EC Commission Publishes Draft on the Creation of a Site Master File

In the GMP News of last week we reported about a new Part III to the EC GMP Guide. As the first document to this new Part III, a 9-page draft with instructions for the creation of a site master file has been published. This document is very important for pharmaceutical enterprises since it represents the basis for a supervisory authority to prepare itself for a GMP inspection. Until 31 March 2010, comments on this document can still be submitted.
The Site Master File concept is based on a document (PE 008-3) of the Pharmaceutical Inspection Conventions Scheme (PIC/S), which has been revised three times and used quite successfully by the pharmaceutical companies for years. This new draft by the EC Commission is meant to replace this PIC/S document, with the finalised version planned to be published as a PIC/S document as well (parallel publication). In the following an examination of the new draft.

In principle, the structure of the new draft corresponds to the already existing PIC/S document:

  • Introduction
  • Purpose
  • Scope
  • Contents

In general, the content is orientated towards the EC GMP Guide - like the current PIC/S document. What is new is the distinction between general requirements regarding the firm and a separate new chapter Quality Management System. Up till now, this has been described together in one chapter. The industry very much appreciates the clear structure in the current PIC/S document. Apart from the requirements on the individual chapters (e. g. The requirement in chapter 2 "Personnel" on the topic of training), in the following the document gives guidance as an interpretation to the corresponding requirements. This goes e. g. as far as to indicate the number of words or pages in order not to exceed the desired total number of pages of the Site Master File of 25-30 A-4 pages. In the case of the requirement on the topic of training, the guidance consists in advice on the ascertainment of the need for training, re-training, success control and so on, which have to be dealt with in the Site Master File later on. Very helpful in the creation. These interpretations are not included in the draft any longer. The individual chapters now rather consist of a mixture between requirement and guidance at the same time. In this respect, some more precise specifications are in fact included, which - in comparison with the current PIC/S document - will probably make existing Site Master Files more comprehensive. Still, the draft, too, desires no more than 30 pages (however, without the appendices).

The introduction mentions (new) an updating and review of the Site Master File. Even a validity date is required on the document! Up till now, many firms used to create the update when the Site Master File was asked for by the supervisory authority before the inspection for preparation purposes (as a rule every 2-3 years).

The area of application (to be found under "Scope") is somewhat unclear. Although orientated towards pharmaceutical companies in the document title, now repackers and API manufacturers are also mentioned. Firms processing blood and tissue are also listed. Keeping in mind that PIC/S has already published separate documents on Site Master Files for source-plasma establishments and their warehouses (PI 019 and 020), each of which contain references to the current PE 008 document.

Among the requirements on the general data of a company, the draft calls for the indication of a clear identification number of the firm. It gives the example of the Data Universal Numbering System (DUNS), a nine-digit number code that identifies companies unambiguously. Furthermore, GPS details are required. Presumably due to the inspection of the wrong firms with fatal consequences in the past.

Apart from describing the maintenance of the QM system and the indication of accreditations and certifications, the - new - separate chapter Quality Management System here already places great emphasis on details regarding the validation- and change control policy. Moreover, in the future, the systems for the Product Quality Review (PQR) and for the Management Review will have to be described. This is an adaptation to the state of the art. Within the framework of the release, which is to be described, the handling of rejected material shall already be dealt with. Another new feature is the procedure for supplier qualification, which is likewise to be described, namely including the application of the corresponding Quality Risk Management principles in this field. The express requirement to describe the Quality Risk Management principles under supplier qualification is a bit surprising, since in the following the description of a separate subchapter "Quality Risk Management Policy of the company" is required. This, too, is completely new compared to the existing PIC/S document PE 008. Here, the draft expressly requires the description of the implementation of the ICH Q9 risk management process in the company.

Few new (and concrete) things can be said about Chapter 3 "Personnel". Only the requirement to describe the handling of the cleaning of clothes is new.

The topic facilities and equipment (Chapter 4) has slightly been modernised. Now information on the use of isolators must e. g. be given if it is available. Information on a DOP test, which is still included in the current PE 008 document, are not mentioned. Details from the current guidance part of PE 008 are not listed any longer (e. g. data on filters, temperature, capacities…). Furthermore, a (brief) description of the qualification- and again also of the validation policy is required. The repeated requirement to describe the validation policy seems to be redundant. The subchapter GMP-critical computerised systems with its call for listing and the requirement of description of the validation policy in this field is completely new.
Now, the chapter Documentation (Chapter 5) points explicitly to the brief description of the archiving system. Apart from that, the chapter is very short.

In the draft, Chapter 6 (production) aims very much at the topics that are mainly connected with the ICH Q8 guideline ("Quality by Design"; Design Space, PAT, Real Time Release). Products affected by this should be mentioned particularly and also - if the design space concept is applied - their manufacture described in detail. Besides, a description of the manufacture of investigational medicinal products (requirement to describe the manufacture, facilities, personnel) is dealt with explicitly. Toxic and dangerous products (e. g. with highly active and/or allergenic potential) shall be named. In the current PIC/S document, the listing of these products is dealt with in its appendix, so it is not really new. What is new, however, is the requirement to name products that fall within campaign manufacture or are manufactured in dedicated facilities. In the subchapter on process validation, the draft requires - if applicable - data on the approach to a continuous validation. This is a genuine novelty!

Chapter 7 (laboratory) is also quite concise. Here, the indication of a validation policy is now required. Yet with the extension "(CA)", which is not explained further.

Unlike in the past, chapter 8 is now called Contract Manufacture, i. e. solely, although contract analyses are also mentioned. A list of all contractors with address and contact information is required as a separate appendix No. 8. Another new feature is the requirements to include flow charts of the supply chain at the time when goods are coming in or going out in case of outsourcing.

Chapter 9 on distribution, complaints, product failures (new term) and recalls now aims at a description of the transport controls (transport validation). Measures for the identification of counterfeit products are now also meant to be described. Specific data regarding the warehouse, as included in the current PIC/S document, have been deleted.

The last chapter (No. 10) on self-inspections has the innovation in store that, within the framework of the description of the self-inspection system, the rationale for the selection of the affected areas should also be explained.

Eight appendices shall finally complete the Site Master File according to the new draft. These contain e. g. a copy of the registration, the current GMP certificate, organisation charts, layouts…

Final conclusion: The draft has clearly been adapted to the state of the art, which will probably have an influence on the scope of the Site Master File. One of the focus points of the document is the requirement to describe the quality risk management activities. The high presence of subjects round about ICH Q8 also shows the topicality. The latter can also be deduced from the targeted listing of the manufacture in "Dedicated Equipment", the requirement to describe transport validation and continuous validation. Importance is also attached by the draft to the regular updating of a Site Master File and the unambiguous (also geographically by means of GPS) identification of the firm in question. Otherwise, the contents are a bit heterogeneous and reach from very general requirements, e. g. as for the important GMP chapter documentation, to highly detailed requirements, almost comparable to a guidance document, like e. g. in the chapter Quality Management System. Comments on the draft can be submitted until 31 March 2010. Benefit from this opportunity!

Sven Pommeranz
On behalf of the European Compliance Academy (ECA )

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