GMP_Medical and Pharmaceutical Biotechnology.pptx

GMP_Medical and Pharmaceutical Biotechnology

1. Quality management in the medicines industry: philosophy and essential elements In the medicines industry at large, quality management is usually defined as the aspect of the management function that determines and implements the “quality policy”, i.e., the overall intention and direction of an organization regarding quality, as formally expressed and authorized by top management. The basic elements of quality management are: • an appropriate infrastructure or “quality system”, encompassing the organizational structure, procedures, processes and resources; • systematic actions necessary to ensure adequate confidence that a product (or service) will satisfy given requirements for quality.

2. The totality of these actions is termed “Quality Assurance (QA)”. Within an organization, QA serves as a management tool. In contractual situations, QA also serves to generate confidence in the supplier. The concepts of QA, Good Manufacturing Practices (GMP), Quality Control (QC) and quality risk management (QRM) are interrelated aspects of quality management and should be the responsibility of all personnel.

3. Pharmaceutical quality system 1.1 Principle. 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 patients at risk due to inadequate safety, quality or efficacy. The attainment of this quality objective is the responsibility of senior management and requires the participation and commitment of staff in many different departments and at all levels within the company, the company’s suppliers and the distributors. To achieve this quality objective reliably there must be a comprehensively designed and correctly implemented pharmaceutical quality system (PQS) incorporating GMP and QRM.

4. 1.2 Senior management has the ultimate responsibility to ensure an effective PQS is in place, is adequately resourced, and that roles, responsibilities, and authorities are defined, communicated and implemented throughout the organization. Senior management’s leadership and active participation in the PQS are essential. This leadership should ensure the support and commitment of staff at all levels and sites within the organization to the PQS.

5. 1.3 Quality management is a wide-ranging concept covering all matters that individually or collectively influence the quality of a product. It is the totality of the arrangements made with the object of ensuring that pharmaceutical products are of the quality required for their intended use. Quality management, therefore, incorporates GMP and other factors, such as product design and development.

6. 1.4 GMP applies to the life-cycle stages from the manufacture of investigational medicinal products, technology transfer, and commercial manufacturing, through to product discontinuation. The PQS can extend to the pharmaceutical development life-cycle stage and should facilitate innovation and continual improvement and strengthen the link between pharmaceutical development and manufacturing activities. All parts of the PQS should be adequately resourced and maintained, including being provided with sufficient competent personnel, suitable premises, equipment and facilities.

7. 1.5 The PQS appropriate to the manufacture of pharmaceutical products should ensure that: a) product realization is achieved by designing, qualifying, planning, implementing, maintaining and continuously improving a system that allows the consistent delivery of products with appropriate quality attributes; b) product and process knowledge is managed throughout all lifecycle stages; c) pharmaceutical products are designed and developed in a way that takes account of the requirements of GMP and other associated codes such as those of good laboratory practice (GLP) and good clinical practice (GCP);

8. d) production and control operations are clearly specified in a written form and GMP requirements are adopted; e) managerial responsibilities are clearly specified in job descriptions; f) arrangements are made for the manufacture, supply and use of the correct starting and packaging materials, the selection and monitoring of suppliers and for verifying that each delivery is the correct material from the approved supply chain; g) all necessary controls on starting materials, intermediate products, and bulk products and other in-process controls, calibrations and validations are carried out; h) the finished product is correctly processed and checked, according to the defined procedures;

9. i ) pharmaceutical products are not sold or supplied before the authorized persons have certified that each production batch has been produced and controlled in accordance with the requirements of the marketing authorization and any other regulations relevant to the production, control and release of pharmaceutical products; j) processes are in place to assure the management of outsourced activities; k) satisfactory arrangements exist to ensure, as far as possible, that the pharmaceutical products are stored, distributed and subsequently handled so that quality is maintained throughout their shelf-life; l) there is a procedure for self-inspection and/or quality audit that regularly appraises the effectiveness and applicability of the PQS; m) product and processes are monitored and the results taken into account in batch release, in the investigation of deviations and, with a view to taking preventive action to avoid potential deviations occurring in the future;

10. n) arrangements are in place for the prospective evaluation and approval of planned changes and their approval prior to implementation taking into account regulatory notification and approval where required. After implementation of any change, an evaluation is undertaken to confirm that the quality objectives were achieved and that there was no unintended adverse impact on product quality; o) regular reviews of the quality of pharmaceutical products are conducted with the objective of verifying the consistency of the process and identifying where there is a need for improvement; p) a state of control is established and maintained by developing and using effective monitoring and control systems for process performance and product quality;

11. q) continual improvement is facilitated through the implementation of quality improvements appropriate to the current level of process and product knowledge; r) there is a system for QRM; s) deviations, suspected product defects and other problems are reported, investigated and recorded. An appropriate level of root cause analysis is applied during such investigations. The most likely root cause(s) should be identified and appropriate corrective actions and/or preventive actions (CAPAs) should be identified and taken. The effectiveness of CAPAs should be monitored.

