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Contents

File 1 to 3 1

1.A 1.A.1 1.A.2 1.A.3 1.A.3.1 1.A.3.2 1.A.4 1.A.5 1.B 1.B.1 1.B.1.1 1.B.1.2 1.B.1.3 1.B.1.4 1.B.1.5 1.B.1.6 1.B.2 1.B.3 1.B.3.1 1.B.3.2 1.B.3.3 1.B.3.4 1.C 1.C.1 1.C.1.1 1.C.1.2 1.C.1.3 1.C.1.4 1.C.1.5 1.C.1.6 1.C.1.7 1.C.2 1.C.2.1 1.C.2.2

Quality Management

Quality management in the pharmaceutical environment Quality assurance in the GMP regulations From quality assurance to quality management Position of quality assurance in the company Quality Unit as a staff function Quality Unit as a matrix function Responsibility of the Quality Unit Tasks of a Quality Unit Documentation of a QM system Structure of a documentation system Management board level Management/superiors Staff level Quality unit documents Procedure description and procedure instruction Operating procedure Documents required in accordance with GMP Quality management handbook Site master file Handbook in accordance with EN ISO 9001:2000 Combined handbooks in accordance with GMP and ISO Functions of the quality management handbook Quality management system in accordance with GMP Management responsibility Responsibility of key personnel Responsibility of the management board Definition of quality policy Definition of quality objectives Support of the quality management system Deciding on resources Management review Change management system Definition of terms Processing of changes and deviations

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1.A (1) 1.A (3) 1.A (4) 1.A (4) 1.A (5) 1.A (7) 1.A (9) 1.B (1) 1.B (3) 1.B (4) 1.B (4) 1.B (4) 1.B (5) 1.B (6) 1.B (7) 1.B (9) 1.B (9) 1.B (11) 1.B (13) 1.B (17) 1.C (2) 1.C (2) 1.C (2) 1.C (5) 1.C (6) 1.C (6) 1.C (7) 1.C (8) 1.C (9) 1.C (9) 1.C (10)

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Contents

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1.C.2.3 1.C.2.4 1.C.3 1.C.3.1 1.C.3.2 1.C.3.3 1.C.3.4 1.C.3.5 1.C.3.6 1.C.4 1.C.4.1 1.C.4.2 1.C.5 1.C.5.1 1.C.6 1.C.6.1 1.C.6.2 1.C.6.3 1.C.6.4 1.C.7 1.C.7.1 1.C.7.2 1.C.7.3 1.C.7.4 1.C.8 1.C.8.1 1.C.8.2 1.C.8.3 1.C.9 1.C.9.1 1.C.9.2 1.C.10 1.C.10.1 1.C.10.2 1.C.10.3 1.C.10.4

Processing of OOS results Involvement of external companies Complaints and recall Definition of terms Processing of complaints Responsibilities Compilation of a standard operating procedure (SOP) Recall Trend analysis Corrective and Preventive Actions (CAPA) Definitions Quality management system for CAPA Risk management Aims of risk management Qualification and validation Tasks of the Quality Unit Tasks of the management board Quality management system for qualification Quality management system for validation Training Compilation of a standard operating procedure (SOP) Compilation of an annual program Compilation of a training plan Guaranteeing participation Inspection Compilation of a standard operating procedure Contents of the audit program Contents of an audit plan Batch record review and annual product review Batch record review Annual product review Qualification of suppliers and service providers Responsibilities Risk analysis for grading Carrying out Requalification

1.C (13) 1.C (14) 1.C (15) 1.C (15) 1.C (16) 1.C (16) 1.C (17) 1.C (21) 1.C (22) 1.C (22) 1.C (23) 1.C (23) 1.C (26) 1.C (27) 1.C (28) 1.C (29) 1.C (29) 1.C (30) 1.C (34) 1.C (35) 1.C (36) 1.C (36) 1.C (36) 1.C (37) 1.C (37) 1.C (38) 1.C (38) 1.C (39) 1.C (42) 1.C (42) 1.C (44) 1.C (45) 1.C (50) 1.C (50) 1.C (51) 1.C (54)

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2.A 2.B 2.B.1 2.B.2 2.C 2.C.1

Personnel

Place of work and job descriptions Requirements of the personnel Qualification requirements Health requirements Training Purpose of training

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2.C.2 2.C.3 2.C.4 2.C.5 2.C.6 2.C.6.1 2.C.6.2 2.C.6.3 2.C.7 2.C.8 2.D 2.D.1 2.D.1.1 2.D.1.2 2.D.1.3 2.D.2 2.D.2.1 2.D.2.2 2.D.3 2.D.3.1 2.D.3.2 2.D.4 2.D.4.1 2.D.4.2 2.D.5 2.D.5.1 2.D.5.2 2.D.6 2.D.6.1 2.D.6.2

Responsibility for training Requirements profiles/learning objectives Training contents and target groups Training planning Carrying out External factors Qualification of the trainer Training methods Reviewing the training and the training system Documentation

2.C (1) 2.C (2) 2.C (3) 2.C (4) 2.C (4) 2.C (4) 2.C (5) 2.C (5) 2.C (8) 2.C (11)

Function owners subject to public law Qualified Person (QP) 2.D (1) Requirements of the Qualified Person in accordance with European law 2.D (1) Area of responsibility of the Qualified Person in accordance with European Law 2.D (3) Organisational appointment/substitution regulations 2.D (7) Head of Production 2.D (12) Individual requirements for Head of Production 2.D (12) Areas of Responsibility of the Head of Production 2.D (12) Head of Quality Control 2.D (17) Individual Requirements for the Head of Quality Control 2.D (17) Areas of Responsibility of the Head of Quality Control 2.D (17) Qualified Person in Accordance with Article 103 of Guideline 2001/83/EC 2.D (21) Individual Requirements for the Qualified Person in Accordance with Article 103 2.D (21) Areas of Responsibility of the Qualified Person in Accordance with Article 103 of Directive 2001/83/EC 2.D (22) Scientific Service in Charge of Information 2.D (24) Individual Requirements for the Scientific Service in Charge of Information 2.D (24) Areas of Responsibility of the Scientific Service in Charge of Information 2.D (24) Medical sales representatives 2.D (26) Individual requirements for medical sales representatives 2.D (26) Areas of responsibility of the medical sales representative 2.D (26)

3

3.A 3.B 3.B.1 3.B.2 3.B.3 3.B.4 3.B.5 3.B.6

Premises

Official requirements General requirements Location, connection to other rooms Size, area, height Installation and supply of utilities Lighting, ventilation, air-conditioning Hygienic construction Room book and layout 3.B (2) 3.B (3) 3.B (3) 3.B (5) 3.B (5) 3.B (5)

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3.C 3.C.1 3.C.2 3.C.3 3.C.4 3.D 3.D.1 3.D.2 3.D.2.1 3.D.2.2 3.E 3.E.1 3.E.2 3.E.3 3.E.4

Material flow, personnel flow and layout Material flow Personnel flow Layout Design concepts in FDA's Sterile Drug Products Produced by Aseptic Processing guideline Room classes EU Aseptic Processing GMPs Critical areas in the FDA's Sterile Drug Products Produced by Aseptic Processing guideline Critical Areas Supporting Clean Areas Construction elements Walls Doors and windows Floors Ceilings Building services Room qualification Heating Ventilation Air Conditioning (HVAC) Introduction Room ventilation systems Pure (100%) external air conditioning system Central recirculating air/mixed air conditioning system Decentralized recirculating air/mixed air conditioning system with central external air preparation Pure recirculating air conditioning system Systems for tempering and volume flow regulation Control-systems of the air volume flows Utilities for the operation of room ventilation systems Filters Particle air filter Suspended matter filter ­ HEPA-Filter Air Filtration in the FDA's Sterile Drug Products Produced by Aseptic Processing guideline Principles for the design and planning of air conditioning ventilation systems Design criteria for the ventilation of premises Air technology design of a sterile room with negative pressure plenum Pressure stages and design of the pressure differential measurement for a sterile area Pressure Differentials in the FDA's Sterile Drug Products Produced by Aseptic Processing guideline

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3.C (1) 3.C (4) 3.C (4) 3.C (5) 3.D (1) 3.D (3) 3.D (3) 3.D (5) 3.E (1) 3.E (6) 3.E (8) 3.E (10)

Contents

3.F 3.G 3.H 3.H.1 3.H.2 3.H.2.1 3.H.2.2 3.H.2.3 3.H.2.4 3.H.2.5 3.H.2.6 3.H.2.7 3.H.3 3.H.3.1 3.H.3.2 3.H.3.3 3.H.4 3.H.5 3.H.5.1 3.H.5.2 3.H.5.3

3.H (1) 3.H (2) 3.H (3) 3.H (4) 3.H (5) 3.H (6) 3.H (7) 3.H (8) 3.H (8) 3.H (10) 3.H (11) 3.H (13) 3.H (20) 3.H (22) 3.H (27) 3.H (28) 3.H (29) 3.H (30)

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3.H.6 3.H.6.1 3.H.6.2 3.H.6.3 3.H.6.4 3.H.6.5 3.H.7

Maintenance of air ventilation systems Time intervals for carrying out inspections or servicing Tolerances for inspection and servicing deadlines Maintenance plan Forms for the inspection and servicing of ventilation systems Log book for air technology systems Qualification of air conditioning ventilation systems

3.H (36) 3.H (39) 3.H (40) 3.H (40) 3.H (41) 3.H (51) 3.H (53)

4

4.A 4.B 4.B.1 4.B.2 4.B.3 4.C 4.D 4.D.1 4.D.2 4.D.3 4.E 4.E.1 4.E.2 4.E.3 4.F 4.F.1 4.F.2 4.F.3 4.F.4 4.G 4.G.1 4.G.2 4.G.3 4.G.4 4.H 4.H.1 4.H.2 4.H.3 4.I 4.I.1 4.I.1.1 4.I.1.2

Facilities and Equipment

Introduction Mechanical components Construction and installation materials GMP-compliant design characteristics Electrical and pneumatic components Control 4.D (1) 4.D (2) 4.D (2) 4.E (1) 4.E (5) 4.E (12) 4.F (1) 4.F (2) 4.F (9) 4.F (12) 4.G (1) 4.G (3) 4.G (4) 4.G (5) 4.H (2) 4.H (2) 4.H (3) 4.I (1) 4.I (1) 4.I (2) 4.B (1) 4.B (2) 4.B (3)

