CHAPTER 1 PHARMACEUTICAL QUALITY SYSTEMPharmaceutical Quality System 6 Principle © Quality Control Pharmaceutical . © Quality System © Prdusggucilty Good Manufacturing Practice for Medicinal Quality Risk Products (GMP) ManagementPRINCIPLE The holder of a Manufacturing Authorisation must manufacture medicinal products so as to ensure that they are fit for their intended use, comply with the requirements of the Marketing Authorisation F Clinical Trial Authorisation, as appropriate, and do not place patients at risk due to inadequate safety, quality or efficacy. The attainment of this quality objective is the responsibilty of senior management and requires the participation and commitment by staff in many different departments and at all levels within the company, by the company’s suppliers and by its distributors, To achieve this quality objective reliably there must be a comprehensively designed ‘and correctly implemented Pharmaceutical Quality System incorporating Good Manufacturing Practice and Quality Risk Management. It should be fully documented and its effectiveness monitored. All parts of the Pharmaceutical Quality System should be adequately resourced with competent personnel, and suitable and sufficient premises, equipment and facilities. There are additional legal responsibilities for the holder of the Manufacturing Authorisation and for the Authorised Person(s). The basic concepts of Quality Management, Good Manufacturing Practice (6MP) and Quality Risk Management are interrelated. They are described here in order to emphasise their relationships ‘and their fundamental importance to the production and controlof medicinal products.Pharmaceutical Quality SystemPharmaceutical Quality System 11 Quality Management covers all matters, which influence the quality of a product. Quality Management therefore incorporates Good Manufacturing Practice. 1.2 GMP applies to the lifecycle stages of the product. However the Pharmaceutical Quality System can extend to the pharmaceutical development lifecycle stage as described in ICH QI0, which facilitate innovation and continual improvement and strengthen the link between pharmaceutical development — and manufacturing activities. 13 The size and complexity of the company’s activities should be taken into consideration. While some aspects of the system can be company-wide and others site-specific, the effectiveness of the system is normally demonstrated at the site level. ¢ “OF A ==]14 A Pharmaceutical Quality System appropriate for the manufacture of medicinal products should ensure that: (i) Product realisation and consistent delivery of products with appropriate quality attributes; (ii) Product and process knowledge is managed throughout all lifecyclestages; (iii) Medicinal products are designed and developed following Good Manufacturing Practice; (iv) Production and control operations are clearly specified and Good Manufacturing Practice adopted; (v) Managerial responsibilities are clearly specified;(vi) 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 from the approved supply chain; (vii) Processes are in place to assure the management of outsourced activities; (viii) A state of control using effective monitoring and control systems for process performance and product quality; (ix) The results of product and processes monitoring are 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; (x) All necessary controls on intermediate products, and any other in- process controls and validations are carried out;(x) Continual improvement is facilitated through the implementation of qu improvements appropriate to the current level of process and product knowledge; (di) Arrangements are in place for the prospective evaluation of planned changes ‘and their approval prior to implementation taking into account regulatory notification and approval where required; (iii) after implementation of any change, an evaluation is undertaken to confirm the quality objectives were achieved and that there was no unintended deleterious impact on product quality; (xiv) An appropriate level of root cause analysis should be applied during the investigation of deviations, suspected product defects and other problems. This can be determined using Quality Risk Management principles. in cases where the true root cause(s) of the issue cannot be determined, consideration should be given to identifying the most likely root cause(s) and to addressing those. Where human error is suspected or identified as the cause, this should be justified having taken care to ensure that process, procedural or system based errors or problems have not been overlooked.inal 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; (xvi) 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; (xvii) There