GMP Manual Ivz

Contents
Contents
File 1 to 3
Quality Management
1.A
Quality management in the pharmaceutical environment
1.A.1
1.A.2
1.A.3
1.A.3.1
1.A.3.2
1.A.4
1.A.5
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
1.B
Documentation of a QM system
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
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
1.A (1)
1.A (3)
1.A (4)
1.A (4)
1.A (5)
1.A (7)
1.A (9)
Contents
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
Quality management system in accordance with GMP
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
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
1.C (2)
1.C (2)
1.C (2)
1.C (5)
1.C (6)
1.C (6)
1.C (7)
GMP Manual (Up01) Maas & Peither GMP Publishing
(1)
Contents
Contents
1.C.1.7
1.C.2
1.C.2.1
1.C.2.2
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
(2)
Management review
Change management system
Definition of terms
Processing of changes and deviations
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 (8)
1.C (9)
1.C (9)
1.C (10)
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)
Contents
Personnel
2.A
Place of work and job descriptions
2.B
Requirements of the personnel
2.B.1
2.B.2
Qualification requirements
Health requirements
2.C
Training
2.C.1
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
Purpose of training
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
Premises
3.A
Official requirements
3.B
General requirements
3.B.1
3.B.2
3.B.3
3.B.4
3.B.5
3.B.6
Location, connection to other rooms

Size, area, height
Installation and supply of utilities
Lighting, ventilation, air-conditioning
Hygienic construction
Room book and layout
3.C
Material flow, personnel flow and layout
3.C.1
3.C.2
3.C.3
Material flow
Personnel flow
Layout
3.D
Room classes
3.E
Construction elements
3.E.1
3.E.2
3.E.3
3.E.4
Walls
Doors and windows
Floors
Ceilings
2.B (1)
2.B (2)
2.C (1)
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)
Contents
3.B (1)
3.B (2)
3.B (3)
3.B (4)
3.B (4)
3.B (4)
3.C (1)
3.C (2)
3.C (4)
3.E (1)
3.E (5)
3.E (7)
3.E (9)
(3)
Contents
3.F
Building services
3.G
Room qualification
3.H
Heating Ventilation Air Conditioning (HVAC)
3.H.1
3.H.2
3.H.2.1
3.H.2.2
3.H.2.3
Introduction
Room ventilation systems
Pure (100%) external air conditioning system
Central recirculating air/mixed air conditioning system
Decentralised 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
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
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
Contents
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.4
3.H.5
3.H.5.1
3.H.5.2
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
(4)
Facilities and Equipment
4.A
Introduction
4.B
Mechanical components
4.B.1
4.B.2
4.B.3
Construction and installation materials

GMP-compliant design characteristics
Electrical and pneumatic components
3.H (1)
3.H (2)
3.H (3)
3.H (4)
3.H (5)
3.H (6)
3.H (6)
3.H (8)
3.H (8)
3.H (9)
3.H (11)
3.H (14)
3.H (20)
3.H (25)
3.H (26)
3.H (27)
3.H (33)
3.H (36)
3.H (36)
3.H (37)
3.H (37)
3.H (47)
3.H (49)
4.B (1)
4.B (2)
4.B (3)
Contents
Control
4.D
Facility concepts
4.D.1
4.D.2
4.D.3
CIP (Cleaning in Place)

Isolator technology
Connected facilities
4.E
Examples of facility qualification
4.E.1
4.E.2
4.E.3
Design qualification
Installation qualification
Operational qualification
4.F
Technical documentation
4.F.1
4.F.2
4.F.3
4.F.4
Necessity
Scope and content
Administration of the technical documentation
Log book
4.G
Calibration
4.G.1
4.G.2
4.G.3
4.G.4
Definitions
Procedure
Documentation
Administration of scheduled calibration dates/times
4.H
Maintenance
4.H.1
4.H.2
4.H.3
Types of maintenance
GMP-conform maintenance
Systems for maintenance
4.I
CIP (Cleaning in Place)
4.I.1
4.I.1.1
4.I.1.2
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
Introduction
Definition
Cleaning mechanisms
CIP systems
CIP facility for stack cleaning
CIP facility for lost cleaning
GMP-conform 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
4.D (1)
4.D (2)
4.D (3)
4.E (1)
4.E (5)
4.E (10)
4.F (1)
4.F (2)
4.F (8)
4.F (10)
Contents
4.C
4.G (1)
4.G (2)
4.G (4)
4.G (4)
4.H (1)
4.H (2)
4.H (3)
4.I (1)
4.I (1)
4.I (2)
4.I (3)
4.I (3)
4.I (4)
4.I (6)
4.I (6)
4.I (6)
4.I (7)
4.I (7)
4.I (9)
4.I (9)
4.I (10)
4.I (10)
4.I (11)
(5)
Contents
Contents
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
Targeted jet/orbital cleaner

