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GMP Manual Contents
Pharmaceutical Quality System (PQS)
1.A
Preface
1.B
The road to a Pharmaceutical Quality System
1.C
1.C.1
1.C.2
Introduction to the PQS

General requirements
Documentation
1.C (1)
1.C (2)
1.D
1.D.1
1.D.2
1.D.3
1.D.4
Main elements of a PQS

Management responsibility
Resource management
Manufacturing operations
Evaluation activities
1.D (1)
1.D (4)
1.D (7)
1.D (10)
1.E
1.E.1
1.E.2
1.E.3
1.E.4
Essentials of a PQS
Principles of a process
Process mapping
Responsibilities
Key Performance Indicators (KPIs)
1.E (1)
1.E (8)
1.E (25)
1.E (26)
1.F
1.F.1
1.F.2
1.F.3
1.F.4
Practical implementation of a PQS

Assistance for implementation
Organizational aspects
Process of developing documents
Document hierarchy
1.F (1)
1.F (3)
1.F (5)
1.F (7)
1.G
Structure of a PQS quality manual example
1.H
Correlation between GMP requirements (WHO) and ISO 9001:2000
1.I
References
Personnel
2.A
Place of work and job descriptions
2.B
2.B.1
2.B.2
Requirements of the personnel

Qualification requirements
Health requirements
GMP Manual (Up12) Maas & Peither AG GMP Publishing
2.B (1)
2.B (2)
(1)
Contents
GMP Manual Contents
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GMP Manual Contents
2.C
2.C.1
2.C.2
2.C.3
2.C.4
2.C.5
2.C.6
2.C.7
2.C.8
Training
Purpose of training
Responsibility for training
Requirements profiles/learning objectives
Training contents and target groups
Training planning
Carrying out
Reviewing the training and the training system
Documentation
2.D
2.D.1
2.D.2
2.D.3
2.D.4
2.D.5
2.D.6
Function owners subject to public law

Qualified Person (QP)
Head of Production
Head of Quality Control
Qualified Person in Accordance with
Article 103 of Guideline 2001/83/EC
Scientific Service in Charge of Information
Medical sales representatives
Premises
3.A
3.A.1
3.A.2
3.A.3
3.A.4
3.A.5
3.A.6
Official 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
3.B.1
3.B.2
3.B.3
3.B.4
Material flow, personnel flow and layout

Material flow
Personnel flow
Layout
Design concepts in FDAs Sterile Drug Products
Produced by Aseptic Processing guideline
3.C
3.C.1
3.C.2
3.C.3
3.C.4
3.C.5
3.C.6
3.C.7
Room classes
General GMP Requirements for Premises
GMP Requirements for Cleanrooms: Air Cleanliness Grades
Corresponding FDA Determinations
GMP Requirements for Premises
Room-specific Allocation of Air Cleanliness Stipulations
Cleanliness Zoning Concepts
Converting GMP Stipulations into Reality
(2)
2.C (1)
2.C (1)
2.C (2)
2.C (3)
2.C (4)
2.C (4)
2.C (8)
2.C (11)
2.D (1)
2.D (12)
2.D (17)
2.D (21)
2.D (24)
2.D (26)
3.A (4)
3.A (5)
3.A (7)
3.A (7)
3.A (8)
3.A (8)
3.B (1)
3.B (4)
3.B (4)
3.B (5)
3.C (1)
3.C (1)
3.C (4)
3.C (6)
3.C (7)
3.C (9)
3.C (12)
3.D
3.D.1
3.D.2
3.D.3
3.D.4
Construction elements
Walls
Doors and windows
Floors
Ceilings
3.D (1)
3.D (6)
3.D (8)
3.D (10)
3.E
3.E.1
3.E.2
3.E.3
3.E.4
Barrier systems and isolators

Protection concepts for maximized sterility assurance
Pharmaceutical isolator technology
Restricted access barrier systems (RABS technology)
Application options for RABS and isolators
3.E (1)
3.E (2)
3.E (8)
3.E (12)
3.F
3.F.1
3.F.2
3.F.3
3.F.4
3.F.5
Building services
Basic requirements for installation
Heating
Sanitary plumbing and sewage
Electrical installations incl. IT-management and control systems
Qualification
3.F (1)
3.F (3)
3.F (3)
3.F (3)
3.F (4)
3.G
3.G.1
3.G.2
3.G.3
3.G.4
3.G.5
3.G.6
Heating Ventilation Air Conditioning (HVAC)

Introduction
Room ventilation systems
Filters
Principles for the design and planning of air
conditioning ventilation systems
Design criteria for the ventilation of premises
Maintenance of air ventilation systems
3.G (23)
3.G (26)
3.G (37)
3.H
3.H.1
3.H.2
3.H.3
3.H.4
Process Gases
Quality Requirements
Generation, Storage and Distribution
System design
Qualification and monitoring
3.H (2)
3.H (4)
3.H (5)
3.H (8)
3.I
3.I.1
3.I.2
3.I.3
3.I.4
3.I.5
3.I.6
3.I.7
3.I.8
Qualification of premises and air-conditioning systems

Objectives of qualification
Regulatory and normative fundamentals of qualification
Project development and qualification
Qualification Master Plan
Qualification Plans and Qualification Reports
Qualification checklists
Requirements for measurement and test reports
Requalification
3.I (1)
3.I (2)
3.I (3)
3.I (4)
3.I (5)
3.I (6)
3.I (29)
3.I (30)
3.J
3.J.1
3.J.2
3.J.3
Monitoring of HVAC systems

Objectives of process monitoring
Data management stipulations
Air cleanliness and other room air data
3.J (1)
3.J (1)
3.J (3)
3.G (1)
3.G (3)
3.G (11)
(3)
Contents
GMP Manual Contents
Contents
GMP Manual Contents
3.J.4
3.J.5
3.J.6
Risks of microbiological monitoring

Alarm and action limits
Operation and maintenance
3.J (4)
3.J (4)
3.J (5)
3.K
References
Facilities and Equipment
4.A
Introduction
4.B
4.B.1
4.B.2
4.B.3
Mechanical components
Construction and installation materials
GMP-compliant design characteristics
Electrical and pneumatic components
4.C
Control
4.D
4.D.1
4.D.2
4.D.3
Facility concepts
CIP (Cleaning in Place)
Isolator technology
Connected facilities
4.D (1)
4.D (2)
4.D (2)
4.E
4.E.1
4.E.2
4.E.3
Examples of facility qualification

Design qualification
Installation qualification
Operational qualification
4.E (1)
4.E (5)
4.E (12)
4.F
4.F.1
4.F.2
4.F.3
4.F.4
Technical documentation
Necessity
Scope and content
Administration of the technical documentation
Log book
4.F (1)
4.F (2)
4.F (9)
4.F (12)
4.G
4.G.1
4.G.2
4.G.3
4.G.4
Calibration
Definitions
Procedure
Documentation
Administration of scheduled calibration dates/ times
4.G (1)
4.G (3)
4.G (4)
4.G (5)
4.H
4.H.1
4.H.2
4.H.3
Maintenance
Types of maintenance
GMP-conforming maintenance
Systems for maintenance
4.H (2)
4.H (2)
4.H (3)
4.I
4.I.1
4.I.2
4.I.3
4.I.4
CIP (Cleaning in Place)