Examples of facility qualification Design qualification Installation qualification Operational qualification Technical documentation Necessity Scope and content Administration of the technical documentation Log book Calibration Definitions Procedure Documentation Administration of scheduled calibration dates/ times Maintenance Types of maintenance GMP-conforming maintenance Systems for maintenance CIP (Cleaning in Place) Introduction Definition Cleaning mechanisms

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Facility concepts CIP (Cleaning in Place) Isolator technology Connected facilities

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4.I.2 4.I.2.1 4.I.2.2 4.I.3 4.I.3.1 4.I.3.2 4.I.3.3 4.I.3.4 4.I.3.5 4.I.3.6 4.I.4 4.I.4.1 4.I.4.2 4.I.4.3 4.I.5 4.I.5.1 4.I.5.2 4.I.5.3 4.I.5.4 4.I.6 4.J 4.J.1 4.J.1.1 4.J.1.2 4.J.2 4.J.3 4.J.4 4.J.5 4.J.5.1 4.J.5.2 4.J.5.3 4.J.5.4 4.J.5.5 4.J.5.6 4.J.6 4.J.7 4.J.7.1 4.J.7.2 4.J.7.3 4.J.8 4.J.8.1 4.J.8.2 4.J.8.3 4.J.8.4

CIP systems CIP facility for stack cleaning CIP facility for lost cleaning GMP-conforming design of CIP facilities Influences of the surfaces Requirements for pipes and tanks Requirements for bonding elements and seals Requirements for pumps Requirement for valves Requirements for measuring instruments Nozzle heads for container cleaning Spray ball Rotating nozzle head Targeted jet/orbital cleaner Measuring technology Flow measurement Pressure measurement Temperature measurement Conductivity measurement Realisation of cleaning systems Containment (personnel protection) in solids handling Significance Use of laminar flow units Working in the full protection suit Definition of terms Containment grades of products Measurement of the residue limits (OEL) Example of containment facility planning The FIBC (Flexible Intermediate Bulk Container) as a containment system Isolators as a containment system Transport and docking system for the FIBC Feasibility study (mock-up) Particle measurement of facilities in accordance with SMEPAC Documentation and results Containment weak points Containment systems for filling and emptying drums Drum filling with endless liner Drum filling and emptying with DCS (Drum Containment System) Big Bag emptying and filling with a protective liner system Container systems Container with outlet cone for discharging Containment Transfer Unit at the container inlet for filling Split valve systems Laminar flow, Glove box systems (isolators)

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4.I (3) 4.I (3) 4.I (4) 4.I (6) 4.I (6) 4.I (7) 4.I (8) 4.I (9) 4.I (10) 4.I (10) 4.I (11) 4.I (12) 4.I (12) 4.I (12) 4.I (13) 4.I (13) 4.I (13) 4.I (14) 4.I (14) 4.I (15)

4.J (1) 4.J (1) 4.J (2) 4.J (3) 4.J (3) 4.J (6) 4.J (7) 4.J (9) 4.J (10) 4.J (12) 4.J (12) 4.J (13) 4.J (15) 4.J (15) 4.J (16) 4.J (16) 4.J (17) 4.J (20) 4.J (23) 4.J (23) 4.J (24) 4.J (25) 4.J (26)

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4.J.9 4.J.10 4.J.10.1 4.J.10.2 4.J.11 4.J.11.1 4.J.11.2 4.J.11.3 4.K 4.K.1 4.K.2 4.K.3 4.K.4 4.K.5 4.L 4.L.1 4.L.1.1 4.L.2 4.L.2.1 4.L.2.2 4.L.3 4.L.3.1 4.L.3.2 4.L.4 4.L.4.1 4.L.4.2 4.L.4.3 4.L.5 4.L.5.1 4.L.5.2 4.L.6 4.L.6.1 4.L.6.2 4.L.7 4.L.7.1 4.L.7.2 4.L.7.3 4.L.7.4 4.L.7.5 4.L.8 4.L.8.1 4.L.8.2 4.L.9 4.L.9.1

Filter systems Sampling System 1: Sampling via a withdrawal screw fitted in the production area System 2: Sampling via a micro Powder Transfer System (MPTS) Containment on equipment Example 1: Shaft leadthroughs Example 2: Filling and discharging cone dryers Practical example of a containment API plant Process control systems Definitions Features of process control systems How to use process control systems Carrying out a process control system project Qualification of process control systems Hygienic (sanitary) design when using solids Introduction Weaknesses in facility planning Surfaces Product-contact surfaces Non-product-contact surfaces Material: stainless steel Coating of stainless steel surfaces Welds Connections Flange and quick release connections Flexible connections Screw connections Hoists and roller conveyors Hoists Roller conveyors Pneumatic conveyor system Vacuum conveyor with separator Powder transport system (PTS) Dosing systems Vibration dosing device Dosing screw Slide dosing gate (knife-gate) Flexidos dosing system Transbatch feeder Platforms and stands Platforms Stands Clean room installations Rail design

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4.J (27) 4.J (28) 4.J (28) 4.J (29) 4.J (30) 4.J (30) 4.J (31) 4.J (31) 4.K (1) 4.K (2) 4.K (5) 4.K (6) 4.K (7) 4.L (1) 4.L (2) 4.L (3) 4.L (3) 4.L (4) 4.L (6) 4.L (8) 4.L (8) 4.L (11) 4.L (11) 4.L (17) 4.L (19) 4.L (22) 4.L (22) 4.L (23) 4.L (25) 4.L (25) 4.L (26) 4.L (26) 4.L (27) 4.L (27) 4.L (27) 4.L (28) 4.L (28) 4.L (28) 4.L (28) 4.L (30) 4.L (31) 4.L (31)

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4.L.9.2 4.L.9.3

Control panels Cable ducts

4.L (32) 4.L (33)

5

5.A 5.A.1 5.A.2 5.A.2.1 5.A.3 5.A.4 5.A.4.1 5.A.4.2 5.B 5.B.1 5.B.1.1 5.B.1.2 5.B.1.3 5.B.1.4 5.B.1.5 5.B.1.6 5.B.1.7 5.B.1.8 5.B.2 5.B.2.1 5.B.3 5.C 5.C.1 5.C.1.1 5.C.1.2 5.C.1.3 5.C.1.4 5.C.1.5 5.C.2 5.C.2.1 5.C.2.2 5.C.2.3 5.C.2.4 5.C.3 5.C.3.1 5.C.3.2 5.C.3.3 5.C.3.4 5.C.3.5 5.C.3.6

Pharmaceutical Water

Water types Potable water Purified water Purified Water filled into containers (Packaged Purified Water) Highly purified water Water for injection Sterilized Water for Injection Water for Injection: special USP monographs Generation of pharmaceutical water Purified water (PW) Softener Removal of chlorine Reverse osmosis Electrodeionization (EDI, CDI) Ultra filtration Ion exchanger Purification plants Water for injection (WFI) Distillation technology Purification of pharmaceutical water treatment systems Distribution and storage of pharmaceutical water Loop Flow rate and turbulent flow Pipes Requirements of welds Dead end piping Use of plastics (PVDF) Fixtures Valves Sensors Sterile filter Sampling points Measuring technique Level measurement Flow measurement Conductivity measurement Pressure measurement Temperature measurement Ozone measurement (online)

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5.A (2) 5.A (3) 5.A (5) 5.A (5) 5.A (7) 5.A (8) 5.A (10) 5.B (2) Airbreak5.B (2) 5.B (2) 5.B (2) 5.B (4) 5.B (6) 5.B (8) 5.B (9) 5.B (9) 5.B (10) 5.B (11) 5.B (14) 5.C (1) 5.C (2) 5.C (3) 5.C (4) 5.C (5) 5.C (6) 5.C (6) 5.C (6) 5.C (7) 5.C (7) 5.C (7) 5.C (7) 5.C (8) 5.C (12) 5.C (15) 5.C (16) 5.C (18) 5.C (19)

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5.C.3.7 5.C.4 5.C.5 5.C.5.1 5.C.5.2 5.C.5.3 5.C.5.4 5.C.5.5 5.C.6 5.C.7 5.C.7.1 5.C.7.2 5.D 5.D.1 5.D.2 5.D.3 5.D.3.1 5.D.3.2 5.D.3.3 5.D.3.4 5.D.4 5.D.4.1 5.D.4.2 5.D.4.3 5.D.5 5.D.5.1 5.D.5.2 5.D.6 5.D.6.1 5.D.7 5.D.7.1 5.D.7.2 5.D.7.3 5.D.8 5.E 5.E.1 5.E.1.1 5.E.1.2 5.E.1.3 5.E.2 5.E.2.1 5.E.2.2 5.E.2.3 5.E.3

TOC measurement (online) Formation of biofilms Rouging What is rouging? Impact on the water quality Handling rouging How can you detect rouging? Measures against rouging Buffering of ultra pure water Loop with subloops Cleanability of the loop for purified water Valve groupings Qualification of water supplies Introduction Risk analysis Design qualification User requirements Technical specifications Test protocol Test record Installation qualification Facility documentation Test protocol IQ test record Operational qualification (OQ) Test protocol (OQ) Test record Transfer to the user Transfer report Process validation/performance qualification (PQ) Microbiological tests for pharmaceutical water Determination of alert and action limits Sampling Qualification report Operation of water supplies Procedures to reduce microbial counts Sanitization Sterilization procedure Disinfection Maintenance of a water supply Quality-relevant maintenance Safety-relevant maintenance Value-maintaining maintenance Calibration of measuring systems

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5.C (20) 5.C (21) 5.C (23) 5.C (23) 5.C (24) 5.C (24) 5.C (25) 5.C (26) 5.C (27) 5.C (29) 5.C (29) 5.C (30) 5.D (1) 5.D (3) 5.D (8) 5.D (8) 5.D (10) 5.D (13) 5.D (14) 5.D (17) 5.D (17) 5.D (20) 5.D (24) 5.D (28) 5.D (30) 5.D (32) 5.D (36) 5.D (36) 5.D (42) 5.D (42) 5.D (45) 5.D (46) 5.D (47) 5.E (1) 5.E (1) 5.E (2) 5.E (3) 5.E (4) 5.E (6) 5.E (8) 5.E (9) 5.E (10)