Measuring technology
Flow measurement
Pressure measurement
Temperature measurement
Conductivity measurement
Realisation of cleaning systems
4.J
Containment (user protection)
4.J.1
4.J.1.1
4.J.1.2
4.J.2
4.J.3
4.J.3.1
4.J.4
4.J.5
Significance
Use of isolators
Working in the full protection suit
Definition of terms
Containment grades of products in accordance with OEL
Measurement of the OEL values.
Containment weak points
Containment systems for filling and emptying
barrels and big bags
Barrel filling with endless liner
Barrel filling and emptying with DCS
(Drum Containment System)
Big bag emptying and filling with a protective foil system
Container systems
Container with outlet cone for emptying
Containment Transfer Unit (CTU) at the container inlet for filling
Split valve systems
Laminar flow, glove box systems (isolators)
Filter systems
Sampling
Containment on equipment
Practical example of a containment API plant
4.J.5.1
4.J.5.2
4.J.5.3
4.J.6
4.J.6.1
4.J.6.2
4.J.6.3
4.J.6.4
4.J.7
4.J.8
4.J.9
4.J.10
(6)
4.K
Process control systems
4.K.1
4.K.2
4.K.3
4.K.4
4.K.5
Definitions
Features of process control systems
How to use process control systems
Carrying out a process control system project
Qualification of process control systems
Pharmaceutical Water
5.A
Water types
5.A.1
5.A.2
5.A.3
Potable water
Purified water
Water for injection
4.I (11)
4.I (11)
4.I (12)
4.I (12)
4.I (13)
4.I (13)
4.I (13)
4.J (1)
4.J (2)
4.J (2)
4.J (2)
4.J (3)
4.J (5)
4.J (6)
4.J (7)
4.J (7)
4.J (9)
4.J (12)
4.J (13)
4.J (14)
4.J (15)
4.J (16)
4.J (17)
4.J (18)
4.J (19)
4.J (21)
4.J (23)
4.K (1)
4.K (2)
4.K (5)
4.K (6)
4.K (7)
5.A (1)
5.A (3)
5.A (4)
Contents
Highly purified water
5.B
Generation of pharmaceutical water
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
Purified water (PW)

Airbreak
Softener
Removal of chlorine
Reverse osmosis
Electrodeionisation (EDI, CDI)
Ultra filtration
Ion exchanger
Purification plants
Water for injection (WFI)
Distillation technology
Purification of pharmaceutical water treatment systems
5.C
Distribution and storage of pharmaceutical water
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
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
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)
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
5.A (6)
5.B (2)
5.B (2)
5.B (2)
5.B (3)
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)
5.C (19)
5.C (20)
5.C (22)
5.C (22)
5.C (23)
5.C (23)
5.C (24)
5.C (25)
5.C (26)
5.C (28)
Contents
5.A.4
(7)
Contents
Contents
5.C.7.1
5.C.7.2
(8)
Cleanability of the loop for purified water

Valve groupings
5.D
Qualification of water supplies
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
Introduction
Risk analysis
Design qualification
User requirements
Technical specification
Test protocol
Test record
Facility documentation
Test protocol
IQ test record
Operational qualification (OQ)
Test protocol (OQ)
OQ test record
Handover to the user
Handover report
Process validation/performance qualification (PQ)
Microbiological tests for pharmaceutical water
Determination of alert and action limits
Sampling
Qualification report
5.E
Operation of water supplies
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
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
Procedure to reduce microbial counts

Sanitisation
Sterilisation procedure
Disinfection
Maintenance of a water supply
Quality-relevant maintenance
Safety-relevant maintenance
Value-maintaining maintenance
Calibration of measuring systems
Change control
Major and minor changes
Requalification
After major changes
After defined interval
Decommissioning/uninstalling
Shutting down the water supply
Disassembly work on the facility
5.C (28)
5.C (29)
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 (33)
5.D (37)
5.D (37)
5.D (43)
5.D (43)
5.D (44)
5.D (45)
5.D (46)
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)
5.E (11)
5.E (11)
5.E (13)
5.E (13)
5.E (13)
5.E (14)
5.E (14)
5.E (14)
Contents
Pure steam systems
5.F.1
5.F.2
5.F.2.1
5.F.2.2
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
Physical principles
Quality requirements for pure steam
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
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
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.B
Preparation of the qualification
6.B.1
6.B.2
6.B.3
6.B.4
6.B.5
6.B.5.1
Commissioning
Sequence
Qualification team
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
6.B.5.2
6.B.5.3
5.F (1)
5.F (3)
5.F (3)
5.F (4)
5.F (5)
5.F (5)
5.F (6)
5.F (7)
5.F (7)
5.F (8)
5.F (9)
5.F (9)
5.F (9)
5.F (14)
5.F (18)
5.F (18)
5.F (19)
5.F (19)
5.F (20)
Contents
5.F
6.A (1)
6.A (3)
6.A (4)
6.A (7)
6.A (8)
6.A (9)
6.A (10)
6.A (12)
6.B (1)
6.B (4)
6.B (5)
6.B (6)
6.B (6)
6.B (7)
6.B (7)
6.B (7)
(9)
Contents
Contents
6.B.6
6.B.6.1
6.B.6.2
6.B.6.3
(10)
Risk analysis
Risk analysis during the life cycle of a facility
Organisation of risk analysis
Implementation of the risk analysis
6.C
Qualification documentation
6.C.1
6.C.2
6.C.3
6.C.4
6.C.5
Qualification master plan

Qualification plan
Qualification report
Labelling of the qualification status
SOP "Qualification of facilities and equipment"
6.D
Design qualification (DQ)
6.D.1
6.D.1.1
6.D.1.2
6.D.2
User requirements (user specifications)