Introduction
CIP systems
GMP-conforming design of CIP facilities
Nozzle heads for container cleaning
4.I (1)
4.I (3)
4.I (6)
4.I (11)
(4)
4.B (1)
4.B (2)
4.B (3)
4.I.5
4.I.6
Measuring technology
Realisation of cleaning systems
4.I (13)
4.I (15)
4.J
4.J.1
4.J.2
4.J.3
4.J.4
4.J.5
4.J.6
4.J.7
4.J.8
4.J.9
4.J.10
4.J.11
Containment (personnel protection)

in solids handling
Significance
Definition of terms
Containment grades of products
Measurement of the residue limits (OEL)
Example of containment facility planning
Containment weak points
Containment systems for filling and emptying drums
Container systems
Filter systems
Sampling
Containment on equipment
4.J (1)
4.J (3)
4.J (3)
4.J (6)
4.J (7)
4.J (15)
4.J (16)
4.J (23)
4.J (27)
4.J (28)
4.J (30)
4.K
4.K.1
4.K.2
4.K.3
4.K.4
4.K.5
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
4.K (1)
4.K (2)
4.K (5)
4.K (6)
4.K (7)
4.L
4.L.1
4.L.2
4.L.3
4.L.4
4.L.5
4.L.6
4.L.7
4.L.8
4.L.9
Hygienic (sanitary) design when using solids

Introduction
Surfaces
Material: stainless steel
Connections
Hoists and roller conveyors
Pneumatic conveyor system
Dosing systems
Platforms and stands
Clean room installations
4.L (1)
4.L (3)
4.L (6)
4.L (11)
4.L (22)
4.L (25)
4.L (26)
4.L (28)
4.L (31)
Pharmaceutical Water
5.A
5.A.1
5.A.2
5.A.3
5.A.4
Water types
Potable water
Purified water
Highly purified water
Water for injection
5.A (2)
5.A (3)
5.A (5)
5.A (7)
5.B
5.B.1
5.B.2
5.B.3
Generation of pharmaceutical water

Purified water (PW)
Water for injection (WFI)
Purification of pharmaceutical water treatment systems
5.B (2)
5.B (11)
5.B (14)
(5)
Contents
GMP Manual Contents
Contents
GMP Manual Contents
5.C
5.C.1
5.C.2
5.C.3
5.C.4
5.C.5
5.C.6
5.C.7
Distribution and storage of pharmaceutical water

Loop
Fixtures
Measuring technique
Formation of biofilms
Rouging
Buffering of ultra pure water
Loop with subloops
5.C (1)
5.C (6)
5.C (7)
5.C (21)
5.C (23)
5.C (27)
5.C (29)
5.D
5.D.1
5.D.2
5.D.3
5.D.4
5.D.5
5.D.6
5.D.7
5.D.8
Qualification of water supplies

Introduction
Risk analysis
Design qualification
Installation qualification
Operational qualification (OQ)
Transfer to the user
Process validation/performance qualification (PQ)
Qualification report
5.D (1)
5.D (3)
5.D (8)
5.D (17)
5.D (28)
5.D (36)
5.D (42)
5.D (47)
5.E
5.E.1
5.E.2
5.E.3
5.E.4
5.E.5
5.E.6
Operation of water supplies

Procedures to reduce microbial counts
Maintenance of a water supply
Calibration of measuring systems
Change control
Requalification
Decommissioning/uninstalling
5.E (1)
5.E (4)
5.E (10)
5.E (11)
5.E (13)
5.E (14)
5.F
5.F.1
5.F.2
5.F.3
5.F.4
Pure steam systems

Physical principles
Quality requirements for pure steam
Pure steam generation
Pure steam distribution system
5.F (1)
5.F (3)
5.F (6)
5.F (10)
Qualification
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
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
(6)
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
6.B.1
6.B.2
6.B.3
6.B.4
6.B.5
6.B.6
Preparation of the qualification

Commissioning
Sequence
Qualification team
Responsibilities
Qualification by external service providers
Risk analysis
6.B (1)
6.B (5)
6.B (6)
6.B (6)
6.B (6)
6.B (10)
6.C
6.C.1
6.C.2
6.C.3
6.C.4
6.C.5
Qualification documentation
Qualification master plan
Qualification plan
Qualification report
Labeling of the qualification status
SOP Qualification of facilities and equipment
6.C (2)
6.C (3)
6.C (9)
6.C (10)
6.C (11)
6.D
6.D.1
6.D.2
Design qualification (DQ)

User requirements (user specifications)
Technical specification
6.D (3)
6.D (12)
6.E
6.E.1
6.E.2
Installation qualification (IQ)

Examples of IQ plans
Example: Fluid bed equipment
6.E (3)
6.E (22)
6.F
6.F.1
6.F.2
Operational qualification(OQ)
Examples of OQ plans
Example: Fluid bed dryer
6.F (3)
6.F (13)
6.G
Performance qualification (PQ)
6.H
6.H.1
6.H.2
6.H.3
6.H.4
6.H.5
Special cases of qualification

Retrospective qualification
Requalification
Content of a review
Maintenance of the qualified status
Qualification of simple equipment
Process Validation
7.A
7.A.1
7.A.2
7.A.3
7.A.4
7.A.5
Regulative aspects
Principles of process validation
Types of process validation
Maintaining the validated status
Documentation of process validation
7.A (1)
7.A (11)
7.A (18)
7.A (23)
7.A (27)
7.B
7.B.1
7.B.2
Validation a key element of quality management

What is the significance of validation?
How is validation defined?
7.B (1)
7.B (2)
6.H (1)
6.H (2)
6.H (3)
6.H (5)
6.H (7)
(7)
Contents
GMP Manual Contents
Contents
GMP Manual Contents
7.B.3
7.B.4
7.B.5
7.B.6
7.B.7
Who must perform validation?

What faults can occur during validation?
What are the benefits of validation?
Current trends in process validation
Process validation from the viewpoint of the FDA
7.B (2)
7.B (3)
7.B (4)
7.B (5)
7.B (5)
7.C
7.C.1
7.C.2
7.C.3
Validation planning and procedure

Process validation approaches
Prerequisites and responsibilities
Scope of Validation
7.C (1)
7.C (8)
7.C (21)
7.D
7.D.1
7.D.2
7.D.3
7.D.4
7.D.5
Validation documentation
Structure and archiving
Validation master plan
Validation protocol
Validation report
Documentation examples
7.D (1)
7.D (3)
7.D (8)
7.D (19)
7.D (22)
7.E
7.E.1
7.E.2
7.E.3
7.E.4
Process Validation and Product Lifecycle

Quality by Design
Process Analytical Technology (PAT)
Maintaining the validated state
Process validation as a three-stage life cycle model
7.E (2)
7.E (11)
7.E (18)
7.E (30)
7.F
References
Cleaning Validation
8.A
8.B
8.B.1
8.B.2
8.B.3
How to validate cleaning procedures

Optimization of cleaning procedures
Compilation of cleaning instructions
Validating manual and automated cleaning procedures
8.C
Cleaning validation master plan
8.D
8.D.1
8.D.2
Establishing the scope of validation

Bracketing: determination of critical substances
8.D (1)
Matrixing: determination of equipment-specific validation protocols 8.D (5)
8.E
8.E.1
8.E.2
8.E.3
Acceptance criteria and limit calculation

Calculation of active pharmaceutical ingredient residues
Calculation of cleansing agent residues
Determination of the microbial status
8.E (1)
8.E (10)
8.E (11)
8.F
8.F.1
8.F.2
8.F.3
Sampling procedures
Swab test
Rinse test
Other procedures
8.F (1)
8.F (4)
8.F (6)
(8)
8.B (1)
8.B (5)
8.B (8)
GMP Manual Contents
Selection of the appropriate sampling procedure

