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Good Manufacturing Practices Purpose and Principles of GMP

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Presentation on theme: "Good Manufacturing Practices Purpose and Principles of GMP"— Presentation transcript:

1 Good Manufacturing Practices Purpose and Principles of GMP
Tony Gould

2 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

3 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

4 Quality assurance of pharmaceuticals
WHO GMP Quality assurance of pharmaceuticals A compendium of guidelines and related materials Volume 2, 2nd updated edition Good manufacturing practices and inspection

5 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) 5

6 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

7 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

8 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

9 Good Manufacturing Practices (cont'd)
11. Personal hygiene 12. Premises General Ancillary areas Storage areas Weighing areas Production areas Quality control area 13. Equipment

10 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

11 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

12 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

13 GMP is actually Good Common Sense
Quality Management Quality Assurance GMP Production and Quality Control Section 1 and 2

14 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

15 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”

16 The five P's Premises Primary materials People Procedures
Processes defined and recorded

17 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

18 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

19 The position of QA

20 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

21 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

22 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

23 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

24 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

25 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

26 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

27 GMP = continuous urge for improvement
Involvement of the management Annual Product Quality Review Quality risk management Complaints handling Self-inspection

28 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

29 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

30 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

31 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)

32 World Health Organization
Complaints handling 19 April 2017 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.” The product complaint principle is defined in the WHO GMP. The manufacturer must assume responsibility for the quality of the pharmaceutical products to ensure that they are fit for their intended use, comply with the requirements of the marketing authorization, and do not place the patient at risk because of inadequate safety, quality or efficacy. Complaints must be handled positively and carefully reviewed, and corrective actions must be taken as necessary. This can mean amending a manufacturing process as well as implementing a recall of a defective product from all markets where it has been distributed. 5.1

33 World Health Organization
Complaints Procedure 19 April 2017 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) First of all a written complaints handling procedure should be available. The basic requirements for such a procedure are: A designated person must be appointed with authority to conduct complaints reviews in accordance with the SOPs. The person designated may be the authorized person responsible for quality control. If not, then that QC person must be kept informed of all complaints being investigated. The designated person must have sufficient staff to be able to review all the complaints received in an effective and rapid manner. They must to be able to access all the relevant records concerning the product under discussion. Required actions are described. The complaint is acknowledged and a response to the customer is provided. Written and verbal comments are recorded. 5.2 – 5.3

34 Complaints Procedure – cont'd
World Health Organization Complaints Procedure – cont'd 19 April 2017 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 The QC department should be involved throughout the investigation. The investigation should be thorough and fully recorded– and reflect all the details of the investigation in the records. Special attention must be given to try and establish whether "counterfeiting" may have been the cause. If there is a product defect (discovered or suspected), then the company should consider checking other batches, and may have to check batches containing reprocessed product. 5.4 – 5.6

35 Complaints Procedure – cont'd
World Health Organization Complaints Procedure – cont'd 19 April 2017 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 Investigation and evaluation should result in appropriate follow up actions taken. This may include a "recall" of the product, or batch. All decisions and measures taken should be recorded. The complaint should also be referenced in batch records – and may thus help during the review or annual product review, trend analysis etc. Complaint records should be reviewed on a regular basis as defined in the SOP. Trends and recurring problems should be identified and proper action taken to prevent recurrence of the problem/cause. As complaints are investigated and records are built up, then trends may start to become clear. A regular review of complaint records to establish whether there is a trend for a particular product, dosage form, customer, distribution channel or similar should be undertaken. This is where the true value of a good complaints handling procedure shows. It may be that a particular formulation or particular machine is giving rise to complaints. This trend analysis process is an opportunity for continuous improvement. It may be that a particular customer is engaged in fraudulent behaviour. 5.7 – 5.9

36 Complaints - other actions
World Health Organization Complaints - other actions 19 April 2017 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 5.10 The competent authority must be informed of any serious quality problems that are revealed by the complaint investigation

37 World Health Organization
Self-Inspection 19 April 2017 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 The purpose of self-inspection is to evaluate the manufacturer’s compliance with GMP in all aspects of production and quality control. It also assists in ensuring quality improvement. There should be a programme that covers all aspects of production and quality control. It should be designed to detect shortcomings in the implementation of GMP and recommend corrective actions. The company should set a timetable for corrective action to be completed. You can verify this during your assessment. 8.1

38 Self-Inspection (cont'd)
World Health Organization Self-Inspection (cont'd) 19 April 2017 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 The self-inspection team is appointed by the management of the company and is made up of a mixture of people, including experts in GMP and persons familiar with the area to be inspected. It is useful to have people from production, QC and engineering on the team, as they will bring different perspectives to the inspection. The team leader needs to be someone who has access to the resources to produce a report at the end of the process, and with the authority and experience to organize and manage a team activity. Hence it is usually, but not always, a manager or supervisor. The leader should be from a different department so that he/she can take a more impartial viewpoint. It is important that the team members are encouraged to be objective in their evaluation. The frequency with which self-inspections are carried out will depend on the company. For a small company that can cover all its operations in one inspection, a three or six-monthly review might be sufficient. However, for a larger company that needs to split the inspection into a number of sections, a programme of monthly inspections covering the whole factory in three to six months might be more appropriate. 8.3, 8.4

39 Self-Inspection (cont'd)
World Health Organization Self-Inspection (cont'd) 19 April 2017 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 All inspections need reports as an outcome; otherwise there is no formal record of the findings and recommendations. This report should be issued as quickly as possible while things are fresh in people’s minds. It does not need to be an elaborate, wordy document that no one will read. A simple list of findings with recommendations for corrective action is sufficient. However, it is important that responsibility for action and a time frame are agreed, either during the inspection or soon after the report is issued. A self-inspection without follow-up is unlikely to be particularly effective and it is important that the company management ensures that the corrective measures are carried out to the agreed timetable. 8.5, 8.6

40 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

41 41

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