12. 1.6 There should be periodic management reviews, with the involvement of senior management, of the operation of the PQS to identify opportunities for continual improvement of products, processes and the system itself. Unless otherwise justified, such reviews should be conducted at least annually. 1.7 The PQS should be defined and documented. A quality manual or equivalent documentation should be established and should contain a description of the quality management system including management responsibilities.

13. Quality risk management QRM is a systematic process for the assessment, control, communication and review of risks to the quality of the medicinal product. It can be applied both proactively and retrospectively. QRM should ensure that: • the evaluation of the risk to quality is based on scientific knowledge, experience with the process and ultimately links to the protection of the patient; • the level of effort, formality and documentation of the QRM process is commensurate with the level of risk.

14. QUALITY ASSURANCE Quality Assurance is a wide-ranging concept, which covers all matters, which individually or collectively influence the quality of a product. It is the sum total of the organised arrangements made with the objective of ensuring that medicinal products are of the quality required for their intended use. Quality Assurance therefore incorporates Good Manufacturing Practice plus other factors.

15. The system of Quality Assurance appropriate for the manufacture of medicinal products should ensure that: i . medicinal products are designed and developed in a way that takes account of the requirements of Good Manufacturing Practice ; ii. production and control operations are clearly specified, and Good Manufacturing Practice adopted; iii. managerial responsibilities are clearly specified; iv. arrangements are made for the manufacture, supply and use of the correct starting and packaging materials;

16. v. all necessary controls on intermediate products, and any other in-process controls and validations are carried out; vi. the finished product is correctly processed and checked, according to the defined procedures; vii. medicinal products are not sold or supplied before an authorised person has certified that each production batch has been produced and controlled in accordance with the requirements of the marketing authorisation and any other regulations relevant to the production, control and release of medicinal products;

17. viii. satisfactory arrangements exist to ensure, as far as possible, that the medicinal products are stored, distributed and subsequently handled so that quality is maintained throughout their shelf life; ix. there is a procedure for self-inspection and/or quality audit, which regularly appraises the effectiveness and applicability of the quality assurance system.

18. GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS (GMP) Good Manufacturing Practice is that part of Quality Assurance which ensures that Medicinal products are consistently produced and controlled to the quality standards appropriate to their intended use and as required by the marketing authorisation or product specification. Good Manufacturing Practice is concerned with both production and quality control. The basic requirements of GMP are that: i . all manufacturing processes are clearly defined, systematically reviewed in the light of experience and shown to be capable of consistently manufacturing medicinal products of the required quality and complying with their specifications;

19. ii. critical steps of manufacturing processes and significant changes to the process are validated; iii. all necessary facilities for GMP are provided including: a. appropriately qualified and trained personnel; b. adequate premises and space; c. suitable equipment and services; d. correct materials, containers and labels; e. approved procedures and instructions; f. suitable storage and transport; iv. instructions and procedures are written in an instructional form in clear and unambiguous language, specifically applicable to the facilities provided; v. operators are trained to carry out procedures correctly; vi. records are made, manually and/or by recording instruments, during manufacture which demonstrate that all the steps required by the defined procedures and instructions were in fact taken and that the quantity and quality of the product were as expected. Any significant deviations are fully recorded and investigated;

20. vii. records of manufacture including distribution which enable the complete history of a batch to be traced, are retained in a comprehensible and accessible form; viii. the distribution (wholesaling) of the products minimises any risk to their quality; ix. a system is available to recall any batch of product, from sale or supply; x. complaints about marketed products are examined, the causes of quality defects investigated, and appropriate measures are taken in respect of the defective products to prevent re-occurrence.