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5.E.4 5.E.4.1 5.E.5 5.E.5.1 5.E.5.2 5.E.6 5.E.6.1 5.E.6.2 5.F 5.F.1 5.F.2 5.F.2.1 5.F.2.2 5.F.2.3 5.F.3 5.F.3.1 5.F.3.2 5.F.3.3 5.F.3.4 5.F.3.5 5.F.3.6 5.F.4 5.F.4.1 5.F.4.2 5.F.4.3 5.F.4.4 5.F.4.5 5.F.4.6 5.F.4.7

Change control Major and minor changes Requalification Requalification after major changes Requalification after a defined interval Decommissioning/uninstalling Shutting down the water supply Disassembly work on the facility Pure steam systems Physical principles Quality requirements for pure steam Pharmacopeial requirements DIN EN 285 (1997-2) DIN 58950 part 7 (April 2003) Pure steam generation Degassing Natural circulation procedure Downdraft procedure Pure steam generator with external heat exchanger Separation systems Quality-relevant measuring points Pure steam distribution system Planning and layout Condensate drain Insulation Pressure reducing valve Safety valve Pipe connections Sampling cooler

5.E (11) 5.E (11) 5.E (13) 5.E (13) 5.E (13) 5.E (14) 5.E (14) 5.E (14) 5.F (1) 5.F (3) 5.F (3) 5.F (4) 5.F (5) 5.F (6) 5.F (6) 5.F (7) 5.F (8) 5.F (8) 5.F (9) 5.F (9) 5.F (10) 5.F (10) 5.F (15) 5.F (19) 5.F (19) 5.F (20) 5.F (21) 5.F (21)

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6.A 6.A.1 6.A.2 6.A.3 6.A.4 6.A.5 6.A.6 6.A.7 6.A.8 6.B 6.B.1 6.B.2 6.B.3

Qualification

Official requirements Legal aspects of qualification Documentation of the qualification Design Qualification (DQ) Installation Qualification (IQ) Operational Qualification (OQ) Performance Qualification (PQ) Qualification of established facilities Requalification Preparation of the qualification Commissioning Sequence Qualification team

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6.A (1) 6.A (4) 6.A (5) 6.A (8) 6.A (9) 6.A (10) 6.A (11) 6.A (13) 6.B (1) 6.B (5) 6.B (6)

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6.B.4 6.B.5 6.B.5.1 6.B.5.2 6.B.5.3 6.B.6 6.B.6.1 6.B.6.2 6.B.6.3 6.C 6.C.1 6.C.2 6.C.3 6.C.4 6.C.5 6.D 6.D.1 6.D.1.1 6.D.1.2 6.D.2 6.E 6.E.1 6.E.1.1 6.E.1.2 6.E.1.3 6.E.1.4 6.E.1.5 6.E.1.6 6.E.1.7 6.E.1.8 6.E.2 6.F 6.F.1 6.F.1.1 6.F.1.2 6.F.1.3 6.F.1.4 6.F.2 6.G 6.H 6.H.1

Responsibilities Qualification by external service providers Integration of external capacities ("consultants") into the qualification process Transfer of parts of qualification activities to consulting engineers Transfer of qualification activities to suppliers, acquisition of qualification packages Risk analysis Risk analysis during the life cycle of a facility Organization of risk analysis Implementation of the risk analysis Qualification documentation Qualification master plan Qualification plan Qualification report Labeling of the qualification status SOP ­ "Qualification of facilities and equipment" Design qualification (DQ) User requirements (user specifications) Example: Reaction vessel Example: Washer Technical specification Installation qualification (IQ) Examples of IQ plans Materials and lubricants Supply of (energy and media) utilities Measuring and control technology points and initial calibration Calibration records P & I diagrams Pipes Technical documentation IQ report Example: Fluid bed equipment Operational qualification(OQ) Examples of OQ plans Safety devices Risk analysis operating functions Check for the presence of screw caps OQ report Example: Fluid bed dryer Performance qualification (PQ) Special cases of qualification Retrospective qualification

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6.B (6) 6.B (6) 6.B (7) 6.B (7) 6.B (8) 6.B (10) 6.B (11) 6.B (12) 6.B (13) 6.C (2) 6.C (3) 6.C (9) 6.C (10) 6.C (11) 6.D (3) 6.D (5) 6.D (8) 6.D (12) 6.E (3) 6.E (4) 6.E (7) 6.E (9) 6.E (11) 6.E (13) 6.E (15) 6.E (17) 6.E (20) 6.E (22) 6.F (3) 6.F (4) 6.F (6) 6.F (8) 6.F (11) 6.F (13)

6.H (1)

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6.H.2 6.H.3 6.H.4 6.H.5

Requalification Content of a review Maintenance of the qualified status Qualification of simple equipment

6.H (2) 6.H (3) 6.H (5) 6.H (7)

7

7.A 7.A.1 7.A.1.1 7.A.1.2 7.A.1.3 7.A.1.4 7.A.2 7.A.2.1 7.A.2.2 7.A.2.3 7.A.2.4 7.A.2.5 7.A.2.6 7.A.2.7 7.A.3 7.A.3.1 7.A.3.2 7.A.3.3 7.A.4 7.A.4.1 7.A.4.2 7.A.4.3 7.A.5 7.A.5.1 7.A.5.2 7.A.5.3 7.A.5.4 7.B 7.C 7.C.1 7.C.2 7.C.3 7.D 7.D.1 7.D.2 7.D.2.1 7.D.2.2

Process Validation

Official requirements Regulative Aspects Legal requirements for drug products Responsibilities GMP Requirements Aspects regarding marketing authorization Principles of process validation Process understanding Type and scope of process validation Traceability of validation investigations Manufacturing under routine conditions Bracketing (product group formation) Challenge tests Deviations Types of validation Prospective validation Concurrent validation Retrospective validation Revalidation Validation master plan Validation protocol and report Archiving Maintaining the validation status General conditions and prerequisites Principles of statistical process control Quality control cards Process capability investigation Validation ­ a key element of quality assurance Process validation approaches Prospective validation Retrospective validation Concurrent validation Revalidation Time intervals for periodic revalidations Incidences requiring revalidation Changes to the manufacturing instructions Extension of the ranges of critical process parameters

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7.A (1) 7.A (1) 7.A (2) 7.A (3) 7.A (4) 7.A (9) 7.A (10) 7.A (10) 7.A (13) 7.A (13) 7.A (14) 7.A (14) 7.A (14) 7.A (15) 7.A (15) 7.A (16) 7.A (18) 7.A (19) 7.A (21) 7.A (22) 7.A (23) 7.A (24) 7.A (24) 7.A (25) 7.A (28) 7.A (32)

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7.C (1) 7.C (3) 7.C (5) 7.D (2) 7.D (2) 7.D (2) 7.D (5)

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7.D.2.3 7.D.2.4 7.E 7.E.1 7.E.2 7.E.3 7.E.4 7.E.4.1 7.E.4.2 7.F 7.F.1 7.F.2 7.F.3 7.F.4 7.G 7.G.1 7.G.2 7.H 7.H.1 7.H.2 7.H.2.1 7.H.2.2 7.I 7.I.1 7.I.2 7.I.3 7.I.4 7.J 7.J.1 7.J.2 7.J.3 7.J.4 7.J.5 7.J.6

Changes in manufacturing site Serious quality problems Planning of process validation projects Responsibilities and task assignment Validation team Timing of validation Prerequisites for carrying out a validation project What action should be taken if not all prerequisites have yet been fulfilled? Manufacture of a development or pilot batch in the run-up to a validation Validation master plan Validation matrix Example of a validation master plan Example for a validation matrix Example for a test plan Risk analysis Finding out the adequate extent of validation Carrying out risk analysis

7.D (5) 7.D (6) 7.E (1) 7.E (4) 7.E (6) 7.E (6) 7.E (11) 7.E (12) 7.F (4) 7.F (6) 7.F (17) 7.F (24) 7.G (1) 7.G (1)

Validation protocol and report Elements of the validation protocol 7.H (1) Content of a validation report 7.H (9) How to deal with deviations from the requirements in the validation protocol 7.H (11) Archiving of the validation documents 7.H (11) Quality by Design Process development Design space Statistical Design of Experiments (DoE) Multivariate Data Analysis (MVDA) Process Analytical Technology (PAT) Process-analytical measurements Evaluation of the data Possible applications Implementations of PAT Advantages of PAT implementation PAT in the USA and Europe 7.I (1) 7.I (3) 7.I (7) 7.I (9) 7.J (1) 7.J (3) 7.J (4) 7.J (6) 7.J (6) 7.J (7)

8

8.A 8.B 8.B.1 8.B.2 8.B.3

Cleaning Validation

Official requirements Validatability of cleaning procedures Optimisation of cleaning procedures Compilation of cleaning instructions Validating manual and automated cleaning procedures

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8.C 8.D 8.D.1 8.D.2 8.E 8.E.1 8.E.2 8.E.3 8.F 8.F.1 8.F.2 8.F.3 8.F.4 8.F.5

Cleaning validation master plan Establishing the scope of validation Bracketing: determination of critical substances Matrixing: determination of equipment-specific validation protocols Acceptance criteria and limit calculation Calculation of active pharmaceutical ingredient residues Calculation of cleansing agent residues Determination of the microbial status Sampling procedures Swab test Rinse test Other procedures Selection of the appropriate procedure Microbiological testing of surfaces Analytical procedures Requirements for method validation Selection of the appropriate analytical method Documentation Validation protocol Validation report Other documents Maintenance of the validated status Changes and deviations Change control Revalidation Change-related revalidation Periodic revalidation New products and equipment New products New equipment Deviations Cleaning validation documentation (example) 8.D (1) 8.D (5)

8.E (1) 8.E (9) 8.E (10) 8.F (1) 8.F (3) 8.F (5) 8.F (7) 8.F (8) 8.G (1) 8.G (6) 8.H (1) 8.H (3) 8.H (7) 8.I (2) 8.I (2) 8.I (3) 8.I (3) 8.I (6) 8.I (7) 8.I (8) 8.I (8) 8.I (10)