Microbiological testing of surfaces
8.F (7)
8.F (9)
8.G
8.G.1
8.G.2
Analytical procedures
Requirements for method validation
Selection of the appropriate analytical procedure
8.G (1)
8.G (6)
8.H
8.H.1
8.H.2
8.H.3
Documentation
Validation protocol
Validation report
Other documents
8.H (1)
8.H (5)
8.H (7)
8.I
8.I.1
8.I.2
8.I.3
8.I.4
8.I.5
Maintenance of the validated status

Changes and deviations
Change control
Revalidation
New products and equipment
Deviations
8.I (2)
8.I (3)
8.I (4)
8.I (9)
8.I (12)
8.J
Cleaning validation documentation (example)
8.K
References
Computer System Validation
9.A
Introduction and terminology
9.B
9.B.1
9.B.2
9.B.3
9.B.4
9.B.5
Legal aspects
Europe
USA
PIC/S
Electronic signatures and electronic records
ISPE GAMP 5 Good Automated Manufacturing Practice
9.B (1)
9.B (4)
9.B (6)
9.B (6)
9.B (8)
9.C
9.C.1
9.C.2
9.C.3
System life cycle

The V model
Software development
Configuration and customisation
9.C (2)
9.C (5)
9.C (7)
9.D
9.D.1
9.D.2
System classification and risk management

System classification according to ISPE GAMP5
Risk management
9.D (1)
9.D (6)
9.E
9.E.1
9.E.2
9.E.3
9.E.4
9.E.5
9.E.6
Validation of computerised systems

Validation organisation
Validation plan
Specifications (user requirements/technical specification)
Unit, integration, system and acceptance tests
Validation report
Data migration and start-up
9.E (2)
9.E (4)
9.E (6)
9.E (9)
9.E (16)
9.E (16)
Contents
8.F.4
8.F.5
(9)
Contents
GMP Manual Contents
9.E.7
9.E.8
Examples
Retrospective validation
9.E (18)
9.E (24)
9.F
9.F.1
9.F.2
9.F.3
9.F.4
9.F.5
9.F.6
9.F.7
9.F.8
9.F.9
Operation of computerised systems

System description
User training
Standard operating procedures (SOPs)
Access and security
Data backup and archiving
Contingency plans
Change management and error reporting
Periodic review
Retirement of computerised systems
9.F (1)
9.F (1)
9.F (1)
9.F (2)
9.F (4)
9.F (5)
9.F (7)
9.F (9)
9.F (9)
9.G
9.G.1
9.G.2
9.G.3
External service providers

Relocation of activities
Service level agreement
Auditing of suppliers and service providers
9.G (1)
9.G (2)
9.G (8)
9.H
References
10
Considerations on Risk Management
10.A
10.A.1
10.A.2
10.A.3
10.A.4
10.A.5
10.A.6
Introduction and Principles

Advantages of Risk Management
Considerations on the Risk-Based Approach
Regulatory Environment
Objectives
Science-Based Approach
Summary
10.B
10.B.1
10.B.2
10.B.3
10.B.4
10.B.5
10.B.6
10.B.7
10.B.8
10.B.9
10.B.10
10.B.11
10.B.12
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)
Project Team
10.B (8)
Analysis of Existing Risk Management Approaches
10.B (8)
Standardization of Methods and Tools
10.B (9)
Considerations on Risk Based Behavior
10.B (9)
Additional Training Required?
10.B (10)
(10)
10.A (2)
10.A (4)
10.A (7)
10.A (12)
10.A (13)
10.A (14)
GMP Manual Contents
10.C.6
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
Example on Process Validation
10.D
Methodologies to be Used to Facilitate Risk Management
10.E
Using Process Mapping
10.F
10.F.1
10.F.2
Using a Fishbone Diagram

Create a Fish Bone Diagram
Advantages and Disadvantages
10.G
Informal Use of Risk Management
10.H
10.H.1
10.H.2
10.H.3
10.H.4
10.H.5
10.H.6
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
10.H (1)
10.H (1)
10.H (2)
10.H (2)
10.H (3)
10.H (5)
10.I
10.I.1
10.I.2
10.I.3
10.I.4
10.I.5
Failure Mode Effects Analysis (FMEA)

Objectives and Areas of Application
General Items on the FMEA Process
Implementation of FMEA in a Project
Advantages and Disadvantages of an FMEA
Application Example of a Modified FMEA
10.I (2)
10.I (3)
10.I (18)
10.I (18)
10.I (23)
10.J
10.J.1
10.J.2
10.J.3
Hazard Analysis of Critical Control Points (HACCP)

Prerequisite and Result to be Expected
Advantages and Disadvantages
Application Example
10.J (2)
10.J (8)
10.J (9)
10.K
Conclusion
11
Production
11.A
11.A.1
11.A.2
11.A.3
Sanitation
Organisational prerequisites
Sources of contamination
Responsibilities and implementation
10.C (1)
10.C (2)
10.C (3)
10.C (4)
10.C (4)
10.C (6)
10.F (2)
10.F (4)
11.A (1)
11.A (2)
11.A (3)
(11)
Contents
10.C
10.C.1
10.C.2
10.C.3
10.C.4
10.C.5
Contents
GMP Manual Contents
11.B
11.B.1
11.B.2
11.B.3
11.B.4
11.B.5
Personnel hygiene
Clothing
Code of Conduct
Hand disinfection
Health requirements
Training
11.B (1)
11.B (11)
11.B (14)
11.B (15)
11.B (16)
11.C
11.C.1
11.C.2
11.C.3
Production hygiene
Cleaning
Disinfection
11.C (4)
11.C (11)
11.C (13)
11.D
11.D.1
11.D.2
Sanitation programme
Organisation of room cleaning
Documentation
11.D (1)
11.D (5)
11.E
11.E.1
11.E.2
11.E.3
11.E.4
11.E.5
11.E.6
Environmental monitoring
General
Sampling plan
Establishment of limits and frequencies
Methods
Investigation areas
Evaluation
11.E (1)
11.E (3)
11.E (4)
11.E (9)
11.E (11)
11.E (16)
11.F
GMP in the production process
11.G
11.G.1
11.G.2
11.G.3
11.G.4
Weigh-in
Legal requirements
Weigh-in principles
Weigh-in procedure
Documentation
11.G (1)
11.G (3)
11.G (7)
11.G (11)
11.H
11.H.1
11.H.2
11.H.3
11.H.4
Identification
Handling of labels
Labelling of starting materials
Labelling of equipment and containers
Labelling of rooms
11.H (1)
11.H (2)
11.H (3)
11.H (7)
11.I
11.I.1
11.I.2
11.I.3
11.I.4
In-process control
Objectives
Organisation and responsibilities
Carrying out
Documentation and evaluation of data
11.I (2)
11.I (3)
11.I (4)
11.I (8)
11.J
11.J.1
11.J.2
11.J.3
Prevention of cross-contamination
Causes of cross-contamination
Measures to prevent cross-contamination
Manufacture of critical products
11.J (1)
11.J (5)
11.J (6)
(12)
11.K
11.K.1
11.K.2
11.K.3
11.K.4
11.K.5
11.K.6
11.K.7
11.K.8
Deviations
Definition
Procedure
Responsibilities
Measures
Failure investigation report
Evaluation of measures
SOP deviations (example)
Check-list for deviation handling
11.K (1)
11.K (2)
11.K (4)
11.K (4)
11.K (5)
11.K (7)
11.K (9)
11.K (14)
11.L
11.L.1
11.L.2
11.L.3
11.L.4
11.L.5
Reworking
Definitions
Procedure
Rework / Reprocessing of rejected products
Rework of returned products
Rework of products that have not been rejected
11.L (1)
11.L (2)
11.L (4)
11.L (8)
11.L (8)
11.M
11.M.1
11.M.2
11.M.3
11.M.4
11.M.5
11.M.6
11.M.7
11.M.8
11.M.9
Warehouse and logistics

