New Draft of Annex 13 – 
Manufacture of Investigational Medicinal Products

The purpose of revising this annex is to take better account of the complex processes involved in the manufacture of investigational medicinal products and to confront the resultant special risks by means of detailed regulations. The additional risks in the area of the manufacture of investigational products are described in the preamble; there are as a rule no fixed routines in the manufacturing process, clinical trial designs vary, different batches consist of small numbers, complex packaging, labelling and blinding procedures must take place within a short time or even simultaneously. All this requires special attention in all areas to GMP conformity by personnel with especially thorough training. These enhanced requirements are reflected in the revision of Annex 13 in the form of some quite strict regulations. These regulations require considerable additional organisational inputs by the industry, and therefore distinct resistance and modification suggestions are to be expected from this quarter.

The most important additions and modifications in comparison with the previously valid Annex 13 are listed below.

The chapter on Quality management requires that premises and equipment be fully qualified. Other requirements are:

• In the validation of aseptic processes whenever possible in the case of small batch sizes a larger number of units should be filled with media than usual, in order to obtain results of greater statistical confidence.
• As regards the operations in aseptic manufacturing often performed manually or semi-automatically in the case of small batch sizes enhanced attention should be given to operator training, and validating the aseptic technique of individual operators. The reference in the current Annex 13 to increased environmental monitoring in case of manual filling and sealing was deleted from the draft since this forms part of such a validation.

Section 3 of the currently valid Annex 13, which refers to the critical operations of packaging and labelling in connection with the error-free execution of the clinical trial and to self-inspection or independent audits was completely deleted from the new draft. However, the subsequent sections "Packaging" and "Labelling" deal with the quality assurance measures in detail.

The chapters Personnel, Premises and Equipment do not mention the "responsible person", as did the previous Annex, but the "Qualified Person" as the person responsible for the compliance with the special requirements in the manufacture of the investigational medicinal products. The "QP" is required to have a broad knowledge of clinical trial processes. Their function is defined in later sections with reference to Annex 16.

In the draft the passage requiring that investigational medicinal products and other medicinal products possibly be manufactured simultaneously in the same premises was deleted and instead the requirement for a stringent cleaning program for the strict prevention of cross-contamination was formulated even more firmly since the risks of a toxic or highly effective substance cannot be reliably evaluated in this early development phase.

In contrast to the existing Annex 13, which contains only four lines on the Product Specification File, the new draft lists the various documents which the file must contain or refer to.

The purpose of this file is described in detail and the "Qualified Person" is mentioned who must have access to the PSF as the basis for assessment of the suitability for release and certification of a particular batch. The information contained in the PSF must be taken into account in the drawing up of all important work instructions.

The chapter on Packaging instructions requires expressly with a view to the complicated procedures in the manufacture of investigational medicinal products that reconciliations should take place for each product and each production stage in order to ensure that the correct quantities of the various test preparations have been manufactured. The previous Annex 13 contains only the requirement for reconciliation at the end of the packaging and labelling processes.

Packaging materials is the title of the section inserted in the draft before the item "Manufacturing operations" which requires special quality control checks for a homogeneous appearance of the packs in order to prevent unintentional unblinding due to a visible difference between the placebo and the active medication packs.

It is expressly pointed out in the chapter on Manufacturing operations that the production parameters and the corresponding in-process controls must be deduced from the knowledge actually available at the time, based on experience from earlier stages of development, i.e. they are to be carefully considered in this respect.

If no stability data is available for the comparator product packed into the clinical sample pack the valid Annex 13 requires in the chapter "Principles applicable to comparator product" that the corresponding expiry date exceed the period between the repackaging operation and the expiry date of the original bulk pack by not more than 25% and not more than 6 months beyond the time of repackaging, whichever is the first to occur. This regulation has been deleted from the draft Annex and no provision has been inserted to replace it. Instead, the expiry date given on the clinical sample packaging may not exceed that given on the original packaging at all and must be justified, whereby the characteristics of the product, of the primary packaging and of the storage conditions are to be taken into account.

The process of blinding the test preparation, comparator product and placebo must be completely identifiable. Here the identification of the product history is expressly required in the draft in the chapters Blinding; Randomisation code in addition to the reliable product identification required in the existing Annex.

The requirements for the randomisation procedure are also more strictly formulated: in addition, safety aspects and the procedure for breaking the code must be described in the corresponding procedures.

The section on the risks of product mix up in the case of simultaneous packaging of different preparations - found in the current Annex under "Premises and Equipment"– is found in the section on Packaging in the draft with the additional reference to relevant staff training in order to reduce this risk. The subsequent sections name additional in-process controls by operators and supervisory staff as precautions against mislabelling. Furthermore, the packaging is to be designed so that any manipulation by unauthorised persons during transport is immediately recognisable.

The chapter on Labelling is much more detailed in the draft; at the same time the catalogue of requirements has been expanded to include, e.g. name, address and telephone number of the sponsor, contract research organisation or the principal contact for the clinical trial on the labels should the code need to be broken in case of an emergency.

Relabelling must be carried out at the manufacturing site; only if this is not possible or if the trial is interrupted may this also take place at the clinical trial site, but in any case subject to strict observation of the GMP principles.

In two additional sections it is defined once again which of the obligatory particulars must appear explicitly on the secondary packaging and which may be given there in encoded, but rapidly identifiable form. The address and telephone number and the dosage instructions (except in the case of liquid dosage forms and injectables) need not appear on the label of the primary packaging.

In the chapter on Quality control the criteria for QC were replaced with the reference to the Product Specification File. It is also recommended to retain samples until finalisation of the clinical report from each period of the clinical testing in order to be able to confirm product identity in case of inconsistent study results.

The chapter on Release of batches has been greatly modified: The description of the two stages of batch release has been deleted; instead this chapter deals with the obligations of the "Qualified Person" with respect to various scenarios (manufacture within the EU; product imported from a third country; with/without marketing authorisation in the EU, etc.) while referring to Directive 2001/20/EC. The assessment criteria for batch release by the "QP" are described in detail and illustrated in a table.

The chapter on Shipping regulates the transfer of investigational medicinal products from one trial site to another: On the basis of records of product history and storage conditions the "Qualified Person" must evaluate whether the product is suitable from the point of view of quality for such a transfer.

In the Complaints chapter the draft names the "Qualified Person" as the instance involved in the processing of a quality-related complaint and the relevant communication between the manufacturer or importer and sponsor.

Under Recalls and returns the draft requires that the retrieval procedure be agreed by the sponsor with the manufacturer or importer. In addition, the sponsor must ensure that they are informed about all recalls initiated by the manufacturer.

According to the chapter on Destruction in the draft Annex, the sponsor is also responsible for the destruction of returned investigational medicinal product. In contrast to the regulation in the current Annex, where the destruction of unused test samples takes place after completion of the final study report, in the new draft the destruction may not take place until after a corresponding reconciliation, separately for each trial site and each study trial phase, and clarification of any discrepancies in the reconciliation.

To obtain the draft of Annex 13 just download here. You will also find all other relevant Annexes there, e.g. Annex 16 ("Certification by a Qualified Person and Batch Release").

The manufacture of investigational medicinal products will be a major topic at the Education Course "EU-GMP and FDA Compliance in Pharmaceutical Development" in Madrid in October 2002.

Writer: 
Dr Gerhard Becker 
CONCEPT HEIDELBERG