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Good Manufacturing Practices in the manufacture of medicines

Good Manufacturing Practices in the manufacture of medicines. The World Health Organization (WHO) GMP rules are the subject of the course. I am afraid, the industrial drug manufacture is a bit more complicated than this…. starting already outside, in the yard. active substance manufacture.

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Good Manufacturing Practices in the manufacture of medicines

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  1. Good Manufacturing Practicesin the manufacture of medicines The World Health Organization (WHO) GMP rules are the subject of the course

  2. I am afraid, the industrial drug manufacture is a bit more complicated than this…

  3. starting already outside, in the yard

  4. active substance manufacture

  5. dosage-form manufacture

  6. computer-aided manufacture

  7. control lab

  8. GMP certificate issued by the national GMP compliance monitoring authority

  9. GMP • Basic Principles • Specific rules

  10. GMP: „soft” and „hard” law „The manufacturer should possess adequate… • number of personnel... • with adequate qualification... • manufacturing area…” Impossible to specify the values in a law! The inspector will decide on the spot whether the requirement is met!

  11. Basic Principles of GMP Introduction to the Training Course

  12. Programme Overview – I Basic Principles of GMP 1. Quality Management 2. Sanitation and hygiene 3. Validation 4. Complaints and recalls

  13. Programme overview II Basic Principles of GMP 5. Contract production and analysis 6. Self Inspection 7. Personnel 8. Premises 9. Equipment

  14. Programme overview - III Basic Principles of GMP 10. Materials 11. Documentation 12. Sterile production 13. Active pharmaceutical ingredients

  15. Programme overview - IV GMP Inspection Process 14. Introduction 15. The role of the inspector 16. Preparation for the inspection 17.Types of GMP inspection 18. The inspection

  16. Basic principles of GMPin more detail

  17. 1. Quality Management

  18. European Union Directive „The manufacturer shall establish and implement an effective pharmaceutical QA system, involving the active participation of the management and personnel of the different services involved”

  19. The Quality Management • The first, introductory chapter of the WHO GMP • Having defined some concepts and terms, it summerises what is also detailed in other chapters (do not be surprised if its parts are also reproduced elsewhere)

  20. Quality Management Objectives • To understand/identify key issues in quality assurance/quality control • To understand/identify specific requirements on organization, procedures, processes and resources • To develop actions to resolve your current problems

  21. Quality Management • Determines and implements the “quality policy” • The basic elements are: • an appropriate infrastructure or “quality system” encompassing the 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 termed “Quality Assurance”

  22. Quality Management • Terminology may differ (e.g. from ISO) • “Quality System” is said to be rarely used in drug manufacturing • The concepts of 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

  23. Quality Management Principles of Quality Assurance • Wide-ranging concept • covers all matters that individually or collectively influence the quality of a product = responsibility of everyone • Totality of the arrangements • to ensure that the drug is of the right quality for the intended use • Quality Assurance incorporates GMP • and also product design and development which is outside the scope of this module

  24. Requirements for QA Systems Think over what should be done properly during drug manufacture!

  25. Quality Management Requirements for QA Systems – I 1. Ensure products are developed correctly 2. Identify managerial responsibilities 3. Provide SOPs for production and controlStandard Operating Procedures 4. Organize supply and use of correct starting materials 5. Define controls for all stages of manufacture and packaging

  26. Quality Management Requirements for QA Systems – II 6. Ensure finished product correctly processed and checked before release 7. Ensure products are released after review by authorized person 8. Provide storage and distribution 9. Organize self-inspection

  27. Quality Management GMP • Ensure that products are consistently produced and controlled • Diminishes risks that cannot be controlled by testing of product • Cross-contamination • Mix-ups the most life-threatening mistakes!

  28. Quality Management Basic Requirements for GMP – I 1. Clearly defined and systematically reviewed processes 2. Critical steps validated 3. Appropriate resources: personnel, buildings, equipment, materials 4. Clearly written procedures 5. Trained operators

  29. „Clearly defined and systematically reviewed manufacturing processes” • = all relevant quality specifications, SOPs and batch documentation must be prepared in harmony with each other • It also means that the Departments involved know each other’s task to eliminate discrepancies • Also: QC/QA staff is acting as coordinator and is involved in all decisions

  30. „Critical steps validated” • There is a variability in the quality of incoming materials and in the performance of the equipment, we need to check whether the process works with all varibaility that can arise • The process of checking and documenting variability = validation • if validation, we have sufficient knowledge of materials, equipment and process = what variables arelikely to arise. • Then we carry out controlled experiments to ensure that whatever variables cab occur, the product still meets the specification • Validation is also needed when there is any change in materials, process or equipment