Contents

8.G 8.G.1 8.G.2 8.H 8.H.1 8.H.2 8.H.3 8.I 8.I.1 8.I.2 8.I.3 8.I.3.1 8.I.3.2 8.I.4 8.I.4.1 8.I.4.2 8.I.5 8.J

9

9.A 9.A.1 9.A.2 9.A.2.1 9.B 9.B.1

Computer Validation

Introduction and basic terminology Introduction Basic terminology Validation of computerised systems Regulatory aspects Europe

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9.B.2 9.B.3 9.B.4 9.B.5 9.C 9.C.1 9.C.2 9.C.3 9.C.4 9.D 9.D.1 9.D.1.1 9.D.1.2 9.D.1.3 9.D.1.4 9.D.1.5 9.D.1.6 9.D.1.7 9.D.2 9.D.2.1 9.D.2.2 9.D.3 9.E 9.E.1 9.E.1.1 9.E.1.2 9.E.1.3 9.E.1.4 9.E.2 9.E.2.1 9.E.2.2 9.E.2.3 9.E.2.4 9.E.3 9.E.4 9.E.4.1 9.E.4.2 9.E.5 9.E.6 9.E.7 9.E.7.1 9.E.7.2 9.E.7.3

PIC/S USA Electronic signature and electronic records GAMP® Good Automated Manufacturing Practice Life cycle of software and systems "V-Model" Software development Purchasing commercial of the shelf systems Configuration and customisation Risk analysis and system classification GAMP classification Class 1 ­ Operating system Class 2 ­ Firmware Class 3 ­ Standard software packages Class 4 ­ Configurable standard software packages Class 5 ­ Customer-specific software Validation tasks depending on classification Risk classification in accordance with GAMP, Risk indexes Determining the risk index Measures that depend on the risk index Risk management at the level of user requirements Validation of computerised systems Responsibility and organisation Responsibilities Organisation Validation policy Inventory of systems Validation plan System description The validation process Acceptance criteria Planned deliverables Specifications (user requirements/technical specification) for hardware and software Unit, integration and acceptance tests Test stages in the V model Test method Documentation for validation (validation plan and report) Data migration and start-up Examples Example: Steam autoclave (low risk index) Example: spreadsheet Laboratory systems

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9.B (4) 9.B (4) 9.B (5) 9.B (8) 9.C (2) 9.C (4) 9.C (6) 9.C (7) 9.D (1) 9.D (1) 9.D (1) 9.D (2) 9.D (2) 9.D (2) 9.D (2) 9.D (5) 9.D (5) 9.D (9) 9.D (13) 9.E (1) 9.E (1) 9.E (1) 9.E (3) 9.E (3) 9.E (4) 9.E (4) 9.E (5) 9.E (5) 9.E (5) 9.E (8) 9.E (11) 9.E (12) 9.E (14) 9.E (17) 9.E (18) 9.E (19) 9.E (19) 9.E (21) 9.E (33)

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9.D (5)

Contents

9.E.8 9.E.8.1 9.E.8.2 9.F 9.F.1 9.F.2 9.F.3 9.F.4 9.F.4.1 9.F.4.2 9.F.5 9.F.5.1 9.F.5.2 9.F.6 9.F.7 9.F.7.1 9.F.7.2 9.F.8 9.F.9 9.G 9.G.1 9.G.2 9.G.2.1 9.G.2.2 9.G.3

Dealing with existing systems (legacy systems) Analysis of the actual status Experience report Operation of computerised systems System description User training Standard operating procedures (SOPs) Authorised access and security (virus protection) Authorised access Security Data backup and archiving Data backup Archiving Contingency plans and data recovery Change management and error reporting Change management Error reporting Periodic review Retirement of computerised systems External service providers Relocation of activities (outsourcing, offshoring, nearshoring, backshoring) Service level agreement Contents of a service level agreement Example of a service level agreement Auditing of suppliers and service providers

9.E (34) 9.E (34) 9.E (36) 9.F (1) 9.F (1) 9.F (1) 9.F (2) 9.F (2) 9.F (4) 9.F (5) 9.F (5) 9.F (6) 9.F (7) 9.F (8) 9.F (8) 9.F (9) 9.F (10) 9.F (11)

Contents

9.G (1) 9.G (2) 9.G (3) 9.G (4) 9.G (8)

10

10.A 10.A.1 10.A.2 10.A.3 10.A.4 10.A.5 10.A.6 10.B 10.B.1 10.B.2 10.B.3 10.B.4 10.B.5 10.B.6 10.B.7

Considerations on Risk Management

Introduction and Principles Advantages of Risk Management Considerations on the Risk-Based Approach Regulatory Environment Objectives Science-Based Approach Summary 10.A (2) 10.A (4) 10.A (7) 10.A (12) 10.A (13) 10.A (14)

Basic Consideration on Implementing Risk Management Into a Process Areas of Hazards 10.B (1) Prerequisites 10.B (3) Use of Knowledge and Experience 10.B (5) Consideration on Manual Operations 10.B (5) Elements of Risk Management 10.B (6) Implementation of a Risk Management Process 10.B (7) Commitment of Management 10.B (7)

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10.B.8 10.B.9 10.B.10 10.B.11 10.B.12 10.C 10.C.1 10.C.2 10.C.3 10.C.4 10.C.5

Project Team Analysis of Existing Risk Management Approaches Standardization of Methods and Tools Considerations on Risk Based Behavior Additional Training Required?

10.B (8) 10.B (8) 10.B (9) 10.B (9) 10.B (10) 10.C (1) 10.C (2) 10.C (3) 10.C (4) 10.C (4) 10.C (6) 10.C (6) 10.C (7) 10.C (9)

Details on Using Risk Management Principles as Behavior Application to the QM System The Team Assessment Criteria Procedure to Determine Conclusions Evaluation on Individual Topics (Detailed Evaluation) Using Risk Management 10.C.6 Example on Process Validation 10.C.6.1 1st level: Quality Management System 10.C.6.2 2nd level: local SOP 10.C.6.3 3rd level: Application to a Specific Manufacturing Process 10.D 10.E 10.F 10.F.1 10.F.1.1 10.F.1.2 10.F.1.3 10.F.2 10.G 10.H 10.H.1 10.H.2 10.H.3 10.H.4 10.H.5 10.H.6 10.I 10.I.1 10.I.2 10.I.2.1 10.I.2.2 10.I.2.3 10.I.2.4 Methodologies to be Used to Facilitate Risk Management Using Process Mapping Using a Fishbone Diagram Create a Fish Bone Diagram Step 1: Prerequisites Step 2: Draw Step 3: Conclusions Advantages and Disadvantages Informal Use of Risk Management Fault Tree Analysis (FTA) Basic Principles Objective: What a FTA Can Do and Where to Use It How to Run the Process of a FTA Prerequisites for an FTA Execution of an FTA Advantages and Disadvantages of an FTA Failure Mode Effects Analysis (FMEA) Objectives and Areas of Application General Items on the FMEA Process Step 1: Preparation of the Necessary Process Information ­ Collect Basic Data Step 2: Preparation of the Necessary Process Information ­ Describe Process Conditions Step 3: Identification of Possible Failures, Consequences and Cause of Failure ­ Hazard Identification Step 4: Identification of Possible Failures, Consequences and Cause of Failure: Hazard Assessment (Risk Analysis)

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10.F (2) 10.F (2) 10.F (2) 10.F (2) 10.F (4)

10.H (1) 10.H (1) 10.H (2) 10.H (2) 10.H (3) 10.H (5) 10.I (2) 10.I (3) 10.I (4) 10.I (4) 10.I (4) 10.I (6)

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Step 5: Evaluation of the Failures and Determination of the Risk Priority Number (RPN) 10.I.2.6 Step 6: Definition of Reduction Measures 10.I.2.7 Step 7: Awareness of the Residual Risks 10.I.2.8 Step 8: Summary of the Results 10.I.2.9 Step 9: Documentation of the Performed Process 10.I.2.10 Step 10: Follow Up and the Implementation of Measures 10.I.3 Implementation of FMEA in a Project 10.I.4 Advantages and Disadvantages of an FMEA 10.I.5 Application Example of a Modified FMEA 10.J 10.J.1 10.J.1.1 10.J.1.2 10.J.1.3 10.J.1.4 10.J.1.5 10.J.1.6 10.J.1.7 10.J.2 10.J.3 10.K Hazard Analysis of Critical Control Points (HACCP) Prerequisite and Result to be Expected Step 1: Identification and Analysis of Potential Hazards (Hazard Analysis) Step 2: Determination of Critical Control Points (CCP) (Risk Evaluation) Step 3: Establish Target Limits and Critical Limits Step 4: Establish System to Monitor the Critical Control Points Step 5: Establish Corrective Actions to be Taken if the CCP is Out of Control Step 6: Establish Verification Procedures of the Operability of the System Step 7: Establish or Update Documentation of Processes Advantages and Disadvantages Application Example Conclusion

10.I.2.5

10.I (8) 10.I (15) 10.I (17) 10.I (17) 10.I (17) 10.I (17) 10.I (18) 10.I (18) 10.I (23) 10.J (2) 10.J (3) 10.J (3) 10.J (6) 10.J (6) 10.J (7) 10.J (7) 10.J (8) 10.J (8) 10.J (9)

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11

11.A 11.B 11.B.1 11.B.2 11.B.3 11.B.4 11.B.5 11.B.6 11.C 11.C.1 11.C.2 11.C.3 11.D 11.D.1 11.D.2 11.E 11.E.1 11.E.2

Production

Sanitation Personnel hygiene Clothing Personnel hygiene Code of conduct Hand disinfection Health requirements Training Production hygiene Sources of contamination Cleaning Disinfection Sanitation programme Cleaning procedure for rooms Documentation Environmental monitoring Sampling plan Establishment of limits and frequencies

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11.B (1) 11.B (11) 11.B (11) 11.B (12) 11.B (13) 11.B (13) 11.C (3) 11.C (6) 11.C (7) 11.D (1) 11.D (6) 11.E (1) 11.E (2)

