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1 Production (23)1.A Sanitation (27)1.A.1 Organisational prerequisites (27)1.A.2 Sources of contamination (28)1.A.3 Responsibilities and implementation (29)

1.B Personnel hygiene (31)1.B.1 Clothing (31)

1.B.1.1 Clothing material (34)1.B.1.2 Design of the clothing (35)1.B.1.3 Preparation/Cleaning (39)1.B.1.4 Gowning procedure (40)

1.B.2 Code of Conduct (41)1.B.2.1 Personal hygiene (41)1.B.2.2 General requirements (42)1.B.2.3 Special requirements for clean rooms (42)1.B.2.4 Policies to be established (43)

1.B.3 Hand disinfection (44)1.B.4 Health requirements (45)1.B.5 Training (46)

1.C Production hygiene (47)1.C.1 Sources of contamination (50)

1.C.1.1 Premises and facilities (50)1.C.1.2 Starting materials (52)1.C.1.3 Packaging materials (52)1.C.1.4 Cleansing agents, disinfectants and aids (53)1.C.1.5 Equipment and utensils (54)1.C.1.6 Process gases (55)1.C.1.7 Ambient air (55)1.C.1.8 Processes (56)

1.C.2 Cleaning (56)1.C.2.1 Cleaning procedure for equipment (57)1.C.2.2 Cleaning procedure for rooms (57)

1.C.3 Disinfection (58)1.C.3.1 General procedure (58)

1.D Sanitation programme (61)1.D.1 Organisation of room cleaning (61)

1.D.1.1 Hygienic areas (61)

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1.D.1.2 General room cleaning (61)1.D.1.3 Cleansing agents and disinfectants (62)1.D.1.4 Cleaning process and aids (64)

1.D.2 Documentation (65)

1.E Environmental monitoring (67)1.E.1 General (67)1.E.2 Sampling plan (69)1.E.3 Establishment of limits and frequencies (70)

1.E.3.1 European requirements (70)1.E.3.2 US requirements (73)1.E.3.3 ISO standards (74)

1.E.4 Methods (75)1.E.4.1 Direct contact test (75)1.E.4.2 Measurement of airborne microbes (75)

1.E.5 Investigation areas (77)1.E.5.1 Surfaces (77)1.E.5.2 Air (78)1.E.5.3 Cleansing agents and disinfectants (80)1.E.5.4 Personnel (81)1.E.5.5 Utilities (82)

1.E.6 Evaluation (82)1.E.6.1 Report (82)1.E.6.2 Trend analyses (82)1.E.6.3 Measures when limit is exceeded (83)

1.F GMP in the production process (85)

1.G Weigh-in (89)1.G.1 Legal requirements (89)1.G.2 Weigh-in principles (91)

1.G.2.1 Product-specific weigh-in (92)1.G.2.2 Raw material-specific weigh-in (92)1.G.2.3 Central/local weigh-in systems (93)1.G.2.4 Manual weigh-in (93)1.G.2.5 Automatic weigh-in (94)

1.G.3 Weigh-in procedure (95)1.G.3.1 Allocation of raw materials (96)1.G.3.2 Weigh-in (96)1.G.3.3 Return (98)1.G.3.4 Allocation for production (98)1.G.3.5 Cleaning (98)

1.G.4 Documentation (99)

1.H Identification (101)1.H.1 Handling of labels (101)1.H.2 Labelling of starting materials (102)

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1.H.3 Labelling of equipment and containers (103)1.H.3.1 General (103)1.H.3.2 Rejection / Quarantine (104)1.H.3.3 Cleaning status (105)

1.H.4 Labelling of rooms (107)

1.I In-process control (109)1.I.1 Objectives (110)

1.I.1.1 Quality control (110)1.I.1.2 Process control (110)

1.I.2 Organisation and responsibilities (111)1.I.3 Carrying out (112)

1.I.3.1 Scope and kind of tests (112)1.I.3.2 Location (115)1.I.3.3 Sampling (115)1.I.3.4 Testing (116)

1.I.4 Documentation and evaluation of data (116)

1.J Prevention of cross-contamination (119)1.J.1 Causes of cross-contamination (119)

1.J.1.1 Rooms (120)1.J.1.2 Equipment (120)1.J.1.3 Processes (122)1.J.1.4 Personnel (122)

1.J.2 Measures to prevent cross-contamination (123)1.J.3 Manufacture of critical products (124)