Regulatory requirements
Stock management system
Responsibilities
Personnel
Storage areas
Storage conditions
Sanitation and pest control
Material Flow
Process Flow
11.M (1)
11.M (2)
11.M (6)
11.M (6)
11.M (7)
11.M (13)
11.M (16)
11.M (18)
11.M (22)
11.N
11.N.1
11.N.2
11.N.3
11.N.4
11.N.5
Transportation
Requirements for logistic service providers
Transportation challenges and monitoring devices
Cool/Cold Chain Distribution
Temperature Profiles
Transportation Risks
11.N (2)
11.N (5)
11.N (9)
11.N (13)
11.N (18)
11.O
References
12
Sterile Production
12.A
12.A.1
12.A.2
12.A.3
12.A.4
Introduction
Manufacturing products that can be sterilised in the final container
Aseptic processing
Production areas/premises
Production equipment
12.A (2)
12.A (3)
12.A (4)
12.A (7)
12.B
12.B.1
12.B.2
Air Lock Concepts

Personnel locks in the clean area
Material locks
12.B (1)
12.B (7)
(13)
Contents
GMP Manual Contents
Contents
GMP Manual Contents
12.C
12.C.1
12.C.2
12.C.3
12.C.4
Manufacturing the solution

Starting materials
Solution batch
Testing the bioburden
Sterile filtration
12.C (1)
12.C (4)
12.C (8)
12.C (9)
12.D
12.D.1
12.D.2
12.D.3
12.D.4
Washing processes
Stoppers
Particulate impurities
Glass containers (ampoules, bottles)
Transport
12.D (1)
12.D (3)
12.D (5)
12.D (8)
12.E
12.E.1
12.E.2
12.E.3
12.E.4
12.E.5
12.E.6
Filling
Filling equipment for solutions
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
12.E (1)
12.E (5)
12.E (8)
12.E (8)
12.E (8)
12.E (13)
12.F
12.F.1
12.F.2
12.F.3
12.F.4
Steam sterilisation
Sterilisers
Description of the procedure
Qualification of a steam steriliser
Validation of the steam sterilisation process
12.F (1)
12.F (2)
12.F (6)
12.F (11)
12.G
12.G.1
12.G.2
12.G.3
12.G.4
12.G.5
12.G.6
12.G.7
Microbiological monitoring
Room classification
Monitoring program
Sampling
Sampling points
Measure if levels are exceeded
Organism identification
12.G (1)
12.G (2)
12.G (4)
12.G (17)
12.G (20)
12.G (22)
12.G (24)
12.H
12.H.1
12.H.2
12.H.3
12.H.4
12.H.5
12.H.6
12.H.7
12.H.8
12.H.9
12.H.10
Test for sterility

Parametric release
Sterility test
Method description
Number of samples
Sample quantity
Reading and evaluating
Procedure in the event of culture medium turbidity
Culture media
Culture media controls
Method validation
12.H (1)
12.H (3)
12.H (10)
12.H (11)
12.H (12)
12.H (12)
12.H (15)
12.H (16)
12.H (17)
12.H (18)
(14)
12.I
12.I.1
12.I.2
12.I.3
Testing for tightness and particles

Testing for tightness
Particle test
Sequence of operation
12.I (1)
12.I (5)
12.I (12)
12.J
12.J.1
12.J.2
12.J.3
Freeze drying
Qualification of a freeze dryer
Validation of the freeze drying process
12.J (1)
12.J (6)
12.J (9)
12.K
12.K.1
12.K.2
12.K.3
12.K.4
Dry Heat Sterilisation

Sterilisation kinetics
Qualification of a sterilisation tunnel
Validation of the sterilisation process
12.K (2)
12.K (3)
12.K (5)
12.K (8)
13
Packaging
13.A
13.A.1
13.A.2
13.A.3
13.A.4
13.A.5
Packaging material
Responsibilities
Contents
Materials
Protection against counterfeit medicinal products
Packaging material testing
13.A (2)
13.A (2)
13.A (2)
13.A (6)
13.A (7)
13.B
13.B.1
13.B.2
13.B.3
13.B.4
13.B.5
13.B.6
13.B.7
13.B.8
13.B.9
13.B.10
13.B.11
13.B.12
13.B.13
Packaging process
Allocation of packaging material
Line clearance
Labelling
Control functions
Release for production
In-process controls
Cleaning primary containers
Labelling
Variable data
Imprints
Reconciliation
Safety features
Completion of a packaging process
13.B (2)
13.B (3)
13.B (6)
13.B (6)
13.B (8)
13.B (15)
13.B (21)
13.B (21)
13.B (22)
13.B (23)
13.B (24)
13.B (26)
13.B (26)
13.C
13.C.1
13.C.2
13.C.3
13.C.4
13.C.5
Qualification of a packaging line

Master qualification plan
Design qualification (DQ)
Installation qualification (IQ)
Operational qualification (OQ)
Performance qualification (PQ)
13.C (2)
13.C (8)
13.C (24)
13.C (34)
13.C (46)
(15)
Contents
GMP Manual Contents
Contents
GMP Manual Contents
14
Laboratory Controls
14.A
14.A.1
14.A.2
14.A.3
Sampling
Requirements
Sampling plan (instructions)
Notes for the sampling process
14.A (2)
14.A (3)
14.A (8)
14.B
14.B.1
14.B.2
14.B.3
Reagents
Labeling
Usage and stability
Documentation
14.B (2)
14.B (2)
14.B (4)
14.C
14.C.1
14.C.2
Standards and reference substances

Definition of different standards and their areas of use
Handling, storage and stability
14.C (1)
14.C (5)
14.D
14.D.1
14.D.2
Qualifying laboratory instruments

Qualification protocols and reports
System suitability test (SST)
14.D (2)
14.D (5)
14.E
14.E.1
14.E.2
14.E.3
14.E.4
Calibration in the lab

Definitions
Calibration instructions and record
Examples
Decision
14.E (1)
14.E (4)
14.E (5)
14.E (20)
14.F
14.F.1
14.F.2
14.F.3
14.F.4
Validation of analytical methods

Principles
Definitions of the parameters
Documentation
Revalidation
14.F (1)
14.F (3)
14.F (6)
14.F (6)
14.G
14.G.1
14.G.2
14.G.3
14.G.4
14.G.5
14.G.6
14.G.8
14.G.9
Stability testing
ICH guidelines for stability tests
Storage and storage conditions
Analyses
Reduction of the study design
Stability testing in the marketing phase
Defining the retest period for an active
pharmaceutical ingredient and the shelf life for a
drug product through evaluation of stability data
(ICH Q1E)
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
(16)
14.G.7
14.G (2)
14.G (4)
14.G (13)
14.G (20)
14.G (24)
14.G (37)
14.G (40)
14.G (40)
14.G (42)
14.H
14.H.1
14.H.2
14.H.3
14.H.4
14.H.5
Out-of-specification results
Significance
Definitions
FDA OOS Guidance
Example for handling of an OOS result
Trend tracking
14.H (1)
14.H (4)
14.H (4)
14.H (12)
14.H (13)
14.I
14.I.1
14.I.2
Raw data documentation

