1 Prequalification Programme: Access to Antimalarial, Antituberculosis and anti HIV/AIDS Drugs and HIV/AIDS Diagnostics of Acceptable Quality Prequalification

1

Prequalification Programme: Access to Antimalarial, Antituberculosis and anti HIV/AIDS Drugs and HIV/AIDS Diagnostics of Acceptable QualityPrequalification Programme: Priority Essential Medicines

Good Manufacturing Practices – Part I

Purpose and Principles of GMP

Anton Norder, MScTechnical Officer

WHO EMRO 1st Workshop on the WHO Prequalification Programme: Priority Essential Medicines,

Cairo, Egypt, 6 and 7 June, 2007

2

20 Avenue AppiaCH-1211 Geneva 27Switzerland E-mail: [email protected]

3


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)

4


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

5


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

6



11. Personal hygiene 12. Premises

General Ancillary areas Storage areas Weighing areas Production areas Quality control areas

13. Equipment

7



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

8



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

9



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

10


GMP is actually Good Common Sense

Quality Management

Quality Assurance

GMP

Production and Quality Control

Section 1 and 2

11


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

12


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”

13


Intermezzo: the five P's

Premises

Primary materials

People

Procedures

Processes defined and recorded

14


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

15


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 design1.1

16


The position of QA

DirectorDirector

QAQA

ProductionProduction QC labQC lab Other DeptsOther Depts

17


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

18


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

19


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 improvement1.1 i - l

20


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

21


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

22


1

10

100

PreliminaryDesign

Code &Debug

ValidateDetailedDesign Integrate Operation

1.21.6

1.4

3

5

2

4

18

8

80

RelativeCost

ofCorrecting

Error Maxim

um

Min

imum

The cost of change

23


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

24


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

25


GMP = continuous urge for improvement

Involvement of the management

Annual Product Quality Review

Complaints handling

Self-inspection

26


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

27


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

28


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

29


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 up-

to-date.

30


5.1

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.”

31


5.2 – 5.3

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)

32


5.4 – 5.6


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

33


5.7 – 5.9


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

34


5.10


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 fitting completely to the complaints handling procedure

Keep track on trends in complaints, their investigations and results

35


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

36


8.3, 8.4

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

37


8.5, 8.6

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

38


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

39


http://www.who.int/prequal