Prequalification Programme: Access to Antimalarial, Antituberculosis and
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1
Good Manufacturing Practices – Part II
3 Specific GMP topics:
Premises, Documentation and Validation
WHO EMRO 1st Workshop on the WHO Prequalification
Programme: Priority Essential Medicines,
Cairo, Egypt, 6 and 7 June, 2007
Anton Norder, MSc
Technical Officer
20 Avenue Appia
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CH-1211
Geneva 27
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Switzerland
2
E-mail: nordera@who.int
Guidelines and references

Booklet:
Quality Assurance of pharmaceuticals. A compendium of guidelines
and related materials. Volume 2, second updated edition. Good
manufacturing practices and inspection. World Health Organization,
Geneva, 2007.



Good Manufacturing Practices for pharmaceutical products: main
principles. WHO Technical Report Series, No. 908, 2003, Annex 4.
Good Manufacturing Practices: starting materials. WHO Technical Report
Series, No. 823, 1992.
ICH Q7A: Good Manufacturing Practice Guide for Active
Pharmaceutical Ingredients, International Conference on
Harmonization http://www.ich.org/cache/compo/276-254-1.html
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WHO Guidelines and references (cont'd)

WHO Good Manufacturing Practices: water for pharmaceutical use.
WHO Technical Report Series, No. 929, 2005, Annex 3
http://whqlibdoc.who.int/trs/WHO_TRS_929_eng.pdf

Supplementary guidelines on good manufacturing practices for
heating, ventilation and air-conditioning systems for non-sterile
pharmaceutical dosage forms. WHO Technical Report Series, No.
937, 2006, Annex 2
http://whqlibdoc.who.int/trs/WHO_TRS_937_eng.pdf

Supplementary guidelines on good manufacturing practices :
validation. WHO Technical Report Series, No. 937, 2006, Annex 4
http://whqlibdoc.who.int/trs/WHO_TRS_937_eng.pdf
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WHO Guidelines and references (cont'd)

WHO guidelines for sampling of pharmaceutical products and related
materials. WHO Technical Report Series, No. 929, 2005, Annex 4
http://whqlibdoc.who.int/trs/WHO_TRS_929_eng.pdf

Good Practices for National Pharmaceutical Control Laboratories. WHO
Technical Report Series, No. 902, 2002, Annex 3.
http://whqlibdoc.who.int/trs/WHO_TRS_902.pdf#page=37

As well as specific GMPs on:





Sterile pharmaceutical products (2002)
Biologicals (1993)
Investigational pharmaceutical products for clinical trials in humans (1996)
Herbal medicinal products (1996/97)
Radiopharmaceutical products (2003)
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However there's more GMP's:

PIC/S GMP (Pharmaceutical Inspection Co-operation Scheme):
www.picscheme.org ; adopted by many countries, e.g.
European Union, or partially (Canada, Australia)

National GMP's in many countries (e.g. USA (www.fda.gov),
China, India, Brazil, Argentina, etc.)

International Conference on Harmonization (ICH): www.ich.org

Also refer to ISO, e.g in cases of filter types in HVACs, clean
room design, risk management, etc.
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Overview of specific GMP topics to be
covered in this presentation:

Part 1:
Premises in relation to buildings, design, equipment, etc.

Part 2:
Documentation

Part 3:
Qualification and validation
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Part 1: Premises
Arrival of goods
Visitors entrance
QC
Workers entrance
Offices
Shipment of goods
Canteen
Material Flow
Gowning
Incoming
goods
Corridor
Shipping
Corridor
Corridor
Raw
Materials
&
Packaging
Storage
People Flow
Zone: Clean
Zone: Packaging
Weighing
Processing
Washing
Packaging
Filling
Finished
Products
Storage
Machine
Shop
Utilities and Services
Corridor
Waste Treatment
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Zone: Controlled
Premises: specific areas
Note that specific requirements are given for specific areas:

Ancillary areas (gowning rooms, toilets, refreshment rooms,
maintenance areas, animal housing etc)

Storage areas

Weighing areas

Production areas

Quality control areas
12.11 – 12.36
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Premises: ancillary areas