1.K Deviations (127)1.K.1 Definition (127)1.K.2 Procedure (128)1.K.3 Responsibilities (130)1.K.4 Measures (130)1.K.5 Failure investigation report (131)1.K.6 Evaluation of measures (133)1.K.7 SOP “deviations” – (example) (135)1.K.8 Check-list for deviation handling (140)

1.L Reworking (145)1.L.1 Definitions (145)

1.L.1.1 Rework (145)1.L.1.2 Reprocessing (145)1.L.1.3 Recovery (145)

1.L.2 Procedure (146)1.L.2.1 Reasons for rework / reprocessing (146)1.L.2.2 Request for rework / reprocessing (146)1.L.2.3 Risk assessment (146)1.L.2.4 Responsibilities (147)

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1.L.2.5 Documentation requirements (147)1.L.2.6 Regulatory submission requirements (148)

1.L.3 Rework / Reprocessing of rejected products (148)1.L.4 Rework of returned products (152)1.L.5 Rework of products that have not been rejected (152)

1.M Warehouse and logistics (155)1.M.1 Regulatory requirements (155)1.M.2 Stock management system (156)1.M.3 Responsibilities (160)1.M.4 Personnel (160)1.M.5 Storage areas (161)

1.M.5.1 Size (161)1.M.5.2 Illumination (161)1.M.5.3 Incoming goods and dispatch (161)1.M.5.4 Sampling (162)1.M.5.5 Quarantine (163)1.M.5.6 Special storage areas (166)

1.M.6 Storage conditions (167)1.M.6.1 Temperature and humidity (167)1.M.6.2 Monitoring (167)1.M.6.3 Deviation handling (170)

1.M.7 Sanitation and pest control (170)1.M.8 Material Flow (172)

1.M.8.1 Stock rotation (172)1.M.8.2 Reconciliation (173)1.M.8.3 Storage systems (173)

1.M.9 Process Flow (176)1.M.9.1 Receipt (176)1.M.9.2 Identification (179)1.M.9.3 Dispatch and transport (181)

2 Packaging (183)2.A Packaging material (185)2.A.1 Responsibilities (186)2.A.2 Contents (186)2.A.3 Materials (186)2.A.4 Protection against counterfeit medicinal products (190)2.A.5 Packaging material testing (191)

2.A.5.1 Control tests carried out at the supplier (191)2.A.5.2 Examples (192)2.A.5.3 Defect evaluation lists (193)2.A.5.4 Storage (195)2.A.5.5 Labelling (196)

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2.B Packaging process (199)2.B.1 Allocation of packaging material (200)2.B.2 Line clearance (201)2.B.3 Labelling (204)2.B.4 Control functions (204)2.B.5 Release for production (206)2.B.6 In-process controls (213)

2.B.6.1 Organisation (213)2.B.6.2 Function inspections (216)2.B.6.3 Checking (partially) packed goods (218)

2.B.7 Cleaning primary containers (219)2.B.8 Labelling (219)2.B.9 Variable data (220)2.B.10 Imprints (221)2.B.11 Reconciliation (222)2.B.12 Safety features (224)2.B.13 Completion of a packaging process (224)

2.C Qualification of a packaging line (225)2.C.1 Master qualification plan (226)2.C.2 Design qualification (DQ) (232)

2.C.2.1 Design qualification protocol (232)2.C.2.2 Design qualification report (234)

2.C.3 Installation qualification (IQ) (248)2.C.3.1 Installation qualification protocol (248)2.C.3.2 Installation qualification report (253)

2.C.4 Operational qualification (OQ) (258)2.C.4.1 Operational qualification protocol (258)2.C.4.2 Operational qualification report (263)

2.C.5 Performance qualification (PQ) (270)2.C.5.1 Performance qualification protocol (270)2.C.5.2 Performance qualification report (273)

3 Laboratory and Analytical Controls (277)3.A Sampling (281)3.A.1 Requirements (282)

3.A.1.1 Personnel (282)3.A.1.2 Equipment (282)3.A.1.3 Containers (283)3.A.1.4 Premises (283)

3.A.2 Sampling plan (instructions) (283)3.A.3 Notes for the sampling process (288)

3.A.3.1 Containers and identification labeling (288)3.A.3.2 Sampling report (288)3.A.3.3 Reference samples (289)

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3.B Reagents (291)3.B.1 Labeling (292)3.B.2 Usage and stability (292)3.B.3 Documentation (294)

3.C Standards and reference substances (297)3.C.1 Definition of different standards and their areas of use (297)3.C.2 Handling, storage and stability (301)