is a process for self-inspection and/or quality audit, which regularly ‘appraises the effectiveness and applicability of the Pharmaceutical Quality system, i Wy X1.5 Senior management has the ultimate responsibility to ensure an effective Pharmaceutical Quality System is in place, adequately resourced and that roles, respon throughout the organisation. Senior management's leadership and active participation in the Pharmaceutical Quality System is essential. This leadership should ensure the support and commitment of staff at all levels and sites within the organisation to the Pharmaceutical Quality System. ies, and authorities are defined, communicated and implemented 1.6 There should be peri management, of the operation of the Pharmaceutical Quality System to identify ‘opportunities for continual improvement of products, processes and the system itself. fic management review, with the involvement of senior 1.7 The Pharmaceutical Quality System 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.GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTSpeered eb ee iter ona Cee ata) Pear ad Eceeey ens eee ee eee) ees Rr ery peat cen eared ee) Rete eran) co eer) ey ecanecliconcet Peoria Clot) ee tem ecard et nietay Crees ar) cersear esac ‘Assystemis avaiable torecall any batch of eee enn foereneateaty Pecos) Ce ta coerced ey perceivesQUALITY CONTROL Concerned with sampling, specifications and testing, Including Organisation, documentation and release proceduresBasic Requirements of Quality Control Requirement that must be followed in QC are: NSTC Ce MC OUR) ceo aka OC ‘Taken by approved personnel and methods mS dulled ee AV ell) Records are made, manually and/or by recording instruments complying with the qualitative and quantitative composition of the Marketing Authorisation or Clinical Trial Authorisation cela e oun eC UT Ro No batch of product is released for sale or supply prior to certification by an Authorised Person Sufficient reference samples of starting materials and products are PCT RU rte ALU aPRODUCT QUALITY REVIEW (PQR) is a mechanism to ensure that data captured by the Pharmaceutical Quality System (PQS) is reviewed for trends. 110 © Regular periodic or rolling quality reviews of all authorised 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 product, © to highlight any trends and to identify product and process improvements. = NOTE: Such reviews should normally be conducted and documented annually. fPRODUCT QUALITY REVIEW (i) those from new sources and in particular the review of supply eae alec eat (ii) A review of critical in-pri ntrols and finished product cCHvicy FO | & (ili) A review of all i TI if Fy ol-Teflitorel (olan elated (iv) A review of all significant deviations or non-conformances, and PCy icra seen eee a tnd em reread (v) A review of all changes carried out to the processes or analytical methods;PRODUCT QUALITY REVIEW (vi) A review of Marketing Authorisation variations submitted, granted or refused, including those for third country (export only) dossiers; (viii) A review of all quality-related returns, complaints and recalls and the investigations performed atthe time; - (x) For new Marketing Authorisations and variations to Marketing Authorisations,a review of post-marketing commitments; Ww (xi) The qualification status of relevant equipment and utilities, (xii) A review of any contractual arrangements.um no - PRODUCT QUALITY REVIEW The manufacturer and/or Marketing Authorisation holder should evaluate the results of the review and an assessment made as to whether corrective and preventive action or any revalidation should be undertaken, under the Pharmaceutical Quality System. Quality reviews may be grouped by product type, e.g. solid dosage forms, liquid Cree eee oe a Rael atic Crore cun ee Mee ee aaa Tala eet hoy Oe en nee kee RR a eee iam g ene seals ee hucd neers temas Swe Re OR ea ROME ree lel ole ted Marketing Authorisation holder should ensure that the quality review is performed eR A UU elo leQUALITY RISK MANAGEMENT Quality Risk Managementis a systematic process for the assessment, control, communication and review of risks to the quality of the medicinal product. It can be applied both proactivelyand retrospectively. a = N wy Bs iThe principles of Quality as Managementare that: (i) The evaluation of the risk to quality is based on scientific knowledge, experiencewith the process and ultimately links to the protection of the patient; (ii) The level of effort, formality and documentation of the Quality Risk Management process is commensurate with the level of risk. Examples of the processes and applications of Quality Risk Management canbe found inter alia in Annex 20 or ICHQ9.THANK YOU wW NY W