Rest and refreshment rooms separate from manufacturing and quality
control areas
Changing, washing and toilet areas accessible and appropriate
numbers
Maintenance workshops separated from production - if not possible –
tools in reserved areas
Animal houses well isolated – separate air handling and entrance
12.11 – 12.14
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Premises: ancillary areas
FACTORY
CHANGE
ROOM
AIR
LOCK
TOILETS
CANTEEN
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Premises: ancillary areas
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Premises: Receipt and storage of goods


Separate receiving and
dispatch bays
 Materials and
products protected
from weather
Area to clean incoming
materials provided
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Premises: Receipt and storage of goods
Cleaning of incoming
containers

Cleaning with a cloth, or
duster

Cleaning by using a vacuum
cleaner

Use of air curtains and air
tunnels
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Premises: Receipt and storage of goods

Storage areas of sufficient capacity

Orderly storage of categories of materials and products

Separate and segregated areas: starting materials, packaging
materials, intermediates, bulk, finished products, quarantined,
released, rejected, returned and recalled products and materials
12.15, 12.16
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Premises: Receipt and storage of goods
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Premises: Receipt and storage of goods
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Premises: Receipt and storage of goods

Appropriate temperature and relative humidity conditions
within defined limits
 Provided, controlled, monitored and recorded

Good storage conditions: clean, dry and appropriate lights
12.16, 12.17
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Premises: Receipt and storage of goods

Quarantine area: clearly marked and access restricted

Separate sampling area is the norm: no risk for contamination or
cross-contamination

Segregated areas for rejected, recalled and returned materials and
products

Safe and secure areas for highly active, radioactive materials,
narcotics and other materials (risk of abuse, fire, explosion)
12.18 – 12.20, 12.22
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Premises: Receipt and storage of goods
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Premises: Receipt and storage of goods
Printed packaging materials
 Critical to ensure correct labelling of products
 Special attention to sampling of printed packaging materials
 Special attention to safe and secure storage
 Ensure compliance with specifications, prevent mix-ups
12.21
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Premises: weighing

Weighing operations – in separated areas

Appropriate design (see also GMP on HVAC)

Provision for dust control

Smooth, impervious, durable, easy-to-clean finishes

Cleaning procedures and records

Documentation, e.g. SOPs, logs and records
12.23
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Premises: weighing
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Requirements on premises:





Design
 Walls, floors, ceilings, ledges, drains, air supply, dust extraction
Prevention of build-up of dirt and dust to avoid unnecessary
risks of contamination
 Cleaning programme, appropriate cleaning, cleaning records
Effective cleaning and disinfection
 Choice of materials and chemicals, validation
12.2, 12.3, 12.7, 12.9, 12.29
Drains – prevent backflow
Protection from insects, birds, vermin and weather
 from receipt of raw materials to dispatch of released product
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Design of premises:



Walls, floors, ceilings –
smooth and easy to
clean
No ledges or areas
where dust can
accumulate
Prevention of build-up
of dirt and dust to avoid
unnecessary risks of
contamination
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Premises: production areas
Minimize risk of cross-contamination:
 Dedicated and self-contained facilities for some products such as
highly sensitizing materials (e.g. penicillins) or biological preparations
(e.g. live microorganisms)
 Separate facilities for other products such as some antibiotics,
hormones, cytotoxic substances
 Non-pharmaceuticals normally not in the same facility, e.g.
pesticides, herbicides
12.24
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Premises: production areas

Layout in accordance with sequence of production

Appropriate cleanliness level

Adequate work and in-process storage space

Orderly and logical positioning of equipment

minimizes risk of contamination, mix-ups and missing production
steps

Specially designed areas for packaging

Layout to avoid mix-ups and cross-contamination
12.32, 12.26, 12.31
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Premises: production areas


Starting and packaging materials, intermediates and bulk
exposed to environment:
 Interior surfaces (walls, floors, ceilings) – smooth, free from
cracks and open joints
 No shedding of particles
 Easy and effective cleaning permitted
Disinfection if needed
12.27
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Premises: production areas