3.D Qualifying laboratory instruments (305)3.D.1 Qualification protocols and reports (305)

3.D.1.1 Design qualification (DQ) (306)3.D.1.2 Installation qualification (IQ) (308)3.D.1.3 Operational qualification (OQ) (308)3.D.1.4 Performance qualification (PQ) (308)

3.D.2 System suitability test (SST) (309)

3.E Calibration in the lab (311)3.E.1 Definitions (311)

3.E.1.1 Persons (311)3.E.1.2 Instruments (311)3.E.1.3 Working (312)3.E.1.4 Laboratory Equipment Inventory List (313)

3.E.2 Calibration instructions and record (314)3.E.2.1 Test intervals, test points, test instructions (314)

3.E.3 Examples (315)3.E.3.1 Balance (315)3.E.3.2 Volume measuring instruments (317)3.E.3.3 Photometer (319)3.E.3.4 HPLC system (321)

3.E.4 Decision (330)3.E.4.1 Requirements, tolerances, specifications (330)3.E.4.2 Equipment release (330)3.E.4.3 Out of calibration (330)

3.F Validation of analytical methods (331)3.F.1 Principles (331)3.F.2 Definitions of the parameters (333)

3.F.2.1 Precision (333)3.F.2.2 Accuracy (333)3.F.2.3 LOD = Limit of Detection (334)3.F.2.4 LOQ = Limit of Quantitation (334)3.F.2.5 Selectivity (335)3.F.2.6 Linearity, Range (335)3.F.2.7 Robustness (335)

3.F.3 Documentation (336)3.F.4 Revalidation (336)

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3.G Stability testing (339)3.G.1 ICH guidelines for stability tests (340)3.G.2 Storage and storage conditions (342)

3.G.2.1 Standard storage conditions (342)3.G.2.2 Packaging (345)3.G.2.3 Sample quantities (346)3.G.2.4 Stress test (346)3.G.2.5 Freeze test (347)3.G.2.6 Temperature cycling test (348)3.G.2.7 Special storage conditions for drug products (348)3.G.2.8 Labeling (350)

3.G.3 Analyses (351)3.G.3.1 Test parameters (352)3.G.3.2 Reference samples (353)3.G.3.3 Consumption test (353)3.G.3.4 Compatibility test for injection solutions for infusions (353)3.G.3.5 Analysis of compatibility of rubber stoppers and plastic components (353)3.G.3.6 Photostability (ICH Q1B) (354)3.G.3.7 Microbiological analyses (356)3.G.3.8 Analysis of standing times (357)3.G.3.9 Analysis of transport conditions (357)

3.G.4 Reduction of the study design (358)3.G.4.1 Bracketing (359)3.G.4.2 Matrixing (359)

3.G.5 Stability testing in the marketing phase (362)3.G.5.1 Follow-up stability testing (FuST) (362)3.G.5.2 Stability commitment (SC) (363)

3.G.6 Defining the retest period for an active pharmaceutical ingredient and the shelf life for a drug product through evaluation of stability data (ICH Q1E) (375)

3.G.6.1 Data evaluation for the retest period for APIs and shelf life for drug products that are intended for storage at room temperature (375)

3.G.6.2 Data evaluation for retest period for APIs and shelf life for drug products intended for storage in refrigerator (2–8 °C) (377)

3.G.6.3 Data evaluation for retest period for APIs and shelf life for drug products for intended storage in a freezer (–20 °C) (378)

3.G.7 Decision tree for data evaluation for retest period or for APIs or drug products (excluding frozen products) (378)

3.G.8 Procedure for statistical analysis (378)3.G.9 Examples of the statistical evaluation of stability data (380)

3.G.9.1 Data analysis for a single batch (380)3.G.9.2 Data analysis of one attribute in each batch for several batches of

the same product (known as One-Factor, Full-Design Studies) (381)

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3.G.9.3 Data analysis of all attributes for several batches (Multi-Factor, Full-Design Studies) (382)

3.H Out-of-specification results (383)3.H.1 Significance (383)

3.H.1.1 The BARR Laboratories case (383)3.H.1.2 The consequences (385)

3.H.2 Definitions (386)3.H.3 FDA OOS Guidance (386)3.H.4 Example for handling of an OOS result (394)3.H.5 Trend tracking (395)

3.I Raw data documentation (403)3.I.1 Principles (403)3.I.2 Single sheet documentation system (405)

3.I.2.1 Cover sheet (405)3.I.2.2 Data sheet (405)3.I.2.3 Index sheet (409)