21. QUALITY CONTROL Quality Control is that part of Good Manufacturing Practice which is concerned with sampling, specifications and testing, and with the organisation , documentation and release procedures which ensure that the necessary and relevant tests are actually carried out and that materials are not released for use, nor products released for sale or supply until their quality has been judged to be satisfactory.

22. The basic requirements of Quality Control are that: i . adequate facilities, trained personnel and approved procedures are available for sampling, inspecting and testing starting materials, packaging materials, intermediate, bulk, and finished products, and where appropriate for monitoring environmental conditions for GMP purposes; ii. samples of starting materials, packaging materials, intermediate products, bulk products and finished products are taken by personnel and by methods approved by Quality Control;

23. iii. test methods are validated; iv. records are made, manually and/or by recording instruments, which demonstrate that all the required sampling, inspecting and testing procedures were actually carried out. Any deviations are fully recorded and investigated; v. the finished products contain active ingredients complying with the qualitative and quantitative composition of the marketing authorisation , are of the purity required, and are enclosed within their proper containers and correctly labelled; vi. records are made of the results of inspection and that testing of materials, intermediate, bulk, and finished products are formally assessed against the specification. Product assessment includes a review and evaluation of relevant production documentation and an assessment of deviations from specified procedures;

24. vii. no batch of product is released for sale or supply prior to certification by an authorised person that it is in accordance with the requirements of the relevant authorisations ; viii. sufficient reference samples of starting materials and products are retained to permit future examination of the product if necessary and that the product is retained in its final pack unless exceptionally large packs are produced.

25. PRODUCT QUALITY REVIEW Regular periodic or rolling quality reviews of all licensed medicinal products, including export-only products, should be conducted with the objective of verifying the consistency of the existing process, the appropriateness of current specifications for both starting materials and finished products to highlight any trends and to identify product and process improvements. Such reviews should normally be conducted and documented annually, taking into account previous reviews, and should include at least: i . A review of starting materials including packaging materials used in the product, especially those from new sources. ii. A review of critical in-process controls and finished product results.

26. iii. A review of all batches that failed to meet established specification(s) and their investigation. iv. A review of all significant deviations or non-conformances, their related investigations, and the effectiveness of resultant corrective and preventative actions taken. v. A review of all changes carried out to the processes or analytical methods. vi. A review of Marketing Authorisation variations submitted/granted/ refused, including those for third country (export only) dossiers. vii. A review of the results of the stability monitoring programme and any adverse trends. viii. A review of all quality-related returns, complaints and recalls and the investigations performed at the time.

27. ix. A review of the adequacy of any other previous product process or equipment corrective actions. x. For new marketing authorisations and variations to marketing authorisations , a review of post-marketing commitments. xi. The qualification status of relevant equipment and utilities, e.g. HVAC, water, compressed gases, etc. xii. A review of any contractual arrangements that they are up to date.

28. The manufacturer and marketing authorisation holder should evaluate the results of this review and an assessment made of whether corrective and preventative action or any revalidation should be undertaken. Reasons for such corrective actions should be documented. Agreed corrective and preventative actions should be completed in a timely and effective manner. There should be management procedures for the ongoing management and review of these actions and the effectiveness of these procedures verified during self-inspection. Quality reviews may be grouped by product type, e.g. solid dosage forms, liquid dosage forms, sterile products, etc. where scientifically justified.

29. Where the marketing authorisation holder is not the manufacturer, there should be a technical agreement in place between the various parties that defines their respective responsibilities in producing the quality review. The authorised person responsible for final batch certification together with the marketing authorisation holder should ensure that the quality review is performed in a timely manner and is accurate.

30. Standard operating procedures (SOPs) Standard operating procedures (SOPs) are the detailed written instructions that specify how a test or administrative procedure is to be performed, or how a piece of equipment is operated, maintained and calibrated. SOPs describe the "standard" approved procedures that are routinely carried out in a GMP facility. They indicate exactly how things are done and are kept current by review and approved revision on a predetermined schedule (usually annual), or when planned changes are made to the procedure or equipment and reagents used in the procedure. The original of a current version of an SOPs is maintained in a central file, and copies are distributed to the locations where the procedure is performed. The procedure for describing the writing, revising and approving of SOPs and the control of distribution of SOPs is one of the important quality assurance procedures.