Design of pipework, light fittings, and ventilation points – no
recesses that are difficult to clean
Access for maintenance from outside production areas
Drains of adequate size, and equipped to prevent back-flow
Open channels avoided
12.28, 12.29
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Premises: production areas




Effective ventilation with air
control facilities
Including filtration of air to a
sufficient level to prevent
contamination and crosscontamination – also external
environment
Control of temperature and
relative humidity where
necessary
Regular monitoring of
conditions during production
and non-production periods
12.30
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Avoiding cross contamination



Special precautions should be taken to prevent generation and
dissemination of dust
Proper air control – supply and extraction, suitable quality
Due to uncontrolled release of:
 dust, gas, particles, vapours, sprays, organisms, residue,
insects
16.10 - 11

Dedicated and self-contained areas for:
 Live vaccines
 Live bacterial preparations
 Certain other biological materials
 Penicillin products
16.12(a)
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Avoiding cross contamination (cont'd)


Campaign production:
 Separation in time
 Followed by appropriate cleaning
 Validated cleaning procedure
16.12(b)
Ventilation systems and airlocks
 Appropriately designed ventilation system with air supply and
extraction systems
 Supply or incoming air should be filtered
 Recirculation of air versus 100% fresh air supply
 Proper airflow patterns
 Pressure differentials
16.12 (c and d)
 Appropriately designed airlocks
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Avoiding cross contamination (cont'd)

Clothing

Protection of operator and product

Fit for its intended use

Highly potent products or those of particular risk - need for
special protective clothing

Personnel should not move between areas producing different
products

Garments need to be cleaned
16.12(e)
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Avoiding cross contamination (cont'd)


Cleaning and decontamination
 Procedure for removing soil and dirt
 Remove all cleaning chemical residues or disinfectant residues
 Remove and/or reduce micro-organisms
 Validated (known effectiveness of the procedure)
 Use cleanliness status labels
16.12(f, h and i)
 Test for residues
Closed processing systems
 For example: totally enclosed water purification systems
 Tanks fitted with appropriate filtration - without removable lids
 Present special cleaning difficulties, sometimes use
clean-in-place (CIP)
16.12(g)
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Sanitation in production operations



Work-flow
 designed to avoid potential contamination
Access
 to production areas restricted to authorized personnel
 direct operators, QC staff, warehouse staff, maintenance
personnel, cleaners
 the more critical the area - fewer number of persons there
Simultaneous operations
 not permissible to process different products in different areas
with a common ventilation system
 permissible to carry out secondary packaging activities for
different products within a packing hall with adequate physical
separation
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Sanitation in production operations (cont'd)
Area clearance checks:
 Process of checking
 all materials and documentation from the previous batch
removed
 all plant and equipment thoroughly cleaned and appropriate
status labelling
 checklist useful
 The area clearance check should be carried out by two persons
 between batches of same product, acceptable for both checks
to be carried out by production personnel

for product changeover, second check carried out by QC staff

all checks carried out in accordance with written SOP and
results recorded on the batch documentation.
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E.g. line clearance in packaging





Absence of all materials
from previous run, including
printing masters
Includes checks on
materials and components
Batch number
Expiry date
Printed packaging material
including cartons, leaflets,
foil . . .
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Sanitation in production operations (cont'd)

Cleaning and cleaning validation

degree of cleaning depends on whether consecutive batches
are of same or different product

Check cleaning agent is fully removed

If possible hot water alone used for cleaning

all cleaning and disinfecting solutions carefully prepared and
expiry dated

For sterile products: Final rinse with purified water, or water for
injection

Full records kept
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Sanitation in production operations (cont'd)

Maintenance and repair
 activities inevitable in manufacturing area
 Should present no risk to product

Whenever possible, all planned maintenance outside normal
operating hours

Emergency work in working area followed by thorough clean
down and disinfection before manufacturing recommences

Area clearance by QC
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Basic Principles on premises in GMP

The temperature and
relative humidity should be
controlled, monitored in
accordance with an SOP,
and the results recorded.
The limits should be
appropriate according to
the materials stored and
product processed
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Premises: maintenance


Careful maintenance done
Repairs and maintenance should not present any hazard to the
quality of the products
12.6
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Premises of Quality Control Labs