Example: Reaction vessel
Example: Washer
Technical specification
6.E
Installation qualification (IQ)
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
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
6.F
Operational qualification(OQ)
6.F.1
6.F.1.1
6.F.1.2
6.F.1.3
6.F.1.4
6.F.2
Examples of OQ plans
Safety devices
Risk analysis Operating functions
Check for the presence of screw caps
OQ report
Example: Fluid bed dryer
6.G
Performance qualification (PQ)
6.H
Special cases of qualification
6.H.1
6.H.2
6.H.3
6.H.4
6.H.5
Retrospective qualification
Requalification
Content of a review
Maintenance of the qualified status
Qualification of simple equipment
6.B (10)
6.B (10)
6.B (11)
6.B (12)
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 (16)
6.E (18)
6.E (21)
6.E (23)
6.F (3)
6.F (4)
6.F (6)
6.F (8)
6.F (11)
6.F (13)
6.H (1)
6.H (1)
6.H (3)
6.H (5)
6.H (7)
Contents
Process Validation
7.A
7.A.1
7.A.2
7.A.3
Legal aspects
The object of and procedure for process validation
Process validation documentation
7.B
Validation a key element of quality assurance
7.C
Process validation approaches
7.C.1
7.C.2
7.C.3
Prospective validation
Retrospective validation
Concurrent validation
7.D
Revalidation
7.D.1
7.D.2
7.D.2.1
7.D.2.2
7.D.2.3
7.D.2.4
Time intervals for periodic revalidations

Incidences requiring revalidation
Changes to the manufacturing instructions
Extension of the ranges of critical process parameters
Changes in manufacturing site
Serious quality problems
7.E
Planning of process validation projects
7.E.1
7.E.2
7.E.3
7.E.4
7.E.4.1
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
7.E.4.2
7.F
Validation master plan
7.F.1
7.F.2
7.F.3
7.F.4
Validation matrix
Example of a validation master plan
Example for a validation matrix
Example for a test plan
7.G
Risk analysis
7.G.1
7.G.2
Finding out the adequate extent of validation

Carrying out risk analysis
7.H
Validation protocol and report
7.H.1
7.H.2
7.H.2.1
Elements of the validation protocol

Content of a validation report
How to deal with deviations from the requirements
in the validation protocol
7.A (1)
7.A (2)
7.A (8)
7.C (1)
7.C (2)
7.C (5)
7.D (1)
7.D (2)
7.D (2)
7.D (4)
7.D (5)
7.D (5)
Contents
7.E (1)
7.E (4)
7.E (5)
7.E (6)
7.E (10)
7.E (11)
7.F (4)
7.F (6)
7.F (17)
7.F (24)
7.G (1)
7.G (1)
7.H (1)
7.H (9)
7.H (10)
(11)
Contents
7.H.2.2
Cleaning Validation
8.A
8.B
Validatability of cleaning procedures
8.B.1
8.B.2
8.B.3
Optimisation of cleaning procedures

Compilation of cleaning instructions
Validating manual and automated cleaning
procedures
Contents
8.C
7.H (11)
8.B (1)
8.B (5)
8.B (7)
Cleaning validation master plan
8.D
Establishing the scope of validation
8.D.1
8.D.2
Bracketing: determination of critical substances

Matrixing: determination of equipment-specific
validation protocols
8.E
Acceptance criteria and limit calculation
8.E.1
Calculation of active pharmaceutical

ingredient residues
Calculation of cleansing agent residues
Determination of the microbial status
8.E.2
8.E.3
(12)
Archiving of the validation documents
8.F
Sampling procedures
8.F.1
8.F.2
8.F.3
8.F.4
8.F.5
Swab test
Rinse test
Other procedures
Selection of the appropriate procedure
Microbiological testing of surfaces
8.G
Analytical procedures
8.G.1
8.G.2
Requirements for method validation

Selection of the appropriate analytical method
8.H
Documentation
8.H.1
8.H.2
8.H.3
Validation protocol
Validation report
Other documents
8.I
Maintenance of the validated status
8.I.1
8.I.2
8.I.3
8.I.3.1
8.I.3.2
Changes and deviations

Change control
Revalidation
Change-related revalidation
Periodic revalidation
8.D (1)
8.D (5)
8.E (1)
8.E (9)
8.E (10)
8.F (1)
8.F (3)
8.F (6)
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)
Contents
New products and equipment

New products
New equipment
Deviations
8.J
Cleaning validation documentation (example)
Computer Validation
10
Risk Management
10.A
Principles
10.A.1
10.A.2
10.A.2.1
10.A.2.2
10.A.2.3
10.A.3
10.A.3.1
Objectives and advantages of risk management

Regulatory environment
ICH Q9 Quality Risk Management
The FDA risk-based approach
Summary
Science-based approach
Summary
10.B
The Risk Management Process
10.B.1
10.B.2
10.B.3
10.B.4
10.B.5
10.B.5.1
10.B.5.2
10.B.5.3
10.B.5.4
10.B.5.5
Risk fields
Prerequisite
Knowledge and experience
Elements of risk management
Implementation of a risk management process
Commitment of management
Project team
Analysis of current status
Standardisation of methods
Training
10.C
Risk management and quality management system
10.C.1
10.C.1.1
10.C.1.2
10.C.2
Application to the QM system

Evaluation of the system (rough evaluation)
Evaluation of individual topics (fine evaluation)
Implementation of risk management
via the QM system
10.C.2.1 Example of process validation
10.D
Methods of risk management
10.D.1
10.D.2
10.D.2.1
10.D.2.2
Application areas of selected methods