Principles
Single sheet documentation system
14.I (1)
14.I (3)
14.J
14.J.1
14.J.2
14.J.3
14.J.4
Batch release
Certification by a Qualified Person and release
in accordance with EC GMP Guidelines
Responsibility for issuing the release
Publication of release
Release procedures in practice
14.J (4)
14.J (8)
14.J (9)
14.J (10)
14.K
14.K.1
14.K.2
14.K.3
14.K.4
Microbiological testing
Total microbial count
Specified microorganisms
Testing frequencies
Miscellaneous tests
14.K (2)
14.K (24)
14.K (48)
14.K (52)
14.L
14.L.1
14.L.2
14.L.3
14.L.4
14.L.5
14.L.6
14.L.7
14.L.8
14.L.9
Pharmacopoeias
Structure of Pharmacopoeias
General considerations
Development of Monographs
European Pharmacopoeia (Ph Eur)
British Pharmacopoeia (BP)
United States Pharmacopeia (USP)
Japanese Pharmacopoeia (JP)
International Pharmacopoeia (Ph Int)
Harmonization
14.L (1)
14.L (2)
14.L (3)
14.L (4)
14.L (7)
14.L (9)
14.L (11)
14.L (13)
14.L (14)
14.M
References
15
Documentation
15.A
15.A.1
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
15.A.2
15.A.3
15.A.4
15.A.5
15.A (1)
15.A (4)
15.A (8)
15.A (13)
15.A (17)
(17)
Contents
GMP Manual Contents
Contents
GMP Manual Contents
15.B
15.B.1
15.B.2
15.B.3
GMP-conforming documentation
Handwritten entries
Archiving
Master-SOP GMP-conforming documentation
15.B (1)
15.B (2)
15.B (3)
15.C
15.C.1
15.C.2
15.C.3
15.C.4
15.C.5
Batch documentation
Manufacturing instructions/record
Packaging instruction and batch packaging record
Electronic batch recording
Testing procedures and test protocol
Batch record review
15.C (3)
15.C (26)
15.C (28)
15.C (31)
15.C (36)
15.D
15.D.1
15.D.2
15.D.3
15.D.4
15.D.5
15.D.6
15.D.7
15.D.8
15.D.9
15.D.10
Standard operating procedures (SOPs)

Compilation
Approval and implementation
Training
Usage
Review
Changes
Withdrawing an operating procedure
Administration
Archiving
Example of an SOP Compilation and
administration of operating procedures
15.D (2)
15.D (7)
15.D (7)
15.D (8)
15.D (9)
15.D (9)
15.D (10)
15.D (10)
15.D (12)
15.D (13)
15.E
15.E.1
15.E.2
15.E.3
15.E.4
15.E.5
Site Master File

Introduction
History
Focus of recent update (PE 008-4)
Regulatory requirements
Guidelines for structure, contents and extent
15.E (1)
15.E (1)
15.E (2)
15.E (3)
15.E (3)
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.F (4)
15.F (6)
15.F (8)
15.F (9)
15.F (14)
15.G
References
16
Research and Development
16.A
General conditions and legal requirements
16.B
16.B.1
16.B.2
Development phases and GMP requirements

Formulation development
Analytical development
(18)
16.B (4)
16.B (7)
GMP Manual Contents
16.B.8
16.B.9
16.C
16.C.1
16.C.2
16.C.3
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
GCP Good Clinical Practice
Interfaces between the areas regulated by GMP
and those regulated by GCP
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 (5)
16.C (10)
16.D
16.D.1
16.D.2
16.D.3
16.D.4
16.D.5
16.D.6
Manufacture and control of clinical samples

Prerequisites for the approval of clinical investigations
Manufacturing of clinical samples and comparator drugs
Packaging and labeling
Control and release of investigational medicinal products
Storage and shipment of investigational drugs
Returns, recalls and destruction of clinical samples
16.E
Documentation and recording of changes during development
16.F
Development report
17
Contractors and Suppliers
17.A
17.A.1
17.A.2
17.A.3
17.A.4
17.A.5
17.A.6
17.A.7
17.A.8
Contract manufacture
Reasons for contract manufacture
Procedure for assigning manufacturing contracts
Duties of the contract giver
Duties of the contract acceptor
Contract manufacturer agreement
Audits of contract manufacturers
SOP for assigning manufacturing contracts
Framework contract for contract manufacture and quality control
17.A (1)
17.A (3)
17.A (9)
17.A (12)
17.A (17)
17.A (21)
17.A (30)
17.A (36)
17.B
17.B.1
17.B.2
17.B.3
17.B.4
17.B.5
17.B.6
Contract Analysis
Introduction
Legal background
Selection of an external testing laboratory
Liability limitation contract
Certificate of Analysis
Transfer of the test to the contract laboratory
17.B (1)
17.B (2)
17.B (3)
17.B (5)
17.B (14)
17.B (15)
16.D (1)
16.D (2)
16.D (6)
16.D (11)
16.D (14)
16.D (15)
(19)
Contents
16.B.3
16.B.4
16.B.5
16.B.6
16.B.7
Contents
GMP Manual Contents
17.C
17.C.1
17.C.2
17.C.3
17.C.4
17.C.5
17.C.6
17.C.7
17.C.8
17.C.9
Suppliers
Introduction
Definitions
Quality systems
Records
Contracts and quality agreements
Supplier review and controls
Supplier audits
Re-evaluation of Suppliers
GMP Manual Cross References to Suppliers
17.D
References
18
Inspections
18.A
Principles
18.B
18.B.1
18.B.2
18.B.3
18.B.4
Inspection procedures
System-based
Product-based
Procedure-based
Area-based
18.B (1)
18.B (2)
18.B (2)
18.B (3)
18.C
18.C.1
18.C.2
Inspectors
Technical qualification requirements
Personal requirements
18.C (1)
18.C (3)
18.D
18.D.1
18.D.2
18.D.3
18.D.4
Organization of inspections
Inspection planning
Inspection preparation
Carrying out the inspections
Evaluation and documentation
18.D (1)
18.D (3)
18.D (4)
18.D (8)
18.E
18.E.1
18.E.2
18.E.3
18.E.4
18.E.5
Self-inspection
Purpose of self-inspection
Carrying out the self-inspection
Self-inspection documentation
Errors and remedial action
Follow-up activities
18.E (1)
18.E (1)
18.E (3)
18.E (9)
18.E (11)
18.F
18.F.1
18.F.2
18.F.3
Inspection of contract manufacturers

Purpose of the inspection of contract manufacturer
Carrying out inspections of contract manufacturer
Handling of changes and deviations
18.F (1)
18.F (1)
18.F (3)
18.G
18.G.1
18.G.2
Inspection of suppliers
Purpose of the supplier inspection
Carrying out the supplier inspection
18.G (1)
18.G (2)
(20)
17.C (1)
17.C (4)
17.C (5)
17.C (14)
17.C (17)
17.C (19)
17.C (21)
17.C (26)
17.C (28)
18.H
Questionnaire for preparing GMP-inspections
18.I
References
19
Quality Unit
19.A
General
This chapter will be part of a later update.
19.B
19.B.1
19.B.2
19.B.3
19.B.4
19.B.5
The Qualified Person according to Directive 2001/83/EC