  31. „Appropriate resources: personnel, buildings, equipment and materials” • These all should be available to produce a quality product. • Thus, the company should evaluate all of the elements it needs to produce a drug to see that it has sufficient resources

  32. „Manufacture is based on clearly written procedures” • Procedures: • batch manufacturing instructions • testing instructions • SOPs needed for all departmants • Preparing these documents is very important task (see Documentation)

  33. „Trained operators” • Documentation, instructions, etc. are not enough if the operators can not work with them properly • Training includes also follow-up training

  34. Quality Management Basic Requirements for GMP – II 6. Complete records, failure investigations 7. Proper storage and distribution 8. Recall system 9. Complaint handling

  35. „Complete records, failure investigations” • (We have just seen there are manufacturing, packaging, QC, etc. instructions how to perform the work) • Also recordsare needed to show what and how was actually done each time, by whom, etc. • If there is a reason later to come back to check what happened with a given batch, the only possibility is to check the records • E.g. when failures are found later

  36. „Proper storage and distribution” • When a new drugis developed, stability studies determine the storage conditions and its shelf-life • However, the storage conditions should be met! • Also during distribution!

  37. „Recall system” • If quality problems detected when the product is already on the market, there should be a system to recall them (from wholesalers or from pharmacy level) • System, for there can be different ways anddegress of severity, depending upon the reasons for the recall Simple circular information by letter<by fax<TV and press warning if life threatening, etc. Involvement of national regulatory authorities – according to local law

  38. Complaint handling • Ifthe complaint of a purchaser or consumer is possibly related to manufacturing defects, it is worth of investigation • This way its re-occurrence can be prevented

  39. Quality Management Cascade Quality relationships Quality Management(overall policy) Quality Assurance(concept ensuring that the policy is achieved) GMP(how to do it) Quality Control including

  40. Quality Management Quality Control (QC) Department • Each holder of a manufacturing authorization should have a QC Department • Independence from production and other departments is considered to be fundamental • Under the authority of an appropriately qualified and experienced person with one orseveral control laboratories at his or her disposal.

  41. Quality Management Basic Requirements for Quality Control Resources • Adequate facilities • Trained personnel • Approved procedures

  42. Quality Management Basic Requirements for Quality Control Tasks • Sampling • Inspecting • Testing • Monitoring(materials, environmental conditions) • Releasing/rejecting

  43. Basic Requirement for Quality Control - I Objects • Starting materials • Packaging materials • Intermediates • Bulk products • Finished products • Environmental conditions

  44. Basic Requirements for QC - II 1. Sampling approved by QC departmentnot necessarily done by them, but ensuring samples are representative 2. Validated test methodsaccurate, precise, robust, specific, linear… 3. Recordsofsampling, inspecting, testing, of incoming materials, intermediates, bulk and packaged finished products 4. Review and evaluation of production documentationfor release: not only test results 5. Failure investigations for all deviations 6. Ingredients comply with the marketing authorization

  45. Basic Requirements for QC - III 7. Ingredients are of the required purity 8. Proper containerscompatibility! 9. Correct labellingmislabelling = life-threatening error 10. Release of batches by the authorized personwho has the right – predetermined persons with adequate qualification and experience 11. Retained samples of starting materials and products

  46. Other Duties of the QC Department 1. Establish QC proceduresand validation in the first time then its „release” 2. Reference standardsand their storage! Mainly test results rely on the comparison with the reference standards… 3. Correct labelling 4. Stability testing 5. Complaint investigations 6. Environmental monitoring

  47. Assessment of Finished Products Should embrace all relevant factors(not only the QC test results!). For example: • production conditions • in-process test results • manufacturing documentation • compliance with finished product specification • examination of the finished pack

  48. QC Access • QC Personnel MUST have access to production areas for sampling and investigation • As appropriate!E.g. not appropriate: entering in aseptic filling suites, or where highly potent dangerous materials are present…

  49. QC - Summary • authorization • definition of product quality • laboratory operations • release decisions • investigation and reporting QC is part of GMP • sampling • specifications • testing • release procedures • recalls and complaints • decision-making in all quality matters

  50. Quality management also means: • identification • assessment • cotrol (keeping under control) • presentation (to all interested persons) of any risk factor that may affect the quality of the medicine

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