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11.E.2.1 Methods 11.E.3 Investigation areas 11.E.4 Evaluation 11.F 11.G 11.G.1 11.G.2 11.G.3 11.G.4 11.H 11.H.1 11.H.2 11.H.3 11.I 11.I.1 11.I.2 11.I.3 11.I.4 11.I.5 11.I.6 11.J 11.J.1 11.J.2 11.J.3 11.J.4 11.J.5 11.J.6 11.K 11.K.1 11.K.2 11.K.3 11.K.4 11.K.5 11.K.6 11.K.7 11.L 11.L.1 11.L.2 GMP in the production process Weigh-in Legal principles Weigh-in principles Weigh-in procedure Weighing process sequence Identification Starting materials Labelling in the manufacturing process Labelling of rooms In-process control Objectives Organisation Carrying out Documentation Scope of tests and limits Responsibilities Prevention of cross-contamination Rooms and facilities Cleaning Labelling Personnel Reviewing the measures Manufacture of critical products Deviations Definition Sequence Responsibilities Measures Failure investigation report Evaluation SOP "deviations" ­ (example) Reworking Reworking rejected products Reworking of products that have not been rejected

11.E (4) 11.E (6) 11.E (7)

11.G (1) 11.G (3) 11.G (4) 11.G (6) 11.H (2) 11.H (3) 11.H (6) 11.I (1) 11.I (3) 11.I (4) 11.I (6) 11.I (7) 11.I (7) 11.J (1) 11.J (2) 11.J (3) 11.J (3) 11.J (4) 11.J (4) 11.K (1) 11.K (2) 11.K (4) 11.K (4) 11.K (5) 11.K (7) 11.K (8) 11.L (1) 11.L (4) 11.M (1) 11.M (1)

11.M Warehouse and logistics 11.M.1 Stock management system 11.M.1.1 Responsibilities

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11.M.1.2 11.M.1.3 11.M.1.4 11.M.2 11.M.2.1 11.M.2.2 11.M.2.3 11.M.2.4 11.M.2.5 11.M.2.6 11.M.3 11.M.3.1 11.M.3.2 11.M.4 11.M.5 11.M.6

Personnel Controlling the turnover of materials Warehouse organisation Storage areas Size Illumination Incoming goods and dispatch Sampling Quarantine Other storage areas Storage conditions Temperature and humidity Sanitation Receipt Identification using material and batch number Dispatch and transport

11.M (2) 11.M (2) 11.M (3) 11.M (4) 11.M (4) 11.M (4) 11.M (5) 11.M (5) 11.M (6) 11.M (7) 11.M (8) 11.M (8) 11.M (10) 11.M (11) 11.M (15) 11.M (16)

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12

12.A 12.A.1 12.A.2 12.A.3 12.A.4 12.B 12.B.1 12.B.1.1 12.B.1.2 12.B.1.3 12.B.1.4 12.B.2 12.C 12.C.1 12.C.1.1 12.C.1.2 12.C.1.3 12.C.2 12.C.3 12.C.4 12.C.4.1 12.C.4.2 12.C.4.3 12.C.4.4 12.C.4.5

Sterile Production

Introduction Manufacturing products that can be sterilised in the final container Aseptic processing Production areas/premises Production equipment Air Lock Concepts Personnel locks in the clean area Air locks in cleanliness grade F/E Air locks in cleanliness grade E/D Air locks in cleanliness grade D/C Air locks in cleanliness grade C/B Material locks Manufacturing the solution Starting materials Rooms used for weighing Processing instructions (manufacturing instructions) Weighing of starting materials Solution batch Testing the bioburden Sterile filtration History Mode of operation Materials, designs and properties Filter integrity test Executing sterile filtration 12.A (2) 12.A (3) 12.A (4) 12.A (7) 12.B (1) 12.B (2) 12.B (2) 12.B (3) 12.B (4) 12.B (7) 12.C (1) 12.C (2) 12.C (2) 12.C (3) 12.C (4) 12.C (8) 12.C (9) 12.C (9) 12.C (10) 12.C (10) 12.C (11) 12.C (12)

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Contents

12.D 12.D.1 12.D.1.1 12.D.1.2 12.D.2 12.D.2.1 12.D.3 12.D.3.1 12.D.3.2 12.D.3.3 12.D.3.4 12.D.4 12.E 12.E.1 12.E.1.1 12.E.2 12.E.3 12.E.4 12.E.5 12.E.6 12.E.6.1 12.E.6.2 12.F 12.F.1 12.F.2 12.F.2.1 12.F.2.2 12.F.2.3 12.F.3 12.F.3.1 12.F.3.2 12.F.4 12.F.4.1 12.F.4.2 12.F.4.3 12.F.4.4 12.F.4.5 12.G 12.G.1 12.G.2 12.G.3 12.G.3.1 12.G.3.2 12.G.3.3

Washing processes Stoppers Material Manufacture Particulate impurities Stopper washing Glass containers (ampoules, bottles) Types of glass Manufacture Washing Ready to fill Transport Filling Filling equipment for solutions System structure Process for filling LVP containers in cleanliness grade C Process for filling ampoules with solution in cleanliness grade A/B Filling ampoules in cleanliness grade C and laminar flow Culture medium filling (Media Fill) Filling with powders System layout of the filling equipment Practical process using a glass bottle as an example Steam sterilisation Sterilisers Description of the procedure Sterilisation Drying Sterilisation kinetics Qualification of a steam steriliser Installation qualification Operational qualification Validation of the steam sterilisation process Description of equipment and process Loading configurations Bioindicators Determining the sterilisation time Executing the validation Microbiological monitoring Sources of contamination Room classification Monitoring program Limits (level) Methods and equipment Microbiological testing of surfaces and personnel

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12.D (1) 12.D (1) 12.D (2) 12.D (3) 12.D (4) 12.D (5) 12.D (5) 12.D (6) 12.D (6) 12.D (8) 12.D (8) 12.E (1) 12.E (1) 12.E (5) 12.E (8) 12.E (8) 12.E (8) 12.E (13) 12.E (13) 12.E (14) 12.F (1) 12.F (2) 12.F (3) 12.F (4) 12.F (4) 12.F (6) 12.F (7) 12.F (9) 12.F (11) 12.F (12) 12.F (16) 12.F (19) 12.F (19) 12.F (20) 12.G (1) 12.G (2) 12.G (4) 12.G (4) 12.G (10) 12.G (12)

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12.G.4 12.G.4.1 12.G.5 12.G.6 12.G.7 12.H 12.H.1 12.H.2 12.H.2.1 12.H.2.2 12.H.3 12.H.3.1 12.H.4 12.H.5 12.H.6 12.H.7 12.H.8 12.H.9 12.H.10 12.I 12.I.1 12.I.1.1 12.I.1.2 12.I.1.3 12.I.1.4 12.I.1.5 12.I.2 12.I.2.1 12.I.2.2 12.I.2.3 12.I.3 12.J 12.J.1 12.J.1.1 12.J.2 12.J.2.1 12.J.2.2 12.J.3 12.J.3.1 12.J.3.2 12.K 12.K.1 12.K.2

Sampling Frequencies Sampling points Measure if levels are exceeded Organism identification Test for sterility Parametric release Sterility test Environmental conditions Environmental monitoring Method description Incubation Number of samples Sample quantity Reading and evaluating Procedure in the event of culture medium turbidity Culture media Culture media controls Method validation Testing for tightness and particles Testing for tightness Testing for tightness using a dye bath Testing for tightness in the water bath (for freeze-dried drug products) Testing for tightness in steam High-frequency crack test Testing for tightness by weighing Particle test Visual inspection Visual control with semi-automated equipment Electronic control for visible particles Sequence of operation Freeze drying Description of the procedure System components Qualification of a freeze dryer Installation qualification (IQ) Operational qualification (OQ) Validation of the freeze drying process Description of equipment and process Executing the validation Dry Heat Sterilisation Description of the procedure Sterilisation kinetics

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12.G (17) 12.G (18) 12.G (20) 12.G (22) 12.G (24) 12.H (1) 12.H (3) 12.H (6) 12.H (6) 12.H (10) 12.H (11) 12.H (11) 12.H (12) 12.H (12) 12.H (15) 12.H (16) 12.H (17) 12.H (18) 12.I (1) 12.I (1) 12.I (3) 12.I (3) 12.I (3) 12.I (5) 12.I (5) 12.I (6) 12.I (8) 12.I (9) 12.I (12) 12.J (1) 12.J (4) 12.J (6) 12.J (7) 12.J (8) 12.J (9) 12.J (9) 12.J (10) 12.K (2) 12.K (3)

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12.K.3 12.K.3.1 12.K.3.2 12.K.4 12.K.4.1 12.K.4.2 12.K.4.3 12.K.4.4 12.K.4.5 12.K.4.6

Qualification of a sterilisation tunnel Installation qualification Operational qualification Validation of the sterilisation process Description of the device Preparation of the endotoxin test objects Description of the process Position of the heat sensors Determining the endotoxin reduction Executing the validation

12.K (5) 12.K (5) 12.K (6) 12.K (8) 12.K (8) 12.K (9) 12.K (10) 12.K (10) 12.K (10) 12.K (11)

13

13.A 13.A.1 13.A.2 13.A.3 13.A.4 13.A.5 13.A.5.1 13.A.5.2 13.A.5.3 13.A.5.4 13.A.5.5 13.B 13.B.1 13.B.2 13.B.3 13.B.4 13.B.5 13.B.6 13.B.6.1 13.B.6.2 13.B.6.3 13.B.7 13.B.8 13.B.9 13.B.10 13.B.11 13.B.12 13.B.13 13.C 13.C.1 13.C.2 13.C.2.1

Packaging

Packaging material Responsibilities Contents Materials Protection against counterfeit medicinal products Packaging material testing Control tests carried out at the supplier Examples Defect evaluation lists Storage Labelling Packaging process Allocation of packaging material Line clearance Labelling Control functions Release for production In-process controls Organisation Function inspections Checking (partially) packed goods Cleaning primary containers Labelling Variable data Imprints Reconciliation Safety features Completion of a packaging process Qualification of a packaging line Master qualification plan Design qualification (DQ) Design qualification protocol

