Administering Files, Records, and Grants

Regulatory control of plasma for fractionation

8.1 Role of national regulatory authority

According to the WHO Guidelines for national regulatory authorities on quality assurance of biological products (72, 73), national regulatory authorities have the duty to ensure that available biological products, whether imported or manufactured locally, are of good quality, safe and effi cacious, and should thus ensure that manufacturers adhere to approved standards of quality assurance and GMP. The responsibilities of the national regulatory authority should also include the enforcement and implementation of effective national regulations, and the setting of appropriate standards and control measures. The evaluation and control of the quality, safety and consistency of production of blood products involve the evaluation of the starting material, production processes and the test methods to characterize batches of the product. This requires specialist expertise by the national regulatory authority.

8.2 Establishment licence and inspections

In many countries, national regulatory authorities have implemented a control system based on licensing the establishments, inspecting them regularly, and enforcing the implementation of the legal requirements and applicable standards.

According to international GMP standards for the manufacturing of blood products, the following two main principles are important for the control of plasma as starting material:

· Quality assurance should cover all stages leading to the fi nished product, from collection (including donor selection) to storage, transport, processing, quality control and delivery of the fi nished product.

· Blood or plasma used as a source material for the manufacture of medicinal products should be collected by establishments and be tested in laboratories which are subject to inspection and approved by a national regulatory authority.

These two points in the GMP requirements summarize an important basic principle which is relevant for the manufacture of plasma derivatives and the control of plasma as starting material. Most national regulations therefore require that the establishments involved in the collection and storage of plasma as a source material (e.g. plasmapheresis centres and blood establishments) need to have an establishment licence and need to be inspected by the competent national regulatory authority. To obtain the licence the establishments have to fulfi l a defi ned set of requirements to guarantee that the plasma collected is safe and of good quality. Since each unit collected represents a single batch, a marketing authorization for the plasma as a “product“ is not required in all countries. Under the latter condition, a “system control”, instead of a “product control”, may be more appropriate. In addition to the establishment licensing system some countries have also introduced a product-specifi c approval system for blood components.

8.3 Impact of good manufacturing practices

The approach of implementing the principles of GMP in the production of medicinal products is not new, and it is widely acknowledged that it is essential in assuring the quality and safety of medicinal products. For blood products, GMP becomes even more important and more complex due to the biological nature of the products. Therefore, taking into account the principles of GMP and the existence of an appropriate system of quality assurance to address and implement these requirements in the manufacturing steps of blood products should be a pivotal element of the preparation of plasma for fractionation. As outlined in the previous sections, implementation of GMP in the manufacture of blood products is essential, and quality assurance and GMP should cover all stages, including the collection of plasma as starting material. The implementation and enforcement of GMP in blood establishments therefore has the following impact:

— introduces the application of quality assurance principles in all steps involved in the collection, preparation and testing of blood components;

— supports systematic application of donor selection criteria for each donation;

— reduces errors and technical problems in collection, preparation, testing, and distribution;

— contributes to the release of products which comply with safety and quality requirements;

— ensures adequate documentation and full traceability for each donation and product;

— enables continuous improvement in collection, preparation and testing of starting material;

— supports regional cooperation networks that may result in the formation of centres of competence by centralizing activities in order to reach compliance at the required level (cost-benefi t for implementing quality assurance measures);

— provides suitable tools for the national regulatory authority to assess the compliance of a plasma collection centre.

An establishment licensing system for blood establishments by the competent national regulatory authorities should therefore exist. The main requirements for obtaining an establishment licence may include:

· Application of quality assurance system and GMP to all steps from donation, to preparation, storage, testing and distribution of plasma.

· Personnel directly involved in the collection, testing, processing, storage and distribution of plasma need to be appropriately qualifi ed and provided with timely and relevant training.

· Adequate premises and equipment should be available.

· An adequate system to ensure traceability of plasma should be established; traceability should be enforced through accurate donor, donation, product and laboratory sample identifi cation procedures, through record maintenance and use of an appropriate labelling system.

· Requirements for selection of donors, including exclusion criteria for donors with risk behaviours; provision of information to donors on risk situations and the donation in general; and the use of a questionnaire to obtain information on donor’s health.

· Requirements for testing of each donation.

· Requirements regarding traceability and documentation.

· Post-donation information system.

8.4 Inspections

In conducting regular inspections as part of the licensing procedure, enforcement of the implementation of GMP is required aiming to ensure the compliance of the blood establishments with the existing provisions. It is the responsibility of the inspector from the national regulatory authority to ensure that the manufacturers and the blood and plasma establishments adhere to the approved standards of GMP and quality assurance, including at sites where plasma is collected as starting material.

The inspections should be carried out by offi cials representing the competent national regulatory authority. These offi cials should be specialized inspectors, trained in GMP inspections, and they should be familiar with blood bank technologies and the special features of quality assurance in the collection of plasma. Inspections may follow common inspection procedures, including:

· an opening meeting;

· a blood establishment tour;

· inspection of main areas and activities;

— donor acceptance and identifi cation

— donor suitability

— collection process

— processing and sampling

— plasma freezing

— testing and availability of test results

— release of plasma units

— storage, transportation and shipment

— quality assurance (including self inspection and change control)

— documentation (standard operating procedures, records, donor record fi les and log books)

— personnel and organization

— qualifi cation and process validations

— error and corrective action system

— look-back information, recalls and complaints

— product quality controls

• a fi nal meeting summarizing the inspection outcome.

A thorough inspection includes the observation of staff during performance operation and comparison with defi ned written procedures. In a “system control”, the inspection can be considered not only as a GMP inspection, but also as an indirect product quality assessment by checking productspecifi c validation and quality control data.

A written report should summarize the main aspects of the inspection including its scope, a description of the company, the defi ciencies listed, specifi ed and classifi ed (e.g. as critical, major or minor), and a conclusion. The written report will be sent to the company. The companies are requested to notify the national regulatory authority about the specifi c steps which are taken or planned to correct the failures and to prevent their recurrence. If necessary, follow-up inspections should be performed e.g. to check that specifi c corrective actions have been implementd.

The national regulatory authority should have the authority to withdraw an establishment licence in a case where inspection results showed critical non-compliance with the requirements or product specifi cations.

Information on the collection and control of the starting material, human blood or plasma, and on the procedures conducted during the preparation of the fi nal blood derived medicinal product have to be documented as part of the dossier in the marketing authorization.

In summary, the implementation of licensing and inspection systems for blood establishments has become an important tool through which the national regulatory authorities confi rm the assurance of quality of plasma as starting material for fractionation. The use of international standards not only further promotes harmonization, but also facilitates regional collaboration and information exchange between the national regulatory bodies.

189

190

189