Preparation using a fishbone diagram
Instructions for execution
Advantages and disadvantages
8.I (7)
8.I (8)
8.I (8)
8.I (10)
10.A (1)
10.A (2)
10.A (3)
10.A (4)
10.A (7)
10.A (7)
10.A (8)
Contents
8.I.4
8.I.4.1
8.I.4.2
8.I.5
10.B (1)
10.B (3)
10.B (4)
10.B (4)
10.B (5)
10.B (6)
10.B (6)
10.B (6)
10.B (7)
10.B (7)
10.C (1)
10.C (2)
10.C (4)
10.C (5)
10.C (5)
10.D (2)
10.D (3)
10.D (4)
10.D (4)
(13)
Contents
10.D.3
Informal method
10.D.3.1 Example
10.E
Fault tree analysis (FTA)
10.E.1
10.E.2
10.E.3
10.E.4
10.E.5
Objectives and areas of application

Process
Prerequisites for an FTA
Execution of an FTA
Advantages and disadvantages of an FTA
10.F
Failure Mode Effects Analysis (FMEA)
10.F.1
10.F.2
10.F.2.1
10.F.2.2
Objectives and areas of application

FMEA process
Preparation of the necessary process information
Identification of possible failures, consequences and
cause of failure
Evaluation of the failures
Evaluation of the risk priority number (RPN)
Measures
Further parameters for assessment of the overall process
Implementation of FMEA in the company
Advantages and disadvantages of an FMEA
Advantages
Disadvantages of an FMEA
Application example of a modified (simplified) FMEA
Contents
10.F.2.3
10.F.2.4
10.F.2.5
10.F.3
10.F.4
10.F.5
10.F.5.1
10.F.5.2
10.F.6
10.G
Application example of a combined FTA and FMEA
10.G.1
10.G.2
10.G.3
10.G.4
10.G.5
Step 1: team formation and working method

Step 2: discussion of the process and
identification of the risk
Step 3: risk evaluation and acceptance
Step 4: risk control
Step 5: further measures and verification
10.H
Hazard Analysis of Critical Control Points (HACCP)
10.H.1
Prerequisite and result
10.H.2
Execution
10.H.2.1 Step 1: Analysis and identification of potential risks
(hazard analysis)
10.H.2.2 Step 2: Determination of the critical control points
(Critical Control Points, CCP)
10.H.2.3 Step 3: Determining the Critical Control Points (CCP)
10.H.2.4 Step 4: In-process control, monitoring of critical control points
10.H.2.5 Step 5: Determining corrective action
10.H.2.6 Step 6: Documentation of processes
10.H.2.7 Step 7: Verification of the HACCP system
(14)
10.D (6)
10.D (6)
10.E (1)
10.E (1)
10.E (2)
10.E (3)
10.E (4)
10.F (2)
10.F (2)
10.F (4)
10.F (4)
10.F (9)
10.F (14)
10.F (14)
10.F (15)
10.F (16)
10.F (16)
10.F (16)
10.F (19)
10.F (20)
10.G (1)
10.G (2)
10.G (4)
10.G (5)
10.G (8)
10.H (2)
10.H (3)
10.H (3)
10.H (4)
10.H (5)
10.H (5)
10.H (6)
10.H (6)
10.H (7)
Contents
Advantages and disadvantages

Application example
Process description
Documentation
11
Production
11.A
Sanitation
11.B
Personnel hygiene
11.B.1
11.B.2
11.B.3
11.B.4
11.B.5
11.B.6
Clothing
Personnel hygiene
Code of conduct
Hand disinfection
Health requirements
Training
11.C
Production hygiene
11.C.1
11.C.2
11.C.3
Sources of contamination
Cleaning
Disinfection
11.D
Sanitation programme
11.D.1
11.D.2
Cleaning procedure for rooms

Documentation
11.E
Environmental monitoring
11.E.1
11.E.2
11.E.2.1
11.E.3
11.E.4
Sampling plan
Establishment of limits and frequencies
Methods
Investigation areas
Evaluation
11.F
GMP in the production process
11.G
Weigh-in
11.G.1
11.G.2
11.G.3
11.G.4
Legal principles
Weigh-in principles
Weigh-in procedure
Weighing process sequence
11.H
Identification
11.H.1
11.H.2
11.H.3
Starting materials
Labelling in the manufacturing process
Labelling of rooms
10.H (7)
10.H (8)
10.H (8)
10.H (9)
11.B (1)
11.B (11)
11.B (11)
11.B (12)
11.B (13)
11.B (13)
Contents
10.H.3
10.H.4
10.H.4.1
10.H.4.2
11.C (3)
11.C (6)
11.C (7)
11.D (1)
11.D (6)
11.E (1)
11.E (2)
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)
(15)
Contents
Contents
(16)
11.I
In-process control
11.I.1
11.I.2
11.I.3
11.I.4
11.I.5
11.I.6
Objectives
Organisation
Carrying out
Documentation
Scope of tests and limits
Responsibilities
11.J
Prevention of cross-contamination
11.J.1
11.J.2
11.J.3
11.J.4
11.J.5
11.J.6
Rooms and facilities

Cleaning
Labelling
Personnel
Reviewing the measures
Manufacture of critical products
11.K
Deviations
11.K.1
11.K.2
11.K.3
11.K.4
11.K.5
11.K.6
11.K.7
Definition
Sequence
Responsibilities
Measures
Failure investigation report
Evaluation
SOP "deviations" (example)
11.L
Reworking
11.L.1
11.L.2
Reworking rejected products