Introduction
Legal background of the European Qualified Person regulations
Qualification and experience
Duties and responsibilities
Qualified Person and Pharmaceutical Quality Systems
19.B (1)
19.B (2)
19.B (5)
19.B (8)
19.B (26)
19.C
19.C.1
19.C.2
19.C.3
Change control
Principles of change control
Introduction and operation of change control programs
Documentation
19.C (1)
19.C (4)
19.C (9)
19.D
References
20
Continual Improvement
20.A
Preface
20.B
20.B.1
20.B.2
20.B.3
20.B.4
20.B.5
20.B.6
20.B.7
Six Sigma
Definition
What it is / what it does / how it works
Goals/Objectives/Benefits
Implementation
Tools
Variations
Examples
20.B (1)
20.B (1)
20.B (19)
20.B (21)
20.B (24)
20.B (25)
20.B (26)
20.C
20.C.1
20.C.2
20.C.3
20.C.4
20.C.5
20.C.6
20.C.7
Statistical Process Control (SPC)

Definition
What it is / what it does / how it works
Goals/Objectives/Benefits
Implementation
Tools
Variations
Examples
20.C (1)
20.C (1)
20.C (32)
20.C (33)
20.C (36)
20.C (36)
20.C (36)
20.D
20.D.1
20.D.2
20.D.3
Process Analytical Technology (PAT)

Definition
The Role of PAT in Pharmaceutical Manufacturing
Regulatory Perspective and Guidances
20.D (1)
20.D (1)
20.D (5)
(21)
Contents
GMP Manual Contents
Contents
GMP Manual Contents
20.D.4
20.D.5
20.D.6
PAT instrumentation
Application of PAT in a GMP environment
Examples of PAT Applications
20.D (11)
20.D (13)
20.D (19)
20.E
References
21
Active and Inactive Ingredients
21.A
21.A.1
21.A.2
21.A.3
21.A.4
21.A.5
21.A.6
21.A.7
21.A.8
21.A.9
21.A.10
21.A.11
21.A.12
21.A.13
21.A.14
21.A.15
21.A.16
21.A.17
21.A.18
21.A.19
GMP for Active Pharmaceutical Ingredients (APIs)

Introduction
Quality management
Personnel
Buildings and facilities
Process equipment
Documentation and records
Materials management
Production and in-process controls
Packaging and identification labelling of APIs and intermediates
Storage and distribution
Laboratory controls
Validation
Change Control
Rejection and re-use of materials
Complaints and Recalls
Contract manufacturers, including laboratories
Agents, brokers, traders, distributors, repackers, and relabellers
Specific guidance for APIs manufactured by
cell culture/fermentation
APIs for use in clinical trials
21.B
21.B.1
21.B.2
21.B.3
21.B.4
GMP for APIs considerations on special topics

Materials management
Production and maintenance
Re-use and recovery of materials
Interaction with brokers
21.B (1)
21.B (9)
21.B (23)
21.B (32)
21.C
21.C.1
21.C.2
21.C.3
21.C.4
21.C.5
21.C.6
21.C.7
Excipients
Introduction
Regulatory aspects and guidance documents
Safety, toxicological, and precedence of use issues
Compendial monographs
Excipient Master Files and other filings
Applicability of ICH guidance to excipients
Other aspects critical to the marketing of excipients
21.C (1)
21.C (6)
21.C (36)
21.C (39)
21.C (45)
21.C (48)
21.C (50)
21.D
References
(22)
21.A (1)
21.A (6)
21.A (13)
21.A (15)
21.A (21)
21.A (25)
21.A (33)
21.A (36)
21.A (43)
21.A (47)
21.A (49)
21.A (55)
21.A (59)
21.A (63)
21.A (70)
21.A (70)
21.A (72)
21.A (75)
21.A (81)
22
Biologics
23
Medical Devices
23.A
23.A.1
23.A.2
23.A.3
23.A.4
Introduction
Definition
Types of medical devices
Regulatory background
Process approach to a Quality Management System
23.A (2)
23.A (3)
23.A (5)
23.A (10)
23.B
23.B.1
23.B.2
23.B.3
23.B.4
23.B.5
23.B.6
Quality Management System (QMS)

Management responsibility
Quality manual
Quality policy
Quality planning
Management review
Audits
23.B (1)
23.B (4)
23.B (5)
23.B (6)
23.B (7)
23.B (10)
23.C
23.C.1
23.C.2
23.C.3
23.C.4
Personnel
General
Training
Health, hygiene, practices, and clothing
Consultants and contractors
23.C (1)
23.C (2)
23.C (3)
23.C (4)
23.D
23.D.1
23.D.2
23.D.3
23.D.4
23.D.5
23.D.6
23.D.7
23.D.8
23.D.9
23.D.10
Design control
General
Design planning
Design input
Design output
Design review
Design verification
Design validation / Clinical evaluation
Design transfer
Design changes
Design history file
23.D (1)
23.D (4)
23.D (5)
23.D (9)
23.D (10)
23.D (12)
23.D (15)
23.D (17)
23.D (18)
23.D (20)
23.E
Human factors
23.F
Statistical techniques
23.G
Risk management
23.H
23.H.1
23.H.2
Document and record control

Control of documents
Control of records
23.H (1)
23.H (4)
23.I
23.I.1
23.I.2
Production and process controls

Manufacturing materials
Automated processes
23.I (2)
23.I (2)
(23)
Contents
GMP Manual Contents
Contents
GMP Manual Contents
23.I.3
23.I.4
23.I.5
Sterile products
Changes
Material acceptance procedures
23.I (3)
23.I (4)
23.I (4)
23.J
23.J.1
23.J.2
Identification and traceability

Identification
Traceability
23.J (1)
23.J (1)
23.K
23.K.1
23.K.2
23.K.3
Buildings, facilities and equipment

Buildings and facilities
Environment
Equipment
23.K (1)
23.K (2)
23.K (3)
23.L
Validation
23.M
23.M.1
23.M.2
Purchasing/supplier control
Purchase orders
Quality agreements
23.M (3)
23.M (3)
23.N
23.N.1
23.N.2
Packaging and labeling

Packaging
Manufacturers information
23.N (1)
23.N (1)
23.O
23.O.1
23.O.2
23.O.3
23.O.4
23.O.5
Handling, storage, distribution, installation and servicing

Handling
Storage
Distribution
Installation
Servicing
23.O (1)
23.O (2)
23.O (2)
23.O (3)
23.O (3)
23.P
23.P.1
23.P.2
23.P.3
23.P.4
Nonconformance, Corrective Action and Preventive Action