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13.A (2) 13.A (2) 13.A (2) 13.A (6) 13.A (7) 13.A (7) 13.A (8) 13.A (9) 13.A (11) 13.A (12) 13.B (2) 13.B (3) 13.B (6) 13.B (6) 13.B (8) 13.B (15) 13.B (15) 13.B (18) 13.B (20) 13.B (21) 13.B (21) 13.B (22) 13.B (23) 13.B (24) 13.B (26) 13.B (26) 13.C (2) 13.C (8) 13.C (8)

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13.C.2.2 13.C.3 13.C.3.1 13.C.3.2 13.C.4 13.C.4.1 13.C.4.2 13.C.5 13.C.5.1 13.C.5.2

Design qualification report Installation qualification (IQ) Installation qualification protocol Installation qualification report Operational qualification (OQ) Operational qualification protocol Operational qualification report Performance qualification (PQ) Performance qualification protocol Performance qualification report

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14

14.A 14.A.1 14.A.1.1 14.A.1.2 14.A.1.3 14.A.1.4 14.A.2 14.A.3 14.A.3.1 14.A.3.2 14.A.3.3 14.B 14.B.1 14.B.2 14.B.3 14.C 14.C.1 14.C.2 14.D 14.D.1 14.D.1.1 14.D.1.2 14.D.1.3 14.D.1.4 14.D.2 14.E 14.E.1 14.E.1.1 14.E.1.2 14.E.1.3 14.E.1.4

Laboratory and Analytical Controls

Sampling Requirements Personnel Equipment Containers Premises Sampling plan (instructions) Notes for the sampling process Containers and identification labeling Sampling report Reference samples Reagents Labeling Usage and stability Documentation Standards and reference substances Definition of different standards and their areas of use Handling, storage and stability Qualifying laboratory instruments Qualification protocols and reports Design qualification (DQ) Installation qualification (IQ) Operational qualification (OQ) Performance qualification (PQ) System suitability test (SST) Calibration in the lab Definitions Persons Instruments Working Laboratory Equipment Inventory List

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14.E.2 14.E.2.1 14.E.3 14.E.3.1 14.E.3.2 14.E.3.3 14.E.3.4 14.E.4 14.E.4.1 14.E.4.2 14.E.4.3 14.F 14.F.1 14.F.2 14.F.2.1 14.F.2.2 14.F.2.3 14.F.2.4 14.F.2.5 14.F.2.6 14.F.2.7 14.F.3 14.F.4 14.G 14.G.1 14.G.2 14.G.2.1 14.G.2.2 14.G.2.3 14.G.2.4 14.G.2.5 14.G.2.6 14.G.2.7 14.G.2.8 14.G.3 14.G.3.1 14.G.3.2 14.G.3.3 14.G.3.4 14.G.3.5 14.G.3.6 14.G.3.7 14.G.3.8 14.G.3.9

Calibration instructions and record Test intervals, test points, test instructions Examples Balance Volume measuring instruments Photometer HPLC system Decision Requirements, tolerances, specifications Equipment release Out of calibration Validation of analytical methods Principles Definitions of the parameters Precision Accuracy LOD = Limit of Detection LOQ = Limit of Quantitation Selectivity Linearity, Range Robustness Documentation Revalidation Stability testing ICH guidelines for stability tests Storage and storage conditions Standard storage conditions Packaging Sample quantities Stress test Freeze test Temperature cycling test Special storage conditions for drug products Labeling Analyses Test parameters Reference samples Consumption test Compatibility test for injection solutions for infusions Analysis of compatibility of rubber stoppers and plastic components Photostability (ICH Q1B) Microbiological analyses Analysis of standing times Analysis of transport conditions

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14.G.4 14.G.4.1 14.G.4.2 14.G.5 14.G.5.1 14.G.5.2 14.G.6

14.G.6.1

14.G.6.2 14.G.6.3 14.G.7

14.G.8 14.G.9 14.G.9.1 14.G.9.2 14.G.9.3 14.H 14.H.1 14.H.1.1 14.H.1.2 14.H.2 14.H.3 14.H.4 14.H.5 14.I 14.I.1 14.I.2 14.I.2.1 14.I.2.2 14.I.2.3 14.J 14.J.1

Reduction of the study design Bracketing Matrixing Stability testing in the marketing phase Follow-up stability testing (FuST) Stability commitment (SC) Defining the retest period for an active pharmaceutical ingredient and the shelf life for a drug product through evaluation of stability data (ICH Q1E) Data evaluation for the retest period for APIs and shelf life for drug products that are intended for storage at room temperature Data evaluation for retest period for APIs and shelf life for drug products intended for storage in refrigerator (2­8 °C) Data evaluation for retest period for APIs and shelf life for drug products for intended storage in a freezer (­20 °C) Decision tree for data evaluation for retest period or for APIs or drug products (excluding frozen products) Procedure for statistical analysis Examples of the statistical evaluation of stability data Data analysis for a single batch Data analysis of one attribute in each batch for several batches of the same product (known as One-Factor, Full-Design Studies) Data analysis of all attributes for several batches (Multi-Factor, Full-Design Studies) Out-of-specification results Significance The BARR Laboratories case The consequences Definitions FDA OOS Guidance Example for handling of an OOS result Trend tracking Raw data documentation Principles Single sheet documentation system Cover sheet Data sheet Index sheet

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14.G (37)

14.G (37) 14.G (39) 14.G (40) 14.G (40) 14.G (40) 14.G (42) 14.G (42) 14.G (43) 14.G (44) 14.H (1) 14.H (1) 14.H (3) 14.H (4) 14.H (4) 14.H (12) 14.H (13) 14.I (1) 14.I (3) 14.I (3) 14.I (3) 14.I (7)

Contents

Batch release Certification by a Qualified Person and release in accordance with EC GMP Guidelines 14.J.1.1 Regulations contained in Directive 2001/83/EC

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14.J.1.2 14.J.1.3 14.J.2 14.J.3 14.J.4 14.K 14.K.1 14.K.1.1 14.K.1.2 14.K.1.3 14.K.1.4 14.K.1.5 14.K.1.6 14.K.2 14.K.2.1 14.K.2.2 14.K.2.3 14.K.2.4 14.K.2.5 14.K.3 14.K.3.1 14.K.3.2 14.K.4 14.K.4.1 14.K.4.2

Objectives of appendix 16 Cases of application Responsibility for issuing the release Publication of release Release procedures in practice Microbiological testing Total microbial count Determination of the total microbial count Product testing Culture media and culture media checks Incubation Evaluation Validation of the method Specified microorganisms Detection of specified microorganisms Detection method for the specified microorganisms Evaluation Culture media and culture media tests Suitability test of the method (validation of the methods) Testing frequencies Preparations Raw materials Miscellaneous tests Monitoring of the hygiene status Aseptic working conditions

14.J (5) 14.J (6) 14.J (8) 14.J (9) 14.J (10) 14.K (2) 14.K (10) 14.K (16) 14.K (18) 14.K (21) 14.K (21) 14.K (23) 14.K (24) 14.K (30) 14.K (32) 14.K (41) 14.K (42) 14.K (47) 14.K (48) 14.K (48) 14.K (49) 14.K (52) 14.K (52) 14.K (55)

15

15.A 15.A.1 15.A.2 15.A.3 15.A.4 15.A.5 15.B 15.B.1 15.B.2 15.B.3 15.C 15.C.1 15.C.1.1 15.C.1.2 15.C.1.3

Documentation

Official requirements GMP-requirements managed and reviewed according to German pharma business regulations Requirements of the EU GMP Guideline Requirements of the US GMP Regulations Formal requirements Management and revision documentation GMP-conforming documentation Handwritten entries Archiving Master-SOP ­ "GMP-conforming documentation" Batch documentation Manufacturing instructions/record Manufacturing instructions Batch processing record Master of manufacturing instructions/batch processing record

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15.C.2 15.C.2.1 15.C.2.2 15.C.3 15.C.3.1 15.C.3.2 15.C.4 15.C.4.1 15.C.4.2 15.C.5 15.C.5.1 15.C.5.2 15.C.5.3 15.C.5.4 15.C.5.5 15.D 15.D.1 15.D.1.1 15.D.1.2 15.D.2 15.D.3 15.D.4 15.D.5 15.D.6 15.D.7 15.D.8 15.D.8.1 15.D.8.2 15.D.8.3 15.D.8.4 15.D.9 15.D.10 15.E 15.E.1 15.E.2 15.E.2.1 15.E.2.2 15.E.2.3 15.E.2.4 15.E.2.5 15.E.2.6 15.E.2.7 15.E.2.8

Packaging instruction and batch packaging record Packaging instruction Batch packaging record Electronic batch recording Strategic objectives of an Electronic Batch Recording System (EBRS) GMP aspects Testing procedures and test protocol Testing procedures Test protocol Batch record review Regulatory requirements Benefits of an independent batch record review Responsibility and competencies Scope of a batch record review Deviations, changes relevant to marketing authorization, recording errors Standard operating procedures (SOPs) Compilation Design and format Identification Approval and implementation Training Usage Review Changes Withdrawing an operating procedure Administration Status identification Distribution Integration Use of computerized systems Archiving Example of an SOP "Compilation and administration of operating procedures" Site master file Introduction Design General information Personnel Premises and equipment Documentation Production Quality control Contract manufacturing and analysis Distribution, complaints and product recall

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15.E.2.9 Self-inspection 15.E.2.10 Appendix 15.F 15.F.1 15.F.2 15.F.3 15.F.4 15.F.5 Annual product review/ Product quality review Documents required for an annual product review Annual product review report Collaboration with a contract manufacturer Example: annual product review Master-SOP for the annual product review

15.E (12) 15.E (13) 15.F (4) 15.F (6) 15.F (8) 15.F (9) 15.F (14)

16

16.A 16.B 16.B.1 16.B.2 16.B.3 16.B.4 16.B.5 16.B.6 16.B.7 16.B.8 16.B.9 16.C 16.C.1 16.C.1.1 16.C.2 16.C.3 16.D 16.D.1 16.D.2 16.D.3 16.D.3.1 16.D.4 16.D.4.1 16.D.5 16.D.6 16.E 16.F