Reworking of products that have not been rejected
11.M
Warehouse and logistics
11.M.1
11.M.1.1
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
Stock management system

Responsibilities
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
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 (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)
Contents
Identification using material and batch number

Dispatch and transport
12
Sterile Production
12.A
Introduction
12.A.1
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.B
Air Lock Concepts
12.B.1
12.B.1.1
12.B.1.2
12.B.1.3
12.B.1.4
12.B.2
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
12.C
Manufacturing the solution
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
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.D
Washing processes
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
Stoppers
Material
Manufacture
Particulate impurities
Stopper washing
Glass containers (ampoules, bottles)
Types of glass
Manufacture
Washing
Ready to fill
11.M (15)
11.M (16)
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)
Contents
11.M.5
11.M.6
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)
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)
(17)
Contents
12.D.4
Transport
12.E
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
12.E.4
Filling ampoules in cleanliness grade C
and laminar flow
12.E.5
Culture medium filling (Media Fill)
12.E.6
Filling with powders
12.E.6.1 System layout of the filling equipment
12.E.6.2 Practical process using a glass bottle as an example
Contents
12.E.1
12.E.1.1
12.E.2
12.E.3
(18)
12.F
Steam sterilisation
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
Sterilisers
Description of the procedure
Sterilisation
Drying
Sterilisation kinetics
Qualification of a steam steriliser
Validation of the steam sterilisation process
Description of equipment and process
Loading configurations
Bioindicators
Determining the sterilisation time
Executing the validation
12.G
Microbiological monitoring
12.G.1
12.G.2
12.G.3
12.G.3.1
12.G.3.2
12.G.3.3
12.G.4
12.G.4.1
12.G.5
12.G.6
12.G.7
Sources of contamination
Room classification
Monitoring program
Limits (level)
Methods and equipment
Microbiological testing of surfaces and personnel
Sampling
Frequencies
Sampling points
Measure if levels are exceeded
Organism identification
12.H
Test for sterility
12.H.1
Parametric release
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)
12.G (17)
12.G (18)
12.G (20)
12.G (22)
12.G (24)
12.H (1)
Contents
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
12.I
Testing for tightness and particles
12.I.1
12.I.1.1
12.I.1.2
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
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
Freeze drying
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

System components
Qualification of a freeze dryer
Validation of the freeze drying process
Description of equipment and process
12.K
Dry Heat Sterilisation
12.K.1
12.K.2
12.K.3
12.K.3.1
12.K.3.2
12.K.4
12.K.4.1
12.K.4.2

Sterilisation kinetics
Qualification of a sterilisation tunnel
Validation of the sterilisation process
Description of the device
Preparation of the endotoxin test objects
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)
Contents
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.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)
12.K (5)
12.K (5)
12.K (6)
12.K (8)
12.K (8)
12.K (9)
(19)
Contents
12.K.4.3
12.K.4.4
12.K.4.5
12.K.4.6
Contents
13
(20)
Description of the process

Position of the heat sensors
Determining the endotoxin reduction
12.K (10)
12.K (10)
12.K (10)
12.K (11)
Packaging
13.A
Packaging material
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
Responsibilities
Contents
Materials
Protection against counterfeit medicinal products
Packaging material testing
Control tests carried out at the supplier
Examples
Defect evaluation lists
Storage
Labelling
13.B
Packaging process
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
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
13.C
Qualification of a packaging line
13.C.1
13.C.2
13.C.2.1
13.C.2.2
13.C.3
13.C.3.1
13.C.3.2
Master qualification plan

Design qualification protocol
Design qualification report
Installation qualification protocol
Installation qualification report
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 (11)
13.C (11)
13.C (14)
13.C (28)
13.C (28)
13.C (33)
Contents

Operational qualification protocol
Operational qualification report
Performance qualification protocol
Performance qualification report
14
Quality Control
14.A
Sampling
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
Requirements
Personnel
Equipment
Containers
Premises
Sampling plan (instructions)
Notes for the sampling process
Containers and identification labelling
Sampling report
Reference samples
14.B
Reagents
14.B.1
14.B.2
14.B.3
Labelling
Usage and stability
Documentation
13.C (41)
13.C (41)
13.C (47)
13.C (55)
13.C (55)
13.C (59)
14.A (2)
14.A (2)
14.A (2)
14.A (2)
14.A (3)
14.A (3)
14.A (5)
14.A (5)
14.A (5)
14.A (8)
Contents
13.C.4
13.C.4.1
13.C.4.2
13.C.5
13.C.5.1
13.C.5.2
14.B (2)
14.B (2)
14.B (3)
14.C
Standards and reference substances
14.C.1
14.C.2
Definition of different standards and their areas of use

Handling, storage and stability
14.D
Qualifying laboratory instruments
14.D.1
14.D.1.1
14.D.1.2
14.D.1.3
14.D.1.4
14.D.2
Qualification protocols and reports