Definitions
CAPA System
Nonconforming product
Advisory notice, device correction or product recall
23.P (1)
23.P (1)
23.P (5)
23.P (5)
23.Q
23.Q.1
23.Q.2
Customer complaints
Complaint evaluation
Complaint investigation
23.Q (2)
23.Q (2)
23.R
Combination products
23.S
References
(24)
Empty Register
Empty Register
EU Directives and Guidelines
C.1
EU GMP Guide: Introduction
C.2
Commission Directive 2003/94/EC
C.3
Commission Directive 91/412/EEC
C.4
Part I
Basic Requirements for Medicinal Products
C.4.1
Chapter 1:
Quality Management
C.4.2
Chapter 2:
Personnel
C.4.3
Chapter 3:
Premises and Equipment
C.4.4
Chapter 4:
Documentation
C.4.5
Chapter 5:
Production
C.4.6
Chapter 6:
Quality Control
C.4.7
Chapter 7:
Contract Manufacture and Analysis
C.4.8
Chapter 8:
Complaints and Product Recall
C.4.9
Chapter 9:
Self Inspection
C.5
Part II
Basic Requirements for Active Substances used as Starting Materials
C.6.1
Annex 1
Manufacture of Sterile Medicinal Products
C.6.2
Annex 2
Manufacture of Biological Medicinal Products for Human Use
C.6.3
Annex 3
Manufacture of Radiopharmaceuticals
Contents
GMP Manual Contents
(25)
Contents
GMP Manual Contents
C.6.4
Annex 4
Manufacture of Veterinary Medicinal Products other than Immunological
Veterinary Medicinal Products
C.6.5
Annex 5
Manufacture of Immunological Veterinary Medicinal Products
C.6.6
Annex 6
Manufacture of Medicinal Gases
C.6.7
Annex 7
Manufacture of Herbal Medicinal Products
C.6.8
Annex 8
Sampling of Starting and Packaging Materials
C.6.9
Annex 9
Manufacture of Liquids, Creams and Ointments
C.6.10
Annex 10
Manufacture of Pressurised Metered Dose Aerosol Preparations for
Inhalation
C.6.11
Annex 11
Computerised Systems
C.6.12
Annex 12
Use of Ionising Radiation in the Manufacture of Medicinal Products
C.6.13
Annex 13
Investigational Medicinal Products
C.6.14
Annex 14
Manufacture of Medicinal Products Derived from Human Blood or Plasma
C.6.15
Annex 15
Qualification and Validation
C.6.16
Annex 16
Certification by a Qualified Person and Batch Release
C.6.17
Annex 17
Parametric Release
C.6.18
Annex 18
Good Manufacturing Practice for Active Pharmaceutical Ingredients
C.6.19
Annex 19
Reference and Retention Samples
C.7
Glossary
C.8
Part III GMP related documents
(26)
C.8.1
Explanatory Notes on the preparation of a Site Master File
C.8.2
Quality Risk Management (ICH Q9)
C.8.3
Pharmaceutical Quality System (ICH Q10)
C.8.4
Internationally harmonised requirements for batch certification
C.9
Note For Guidance on Quality of Water for Pharmaceutical Use
C.10
Compilation of Community Procedures on Inspections and Exchange of

Information
C.10.1
Conduct of Inspections of Pharmaceutical Manufacturers
C.10.2
Outline of a Procedure for Co-Ordinating the Verification of the GMP Status

of Manufacturers in Third Countries
C.10.3
Guideline on Training and Qualifications of GMP Inspectors
C.10.4
Guidance on the Occasions when it is Appropriate for Competent

Authorities to Conduct Inspections at the Premises of Manufacturers of
Active Substances Used as Starting Materials
C.10.5
The Issue and Update of GMP Certificates
C.10.6
A Model for Risk Based Planning for Inspections of Pharmaceutical

Manufacturers
C.10.7
Procedure for dealing with serious GMP non-compliance or voiding/

suspension of CEPS thus requiring co-ordinated administrative action
C.11
EU Directives on Medical Devices
C.11.1
Council Directive of 20 June 1990

on the approximation of the laws of the member states relating to active
implantable medical devices
(90/385/EEC)
C.11.2
Council Directive of 14 June 1993 concerning medical devices

(93/42/EEC)
C.11.3
Directive of the European Parliament and of the Council of 27 October 1998

on in vitro diagnostic medical devices
(98/79/EC)
USA: CFR and FDA Guidelines
D.1
Code of Federal Regulations
D.2
Guidance for Industry

Process Validation: General Principles and Practices
D.3
Guide to Inspections of High Purity Water Systems

(27)
Contents
GMP Manual Contents
Contents
GMP Manual Contents
D.4
Guide to Inspections of Validation of Cleaning Processes
D.5
Guide to Inspections of oral solid dosage forms pre/post approval issues for
development and validation
D.6
Guide to Inspections of Validation Documentation
D.7
Guide to Inspections:
Computerized Systems in Drug Establishments (2/83)
D.8
Guide to Inspections of Pharmaceutical Quality Control Laboratories
D.9

Investigating Out-of-Specification (OOS)
Test Results for Pharmaceutical Production
D.10

Sterile Drug Products Produced by Aseptic Processing Current Good
Manufacturing Practice
D.11

PAT A Framework for Innovative Pharmaceutical Development,
Manufacturing, and Quality Assurance
D.12

Part 11, Electronic Records; Electronic Signatures Scope and Application
D.13
21 CFR Part 820 Quality System Regulation
D.14

Quality Systems Approach to Pharmaceutical CGMP Regulations
D.15

cGMP for Phase 1 Investigational Drugs
D.16
Federal Food, Drug, and Cosmetic Act (FD&C Act)
D.17
Pre-Approval Inspections
ICH-Guidelines
E.1.A
ICH Q1A(R2):
Stability Testing of New Drug Substances and Products
E.1.B
ICH Q1B:
Stability Testing: Photostability Testing of New Drug Substances and
Products
E.1.C
ICH Q1C:
Stability Testing for New Dosage Forms
(28)
E.1.D
ICH Q1D:
Bracketing and Matrixing Designs for Stability Testing of New Drug
Substances and Products
E.1.E
ICH Q1E:
Evaluation of Stability Data
E.2
ICH Q2(R1):
Validation of Analytical Procedures:
Text and Methodology
E.3.A
ICH Q3A(R2):
Impurities in New Drug Substances
E.3.B
ICH Q3B(R2):
Impurities in New Drug Products
E.3.C
ICH Q3C(R5):
Impurities: Guideline for Residual Solvents
E.4
ICH Q4:
Pharmacopoeias
E.4.A
ICH Q4A:
Pharmacopoeial Harmonisation
E.4.B
ICH Q4B:
Evaluation and Recommendation of Pharmacopoeial Texts for Use in the
ICH Regions
E.4.B.1
ICH Q4B Annex 1:

Evaluation and Recommendation
of Pharmacopoeial Texts for Use
in the ICH Regions
on Residue on Ignition/Sulphated Ash
General Chapter
E.4.B.2
ICH Q4B Annex 2:

in the ICH Regions
on Test for Extractable Volume of Parenteral Preparations
General Chapter
E.4.B.3
ICH Q4B Annex 3:

in the ICH Regions
on Test for Particulate Contamination: Sub-Visible Particles
General Chapter
(29)
Contents
GMP Manual Contents
GMP Manual Contents
ICH Q4B Annex 4A:

of Pharmacopoeial Texts
for Use in the ICH Regions
Microbiological Examination
of Non-Sterile Products:
Microbial Enumerations Tests
General Chapter
E.4.B.4.2
ICH Q4B Annex 4B :