3.J Batch release (411)3.J.1 Certification by a Qualified Person and release

in accordance with EC GMP Guidelines (414)3.J.1.1 Regulations contained in Directive 2001/83/EC (414)3.J.1.2 Objectives of appendix 16 (415)3.J.1.3 Cases of application (416)

3.J.2 Responsibility for issuing the release (418)3.J.3 Publication of release (419)3.J.4 Release procedures in practice (420)

3.K Microbiological testing (423)3.K.1 Total microbial count (424)

3.K.1.1 Determination of the total microbial count (432)3.K.1.2 Product testing (438)3.K.1.3 Culture media and culture media checks (440)3.K.1.4 Incubation (443)3.K.1.5 Evaluation (443)3.K.1.6 Validation of the method (445)

3.K.2 Specified microorganisms (446)3.K.2.1 Detection of specified microorganisms (452)3.K.2.2 Detection method for the specified microorganisms (454)3.K.2.3 Evaluation (463)3.K.2.4 Culture media and culture media tests (464)3.K.2.5 Suitability test of the method (validation of the methods) (469)

3.K.3 Testing frequencies (470)3.K.3.1 Preparations (470)3.K.3.2 Raw materials (471)

3.K.4 Miscellaneous tests (474)

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3.K.4.1 Monitoring of the hygiene status (474)3.K.4.2 Aseptic working conditions (477)

4 Documentation (479)4.A Official requirements (481)4.A.1 GMP-requirements managed and reviewed

according to German pharma business regulations (481)4.A.2 Requirements of the EU GMP Guideline (484)4.A.3 Requirements of the US GMP Regulations (488)4.A.4 Formal requirements (493)4.A.5 Management and revision documentation (497)

4.B GMP-conforming documentation (501)4.B.1 Handwritten entries (501)4.B.2 Archiving (502)4.B.3 Master-SOP – “GMP-conforming documentation” (503)

4.C Batch documentation (509)4.C.1 Manufacturing instructions/record (511)

4.C.1.1 Manufacturing instructions (511)4.C.1.2 Batch processing record (512)4.C.1.3 Master of manufacturing instructions/batch processing record (514)

4.C.2 Packaging instruction and batch packaging record (534)4.C.2.1 Packaging instruction (534)4.C.2.2 Batch packaging record (535)

4.C.3 Electronic batch recording (536)4.C.3.1 Strategic objectives of an Electronic Batch Recording System (EBRS) (537)4.C.3.2 GMP aspects (537)

4.C.4 Testing procedures and test protocol (539)4.C.4.1 Testing procedures (539)4.C.4.2 Test protocol (541)

4.C.5 Batch record review (544)4.C.5.1 Regulatory requirements (544)4.C.5.2 Benefits of an independent batch record review (544)4.C.5.3 Responsibility and competencies (545)4.C.5.4 Scope of a batch record review (545)4.C.5.5 Deviations, changes relevant to marketing authorization,

recording errors (546)

4.D Standard operating procedures (SOPs) (549)4.D.1 Compilation (550)

4.D.1.1 Design and format (552)4.D.1.2 Identification (554)

4.D.2 Approval and implementation (555)4.D.3 Training (555)4.D.4 Usage (556)

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4.D.5 Review (557)4.D.6 Changes (557)4.D.7 Withdrawing an operating procedure (558)4.D.8 Administration (558)

4.D.8.1 Status identification (558)4.D.8.2 Distribution (558)4.D.8.3 Integration (559)4.D.8.4 Use of computerized systems (559)

4.D.9 Archiving (560)4.D.10 Example of an SOP “Compilation and

administration of operating procedures” (561)

4.E Site master file (577)4.E.1 Introduction (577)4.E.2 Design (577)

4.E.2.1 General information (578)4.E.2.2 Personnel (579)4.E.2.3 Premises and equipment (580)4.E.2.4 Documentation (583)4.E.2.5 Production (585)4.E.2.6 Quality control (586)4.E.2.7 Contract manufacturing and analysis (586)4.E.2.8 Distribution, complaints and product recall (587)4.E.2.9 Self-inspection (588)4.E.2.10 Appendix (589)

4.F Annual product review / Product quality review (591)4.F.1 Documents required for an annual product review (594)4.F.2 Annual product review report (596)4.F.3 Collaboration with a contract manufacturer (598)4.F.4 Example: annual product review (599)4.F.5 Master-SOP for the annual product review (604)

Index (609)