System suitability test (SST)
14.E
Calibration in the lab
14.E.1
14.E.1.1
14.E.1.2
14.E.1.3
14.E.2
14.E.2.1
14.E.3
Definitions
Persons
Instruments
Working
Calibration instructions and record
Test intervals, test points, test instructions
Examples
14.C (1)
14.C (4)
14.D (2)
14.D (2)
14.D (3)
14.D (4)
14.D (4)
14.D (5)
14.E (1)
14.E (1)
14.E (1)
14.E (2)
14.E (2)
14.E (3)
14.E (3)
(21)
Contents
Contents
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
Validation of analytical methods
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
Principles
Definitions of the parameters
Precision
Accuracy
LOD = Limit of Detection
LOQ = Limit of Quantitation
Selectivity
Linearity, Range
Robustness
Documentation
Revalidation
14.G
Stability testing
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
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
Labelling
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
Reduction of the study design
14.G.3.6
14.G.3.7
14.G.3.8
14.G.3.9
14.G.4
(22)
Balance
Volume measuring instruments
Photometer
HPLC system
Decision
Requirements, tolerances, specifications
Equipment release
Out of calibration
14.E (3)
14.E (5)
14.E (7)
14.E (9)
14.E (18)
14.E (18)
14.E (18)
14.E (18)
14.F (1)
14.F (2)
14.F (2)
14.F (3)
14.F (3)
14.F (4)
14.F (4)
14.F (4)
14.F (4)
14.F (5)
14.F (5)
14.G (2)
14.G (3)
14.G (3)
14.G (6)
14.G (7)
14.G (7)
14.G (8)
14.G (9)
14.G (9)
14.G (11)
14.G (12)
14.G (13)
14.G (14)
14.G (14)
14.G (14)
14.G (14)
14.G (15)
14.G (17)
14.G (18)
14.G (18)
14.G (19)
Contents
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
Bracketing
14.G (19)
Matrixing
14.G (20)
Stability testing in the marketing phase
14.G (23)
Follow-up stability testing (FuST)
14.G (23)
Stability commitment (SC)
14.G (24)
Defining the retest period for an active
pharmaceutical ingredient and the shelf life for a
drug product through evaluation of stability data
(ICH Q1E)
14.G (35)
Data evaluation for the retest period for APIs and shelf life
for drug products that are intended for storage at room
temperature
14.G (35)
Data evaluation for period for APIs and shelf life
for drug products intended for storage
in refrigerator (28 C)
14.G (37)
Date evaluation for retest period for APIs and shelf life
for drug products for intended storage
in a freezer (20 C)
14.G (37)
Decision tree for data evaluation for retest period
or for APIs or drug products (excluding frozen products) 14.G (38)
Procedure for statistical analysis
14.G (38)
Examples of the statistical evaluation of stability data
14.G (38)
Data analysis for a single batch
14.G (38)
Data analysis of one attribute in each batch for several batches
of the same product (known as One-Factor, Full-Design Studies) 14.G (41)
Data analysis of all attributes for several batches
(Multi-Factor, Full-Design Studies)
14.G (41)
14.H
Out-of-specification results
14.H.1
14.H.1.1
14.H.1.2
14.H.2
14.H.3
14.H.4
14.H.5
Significance
The BARR Laboratories case
The consequences
Definitions
FDA Draft Guidance and Comments
Example for handling of an OOS result
Trend tracking
14.I
Raw data documentation
14.I.1
14.I.2
14.I.2.1
14.I.2.2
14.I.2.3
Principles
Single sheet documentation system
Cover sheet
Data sheet
Index sheet
Contents
14.G.4.1
14.G.4.2
14.G.5
14.G.5.1
14.G.5.2
14.G.6
14.H (1)
14.H (1)
14.H (2)
14.H (3)
14.H (5)
14.H (9)
14.H (16)
14.I (1)
14.I (3)
14.I (3)
14.I (3)
14.I (7)
(23)
Contents
14.J
Batch release
14.J.1
Certification by a qualified person and release

in accordance with EC GMP Guidelines
14.J.1.1 Regulations contained in Directive 2001/83/EC
14.J.1.2 Objectives of appendix 16
14.J.1.3 Cases of application
14.J.2
Responsibility for issuing the release
14.J.3
Publication of release
14.J.4
Release procedures in practice
15
15.A.1
GMP-requirements managed and reviewed

according to german pharma business regulations
Requirements of the EU GMP Guideline
Formal requirements
Management and revision documentation
Contents
15.B
GMP-conforming documentation
15.B.1
15.B.2
15.B.3
Handwritten entries
Archiving
Master-SOP "GMP-conforming documentation"
15.C
Batch documentation
15.C.1
15.C.1.1
15.C.1.2
15.C.1.3
15.C.2
15.C.2.1
15.C.2.2
15.C.3
15.C.3.1
Manufacturing instructions/record
Manufacturing instructions
Batch processing record
Master of manufacturing instructions/batch processing record
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
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
(24)
Documentation
15.A
15.A.2
15.A.3
15.A.4
14.J (1)
14.J (2)
14.J (3)
14.J (5)
14.J (6)
14.J (7)
14.J (8)
15.A (1)
15.A (4)
15.A (8)
15.A (12)
15.B (1)
15.B (2)
15.B (3)
15.C (3)
15.C (3)
15.C (4)
15.C (5)
15.C (25)
15.C (25)
15.C (26)
15.C (26)
15.C (27)
15.C (28)
15.C (29)
15.C (29)
15.C (31)
15.C (33)
15.C (33)
15.C (33)
15.C (34)
15.C (34)
Contents
15.D
Standard operating procedures (SOPs)
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
Compilation
Design and format
Identification
Approval and implementation
Training
Usage
Review
Changes
Withdrawing an operating procedure
Administration
Status identification
Distribution
Integration
Use of computerised systems
Archiving
Example of an SOP "Compilation and
administration of operating procedures"
15.E
Site master file
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
15.E.2.9
15.E.2.10
Introduction
Design
General information
Personnel
Premises and equipment
Documentation
Production
Quality control
Contract manufacturing and contract qualitiy control
Distribution, complaints and product recalls
Self-inspection
Appendix
15.F
Annual product review
15.F.1
15.F.2
15.F.3
15.F.4
15.F.5
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.C (36)
15.D (2)
15.D (4)
15.D (6)
15.D (7)
15.D (7)
15.D (8)
15.D (8)
15.D (9)
15.D (9)
15.D (10)
15.D (10)
15.D (10)
15.D (10)
15.D (11)
15.D (11)
Contents
15.C.5.5 Deviations, changes relevant to marketing authorisation,

