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

HIV/AIDS Diagnostics of Acceptable Quality 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 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 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 8 5 3 1.6 1.2 2 4

10

1.4
Code & Debug

1 Preliminary Detailed Design Design Integrate Validate Operation

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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


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 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 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

Prequalification Programme: Access to Antimalarial, Antituberculosis and Prequalification Programme: Priority Essential Medicines anti HIV/AIDS Drugs and HIV/AIDS Diagnostics of Acceptable Quality 38

http://www.who.int/prequal

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