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 or 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 responsibility 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 System1 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 Qualified Person(s).
The basic concepts of Quality Management, Good Manufacturing Practice and Quality Risk Management are inter-related. They are described here in order to emphasise their relationships and their fundamental importance to the production and control of medicinal products.
Pharmaceutical Quality System1
1.1 Quality Management 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 Management therefore incorporates Good Manufacturing Practice.
1.2 GMP applies to the lifecycle stages from the manufacture of investigational medicinal products, technology transfer, commercial manufacturing through to product discontinuation. However the Pharmaceutical Quality System can extend to the pharmaceutical development lifecycle stage as described in ICH Q10, which while optional, should facilitate innovation and continual improvement and strengthen the link between pharmaceutical development and manufacturing activities. ICH Q10 is reproduced in Part III of the Guide and can be used to supplement the contents of this chapter.
1.3 The size and complexity of the company's activities should be taken into
consideration when developing a new Pharmaceutical Quality System or modifying
an existing one. The design of the system should incorporate appropriate risk
management principles including the use of appropriate tools. 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.
1.4 A Pharmaceutical Quality System appropriate for the manufacture of medicinal products should ensure that:
(i) Product realisation is achieved by designing, planning, implementing, maintaining and continuously improving a system that allows the consistent delivery of products with appropriate quality attributes;
(ii) Product and process knowledge is managed throughout all lifecycle stages;
(iii) Medicinal products are designed and developed in a way that takes account of the requirements of 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 is established and maintained by developing and using effective monitoring and control systems for process performance and product
(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;
(xi) Continual improvement is facilitated through the implementation of quality improvements appropriate to the current level of process and product knowledge.
(xii) 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;
(xiii) 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 systembased errors or problems have not been overlooked, if present. Appropriate corrective actions and/or preventative actions (CAPAs) should be identified and taken in response to investigations. The effectiveness of such actions should be monitored and assessed, in line with Quality Risk Management principles.
(xv) Medicinal products are not sold or supplied before a Qualified 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
(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.
1.5 Senior management has the ultimate responsibility to ensure an effective Pharmaceutical Quality System is in place, adequately resourced and that roles, responsibilities, and authorities are defined, communicated and implemented 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.
1.6 There should be periodic management review, with the involvement of senior management, of the operation of the Pharmaceutical Quality System to identify opportunities for continual improvement of products, processes and the system itself.
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
1.8 Good Manufacturing Practice is that part of Quality Management which ensures that products are consistently produced and controlled to the quality standards appropriate to their intended use and as required by the Marketing Authorisation, Clinical Trial 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;
(ii) Critical steps of manufacturing processes and significant changes to the process are validated;
(iii) All necessary facilities for GMP are provided including:
• Appropriately qualified and trained personnel;
• Adequate premises and space;
• Suitable equipment and services;
• Correct materials, containers and labels;
• Approved procedures and instructions, in accordance with the Pharmaceutical Quality System;
• 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) Procedures are carried out correctly and operators are trained to do so;
(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 was as expected.
(vii) Any significant deviations are fully recorded, investigated with the objective of determining the root cause and appropriate corrective and preventive action implemented;
(viii) Records of manufacture including distribution which enable the complete history of a batch to be traced are retained in a comprehensible and accessible form;
(ix) The distribution of the products minimises any risk to their quality and takes account of Good Distribution Practice;
(x) A system is available to recall any batch of product, from sale or supply;
(xi) Complaints about products are examined, the causes of quality defects investigated and appropriate measures taken in respect of the defective products and to prevent reoccurrence.