Good Manufacturing Practices and Inspections

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Objectives

The objective is to have a harmonized medicines inspection and Good Manufacturing Practice system that support public health interventions and ensures timely access to safe, efficacious, quality and affordable medicines for the people of the West African region. This will ensure;

• Commencement of Medicines Registration Harmonization in West African region Member States with a common set of harmonized technical guidelines and SOPs for GMP inspection to support medicines registration in the region.
• Harmonized GMP inspection guidelines that facilitate joint inspection of manufacturing sites as part of implementation of harmonized medicines regulatory system in the West African region.
• Improved capacity for GMP inspection in the region through joint inspection of manufacturing sites and report sharing.

Good Manufacturing Practice for Medicinal Products in ECOWAS

• In order to further facilitate the removal of barriers to trade in medicinal products, to promote uniformity in licensing decisions and to ensure the maintaining of high standards of quality assurance in the development, manufacture, and control of medicinal products
• The following Guide to Good Manufacturing Practice for Medicinal Products and its Annexes has been adapted from WHO TRS 986 Annex 2 by the WA-MRH Expert Working Group for Good Manufacturing Practice.

WAHO Guidelines for GMP

• The West African Health Organisation (WAHO) proposed the Certification Scheme for finished pharmaceutical products which are a regional agreement among ECOWAS members’ states to provide assurance to countries participating in the scheme about the quality of pharmaceutical products moving in regional and international commerce. The WAHO certification Scheme seeks to assist resource-limited countries in the region to have more control in the assessment of the quality of pharmaceutical products imported into or exported out of West Africa; the scheme will also support the current processes of establishing harmonised regional medicines registration and procurement systems based on legislation and regulation as pre-requisites for decision making and also assist member states to develop their own medicines quality assurance systems.
• This guideline will help to harmonize the medicines inspection and Good Manufacturing Practice system that support public health interventions and ensure timely access to safe, efficacious, quality and affordable medicines for the people of the West African region.

The GMP Requirements

• The draft requirements for Good Manufacturing Pratice were presented in seventeen sections which include:
• 1) Pharmaceutical quality system,
• 2) Good manufacturing practices for pharmaceutical products
• 3) Sanitation and hygiene
• 4) Qualification and Validation
• 5) Complaints
• 6) Product recalls
• 7) Contract production, analysis and other activities
• 8) Self-inspection, quality audits and suppliers’ audits and approval
• 9) Personnel
• 10) Training
• 11) Personal hygiene
• 12) Premises
• 13) Equipment
• 14) Materials Products registered by Stringent Regulatory Authorities, prequalified by WHO, registered under Swissmedic MAGHP Procedure or EMA Article 58 (Positive Scientific opinion)
• 15) Documentation
• 16) Good practices in production
• 17) Good practices in quality control.

Pharmaceutical Quality System

• 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.
• 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 is essential. This leadership should ensure the support and commitment of staff at all levels and sites within the organization to the PQS.
• 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, including those outside the scope of this guide such as product design and development.

Life-cycle Stages

• 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.

The PQS for GMP

• 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 life-cycle 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);
• 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;
• 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;
• 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;
• 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.

PQS Standards

• 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.
• 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.

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.

Product quality review

• Regular, periodic or rolling quality reviews of all pharmaceutical products, including export-only products, should be conducted with the objective of verifying the consistency of the existing process and the appropriateness of current specifications for both starting materials and finished product, 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:
• a) review of starting materials and ackaging materials used for the product, especially those from new sources and in particular the review of supply chain traceability of active substances;
• b) a review of critical in-process controls, and finished product results;

Good manufacturing practices for pharmaceutical products

• GMP is that part of quality management which ensures that products are consistently produced and controlled according to the quality standards appropriate to their intended use and as required by the marketing authorization, clinical trial authorization or product specification. GMP is concerned with both production and QC.
• GMP is aimed primarily at managing and minimizing the risks inherent in pharmaceutical manufacture to ensure the quality, safety and efficacy of products.

Under GMP:

• a) all manufacturing processes are clearly defined, systematically reviewed for associated risks in the light of scientific knowledge and experience, and shown to be capable of consistently manufacturing pharmaceutical products of the required quality that comply with their specifications;
• b) Qualification and validation are performed;
• c) All necessary resources are provided
• d) instructions and procedures are written in clear and unambiguous language, specifically applicable to the facilities provided;
• e) procedures are carried out correctly and personnel are trained to do so;
• f) records are made (manually and/or by recording instruments) during manufacture to show that all the steps required by the defined procedures and instructions have in fact been taken and that the quantity and quality of the product are as expected. Any significant deviations are fully recorded and investigated with the objective of determining the root cause and appropriate corrective and preventive action is implemented;
• j) complaints about marketed products are examined, the causes of quality defects investigated and appropriate measures taken in respect of the defective products to prevent recurrence.

Qualification and validation

• In accordance with GMP, each pharmaceutical company should identify what qualification and validation work is required to prove that the critical aspects of their particular operation are controlled.
• The key elements of a qualification and validation programme of a company should be clearly defined and documented in a validation master plan.
• Qualification and validation should establish and provide documentary evidence
• Any aspect of operation, including significant changes to the premises, facilities, equipment or processes, which may affect the quality of the product, directly or indirectly, should be qualified and validated.
• Qualification and validation should not be considered as one-off exercises. An ongoing program should follow their first implementation and should be based on an annual review.
• The commitment to maintain continued validation status should be stated in the relevant company documentation, such as the quality manual or validation master plan.
• The responsibility for performing validation should be clearly defined.
• Validation studies are an essential part of GMP and should be conducted in accordance with predefined and approved protocols.
• A written report summarizing the results recorded and the conclusions reached should be prepared and stored.
• Processes and procedures should be established on the basis of the results of the validation performed.
• Particular attention should be paid to the validation of analytical test methods, automated systems and cleaning procedures.

Documentary Evidence

• Qualification and validation should establish and provide documentary evidence that:
• a) the premises, supporting utilities, equipment and processes have been designed in accordance with the requirements for GMP (design qualification or DQ);
• b) the premises, supporting utilities and equipment have been built and installed in compliance with their design specifications (installation qualification or IQ);
• c) the premises, supporting utilities and equipment operate in accordance with their design specifications (operational qualification or OQ);
• d) a specific process will consistently produce a product meeting its predetermined specifications and quality attributes (process validation or PV, also called performance qualification or PQ).