Good Manufacturing Practices

Purpose and Principles of GMP

Tony Gould
 Why GMP?

Provides a high level assurance that medicines

are manufactured in a way that ensures their
safety, efficacy and quality

Medicines are manufactured to comply with their

marketing authorization

Quality is built in
Testing is part of GMP, but alone does not provide a
good level of quality assurance

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 Why inspect?

Verify compliance with GMP

Verify compliance with marketing authorization
Dossier: "Dedicated equipment is used"
Inspection: Observation that this means "dedicated while used
for the product or not being used for another product"
Dossier: "The vials are removed from the lyophilliser and
crimped in a grade A environment"
Inspection: Correct, but before crimping they are stored in an
uncontrolled corridor

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 WHO GMP

Quality assurance of pharmaceuticals

A compendium of guidelines and related materials

Volume 2, 2nd updated edition

Good manufacturing practices

and inspection

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 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 for active
pharmaceutical ingredients - Annex 2, WHO
Technical Report Series 957, 2010 (Based on ICH
5
Q7)
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 Other WHO GMP Guidelines

Pharmaceutical excipients
Sterile pharmaceutical products
Biological products
Pharmaceutical products containing hazardous
substances
Investigational pharmaceutical products for clinical trials i
Herbal medicinal products
Radiopharmaceutical products
Water for pharmaceutical use
HVAC for non-sterile pharmaceutical dosage forms
Validation

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 Good Manufacturing Practices (FPP):

1. Quality assurance
2. Good manufacturing practices for pharmaceutical
products
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 area

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 in the drug industry

Philosophy and essential elements:

"The concepts of quality assurance, GMP, quality

control and quality risk management are
interrelated aspects of quality management, and
should be the responsibility of all personnel.
their relationship and their fundamental
importance to the production and control of
pharmaceutical products."
Glossary

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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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 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
1.1
pharmaceutical products

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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 Other Depts

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 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
1.1 e - h

Proper storage, distribution and handling

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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 1.1 i - l

improvement

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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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 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
2.1 a - c

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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

Quality risk management

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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 Product Quality Review

Objectives of 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

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 Product Quality Review (cont'd)

Review of starting materials/ packaging

materials, especially 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 investigations and 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 programme and 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)

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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 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 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 Procedure cont'd

Investigation and evaluation should result in

appropriate follow-up 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 - other actions
Inform competent authorities in case of serious
quality problems such as:
Faulty manufacture
Product deterioration
Counterfeiting 5.10

Have a thorough recall procedure that is consistent

with the complaints handling procedure

Trend complaints, their investigations and results

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 Self-Inspection
Purpose is to evaluate whether a companys 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
Should be performed routinely
Also on special occasions such as
Recalls
Repeated rejections 8.1

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 Self-Inspection (cont'd)

Performed by 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)

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 compliance is not an option

Quality should be built into the product
GMP's are very similar and are really
Good Common Sense
Good Practices cover all aspects of
manufacturing activities prior to supply
The role and involvement of senior
management is crucial

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 http://www.who.int/prequal

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