recording errors
15.D (12)
15.E (1)
15.E (1)
15.E (2)
15.E (3)
15.E (3)
15.E (5)
15.E (7)
15.E (8)
15.E (8)
15.E (9)
15.E (9)
15.E (10)
15.F (3)
15.F (4)
15.F (6)
15.F (7)
15.F (12)
(25)
Contents
Contents
16
Research and Development
17
Contract Manufacturing
and Analysis
17.A
Contract manufacture
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
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
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
(26)
17.B
Contract Analysis
17.B.1
17.B.2
Introduction
Legal basis
17.A (1)
17.A (3)
17.A (8)
17.A (9)
17.A (10)
17.A (11)
17.A (11)
17.A (11)
17.A (11)
17.A (12)
17.A (12)
17.A (12)
17.A (13)
17.A (15)
17.A (15)
17.A (16)
17.A (16)
17.A (17)
17.A (17)
17.A (19)
17.A (19)
17.A (19)
17.A (20)
17.A (20)
17.A (21)
17.A (22)
17.A (22)
17.A (27)
17.A (27)
17.A (27)
17.A (28)
17.A (34)
17.B (1)
17.B (1)
Contents
17.B.3
17.B.4
17.B.5
17.B.5.1
17.B.6
17.B.6.1
17.B.6.2
17.B.6.3
17.B.6.4
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?
Questions of liability
Test certificates containing evaluations
Typical errors
18
Inspections
18.A
Principles
18.B
Inspection procedures
18.B.1
18.B.2
18.B.3
18.B.4
System-based
Product-based
Procedure-based
Area-based
17.B (3)
17.B (3)
17.B (4)
17.B (6)
17.B (9)
17.B (9)
17.B (9)
17.B (10)
17.B (11)
18.C
Inspectors
18.C.1
18.C.2
Technical qualification requirements

Personal requirements
18.D
Organisation of inspections
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
Inspection planning
Inspection preparation
Carrying out the inspections
Opening discussion
Site inspection
Documentation check
Concluding discussion
Evaluation and documentation
18.E
Self-inspection
18.E.1
18.E.2
18.E.3
18.E.4
18.E.5
Purpose of self-inspection
Carrying out the self-inspection
Self-inspection documentation
Errors and remedial action
Follow-up activities
18.F
Inspection of contract manufacturers
18.F.1
18.F.2
18.F.3
Purpose of the inspection of contract manufacturer

Carrying out inspections of contract manufacturer
Handling of changes and deviations
Contents
18.B (1)
18.B (2)
18.B (2)
18.B (3)
18.C (1)
18.C (3)
18.D (1)
18.D (3)
18.D (4)
18.D (4)
18.D (5)
18.D (6)
18.D (7)
18.D (8)
18.E (1)
18.E (1)
18.E (3)
18.E (9)
18.E (12)
18.F (1)
18.F (1)
18.F (3)
(27)
Contents
Contents
(28)
18.G
Inspection of suppliers
18.G.1
18.G.2
Purpose of the supplier inspection

Carrying out the supplier inspection
18.H
Questionnaire for preparing

GMP-inspections
18.I
Supplier qualification
18.I.1
18.I.2
18.I.3
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
Suppliers (traders) and manufacturers of raw materials

Selection of manufacturer or supplier
Audit of active pharmaceutical ingredient manufacturers
Preparation
Type of inspection
Questions for opening discussion
Inspection sequence: Documents versus site visit
Inspection questionnaire
Change of supplier
Suppliers of packaging materials
19
Tools for Quality Assurance
19.A
Project management
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
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
19.B
Risk analysis
19.B.1
Development of the risk analysis
18.G (1)
18.G (2)
18.I (1)
18.I (3)
18.I (4)
18.I (5)
18.I (14)
18.I (15)
18.I (16)
18.I (16)
18.I (27)
18.I (28)
19.A (1)
19.A (2)
19.A (2)
19.A (2)
19.A (2)
19.A (3)
19.A (4)
19.A (4)
19.A (5)
19.A (5)
19.A (5)
19.A (5)
19.A (6)
19.A (6)
19.A (9)
19.A (9)
19.A (9)
19.A (9)
19.A (10)
19.B (1)
Contents
19.B.3.1
19.B.3.2
19.B.4
19.B.4.1
19.B.4.2
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
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
Procedure
Example
Hazard Analysis of Critical Control Points
Failure finding
Evaluation of problem points
Definition of measures
Documentation
HACCP summary
19.C
Change control
19.C.1
19.C.2
19.C.3
Principles of change control

Introduction and operation of change control programs
Documentation
20
Active Pharmaceutical Ingredient (API)

