In June 2003, European legislation (Commission Directive 2003/63/EC) established the ‘Plasma Master File’ (PMF) which is a documentation related to the starting material ‘human plasma for fractionation’. The PMF is a stand-alone documentation which is separate from the medicinal product dossier for a marketing authorization (MA). It is a compilation of all the required scientific data (Commission directives, scientific guidelines, European Pharmacopoeia monographs, WHO and CPMP/CHMP statements) on the quality and safety of human plasma which is used for the manufacture of plasma-derived medicinal products, medical devices incorporating plasma-derived medicinal products and investigational products that use human plasma in their manufacture. These data cover all aspects from collection of plasma to the manufacture and testing of the (manufacturing) plasma pool.
The introduction of the PMF was a desire by Industry as well as Competent Authorities. The establishment of a PMF was seen as a chance to simplify and reduce the burden of documentation but also to improve harmonization of requirements and assessment for the starting material plasma for fractionation. Considering the manufacturing procedures of plasma-derived medicinal products, it is self-evident that the same starting material is used for the manufacture of different blood products, e.g. immunoglobulins, albumins, fibrin sealants, coagulation factors as well as inhibitors. This means that the documentation related to the starting material plasma for fractionation is applicable to several products. Before implementation of the PMF, it was necessary to include this information in each MA file which sometimes led to inconsistent information for the plasma documentation of different products of a given manufacturer or marketing authorization holder (MAH). Beside national MAs, the MAH can license products via the mutual recognition procedure (MRP), decentralized procedure (DCP) and centralized procedure. For MRPs and DCPs, different reference member states could be in charge of the procedure, and they could come to different assessments with respect to compliance of the plasma with EU legislation. Thus, the PMF does not only provide consistent documentation regarding plasma for fractionation for a given manufacturer, but it also contributes to harmonization of the assessment and reduction of workload by avoiding redundant assessments of plasma documentations. In summary, the idea behind the PMF was to avoid multiplication of documentation, to avoid multiple assessments of the same documentation, and to improve and harmonize the assessment of the documentation related to the starting material ‘plasma for fractionation’ within the EU/EEA. A PMF can be prepared by every centre or establishment for fractionation/processing of human plasma and submitted to the Agency for certification. An application for PMF certification may be submitted in the framework of new marketing authorization applications (MAAs) via the centralized procedure or MRP or DCP. In the framework of a purely national MAA, it is possible if the PMF corresponds to plasma-derived medicinal products with MAs in more than one member state. In case of existing MAs, the PMF certification may be initiated when the data for certification are identical to the approved data of all proposed linked MAs, a change to the data approved in all linked MAs is proposed or the annual update is due. A new PMF can be submitted for certification separately at any time in advance of any application for a MA or a consultation procedure on a blood derivative incorporated in a medical device.
The PMF system is a two-step procedure (Fig. 1). In the first step, the documentation is evaluated resulting in a PMF certificate, and in the second step the PMF is linked to respective MAs. This two-step system separates certification (certification of compliance with EU regulations) from regulatory decisions on licences (national, MRP, DCP) because the latter are taken by the respective competent authorities.
For medicinal products derived from human blood or plasma, the dossier requirements mentioned in ‘Information related to the starting and raw materials’, for starting materials made of human blood/plasma may be replaced by a PMF certified in accordance with Directive 2003/63/EC. This means that PMF certification is not mandatory, but the MAH can still decide which route he likes to follow for providing the data related to plasma for fractionation. In any case, the content should be the same and follow the ‘Guideline on scientific data requirement for a Plasma Master File’ (EMEA/CHMP/BWP/3794/03, current version). The certification procedure is similar to the evaluation system of an application for a MA under the ‘centralized procedure’ at the Agency (EMA). On behalf of the Committee for Human Medicinal products (CHMP), the initial scientific evaluation of the PMF dossier is carried out by the Biologics Working Party which appoints two coordinators (coordinator 1 and coordinator 2) working on the assessment report in liaison with coordinators of the member states. A final decision on the PMF application is given by the CHMP. Following the satisfactory outcome of the evaluation, the Agency issues a PMF certificate of compliance with Community legislation, which is valid throughout the European Community. This certificate is accompanied by the evaluation report.
In the so-called 2nd step, it is the responsibility of the MAH to update his medicinal product licence(s) and to incorporate the certified PMF in his Marketing Authorization(s), e.g. the documentation of a given product in part ‘Information related to the starting and raw materials’ (3.2.S.2.3) refers to the respective PMF. The Competent Authority that will grant or has granted the MA will take into account the effect of the PMF (re-)certification with respect to the quality and safety of the respective plasma-derived medicinal product.
The PMF shall be submitted and approved (re-certified) on an annual basis. Within the annual update, information shall be provided including a summary of all changes and updates, a ‘check list on annual update’, responses to all outstanding commitments and related data of previous evaluations, an integrated dossier including all changes and updates since the initial or annual update, new available epidemiological data, etc. (refer to guideline EMEA/CHMP/BWP/3794/03, current version). Within the annual update, changes can also be introduced. Changes that are intended to be introduced between annual recertification procedures should be addressed in variation procedures leading also to a recertification.
In general, it is possible that a given MA refers to more than one PMF. Because the MAH is responsible for the product, he must have available all information about the plasma for fractionation which means that he has the PMF certificate, the PMF dossier and the evaluation report of the respective PMF. If the MAH of a plasma-derived medicinal product is also a PMF holder, it would also be possible to integrate all necessary information of plasma of another PMF into his own PMF.
If a PMF corresponds only to blood/plasma-derived medicinal products of which the MA is restricted to a single Member State, then the scientific and technical evaluation of the respective PMF shall be carried out by the national competent authority of that Member State.
Since the last 5–6 years, the PMF has been accepted by all parties involved, e.g. industry (PMF holders) and competent authorities. Certification and recertification procedures as well as issues for discussion within coordinators’ evaluations and BWP meetings have contributed to harmonization of assessments and improvement in quality aspects of plasma for fractionation. Harmonization of assessments were also strengthened with Directives 2002/98/EC (‘Blood Directive’) and 2004/33/EC laying down requirements for blood components and plasma for fractionation also in case the plasma is imported from third countries.
Links and documents with respect to the PMF certification including commission directives, scientific guidelines, procedural and regulatory guidelines and announcements, European Pharmacopoeia and WHO documents as well as CHMP statements and meeting reports can be found at http://www.ema.europa.eu/htms/human/pmf/background.htm.