) Contamination control, sterile products 211.113(b) Validation of aseptic and sterilization processes 211.113(b) 211.113(b) Reprocessing 211.115(a) Examination of packaging and labeling materials 211.122(a) 211.122(c ), 211.184 (b), 211.184(d) 211.122(d) Reconciliation of labeling 211.125(c) 122.125(e ) Issuance of labeling 211.125(f) Packaging and labeling 211.130 211.130(d)&(e ), 211.184(d) 211.130(b)&(c ) Drug product inspection 211.134(c ) Expiration dating 211.137(c )&(d ) Warehousing 211.142 13
2016 Key2Compliance AB Annex B Annex B. Referral to the requirements for verification of a second individual (or equivalent systems) In the different GMP texts there are specific referrals to different forms of verifications or double checks of a second individual that is presented in this annex. 21CFR210/211 211.67(b)(6) Inspection of equipment 211.101(c) Weighing of drug components 211.101(d) Adding of drug components 211.103 Calculation of yield 211.122(g)(3) Use of cut labeling 211.182 Equipment cleaning and maintenance 211.188(b)(11) Significant steps EU Guide to GMP Part I 4.18(c) Manufacturing equipment checks 4.19(f) Packing equipment checks 4.20(c)&4.21(c) Significant steps, e.g. weighing 5.38 Dispensed material 6.16 Test result calculations 6.17(g) Laboratory test result verification EU Guide to GMP Part II 5.21 Inspection of equipment 5.45 Entering critical data manually in computerized systems 6.52 Critical steps in production 6.60 Laboratory records 8.12 Critical weighing, measuring, or subdividing operations 8.13 Critical activities 9.44 Inspection of packaging and labelling facilities 17
The GMP Handbook quality systems for the pharmaceutical industry Annexes Annex C. Reference matrix ISO 9001 and GMP texts In this annex we have used the structure from ISO 9001:2015 as the base and correlated it to the corresponding requirements in the GMP s. Note that the requirements of the ISOstandard does not have the same degree of detail and not specifically require procedures and ISO 9001 4.4.1; 7.5.1 Requirement description Quality management system established 4.4.1 a, b Determining processes, sequence and their interaction 4.4.1 c,d,e,f Criteria, methods and resources for control of processes 4.4.1 f; Risk management 6.1 4.4.1 g Monitor, measure and analyze processes and act on the results. na Quality manual 4.4.2 Documented procedures and specifications 4.4.2 Records 5.1.1 f Top management shall communicate the importance of quality 5.2.1 ; Quality policy and quality objectives established by management 5.1.1 b; 6.2.1 5.2.2 Quality policy communicated and understood within the organization 18
2016 Key2Compliance AB Annex C records the same way as in the GMP s, but contains general principles for a complete quality management system. Requirements in the ISO standard where there is no equivalent in the GMP s have been omitted (eg requirements related to design and development). EU GMP PART I 21CFR210/211 EU GMP PART II Ch. 1, Principle; 1.1; 1.7 na 2.11; 2.19; 17.30 1.8(i) na 2.12 1.4(i)&(iv) na 2.12 Ch. 1, Principle; na 2.20-21 1.3; 1.12-13 5.20-21; Ch. 8, Principle; Ch. 1, Principle; 1.4(vi); 1.4(viii)&(ix); 1.10; 211.100; 211.180(e); 211.192 2.60; 6.71; 11.15; 15.12 2.8-9; Ch. 4, Principle; 6.2; 6.9; 6.26-36; 7.7 1.7; na na 4.32 Ch. 4, Principle 211.22(c)&(d); 2.12 211.100(a); 211.160(a) Ch. 4, Principle; 4.8 211.180 2.15; 6.14 1.5 na 2.11 Ch. 1, Principle; 2.4 na 2.19 Ch. 1, Principle; 1.5 na 2.10-11 19