QC laboratories should be separate from production areas
Separate areas for biological, microbiological and radioisotope
methods
Suitable design with sufficient space to avoid mix-ups and
cross-contamination
Suitable space for storage samples, reference standards,
solvents, reagents and records
12.33, 12.34
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Premises of Quality Control Labs
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Part 2: Documentation
Objectives
1. To review general requirements for documents
2. To review specific requirements for each document
3. To consider current issues applicable to your countries
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Documentation



Essential part of the QA system, for all aspects of GMP
Purpose of documentation
 Defines specifications and procedures for all materials and
methods of manufacture and control
 Ensures all personnel know what to do and when to do it
 Ensure that authorized persons have all information necessary
for release of product
 Ensures documented evidence, traceability, provide records and
audit trail for investigation
 Ensures availability of data for validation, review and statistical
analysis
Design and use
15.1
 Depends upon manufacturer
 Some documents combined into one, sometimes separate
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Documentation
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Documentation
Why are documents so important?

Communication

Cost

Audit trail
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Documentation: general principles

Documents should be
 Designed, prepared, reviewed, distributed with care
 Approved by appropriate responsible persons
Comply with marketing authorization
Design of documentation important

Look at the “Style” of the document



Instructions in the imperative

Short sentences preferred to long sentences
15.2
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Documentation: general principles (cont'd)

Contents of documents should be clear (easy to understand) and
include, e.g.

Title, nature, objective or purpose

Layout in orderly fashion

Easy to be filled in and checked

Clear and readable – including copies made

No errors if master documents are copied for working documents
15.4
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Documentation: general principles (cont'd)
Documentation control




Regular review of documents
Kept up to date (current) - amended
Superseded documents removed and not used
 Distribution and retrieval of documentation
Retention time for superseded documents
15.5
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Data entry in documents:

Clear, readable and indelible

Design to allow for sufficient space for entries

Changes to entries:
 signed, dated and reason given
 original entry still readable

Entries at the time of action

All significant actions recorded – traceable
15.6 – 15.8
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Data entry in e-documents:


Electronic data processing systems, photographic systems or other
reliable means:
 Systems require SOPs and records
 Accuracy of records checked
 Authorized persons - access and changes
 Password controlled
 Entries checked
Batch records stored electronically:
 Protected
 Back-up transfer, e.g. magnetic tape, microfilm, paper print-outs

Records kept 1 year after expiry date of product

Data readily available during retention period
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15.9
Different types of documents

Labels

Specifications and testing procedures

Master formulae and instructions

Batch processing and batch packaging records

Standard Operating Procedures (SOPs)

Records

Stock control and distribution records

Log books

Other documents …
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Labels





What must be labelled?
 Containers, equipment, premises
Label information?
 Clear, unambiguous, company
format
 Intermediates and bulk products
Colours can be used, e.g. green
(accepted), red (rejected)
Different types of labels, e.g.
cleaning status, production stage,
status of materials
Other types of labels?
15.10
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Specifications

Authorized, approved, signed and dated
 Starting, packaging materials and finished products: include tests
on identity, content, purity, quality
 Intermediates and bulk
 Water, solvents and reagents

QC, QA or documentation centre
Periodic review
Compliance with current pharmacopoeia
Pharmacopoeia, reference standards and spectra available



15.14 - 15.17
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Specifications: Starting and packaging
materials
Include:

Name (e.g. INN) and internal code

Pharmacopoeia (if applicable)

Qualitative and quantitative requirements and limits
Other data may include:

Supplier

Sampling procedure or reference

Storage conditions, precautions

Retest date
15.18 -15.19
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Specifications: Finished products
Include:

Name and code reference

Names of actives (e.g. INN)

Formula

Dosage form, package details

Reference to sampling

Qualitative and quantitative requirements and limits

Storage conditions and precautions

Shelf life
15.21
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Production documentation


Bulk manufacturing:

Master formulae

Batch Processing Records
Packaging:

Packaging instructions

Batch Packaging Records
15.22 – 15.30
The Master formulae and the Packaging instructions are the
connection document between Marketing Authorization,
Specifications and the actual records
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Documentation
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Documentation
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Standard Operating procedures (SOPs)

