Prequalification Programme: Access to Antimalarial, Antituberculosis and
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1
Good Manufacturing Practices – Part I
Purpose and Principles of GMP
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
CH-1211 Geneva 27
Switzerland
2
E-mail: nordera@who.int
Guidelines and references
GMP applies to both Active Pharmaceutical Ingredients (APIs) and
Finished Pharmaceutical Products (FPPs)


FPP:
WHO Good Manufacturing Practices for pharmaceutical products: main
principles. WHO Technical Report Series, No. 908, 2003, Annex 4.
API:
WHO 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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Good Manufacturing Practices (FPP):







1. Quality assurance
2. Good manufacturing practices for pharmaceutical products
(GMP)
3. Sanitation and hygiene
4. Qualification and validation
5. Complaints
6. Product recalls
7. Contract production and analysis




General
The contract giver
The contract accepter
The contract
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Good Manufacturing Practices (cont'd)

8. Self-inspection and quality audits







Items for self-inspection
Self-inspection team
Frequency of self-inspection
Self-inspection report
Follow-up action
Quality audit
Suppliers’ audits and approval

9. Personnel

General

Key personnel
10. Training

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Good Manufacturing Practices (cont'd)



11. Personal hygiene
12. Premises

General

Ancillary areas

Storage areas

Weighing areas

Production areas

Quality control areas
13. Equipment
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Good Manufacturing Practices (cont'd)

14. Materials

General

Starting materials

Packaging materials

Intermediate and bulk products

Finished products

Rejected, recovered, reprocessed and reworked materials

Recalled products

Returned goods

Reagents and culture media

Reference standards

Waste materials

Miscellaneous
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Good Manufacturing Practices (cont'd)

15. Documentation

General

Documents required:
 Labels
 Testing procedures
 Specifications for starting and packaging materials, for
intermediate and bulk products and for finished products
 Master formulae and Batch Processing Records
 Packaging instructions and Batch Packaging Records
 Standard Operating procedures (SOP's) and records
 Logbooks
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Good Manufacturing Practices (cont'd)

16. Good practices in production





General
Prevention of cross-contamination and bacterial contamination during
production
Processing operations
Packaging operations
17. Good practices in quality control




Control of starting materials and intermediate, bulk and finished products
Test requirements
Batch record review
Stability studies
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GMP is actually Good Common Sense
Quality Management
Quality Assurance
GMP
Section 1 and 2
Production and Quality Control
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Quality Management:
Philosophy and essential elements
What is Quality Management?

The aspect of management function that determines and
implements the “quality policy”

The overall intention and direction regarding quality, as
formally expressed and authorized by top management
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Quality Management

The basic elements are:

An appropriate infrastructure or “quality system” encompassing
the organization structure, procedures, processes and resources

The systematic actions necessary to ensure adequate confidence
that a product (or service) will satisfy given requirements for
“Quality”
The totality of these actions is referred to as “Quality
Assurance”
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Intermezzo: the five P's

Premises

Primary materials

People

Procedures

Processes defined and recorded
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Quality Assurance

Quality assurance is a management tool

In contractual situations, it also serves to generate confidence in
a supplier

QA, GMP and Quality Control are interrelated aspects of Quality
Management

They are described on the following slides in order to emphasize
their relationship and their fundamental importance to the
production and control of pharmaceutical products
1.1
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Quality Assurance

Wide-ranging concept
 covers all matters that individually or collectively influence
the quality of a product

Totality of the arrangements
 to ensure that the drug is continuously of the right quality for
the intended use

Quality Assurance incorporates GMP
 and also includes product design and development, with
special focus on process design
1.1
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The position of QA
Director
QA
Production
QC lab
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Other Depts
Quality Assurance means to assure:




Products are designed and developed correctly
 Complying with, e.g. GMP, GCP, GLP
Production and control operations are defined
Managerial responsibilities are defined
 In job descriptions
The manufacture, supply and use of correct starting and
packaging materials
1.1 a- d
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Quality Assurance means to assure:
(cont'd)




Controls are performed, including intermediates, bulk,
calibration and validation
Correct processing and checking of the finished product
Products are sold/supplied only after review by the
authorized person
 Complying with marketing authorization, production and
QC requirements
Proper storage, distribution and handling
1.1 e - h
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Quality Assurance means to assure:
(cont'd)

Procedures for self-inspection and quality audits are
applied

Deviations are reported, investigated and recorded
System for change control is applied
Regular evaluation of product quality to verify consistency
and continued improvement


1.1 i - l
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Quality Assurance includes:





Responsibility of the Manufacturer for the quality of the product
 Fit for intended use
 Comply with marketing authorization
 Safety, efficacy and quality
Commitment of senior management and involvement of all staff
Comprehensively designed and well implemented quality system
Full documentation and monitoring of effectiveness
Competent personnel, sufficient premises, equipment and facilities
1.3
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Good Manufacturing Practices

That part of QA that ensures that products are consistently
produced and controlled
 Quality standards
 Marketing authorization

Aim: Diminishing risks that cannot be controlled by testing of
product
 Contamination and cross-contamination
 Mix-ups (confusion)
2.1
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The cost of change
100
80
Relative
Cost
of
Correcting
Error
18
10
8
5
4
3
1.6
1.2
2
1.4
1
Preliminary Detailed
Design Design
Code &
Debug
Integrate
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Validate
Operation
Basic requirements for GMP:

Clearly defined and systematically reviewed processes

Qualification and validation is performed
Appropriate resources are provided:
 Qualified and trained personnel
 Premises, space, equipment and services
 Materials, containers, labels
 Procedures, storage, transport
 Laboratories and in-process control

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2.1 a - c
Basic requirements for GMP:






(cont'd)
Clear, written instructions and procedures
Trained operators
Records of actions, deviations and investigations
Records for manufacture and distribution
Proper storage and distribution
Systems for complaints and recalls
2.1 d - j
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GMP = continuous urge for improvement

Involvement of the management

Annual Product Quality Review

Complaints handling

Self-inspection
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Involvement of the management





The senior management is responsible to attain the company's quality
objectives
All different departments and all levels within departments should be
involved; and it's the senior management who should facilitate this
Also suppliers and distributors should be involved
The senior management should make available the required
resources
The basis of the quality system is the quality statement and quality
policy, by the senior management
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Annual Product Quality Review
Objectives to do an Annual Product Quality Review:

To review and verify the consistency and appropriateness of the
existing process

To identify and highlight any trends in the process, e.g. in analytical
results, yields etc.

To identify any possible product or process improvements
Not yet mandatory in WHO GMP, but it is likely to become mandatory like
it is in other GMP's
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Annual Product Quality Review (cont'd)




Review of starting materials/ packaging materials, esp from new
sources
Review of in-process control results and finished product analytical
control results
Amount of batches and packaging units produced and their yields
Reviews of:
 Out-of-spec situations
 Rejections
 Deviations
 Changes
 Plus their investigations as well as a trend analysis of causes
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Annual Product Quality Review (cont'd)

Review of Marketing Authorization variations submitted, granted
or refused (incl. third countries)

Review of stability monitoring programme and its trends
Review of adequacy of previous decisions on changes or
improvements or corrective actions
For new Marketing Authorizations (plus new variations) a review of
post marketing commitment
The qualification status of all relevant equipment and utilities (like
water, HVAC, gases, etc.)
Review of Technical Agreements (if applicable), to verify they are upto-date.




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Complaints handling
Complaints: Principle
“All complaints and other information concerning potentially
defective products must be carefully reviewed according to
written procedures and corrective action should be taken.”
5.1
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Complaints handling (cont'd)
Complaints Procedure:


Designated responsible person:
 To handle complaint
 Decide on measure to be taken
 May be authorized person - if not, must advise authorized
person of results
 Sufficient support staff
 Access to records
Written procedure (SOP):
 Describes action to be taken
 Includes need to consider a recall (e.g. possible product defect)
5.2 – 5.3
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Complaints handling (cont'd)
Complaints Procedure – cont'd

Thorough investigation:
 QC involved
 With special attention to establish whether "counterfeiting"
may have been the cause
 Fully recorded investigation – reflect all the details

Due to product defect (discovered or suspected):
 Consider checking other batches
 Batches containing reprocessed product
5.4 – 5.6
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Complaints handling (cont'd)
Complaints Procedure – (cont'd)

Investigation and evaluation should result in appropriate followup actions
 May include a "recall"

All decisions and measures taken should be recorded
Referenced in batch records
Records reviewed - trends and recurring problems


5.7 – 5.9
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Complaints handling (cont'd)
Other actions



Inform competent authorities in case of serious quality
problems such as:
 Faulty manufacture
5.10
 Product deterioration
 Counterfeiting
Have a thorough recall procedure that is fitting completely to
the complaints handling procedure
Keep track on trends in complaints, their investigations and
results
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Self-Inspection
Purpose is to evaluate whether a company’s operations
remain compliant with GMP



The programme should
 cover all aspects of production and quality control
 be designed to detect shortcomings in the implementation of GMP
 recommend corrective actions
 set a timetable for corrective action to be completed
Be performed routinely
Also on special occasions such as
 Recalls
 Repeated rejections
 When a GMP inspection is announced by the national drug
regulatory authority
8.1
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Self-Inspection (cont'd)
The Self-Inspection Team


Team appointed by management, with:
 authority
 sufficient experience, expertise in their own field. knowledge of
GMP
 may be from inside or outside the company
Frequency should normally be at least once a year
 May depend on company requirements
 Size of the company and activities
8.3, 8.4
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Self-Inspection (cont'd)
Carrying out a Self-Inspection


Report prepared at completion of inspection, including:
 results
 evaluation
 conclusions
 recommended corrective measures
Follow-up action
 Effective follow-up programme
 Company management to evaluate both
the report and corrective actions
8.5, 8.6
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Summary and conclusions:


GMP is mandatory in countries with a regulated pharmaceutical market, and
in the WHO Prequalification Programme too.
GMP's are very similar, they are nothing but Good Common Sense

Good Practices cover all aspects of company's activities prior to sales
GMP is not a reward, nor an external assignment, it should be built into the
company
Just like quality, which should be built into the product
The role and involvement of senior management is crucial

GMP means an urge for continuous improvement, 3 of the tools to do so are:






Annual Product Quality Reviews
Complaint handling and trending
Self-inspection
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http://www.who.int/prequal
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