Research and Development

General conditions and legal requirements Development phases and GMP requirements Formulation development Analytical development Manufacturing and testing of stability samples Packaging development Process development Cleaning verification and validation Process optimization: Basic principles for process validation Up scaling to pilot plant and production scale Handover to other manufacturing sites Interfaces to GLP and GCP GLP ­Good Laboratory Practice Comparison of GLP ­ GMP GCP ­Good Clinical Practice Interfaces between the areas regulated by GMP and those regulated by GCP 16.B (4) 16.B (7) 16.B (11) 16.B (14) 16.B (16) 16.B (19) 16.B (22) 16.B (25) 16.B (27) 16.C (1) 16.C (2) 16.C (5) 16.C (10)

Manufacture and control of clinical samples Prerequisites for the approval of clinical investigations 16.D (1) Manufacturing of clinical samples and comparator drugs 16.D (2) Packaging and labeling 16.D (6) Blinding and randomization 16.D (10) Control and release of investigational medicinal products 16.D (11) Product release of investigational drugs is often performed in several stages 16.D (11) Storage and shipment of investigational drugs 16.D (14) Returns, recalls and destruction of clinical samples 16.D (15) Documentation and recording of changes during development Development report

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17

17.A 17.A.1 17.A.2 17.A.3 17.A.3.1 17.A.3.2 17.A.3.3 17.A.3.4 17.A.3.5 17.A.4 17.A.4.1 17.A.4.2 17.A.4.3 17.A.4.4 17.A.4.5 17.A.4.6

Contract Manufacturing and Analysis

Contract manufacture Reasons for contract manufacture Procedure for assigning manufacturing contracts Duties of the contract giver Selection of one or more contract acceptors Handover of the necessary documents to the contract acceptor Secrecy agreement Carrying out an audit and approval of the contract acceptor Approval of manufacturing instructions Duties of the contract acceptor Flexibility of a contract acceptor Full-service contract acceptor Procurement and testing of starting materials Analysis of products manufactured under contract Implementation of the contract giver's requirements Manufacture and analysis in accordance with the relevant instructions from the contract giver Existence of quality assurance activities Contract manufacturer agreement Legal principles Minimum requirements Compilation of a secrecy agreement Time needed Contract manufacturer agreements for audits Audits of contract manufacturers Frequency of audits Types of audits Main audit priorities Result of an audit How does a contract acceptor prepare for an audit? Carrying out follow-up audits Positive spin offs of audits SOP for assigning manufacturing contracts Framework contract for contract manufacture and quality control Contract Analysis Introduction Legal basis Selection of a suitable external testing laboratory Sequence of external contracting Liability limitation contract Sample contract for contract analysis Questions that emerge in practise Test procedure ­ who is responsible for what?

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Contents

17.A.4.7 17.A.5 17.A.5.1 17.A.5.2 17.A.5.3 17.A.5.4 17.A.5.5 17.A.6 17.A.6.1 17.A.6.2 17.A.6.3 17.A.6.4 17.A.6.5 17.A.6.6 17.A.6.7 17.A.7 17.A.8 17.B 17.B.1 17.B.2 17.B.3 17.B.4 17.B.5 17.B.5.1 17.B.6 17.B.6.1

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17.B.6.2 Questions of liability 17.B.6.3 Test certificates containing evaluations 17.B.6.4 Typical errors

17.B (9) 17.B (10) 17.B (11)

18

18.A 18.B 18.B.1 18.B.2 18.B.3 18.B.4 18.C 18.C.1 18.C.2 18.D 18.D.1 18.D.2 18.D.3 18.D.3.1 18.D.3.2 18.D.3.3 18.D.3.4 18.D.4 18.E 18.E.1 18.E.2 18.E.3 18.E.4 18.E.5 18.F 18.F.1 18.F.2 18.F.3 18.G 18.G.1 18.G.2 18.H 18.I 18.I.1 18.I.2 18.I.3

Inspections

Principles Inspection procedures System-based Product-based Procedure-based Area-based Inspectors Technical qualification requirements Personal requirements Organization of inspections Inspection planning Inspection preparation Carrying out the inspections Opening discussion Site inspection Documentation check Concluding discussion Evaluation and documentation Self-inspection Purpose of self-inspection Carrying out the self-inspection Self-inspection documentation Errors and remedial action Follow-up activities Inspection of contract manufacturers Purpose of the inspection of contract manufacturer Carrying out inspections of contract manufacturer Handling of changes and deviations Inspection of suppliers Purpose of the supplier inspection Carrying out the supplier inspection Questionnaire for preparing GMP-inspections Supplier qualification Suppliers (traders) and manufacturers of raw materials Selection of manufacturer or supplier Audit of active pharmaceutical ingredient manufacturers

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18.I.3.1 18.I.3.2 18.I.3.3 18.I.3.4 18.I.3.5 18.I.3.6 18.I.3.7

Preparation Type of inspection Questions for opening discussion Inspection sequence: Documents versus site visit Inspection questionnaire Change of supplier Suppliers of packaging materials

18.I (5) 18.I (6) 18.I (7) 18.I (7) 18.I (8) 18.I (59) 18.I (59)

19

19.A 19.A.1 19.A.2 19.A.2.1 19.A.2.2 19.A.2.3 19.A.3 19.A.3.1 19.A.3.2 19.A.3.3 19.A.4 19.A.4.1 19.A.4.2 19.A.4.3 19.A.5 19.A.6 19.A.6.1 19.A.6.2 19.A.6.3 19.A.7 19.B 19.B.1 19.B.2 19.B.2.1 19.B.2.2 19.B.2.3 19.B.2.4 19.B.2.5 19.B.3 19.B.3.1 19.B.3.2 19.B.4 19.B.4.1 19.B.4.2

Tools for Quality Assurance

Project management Definition of project and project management Project sequence Project planning Project controlling Project conclusion Project organisational structure Project manager Project team Steering team Project phases Project start Project implementation Project conclusion Aids Multi-project organisation Project classes Project priorities Management information Frequently occurring problems in the context of project management Risk analysis Development of the risk analysis FMEA ­ Failure Mode and Effects Analysis Development Procedure during FMEA Failure finding Failure evaluation Measures to eliminate failures Introduction of a GMP risk analysis according to FMEA method Advantages Disadvantages Company-specific risk analysis Advantages Disadvantages

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19.B.4.3 19.B.4.4 19.B.5 19.B.5.1 19.B.5.2 19.B.5.3 19.B.5.4 19.B.5.5 19.C 19.C.1 19.C.2 19.C.3

Procedure Example Hazard Analysis of Critical Control Points Failure finding Evaluation of problem points Definition of measures Documentation HACCP summary Change control Principles of change control Introduction and operation of change control programs Documentation

19.B (28) 19.B (28) 19.B (37) 19.B (39) 19.B (40) 19.B (40) 19.B (41) 19.B (42) 19.C (1) 19.C (4) 19.C (9)

20 21

21.A 21.A.1 21.A.2 21.A.2.1 21.A.2.2 21.B 21.B.1 21.B.2 21.B.3 21.B.4 21.B.5 21.C 21.C.1 21.D 21.D.1 21.D.2 21.D.3 21.D.4 21.D.5 21.E 21.E.1 21.E.2 21.E.3 21.E.4

Quality Tools

will be published in one of the following updates.

GMPs for APIs

Introduction Objective Scope API Starting Materials Guidance on how to define API Starting Materials Quality management Principles Responsibilities of the Quality Unit(s) ­ QU Responsibility for Production Activities Internal Audits (Self-Inspections) Product Quality Review Personnel Personnel hygiene Buildings and Facilities Design and Construction Utilities Water Containment Sanitation and Maintenance Process Equipment Design and Construction Equipment Maintenance and Cleaning Calibration Computerized Systems 21.A (1) 21.A (2) 21.A (2) 21.A (3) 21.B (1) 21.B (2) 21.B (4) 21.B (4) 21.B (6) 21.C (2) 21.D (1) 21.D (3) 21.D (4) 21.D (6) 21.D (6) 21.E (1) 21.E (2) 21.E (2) 21.E (3)

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21.F 21.F.1 21.F.2 21.F.3 21.F.4 21.F.5 21.F.6 21.F.7 21.G 21.G.1 21.G.2 21.G.3 21.G.4 21.H 21.H.1 21.H.2 21.H.3 21.H.4 21.H.5 21.I 21.I.1 21.I.2 21.I.3 21.I.4 21.J 21.J.1 21.J.2 21.K 21.K.1 21.K.2 21.K.3 21.K.4 21.K.5 21.K.6 21.K.7 21.L 21.L.1 21.L.2 21.L.3 21.L.4

Documentation and Records Documentation System and Specification Equipment Cleaning and Use Record Records of Raw Materials, Intermediates, API Labelling and Packaging Materials Master Production Instructions (Master Production and Control Records) Batch Production Records (Batch Production and Control Records) Laboratory Control Records Batch Production Record Review Materials Management General Controls Receipt and Quarantine Sampling and Testing of Materials Storage Production and In-Process Controls Production Operations Time Limits In-process Sampling and Controls Blending Batches of Intermediates or APIs Contamination Control Packaging and Identification Labelling of APIs and Intermediates General Packaging Materials Label Issuance and Control Packaging and Labelling Operations Storage and Distribution Warehousing procedures Distribution procedures Laboratory Controls General Control Testing of Intermediates and APIs Validation of Analytical Procedures Certificates of Analysis Stability Monitoring of APIs Expiry and Retest Dating Reserve/Retention Samples Validation Validation Policy Validation Documentation Qualification Approaches to Process Validation

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21.F (1) 21.F (3) 21.F (4) 21.F (4) 21.F (4) 21.F (6) 21.F (6) 21.G (1) 21.G (1) 21.G (2) 21.G (2) 21.H (1) 21.H (4) 21.H (5) 21.H (6) 21.H (6) 21.I (1) 21.I (1) 21.I (2) 21.I (3) 21.J (1) 21.J (2) 21.K (1) 21.K (4) 21.K (4) 21.K (4) 21.K (4) 21.K (6) 21.K (6) 21.L (1) 21.L (1) 21.L (2) 21.L (2)

