Prequalification Programme: Access to Antimalarial, Antituberculosis and

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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
Prequalification
Programme: Access to Antimalarial, Antituberculosis and
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
Incoming
goods

Workers entrance

Offices

Shipment of goods

Canteen
Gowning

Material Flow

Corridor

Shipping

Corridor
Corridor
Raw
Materials
&
Packaging Weighing
Storage

People Flow
Zone: Clean
Zone: Packaging
Zone: Controlled

Processing

Washing

Packaging Finished
Products
Storage

Filling

Machine
Shop

Utilities and Services

Corridor
Waste Treatment

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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

FA CTO RY

CHA NG E
RO O M

A IR
LO CK
T O IL E T S

CA NTE E N

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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

Prevention of build-up of dirt and dust to avoid unnecessary

risks of contamination

Walls, floors, ceilings, ledges, drains, air supply, dust extraction

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
16.12(g)
clean-in-place (CIP)

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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
15.1
Design and use
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?

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15.10

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

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15.21

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

Aging

Con

cept
u

aliza
tion

Project Initiation

R
A

Development
Ea
rl

Maturity

Release
for Use

yO

per
a
Lif tiona
e
l

I
O
N
A

L
L
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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
4.3
pre-determined specifications and quality attributes

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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
4.7 4.11
Cleaning procedures

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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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