Evaluation and Recommendation of Pharmacopoeial Texts
for Use in the ICH Regions on
Microbiological Examination of
Non-Sterile Products:
Test for Specified Micro-Organisms
General Chapter
E.4.B.4.3
ICH Q4B Annex 4C:

on Microbiological Examination
of Non-Sterile Products:
Acceptance Criteria For Pharmaceutical Preparations and Substances for
Pharmaceutical Use
General Chapter
E.4.B.5
ICH Q4B Annex 5:

on Disintegration Test
General Chapter
E.4.B.6
ICH Q4B Annex 6:

on Uniformity of Dosage Units
General Chapter
E.4.B.7
ICH Q4B Annex 7:

on Dissolution Test
General Chapter
(30)
Contents
E.4.B.4.1
E.4.B.8
ICH Q4B Annex 8:

on Sterility Test
General Chapter
E.4.B.9
ICH Q4B Annex 9:

on Tablet Friability
General Chapter
E.4.B.10
ICH Q4B Annex 10:

on Polyacrylamide Gel Electrophoresis
General Chapter
E.5.A
ICH Q5A(R1):
Viral Safety Evaluation of Biotechnology Products Derived from Cell Lines of
Human or Animal Origin
E.5.B
ICH Q5B:
Quality of Biotechnological Products: Analysis of the Expression Construct
in Cells Used for Production of R-DNA Derived Protein Products
E.5.C
ICH Q5C:
Quality of Biotechnological Products: Stability Testing of Biotechnological/
Biological Products
E.5.D
ICH Q5D:
Derivation and Characterisation of Cell Substrates used for Production of
Biotechnological/Biological Products
E.5.E
ICH Q5E:
Comparability of Biotechnological/Biological Products Subject to Changes
in their Manufacturing Process
E.6.A
ICH Q6A:
Specifications: Test Procedures and Acceptance Criteria for New Drug
Substances and New Drug Products: Chemical Substances
E.6.B
ICH Q6B:
Specifications: Test Procedures and Acceptance Criteria for
Biotechnological/Biological Products
(31)
Contents
GMP Manual Contents
Contents
GMP Manual Contents
E.7
ICH Q7:
Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients
E.7.1
How to do Document
Interpretation of the ICH Q7a Guide
E.8
ICH Q8 (R2):
Pharmaceutical Development
E.9
ICH Q9:
Quality Risk Management
E.10
ICH Q10:
Pharmaceutical Quality System
E.10.1
Quality Implementation Working Group

on Q8, Q9 and Q10
Questions & Answers
PIC/S Guidelines
F.1
PIC/S PI 006-3:
Recommendations on
Validation Master Plan
Installation and Operational Qualification
Non-Sterile Process Validation
Cleaning Validation
F.2
PIC/S PI 007-6:
Recommendation on the
Validation of Aseptic Processes
F.3
PIC/S PI 011-3:
PIC/S Guidance
Good Practices for
Computerised Systems in Regulated GXP Environments
F.4
PIC/S PI 023-2:
Aide-mmoire
Inspection of Pharmaceutical Quality Control Laboratories
F.5
PIC/S PE 008-4:
Explanatory notes for pharmaceutical manufacturers on the preparation of
a Site Master File
F.6
PIC/S PI 009-3:
Aide-mmoire
Inspection of Utilities
(32)
GMP Manual Contents
F.7
PIC/S PI 028-1:
Aide-mmoire
GMP Inspection Related to Packaging
F.8
PIC/S PI 032-2:
Recommendation
GMP Annex 1 Revision 2008,
Interpretation of Most Important Changes for the Manufacture of Sterile
Medicinal Products
GMP of other Regions

This chapter is supplied on CD-ROM and online (www.gmp-manual.com) only.
WHO Guidelines
G.1.1
Quality assurance of pharmaceuticals
G.1.1.1
1. WHO good manufacturing practices: main principles for pharmaceutical

products
G.1.1.2
2. WHO good manufacturing practices: starting materials
G.1.1.3
3. WHO good manufacturing practices:

specific pharmaceutical products
G.1.1.4
4. Inspection
G.1.1.5
5. Hazard and risk analysis in pharmaceutical products
G.1.1.6
6. Sampling operations
G.1.2
Guide to good storage practices for pharmaceuticals
G.1.3
Annex 5
WHO good distribution practices for pharmaceutical products
G.2
Canada
Good Manufacturing Practices (GMP) Guidelines 2009 Edition
(GUI-0001)
G.2.1
Annex 1
to the Current Edition of the Good Manufacturing Practices Guidelines
Selected Category IV Monograph Drugs
(GUI-0066)
G.2.2
Annex 2
Schedule D Drugs, Biological Drugs Including Fractionated Blood Products
(GUI-0027)
Contents
G.1
(33)
Contents
GMP Manual Contents
G.2.3
Annex 3
Schedule C Drugs
(GUI-0026)
G.2.4
Annex 4
Veterinary Drugs
(GUI-0012)
G.2.5
Annex 5
Positron Emitting Radiopharmaceuticals (PERs)
(GUI-0071)
G.2.6
Annex 13
Drugs Used in Clinical Trials
(GUI-0036)
G.2.7
Annex 14
Schedule D Drugs, Human Blood and Blood Components
(GUI-0032)
G.3
Japanese Regulations
G.3.1
MHW Ministerial Ordinance No. 2,1961:

Regulations for Buildings and Facilities of Pharmacies, etc.
G.3.2
MHLW Ministerial Ordinance No. 136,2004 :

Standards for Quality Assurance for Drugs, Quasi-drugs, Cosmetics and
Medical Devices
G.3.3
MHLW Ministerial Ordinance No. 179, 2004:

Standards for Manufacturing Control and Quality Control for Drugs and
Quasi-drugs
Information
H.1
GMP Abbreviations
H.2
GMP Glossary
H.3
Adress-Register
H.4
References
(34)

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GMP-ManualIVZ.fm Seite 1 Mittwoch, 17.

August 2011 5:05 17

GMP Manual Contents

Pharmaceutical Quality System (PQS)

The road to a Pharmaceutical Quality System

Introduction to the PQS

Main elements of a PQS

Practical implementation of a PQS

Structure of a PQS quality manual example

Correlation between GMP requirements (WHO) and ISO 9001:2000

Place of work and job descriptions

Requirements of the personnel

GMP Manual (Up12) Maas & Peither AG GMP Publishing

GMP Manual Contents

GMP-ManualIVZ.fm Seite 2 Mittwoch, 17. August 2011 5:05 17

GMP Manual Contents

Function owners subject to public law

Material flow, personnel flow and layout

GMP Manual (Up12) Maas & Peither AG GMP Publishing

GMP-ManualIVZ.fm Seite 3 Mittwoch, 17. August 2011 5:05 17

Barrier systems and isolators

Heating Ventilation Air Conditioning (HVAC)

Qualification of premises and air-conditioning systems

Monitoring of HVAC systems

GMP Manual (Up12) Maas & Peither AG GMP Publishing

GMP Manual Contents

GMP-ManualIVZ.fm Seite 4 Mittwoch, 17. August 2011 5:05 17

GMP Manual Contents

Risks of microbiological monitoring

Facilities and Equipment

Examples of facility qualification

CIP (Cleaning in Place)

GMP Manual (Up12) Maas & Peither AG GMP Publishing

GMP-ManualIVZ.fm Seite 5 Mittwoch, 17. August 2011 5:05 17

Containment (personnel protection)

Process control systems

Hygienic (sanitary) design when using solids

Generation of pharmaceutical water

GMP Manual (Up12) Maas & Peither AG GMP Publishing

GMP Manual Contents

GMP-ManualIVZ.fm Seite 6 Mittwoch, 17. August 2011 5:05 17

GMP Manual Contents

Distribution and storage of pharmaceutical water

Qualification of water supplies

Operation of water supplies

Pure steam systems

GMP Manual (Up12) Maas & Peither AG GMP Publishing

GMP-ManualIVZ.fm Seite 7 Mittwoch, 17. August 2011 5:05 17

Preparation of the qualification

Design qualification (DQ)

Installation qualification (IQ)

Performance qualification (PQ)

Special cases of qualification

Validation a key element of quality management

GMP Manual (Up12) Maas & Peither AG GMP Publishing

GMP Manual Contents

GMP-ManualIVZ.fm Seite 8 Mittwoch, 17. August 2011 5:05 17

GMP Manual Contents

Who must perform validation?

Validation planning and procedure

Process Validation and Product Lifecycle

How to validate cleaning procedures

Cleaning validation master plan