31. Any SOP describing the distribution and control of documents must clearly indicate the mechanisms by which SOPs can be modified or changed: from assessment and rationale for the need for a change, to the evaluation of other SOPs that might be changed as a result, to the final approval of changes and the implementation of the changed procedure. SOPs are used as a reference by the persons responsible for the performance and are also used for training new operators in the performance of the procedure. Quality assurance procedures should be in place to ensure that SOPs are enforced and properly used. SOPs follow a scientific format and are written with the view that they will be used by persons trained in the procedure. There should be specific instructions for each step in sequential order including the preparatory work which must be done before starting the main procedure, as well as instructions for recording and reporting the results. There is little need for excess text on theory and background - what is required is clear concise instructions for carrying out a procedure which has been approved.

32. Usually, the initial draft of an SOP is written by the person performing the procedure or by someone who knows the procedure well and must be written including the details and the time course of the tasks. Supervisors review the SOPs for completeness and content and QC or QA staff approve for regulatory compliance. When appropriate, a formal data sheet or data record form is prepared for an SOP. This form is a parallel summary document with checklists, checkboxes, and blanks for all data to be recorded during the performance of the procedure. It also has spaces for signatures of the operator and other technicians who verify and countersign certain critical operations during the procedure. Finally, there is the space for the signature of the department supervisor who reviewed the completed data record form. Such blanks and checklists ensure that the required data are collected, that nothing is overlooked and also provide the evidence that the procedure was performed according to the SOP. The datasheets also provide instructions for recording deviations to the procedure, for calculations or reporting requirements, for comparison of results with predetermined specifications, and the criteria for repeating procedures in cases where unacceptable results were obtained.

33. Format for standard operating procedures (SOPs) The formats and sample SOPs can be used, modified, or redesigned by each manufacturer according to their organizational structure, and by the complexity of their manufacturing operations.

34. Priorities for the preparation of SOPs The WHO Guidelines for Good Manufacturing Practice and all other national and international GMP Regulations and Guidelines clearly indicate that written procedures must be established and followed to be in compliance with GMP. The term "written" occurs many times and covers all production, control, and administrative operations. Each manufacturer should evaluate the present status of their documentation system and prepare a list of SOPs, forms and other documents needed to meet WHO GMP requirements. If many documents are to be written, it is most productive if the staff performing the procedure writes the initial draft, another operator or the supervisor reviews and revises it, and the department head accepts the final version. The staff performing the procedure usually know it the best, and it also is easier for a supervisor to revise several SOPs than prepare them. Signatures of the personnel from QC or QA department, as appropriate, must be obtained for final approval. An SOP for the review and approval of SOPs for each department should be one of the first administrative procedures to be developed.

35. In most cases, it is fairly easy to prepare the written procedure for the QC testing of raw materials, in-process intermediates and final product for traditional vaccines currently in production. Most of these tests are well described in WHO technical reports and manuals. Many chemical and biochemical assays are available in Pharmacopoeia, in Chemical Society Standards, and others and are internationally recognized standardized methods. Each of these assays can be printed in the format as presented, or in another suitable format adopted by the manufacturer. These standard procedures should be put into the manufacturer’s formal SOP format. It should also be straightforward to prepare Master Formulae for the manufacturing instructions for manufacturers’ current vaccines. The steps of the production process, the equipment and materials used, and the time-frames should be well defined.

36. SOPs for equipment operation, maintenance, and calibration can also be put in written form fairly quickly because very often the equipment manuals provide the detailed information needed. However, the requirement for written procedures is not limited to the production method, equipment operation and test methods. The more difficult SOPs to prepare are those describing control of materials at every stage, monitoring of storage conditions, requirements for storage segregation, SOPs for gowning, cleaning, fumigating the facility, monitoring equipment, monitoring the facility air and surfaces, SOPs for entry of materials in and out of the clean and aseptic areas, SOPs for personnel health and hygiene, animal care SOPs (raising, feeding, treating, health, cleaning and maintenance of animal facilities, cage washing, quarantine of animals, etc.), SOPs for testing cell, viral and bacterial characteristics, SOP for egg candling, SOPs for self-inspections and audits, SOPs for sampling, and even an SOP for writing, revising SOPs, and one for controlling the distribution of all the other SOPs.

37. (Forms for recording the data or information obtained during the course of carrying out these procedures must be generated for each SOP, as appropriate, to ensure accurate records). All of these procedures have an impact on the quality of the product because each is concerned with the quality of the incoming materials, with the operating conditions and cleanliness of premises and equipment used, and with the animals, or biological materials used to produce or test the product.

38. List of document requirements