Describe one particular process in detail

Required for a lot of activities mentioned in WHO chapter 15

Many other activities outlined elsewhere in GMPs also require
SOPs

SOPs are non-batch related

Authorization

Periodic review

Version management

Clear instruction, no ambiguities
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15.31 – 15.48
Standard Operating procedures (SOPs)
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Part 3: Qualification and Validation
Definitions:
Validation
Action of proving, in accordance with the principles of GMP, that any
procedure, process, equipment, material, activity or system actually
leads to the expected results
Qualification
Action of proving that any premises, systems and items of equipment
work correctly and actually lead to the expected results
(Validation usually incorporates the concept of qualification)
Glossary
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System life cycle:
Recommendation
Retirement
Project Initiation
O
Aging
P
E
Development
R
Release
for Use
A
T
Maturity
I
O
N
A
E
L
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L
I
F
Qualification and Validation

Design Qualification (DQ): documentary evidence that a
premises, equipment or process has been designed in
accordance with GMP requirements

Installation Qualification (IQ): documentary evidence that a
premises, equipment or process has been built and installed in
accordance with GMP requirements

Operational Qualification (OQ): documentary evidence that a
premises, equipment or process operate in accordance with GMP
requirements

Performance Qualification (PQ): documentary evidence that a
specific process will consistently produce a product meeting its
pre-determined specifications and quality attributes
4.3
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Qualification and Validation
Principle

Qualification and validation should be done in accordance with an
ongoing programme


Initial qualification and validation
Annual review

Maintain continued validation status

Policy described in relevant documentation, e.g. quality manual, or
Validation Master Plan
4.5, 4.6
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Types of validation documentation

Validation Master Plan (VMP): policy, responsibilities, management of
validation process etc.

Validation protocols

Validation reports

Standard Operating Procedures (SOPs)
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Validation Master Plan (VMP)











Approval page and table of contents
Introduction and objectives
Facility and process description
Personnel, planning and scheduling
Responsibilities of validation team members
Process control aspects
Equipment, apparatus, processes and systems qualified, validated –
and to be qualified or validated
Acceptance criteria
Documentation, e.g.validation protocols and reports
SOPs
Training requirements and other elements…
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Requirements to Validation documentation







Clearly defines responsibility of performing validation
Conducted in accordance with predefined, approved validation
protocols
Conducted in accordance with predefined, approved acceptance
criteria
Recorded results and conclusions presented in written validation
reports – prepared and stored
Processes and procedures should be established on the basis of
these results
Premises, utilities, equipment and processes
Critical importance and particular attention paid to validation of:
 Analytical test methods
 Automated systems
 Cleaning procedures
4.7 – 4.11
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Qualification and Validation
WHO References

Good manufacturing practices (GMP): guidelines on the
validation of manufacturing processes

Validation of analytical procedures used in the examination of
pharmaceutical materials
Annex 6
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Example of priorities for process validation
Type of process
Requirement

New
Every new process before approval for routine

Existing:

Sterile products
All processes affecting the sterility, and
manufacturing environment including
sterilization stage

Non-sterile
Low dose tablets and capsules: mixing and
granulation; content uniformity (and other
parameters)
Other tablets and capsules: uniformity of mass
(and other parameters)
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Qualification and Validation

A qualification or validation protocol may contain:







Objectives of the validation and qualification study
Site of the study
Responsible personnel
Description of the equipment
SOPs
Standards
Criteria for the relevant products and processes
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Qualification and Validation

A qualification or validation report should reflect the elements
of the protocol, and may contain elements such as:
Title
 Objective of the study
 Reference to the protocol
 Details of materials, equipment, instruments, personnel
 Programmes and cycles used
 Details of procedure and test methods
… etc.

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Possible problems in Qualification and
Validation

Lack of time

Lack of personnel

Lack of experience and knowledge

Changes to the process

Prospective versus retrospective validation

Lack of documentation infrastructure

Lack of implementation of validation

Poorly designed documents
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Some GMP topics not covered today:

Vendor evaluation

Personnel

Training

Recall

QC laboratories

Stability

Etc.
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http://www.who.int/prequal
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