QUALITY MANAGEMENT

PRINCIPLE

The Pharmaceutical Industry must manufacture pharmaceutical products so as 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/top management who determines the “Quality Policy”, requires the participation and commitment by staff in all departments and at all levels within the company, by the company's suppliers and by the distributors. To achieve the quality objective reliably there must be a comprehensively designed and correctly implemented quality management.

The basic elements of the 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. The totality of these actions is termed Quality Assurance.

All parts of the Quality Assurance systems should be adequately resourced with competent personnel, and suitable and sufficient premises, equipment and facilities. There are additional legal responsibilities for the head of Quality Management (Quality Assurance).

The basic concepts of Quality Assurance, Good Manufacturing Practices and Quality Control are inter-related aspects of quality management. They are described here in order to emphasize their relationships and their fundamental importance to the production and control of pharmaceutical products. 

 

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 organized arrangements made with the object of ensuring that pharmaceutical products are of the quality required for their intended use. Quality Assurance therefore incorporates Good Manufacturing Practices plus other factors outside the scope of this Guide such as product design and development.

The system of Quality Assurance appropriate for the manufacture of pharmaceutical products should ensure that:

pharmaceutical products are designed and developed in a way that takes account of the requirements of Good Manufacturing Practices and Good Laboratory Practices;

production and control operations are clearly specified and Good Manufacturing Practices adopted;

managerial responsibilities are clearly specified in job description;

arrangements are made for the manufacture, supply and use of the correct starting and packaging materials;

all necessary controls on intermediate products, and any other in-process controls and validations are carried out;

all documentation relating to the batch process­ing, packaging and testing of each batch of finished product has been reviewed before authorizing release for distribution, assessment should embrace all relevant factors, including production conditions, results of in-process testing, a review of manufacturing (including, packaging) documentation an assessment of deviations from specified procedures, compliance with Finished Product Specification, and examination of the final finished pack

pharmaceutical products are not sold or supplied before the head of Quality Management (Quality Assurance) has 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;

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;

there is a procedure for self inspection and/or quality audit which regularly appraises the effectiveness and applicability of the quality assurance system;

suppliers of starting materials and packaging materials are evaluated and approved to meet the company's established quality specifications;

deviations are reported, investigated and recorded;

there are systems of approving changes that may have an impact on product quality;

reprocessing procedures for products are evaluated and approved; and

regular evaluations of the quality of pharmaceutical products are conducted with the objective of verifying the consistency of the process and ensuring its continuous improvement.

GOOD MANUFACTURING PRACTICES FOR PHARMACEUTICAL PRODUCTS (GMP)

Good Manufacturing Practice is that part of Quality Assurance which ensures that products are consistently produced and controlled to the quality standards appropriate to their intended use and as required by the marketing authorization and product specification.

Good Manufacturing Practice is concerned with both production and quality control. The basic requirements of GMP are that:

all manufacturing processes are clearly defined, systematically reviewed in the light of experience and shown to be capable of consistently manufacturing pharmaceutical products of the required quality and complying with their specifications;

critical steps of manufacturing processes, control and supports and their significant changes are validated;

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;

suitable storage and transport;

instructions and procedures are written in an instructional form in clear and unambiguous language, specifically applicable to the facilities provided;

operators are trained to carry out procedures correctly;

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. Any deviation is fully recorded and investigated;

records of manufacture including distribution which enable the complete history of a batch to be traced, are retained in a comprehensible and accessible form;

the storage and distribution (wholesaling) of the products minimizes any risk to their quality;

a system is available to recall any batch of product, from sale or supply; and

complaints about marketed products are examined, the causes of quality defects investigated and appropriate measures taken in respect of the defective products and to prevent re-occurrence.

QUALITY CONTROL

Quality Control is that part of Good Manufacturing Practice which is concerned with sampling, specifications and testing, and with the organization, 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.

Each manufacturer (the holder of a manufacturing authorization) should have a quality control function. The quality control function should be independent of other departments. Adequate resources must be available to ensure that all the quality control arrangements are effectively and reliably carried out.

The basic requirements of Quality Control are that:

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;

samples of starting materials, packaging materials, intermediate products, bulk products and finished products are taken by personnel and by methods approved by Quality Control;

test methods are established and validated (where applicable);

the finished products contain active pharmaceutical ingredients (APIs) complying with the qualitative and quantitative composition of the marketing authorization, are of the purity required, and are enclosed within their proper container and correctly labeled;

records are made of the results of inspection and that testing of materials, intermediate, bulk, and finished products is formally assessed against specification; and

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.

Quality control as a whole will also have other duties, such as to establish, validate and implement all quality control procedures, to evaluate, maintain, and store the reference standards for substances, to ensure the correct labeling of containers of materials and products, to ensure that the stability of the active pharmaceutical ingredients and products is monitored, to participate in the investigation of complaints related to the quality of the product, and to participate in environmental monitoring. All these operations should be carried out in accordance with written procedures and, where necessary, recorded.

Quality control personnel must have access to production areas for sampling and investigation as appropriate

PRODUCT QUALITY REVIEW

Regular periodic or rolling quality reviews of all licensed pharmaceutical 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. Such reviews should normally be conducted and documented annually, taking into account previous reviews, and should include at least:

review of starting materials and packaging materials used for the product, especially those from new sources;

review of critical in-process controls and finished product results;

review of all batches that failed to meet established specification(s) and their investigation;

review of all significant deviations or non-conformances, their related investigations, and the effectiveness of resultant corrective and preventative actions taken;

review of all changes carried out to the processes or analytical methods;

a review of Marketing Authorization variations submitted/ granted/ refused, including those for third country (export only) dossiers;

review of the results of the stability monitoring programme and any adverse trends;

review of all quality-related returns, complaints and recalls and the investigations performed at the time;

review of adequacy of any other previous product process or equipment corrective actions;

for new marketing authorizations and variations to marketing authorizations, a review of post-marketing commitments;

qualification status of relevant equipment and utilities, e.g. HVAC, water, compressed gases, etc. ; and

review of Technical Agreements to ensure that they are up to date.

The manufacturer and marketing authorization holder, where different, should evaluate the results of this review and an assessment should be made 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.

Where the marketing authorization 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 head of Quality Management (Quality Assurance) responsible for final batch certification together with the marketing authorization holder should ensure that the quality review is performed in a timely manner and is accurate.