good manufacturing practices purpose and principles...

Good Manufacturing Practices

Purpose and Principles of GMP

Tony Gould

2 | PQ Workshop, Abu Dhabi | October 2010

Why GMP? 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


Why inspect? 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


WHO GMP WHO GMP

Quality assurance of pharmaceuticals

A compendium of guidelines and related materials

Volume 2, 2nd updated edition

Good manufacturing practices and inspection


Guidelines and references 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

Q7)


Other WHO GMP Guidelines 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


Good Manufacturing Practices (FPP): 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


Good Manufacturing Practices (cont'd) 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



11. Personal hygiene

12. Premises

– General

– Ancillary areas

– Storage areas

– Weighing areas

– Production areas

– Quality control area

13. Equipment



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



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



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


GMP is actually Good Common Sense GMP is actually Good Common Sense

Quality Management

Quality Assurance

GMP

Production and Quality Control

Section 1 and 2


Quality management in the drug industry 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


Quality Management 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”


The five P's The five P's

�Premises

�Primary materials

�People

�Procedures

�Processes defined and recorded


Quality Assurance 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


Quality Assurance 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


The position of QA The position of QA

Director

QA

Production

QC lab

Other Depts


Quality Assurance means to assure: 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


Quality Assurance means to assure:

(cont'd)


(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



(cont'd)


(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


Quality Assurance includes: 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


Good Manufacturing Practices 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


Basic requirements for GMP: 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


Basic requirements for GMP: (cont'd) 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


GMP = continuous urge for improvement GMP = continuous urge for improvement

� Involvement of the management

� Annual Product Quality Review

� Quality risk management

� Complaints handling

� Self-inspection


Involvement of the management 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


Product Quality Review 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


Product Quality Review (cont'd) 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


Annual Product Quality Review (cont'd) 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)


5.1

Complaints handling

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.”


5.2 – 5.3

Complaints Procedure

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)


5.4 – 5.6

Complaints Procedure – 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


5.7 – 5.9

Complaints Procedure – cont'd 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


5.10

Complaints - other actions

Complaints - other actions

� Inform competent authorities in case of serious

quality problems such as:

– Faulty manufacture

– Product deterioration

– Counterfeiting

�Have a thorough recall procedure that is consistent with the complaints handling procedure

�Trend complaints, their investigations and results


Self-Inspection 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

�Should be performed routinely

�Also on special occasions such as – Recalls

– Repeated rejections

8.1


8.3, 8.4

Self-Inspection (cont'd) 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


8.5, 8.6

Self-Inspection (cont'd) 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


Summary and conclusions: 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


http://www.who.int/prequal http://www.who.int/prequal