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21.L.5 21.L.6 21.L.7 21.L.8 21.M 21.N 21.N.1 21.N.2 21.N.3 21.N.4 21.N.5 21.O 21.P 21.Q 21.Q.1 21.Q.2 21.Q.3 21.Q.4 21.Q.5 21.Q.6 21.R 21.S 21.S.1 21.S.2 21.S.3 21.S.4 21.S.5 21.S.6 21.S.7 21.S.8 21.S.9

Process Validation Program Periodic Review of Validated Systems Cleaning Validation Validation of Analytical Methods Change Control Rejection and Re-use of Materials Rejection Reprocessing Reworking Recovery of Materials and Solvents Returns Complaints and Recalls Contract Manufacturers, including laboratories Agents, Brokers, Traders, Distributors, Repackers, and Relabelers Applicability Traceability of Distributed APIs and Intermediates Quality Management Repackaging, Relabeling and Holding of APIs and Intermediates Stability Transfer of Information

21.L (3) 21.L (3) 21.L (3) 21.L (4)

21.N (1) 21.N (2) 21.N (4) 21.N (5) 21.N (6)

Specific Guidance for APIs Manufactured by Cell Culture/Fermentation APIs for Use in Clinical Trials General Quality Equipment and Facilities Control of Raw Materials Production Validationon Changes Laboratory Controls Documentation 21.S (1) 21.S (1) 21.S (1) 21.S (2) 21.S (2) 21.S (2) 21.S (2) 21.S (3) 21.S (3)

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21.Q (1) 21.Q (1) 21.Q (1) 21.Q (2) 21.Q (2) 21.Q (2)

Contents

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Contents file 4 to 5

Contents file 4 to 5

File 4 to 5 A

A.1 A.2 A.3 A.4 A.5 A.6

Information

Contents file 4 to 5 Index file 4 to 5 List of Abbreviations Glossary Adress-Register References

B.1 B.2

B.3

MHW Ministerial Ordinance No. 2,1961: Regulations for Buildings and Facilities of Pharmacies, etc. MHLW Ministerial Ordinance No. 136,2004 : Standards for Quality Assurance for Drugs, Quasi-drugs, Cosmetics and Medical Devices MHLW Ministerial Ordinance No. 179, 2004: Standards for Manufacturing Control and Quality Control for Drugs and Quasi-drugs

C

C.1 C.2 C.3 C.4 C.5 C.6.1 C.6.2 C.6.3 C.6.4

EU GMP Guide

Introduction Commission Directive 2003/94/EC Directive 91/412/EEC Part I Basic Requirements for Medicinal Products Part II Basic Requirements for Active Substances used as Starting Materials Annex 1 Manufacture of Sterile Medicinal Products Annex 2 Manufacture of Biological Medicinal Products for Human Use Annex 3 Manufacture of Radiopharmaceuticals Annex 4 Manufacture of Veterinary Medicinal Products other than Immunological Veterinary Medicinal Products

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B

Japanese Regulations

Contents

C.6.5 C.6.6 C.6.7 C.6.8 C.6.9 C.6.10 C.6.11 C.6.12 C.6.13

C.6.14 C.6.15 C.6.16 C.6.17 C.6.18

C.6.19 C.6.20 C.7 C.8 C.9 C.9

Annex 5 Manufacture of Immunological Veterinary Medicinal Products Annex 6 Manufacture of medicinal gases Annex 7 Manufacture of Herbal Medicinal Products Annex 8 Sampling of Starting and Packaging Materials Annex 9 Manufacture of Liquids, Creams and Ointments Annex 10 Manufacture of Pressurised Metered Dose Aerosol Preparations for Inhalation Annex 11 Computerised Systems Annex 12 Use of Ionising Radiation in the Manufacture of Medicinal Products Annex 13 ­ Revision 1 Manufacture of Investigational Medicinal Products Annex 14 ­ Revision Manufacture of medicinal Products derived from human Blood or Plasma Annex 15 Final Version ­ Qualification and validation Annex 16 Final Version: Certification by a Qualified Person and Batch Release Annex 17 Final version ­ Parametric Release Annex 18 Final version ­ Good Manufacturing Practice for Active Pharmaceutical Ingredients Annex 19 Reference Samples and Retention Samples Annex 20: Quality Risk Management Glossary Index EU GMP Guide C.1 to C.6.20 Note For Guidance on Quality of Water for Pharmaceutical Use Index C.9

Contents

D

D.1 D.1 D.2 D.2 D.3

USA: CFR and FDA Guidelines

Code of Federal Regulations Index chapter D.1 Guideline on General Principles of Process Validation Index chapter D.2 Guide to Inspections of High Purity Water Systems

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Contents

D.3 D.4 D.4 D.5 D.5 D.6 D.6 D.7 D.7 D.8 D.8 D.9 D.9 D.10

D.10 D.11

D.11 D.12 D.12 D.13 D.13 D.14 D.14 D.15

Index chapter D.3 Guide to Inspections of Validation of Cleaning Processes Index chapter D.4 Guide to inspections of oral solid dosage forms pre/post approval issues for development and validation Index chapter D.5 Guide to Inspections of Validation Documentation Index chapter D.6 Guide to Inspection of Computerized Systems in Drug Processing Index chapter D.7 Guide to Inspections of Pharmaceutical Quality Control Laboratories Index chapter D.8 Guidance for Industry: Investigating Out-of-Specification (OOS) Test Results for Pharmaceutical Production Index chapter D.9 Guidance for Industry Sterile Drug Products Produced by Aseptic Processing ­ Current Good Manufacturing Practice Index chapter D.10 Guidance for Industry PAT ­ A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance Index chapter D.11 Guidance for Industry Part 11, Electronic Records; Electronic Signatures ­ Scope and Application Index chapter D.12 21 CFR Part 820 ­ Quality System Regulation Index chapter D.13 Guidance for Industry Quality Systems Approach to Pharmaceutical CGMP Regulations Index chapter D.14 Federal Food, Drug, and Cosmetic Act

E

E.1.A E.1.B E.1.C E.1.D E.1.E

ICH-Guidelines

ICH Q1A(R2): Stability Testing of New Drug Substances and Products ICH Q1B: Stability Testing: Photostability Testing of New Drug Substances and Products ICH Q1C: Stability Testing: Requirements for New Dosage Forms ICH Q1D: will be published in one of the following updates. ICH Q1E: will be published in one of the following updates.

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Contents

Contents

E.1.F E.1 E.2

E.2 E.3.A E.3.B E.3.C E.3 E.4 E.4.A

E.4.B

E.4.B.1

E.4.B.2

E.4.B.3

E.4 E.5.A

E.5.B

E.5.C

E.5.D

ICH Q1F: will be published in one of the following updates. Index ICH Q1 ICH Q2(R1): Validation of Analytical Procedures: Text and Methodology Index ICH Q2(R1) ICH Q3A(R2): Impurities in New Drug Substances ICH Q3B(R2): Impurities in New Drug Products ICH Q3C(R3): Guideline for Residual Solvents Index ICH Q3 ICH Q4: Pharmacopoeias ICH Q4A: Pharmacopoeial Harmonisation ICH Q4B: Evaluation and Recommendation of Pharmacopoeial Texts for Use in the ICH Regions ICH Q4B Annex 1: Evaluation and Recommendation of Pharmacopoeial Texts for Use in the ICH Regions on Residue on Ignition/Sulphated Ash ­ General Chapter ICH Q4B Annex 2: Evaluation and Recommendation of Pharmacopoeial Texts for Use in the ICH Regions on Test for Extractable Volume of Parenteral Preparations General Chapter ICH Q4B Annex 3: Evaluation and Recommendation of Pharmacopoeial Texts for Use in the ICH Regions on Test for Particulate Contamination: Sub-Visible Particles General Chapter Index ICH Q4 ICH Q5A(R1): Viral Safety Evaluation of Biotechnology Products Derived from Cell Lines of Human or Animal Origin ICH Q5B: Quality of Biotechnological Products: Analysis of the Expression Construct in Cells Used for Production of R-DNA Derived Protein Products ICH Q5C: Quality of Biotechnological Products: Stability Testing of Biotechnological/ Biological Products ICH Q5D: Derivation and Characterisation of Cell Substrates used for Production of Biotechnological/Biological Products

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Contents

E.5.E

E.5 E.6.A

E.6.B

E.6 E.7 E.7.1 E.7 E.8 E.8.1 E.8 E.9 E.9 E.10 E.10

ICH Q5E: Comparability of Biotechnological/Biological Products Subject to Changes in their Manufacturing Process Index ICH Q5 ICH Q6A: Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances ICH Q6B: Specifications: Test Procedures and Acceptance Criteria for Biotechnological/ Biological Products Index ICH Q6 ICH Q7: Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients "How to do" Document ­ Interpretation of the ICH Q7a Guide Index ICH Q7 ICH Q8: Pharmaceutical Development Annex to ICH Q8: Pharmaceutical Development Index ICH Q8 ICH Q9: Quality Risk Management Index ICH Q9 ICH Q10: Pharmaceutical Quality System Index ICH Q10

F

F.1

PIC/S Guidelines

Recommendations on Validation Master Plan Installation and Operational Qualification Non-Sterile Process Validation Cleaning Validation (PIC/S PI 006) Index chapter F.1 Recommendations on the Validation of Aseptic Processes (PIC/S PI 007) Index chapter F.2 PIC/S Guidance Good Practices for Computerised Systems in Regulated "GXP" Environments (PIC/S PI 011) Index chapter F.3 Aide-Memoire Inspection of Pharmaceutical Quality Control Laboratories (PIC/S PI 023-1) Annex to PIC/S PI 023-1 Aide-Memoire for Inspections of Pharmaceutical Quality Control Laboratories Index chapter F.4 Explanatory Notes for Industry on the Preparation of a Site Master File Index chapter F.5

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F.1 F.2 F.2 F.3 F.3 F.4 F.4

F.4 F.5 F.5

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Contents

Contents

F.6 F.6

Aide mémoire Inspection of Utilities Index chapter F.6

G

G.1 G.1

WHO Guidelines

Guide to good storage practices for pharmaceuticals Index chapter G.1

H

Other Organizations

This chapter is left empty in order to facilitate later additions.

Contents (42)

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