Production
21
References
19.B (4)
19.B (4)
19.B (4)
19.B (5)
19.B (9)
19.B (11)
19.B (13)
19.B (13)
19.B (16)
19.B (26)
19.B (26)
19.B (27)
19.B (28)
19.B (28)
19.B (37)
19.B (39)
19.B (40)
19.B (40)
19.B (41)
19.B (42)
Contents
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.C (1)
19.C (4)
19.C (9)
(29)
Contents
Contents
(30)
Contents
Contents file 4 to 5
Index file 4 to 5
Information
B.1
B.2
B.3
List of Abbreviations
Glossary
Adress-Register
EU GMP Guide
C.1
C.2
C.3
C.4
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
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
C.5
C.6.1
C.6.2
C.6.3
C.6.4
C.6.5
C.6.6
C.6.7
C.6.8
Contents
(31)
Contents
C.6.9
C.6.10
C.6.11
C.6.12
C.6.13
C.6.14
Contents
C.6.15
C.6.16
C.6.17
C.6.18
C.6.19
C.7
C.8
C.9
C.9
USA: CFR and FDA Guidelines
D.1
21 CFR Part 210

Current good manufacturing practice in manufacturing,
processing, packing, or holding of drugs
21 CFR Part 211
Current Good Manufacturing Practice for Finished
Pharmaceuticals
D.1
(32)
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
Glossary
Index EU GMP Guide
C.1 to C.6.19
Note For Guidance on Quality of Water for Pharmaceutical
Use
Index C.9
D.1
D.12
21 CFR Part 11
Electronic records; electronic signature
Index chapter D.1
Guideline on General Principles of Process Validation
Index chapter D.2
Guide to Inspections of High Purity Water Systems
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
Sterile Drug Products Produced by Aseptic Processing
Current Good Manufacturing Practice
Index chapter D.10
PAT A Framework for Innovative Pharmaceutical
Development, Manufacturing, and Quality Assurance
Index chapter D.11
Part 11, Electronic Records; Electronic Signatures Scope
and Application
Index chapter D.12
ICH-Guidelines
E.1
ICH Q1A Stability Testing of New Drug Substances And

Products
Index chapter E.1
D.1
D.2
D.2
D.3
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
E.1
Contents
Contents
(33)
Contents
E.2
E.2
E.3
E.4
E.4
E.5
E.5
E.6
Contents
E.6
E.7
E.7
E.8
E.8
PIC/S Guidelines
F.1
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
F.1
F.2
F.2
F.3
F.3
F.4
F.4
F.4
(34)
ICH Q1B: Stability Testing: Photostability Testing of New

Drug Substances and Products
Index chapter E.2
ICH Q1C: Stability Testing: Requirements for New Dosage
Forms
Guideline for Industry: Q2A Text on Validation of Analytical
Procedures: Definitions and Terminology
Index chapter E.4
Guidance for Industry: Q2B Validation of Analytical
Procedures: Methodology
Index chapter E.5
ICH Q7A: Good Manufacturing Practice for Active
Pharmaceutical Ingredients
Index chapter E.6
ICH Q8: Pharmaceutical Development
Index chapter E.7
ICH Q9: Quality Risk Management
Index chapter E.8
Contents
WHO Guidelines
G.1
G.1
Guide to good storage practices for pharmaceuticals

Index chapter G.1
Empty Register
Contents
(35)
Contents
Contents
(36)

GMP Manual Ivz

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Contents

Quality management in the pharmaceutical environment

Quality assurance in the GMP regulations

Structure of a documentation system

Quality management system in accordance with GMP

GMP Manual (Up01) Maas & Peither GMP Publishing

GMP Manual (Up01) Maas & Peither GMP Publishing

Place of work and job descriptions

Requirements of the personnel

Location, connection to other rooms

Material flow, personnel flow and layout

GMP Manual (Up01) Maas & Peither GMP Publishing

Heating Ventilation Air Conditioning (HVAC)

Facilities and Equipment

Construction and installation materials

GMP Manual (Up01) Maas & Peither GMP Publishing

CIP (Cleaning in Place)

Examples of facility qualification

CIP (Cleaning in Place)

GMP Manual (Up01) Maas & Peither GMP Publishing

Targeted jet/orbital cleaner

Containment (user protection)

Process control systems

GMP Manual (Up01) Maas & Peither GMP Publishing

Highly purified water

Generation of pharmaceutical water

Purified water (PW)

Distribution and storage of pharmaceutical water

GMP Manual (Up01) Maas & Peither GMP Publishing

Cleanability of the loop for purified water

Qualification of water supplies

Operation of water supplies

Procedure to reduce microbial counts

GMP Manual (Up01) Maas & Peither GMP Publishing

Pure steam systems

Legal aspects of qualification

Preparation of the qualification

GMP Manual (Up01) Maas & Peither GMP Publishing

Qualification master plan

Design qualification (DQ)

User requirements (user specifications)

Installation qualification (IQ)

Performance qualification (PQ)

Special cases of qualification

GMP Manual (Up01) Maas & Peither GMP Publishing

Validation a key element of quality assurance

Process validation approaches

Time intervals for periodic revalidations

Planning of process validation projects

Responsibilities and task assignment

Validation master plan

Finding out the adequate extent of validation

Validation protocol and report

Elements of the validation protocol

GMP Manual (Up01) Maas & Peither GMP Publishing

Validatability of cleaning procedures

Optimisation of cleaning procedures

Cleaning validation master plan

Establishing the scope of validation

Bracketing: determination of critical substances

Acceptance criteria and limit calculation

Calculation of active pharmaceutical

Archiving of the validation documents