New Draft of Annex 13 - Manufacture of Investigational Medicinal Products

GMP News No. 177

GMP News
8 March 2002

 NewDraft of Annex 13 – 
Manufacture of Investigational Medicinal Products

In November 2001 the EC Commission published a revised version of Annex 13of the GMP Guide. Industry and authorities are requested to comment onthis draft by 1 May 2002.

The purpose of revising this annex is totake better account of the complex processes involved in the manufactureof investigational medicinal products and to confront the resultantspecial risks by means of detailed regulations. The additional risks inthe area of the manufacture of investigational products are described inthe preamble; there are as a rule no fixed routines in the manufacturingprocess, clinical trial designs vary, different batches consist of smallnumbers, complex packaging, labelling and blinding procedures must takeplace within a short time or even simultaneously. All this requiresspecial attention in all areas to GMP conformity by personnel withespecially thorough training. These enhanced requirements are reflected inthe revision of Annex 13 in the form of some quite strict regulations.These regulations require considerable additional organisational inputs bythe industry, and therefore distinct resistance and modificationsuggestions are to be expected from this quarter.

The most important additions andmodifications in comparison with the previously valid Annex 13 are listedbelow.

The chapter on Quality management requiresthat premises and equipment be fullyqualified. Other requirements are:

  • In the validation of asepticprocesses whenever possible in the case of small batch sizes alarger number of units should be filled with media than usual,in order to obtain results of greater statistical confidence.
  • As regards the operationsin aseptic manufacturing often performed manually orsemi-automatically in the case of small batch sizes enhancedattention should be given to operator training, and validating theaseptic technique of individual operators. The reference in thecurrent Annex 13 to increased environmental monitoring in case ofmanual filling and sealing was deleted from the draft since this formspart of such a validation.

Section 3 of the currently valid Annex13, which refers to the critical operations of packaging and labelling inconnection with the error-free execution of the clinical trial and toself-inspection or independent audits was completely deleted from the newdraft. However, the subsequent sections "Packaging" and"Labelling" deal with the quality assurance measures in detail.

The chapters Personnel, Premises andEquipment do not mention the "responsible person", as didthe previous Annex, but the "QualifiedPerson" as the person responsible for the compliance with thespecial requirements in the manufacture of the investigational medicinalproducts. The "QP" is required to have abroad knowledge of clinical trial processes. Their function isdefined in later sections with reference to Annex 16.

In the draft the passage requiring thatinvestigational medicinal products and other medicinal products possiblybe manufactured simultaneously in the same premises was deleted andinstead the requirement for a stringent cleaningprogram for the strict prevention ofcross-contamination was formulated even more firmly since the risksof a toxic or highly effective substance cannot be reliably evaluated inthis 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 orrefer to.

The purpose of this file is described indetail and the "Qualified Person"is mentioned who must have access to the PSF as thebasis for assessment of the suitability for release and certification of aparticular batch. The information contained in the PSF must betaken into account in the drawing up of all important work instructions.

The chapter on Packaging instructions requiresexpressly with a view to the complicated procedures in the manufacture ofinvestigational medicinal products that reconciliationsshould take place for each product and each production stage inorder to ensure that the correct quantities of the various testpreparations have been manufactured. The previous Annex 13 contains onlythe requirement for reconciliation at the end of the packaging andlabelling processes.

Packaging materialsis the title of the section inserted in the draft before the item"Manufacturing operations" which requires specialquality control checks for a homogeneous appearance of the packs inorder to prevent unintentional unblinding due to a visible differencebetween the placebo and the active medication packs.

It is expressly pointed out in thechapter on Manufacturing operations that the productionparameters and the corresponding in-processcontrols must be deduced from the knowledgeactually available at the time, based on experience from earlierstages of development, i.e. they are to be carefully considered in thisrespect.

If no stability data is available for thecomparator product packed into the clinical sample pack the valid Annex 13requires in the chapter "Principles applicable to comparatorproduct" that the corresponding expiry date exceed the periodbetween the repackaging operation and the expiry date of the original bulkpack by not more than 25% and not more than 6 months beyond the time ofrepackaging, whichever is the first to occur. This regulation has beendeleted from the draft Annex and no provision has been inserted to replaceit. Instead, the expiry date given on theclinical sample packaging may not exceed that givenon the original packaging at all and must bejustified, whereby the characteristics of the product, of theprimary packaging and of the storage conditions are to be taken intoaccount.

The process of blindingthe test preparation, comparator product and placebo must be completelyidentifiable. Here the identificationof the product history is expressly required in the draft in thechapters Blinding; Randomisation code in addition to the reliableproduct identification required in the existing Annex.

The requirements for the randomisationprocedure are also more strictly formulated: in addition, safety aspectsand the procedure for breaking the code mustbe described in the corresponding procedures.

The section on the risks of product mixup in the case of simultaneous packaging of different preparations - foundin the current Annex under "Premises and Equipment"– is foundin the section on Packaging in the draft with the additionalreference to relevant staff training in orderto reduce this risk. The subsequent sections name additionalin-process controls by operators and supervisory staff asprecautions against mislabelling.Furthermore, the packaging is to be designed so that any manipulation byunauthorised persons during transport is immediately recognisable.

The chapter on Labelling is muchmore detailed in the draft; at the same time the catalogue of requirementshas been expanded to include, e.g. name, address andtelephone number of the sponsor, contract research organisation or theprincipal contact for the clinical trial on the labels should thecode need to be broken in case of an emergency.

Relabellingmust be carried out at the manufacturing site;only if this is not possible or if the trial is interrupted may this alsotake place at the clinical trial site, but in any case subject to strictobservation of the GMP principles.

In two additional sections it is definedonce again which of the obligatory particulars must appear explicitly onthe secondary packaging and which may be given there in encoded, butrapidly identifiable form. The address and telephone number and the dosageinstructions (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 controlthe criteria for QC were replaced with the reference to the ProductSpecification File. It is also recommended to retainsamples until finalisation of the clinical report from each periodof the clinical testing in order to be able to confirm product identity incase of inconsistent study results.

The chapter on Release of batcheshas been greatly modified: The description of the two stages of batchrelease has been deleted; instead this chapter deals with the obligationsof 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 toDirective 2001/20/EC. The assessment criteria forbatch release by the "QP" are described in detail andillustrated in a table.

The chapter on Shipping regulatesthe transfer of investigational medicinal productsfrom one trial site to another: On the basis of records of product historyand storage conditions the "Qualified Person" must evaluatewhether the product is suitable from the point of view of quality for sucha transfer.

In the Complaints chapter thedraft names the "Qualified Person" as the instance involved inthe processing of a quality-related complaint and the relevantcommunication between the manufacturer or importer and sponsor.

Under Recalls and returns thedraft requires that the retrieval procedure beagreed by the sponsor with the manufacturer orimporter. In addition, the sponsor must ensure that they areinformed about all recalls initiated by the manufacturer.

According to the chapter on Destructionin the draft Annex, the sponsor is also responsible for the destruction ofreturned investigational medicinal product. In contrast to the regulationin the current Annex, where the destruction of unused test samples takesplace after completion of the final study report, in the new draft the destructionmay not take place until after acorresponding reconciliation, separately for eachtrial site and each study trial phase, and clarificationof 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 BatchRelease").


Dr Gerhard Becker 



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