53 The Sponsor is responsible for the destruction of unused and/or returned investigational medicinal products. Investigational medicinal products should therefore not be destroyed without prior written authorisation by the Sponsor.
54 The delivered, used and recovered quantities of product should be recorded, reconciled and verified by or on behalf of the Sponsor for each trial site and each trial period. Destruction of unused investigational medicinal products should be carried out for a given trial site or a given trial period only after
any discrepancies have been investigated and satisfactorily explained and the reconciliation has been accepted. Recording of destruction operations should be carried out in such a manner that all operations may be accounted for. The records should be kept by the Sponsor.
55 When destruction of investigational medicinal products takes place a dated certificate of, or receipt for destruction, should be provided to the Spon-sor. These documents should clearly identify, or allow traceability to, the batches and/or patient numbers involved and the actual quantities destroyed.
Summary
Table 1 of labelling details (§26 to 30) (a) name, address and telephone number of the sponsor, contract research organisation or
investigator (the main contact for information on the product, clinical trial and emergency unblinding)
GENERAL CASE For both the outer packaging and immediate container (§26) (b) pharmaceutical dosage form, route of
administration, quantity of dosage units, and in the case of open trials, the name/identifier and strength/potency;
(c) the batch and/or code number to identify the contents and packaging operation;
Particulars a1 to k
(d) a trial reference code allowing identification of the trial, site, investigator and sponsor if not given elsewhere;
(e) the trial subject identification number/treatment number and where relevant, the visit number;
(f) the name of the investigator (if not included in (a) or (d));
IMMEDIATE CONTAINER Where immediate container and outer packaging remain together
(§29)5 (g) directions for use (reference may be made to a
leaflet or other explanatory document intended for
the trial subject or person administering the product); a2 b3 c d e (h) “for clinical trial use only” or similar wording;
(i) the storage conditions;
(j) period of use (use-by date, expiry date or re-test date as applicable), in month/year format and in a manner that avoids any ambiguity;
IMMEDIATE CONTAINER Blisters or small packaging units (§30)5 (k) “keep out of reach of children” except when the
product is for use in trials where the product is not taken home by subjects.
a2 b3,4 c d e
1The address and telephone number of the main contact for information on the product, clinical trial and for emergency unblinding need not appear on the label where the subject has been given a leaflet or card which provides these details and has been instructed to keep this in their possession at all times (§27).
2The address and telephone number of the main contact for information on the product, clinical trial and for emergency unblinding need not be included.
3Route of administration may be excluded for oral solid dose forms.
4The pharmaceutical dosage form and quantity of dosage units may be omitted.
5When the outer packaging carries the particulars listed in Article 26.
throughout
Batch release of products
TS TO BE TAKEN INTO ACCOUNT(3)PRODUCT AVAILABLE IN THE EUPRODUCT IMPORTED FROM THIRD COUNTRIES
Product
manufacturedinEUwithout
MA Productwith
MAandavailableon
EU market Product
withoutanyEUMA Product
withaEUMA Comparatorwhere
documentationcertifyingthateachbatchhasbeen
manufacturedinconditionsatleastequivalenttothoselaid
downinDirective91/356/EECcannotbeobtained
E CLINICAL TRIAL PROCESSING
andstorageconditionsYes
(1)showingthateachbatchhasbeenmanufacturedandreleasedinwith:Yes(2) 91/356/EEC,or–Yes
andardsatleastequivalenttothoselaiddowninDirective91/356/EEC.
ationshowingthateachbatchhasbeenreleasedwithintheEUaccordingtoEUGMP(seeDirective2001/83/EC,article51),ordocumentationshowingthattheproductisontheEUmarketandhasbeenprocuredinaccordancewitharticle80(b)ofDirectiveEC. Yes ationshowingthattheproductisavailableonthelocalmarketanddocumentationtoconfidenceinthelocalregulatoryrequirementsformarketingauthorisationandrelease Yes
ofallanalysis,testsandchecksperformedtoassessthequalityoftheimportedbatchto:
oftheMA(seeDirective2001/83/EC,article51b),or–Yes–
SpecificationFile,theOrder,article9.2submissiontotheregulatoryauthorities.Yes–Yes
analysesandtestsarenotperformedintheEU,thisshouldbejustifiedandtheQPthattheyhavebeencarriedoutinaccordancewithGMPstandardsatleastequivalentlaiddowninDirective91/356/EEC. YesYesYes
LINICAL TRIAL PROCESSING
totheassessmentbeforeclinicaltrialprocessing,allfurtherrelevantfactors(1)thateachbatchhasbeenprocessedforthepurposesofblinding,trial-specificpackaging,andtestinginaccordancewith:
91/356/EEC, orYes(2)
andardsatleastequivalenttothoselaiddowninDirective91/356/EEC.–Yes
factorsaresummarisedinparagraph40.anMRAorsimilararrangementsareinplacecoveringtheproductsinquestion,equivalentstandardsofGMPapply.casestheinformationnotifiedpursuanttoArticle9(2)ofDirective2001/20/ECshouldbeconsistentwiththeelementsactuallytakenintoaccountbytheQPwhocertifiesthebatchpriortorelease.
ANNEX 14 MANUFACTURE OF MEDICINAL1 PRODUCTS DERIVED FROM HUMAN BLOOD OR PLASMA
Principle
In accordance with Directive 75/318/EEC2, for biological medicinal prod-ucts derived from human blood or plasma, starting materials include the source materials such as cells or fluids including blood or plasma. Medic-inal products derived from human blood or plasma have certain special features arising from the biological nature of the source material. For example, disease-transmitting agents, especially viruses, may contaminate the source material. The safety of these products relies therefore on the control of source materials and their origin as well as on the subsequent manufacturing procedures, including virus removal and inactivation.
The general chapters of the guide to GMP apply to medicinal products derived from human blood or plasma, unless otherwise stated. Some of the Annexes may also apply, e.g. manufacture of sterile medicinal prod-ucts, use of ionising radiation in the manufacture of medicinal prodprod-ucts, manufacture of biological medicinal products and computerised systems.
Since the quality of the final products is affected by all the steps in their manufacture, including the collection of blood or plasma, all operations should, therefore, be done in accordance with an appropriate system of Quality Assurance and current Good Manufacturing Practice.
By virtue of Directive 89/381/EEC, the necessary measures shall be taken to prevent the transmission of infectious diseases and the requirements and standards of the European Pharmacopoeia monographs regarding plasma for fractionation and medicinal products derived from human blood or plasma shall be applicable. These measures shall also comprise the Coun-cil Recommendation of 29 June 1998 “On the suitability of blood and plasma donors and the screening of donated blood in the European Com-munity3(98/463/EC), the recommendations of the Council of Europe (see
1 Council Directive 89/381/EEC of 14 June 1989 extending the scope of Directives 65/65/EEC and 75/319/EEC on the approximation of provisions laid down by law, regulation or administrative action relating to proprietary medicinal prod-ucts and laying down special provisions for medicinal prodprod-ucts derived from human blood or human plasma (OJ No L 181 of 28.6.1989).
2 Council Directive 75/318/EEC, of 20 May 1975, on the approximation of the laws of Member States relating to analytical, pharmacotoxicological and clinical standards and protocols in respect of the testing of medicinal products (OJ No L 147 of 9.6.1975, p. 1) as last amended by Council Directive 93/39/EEC (OJ No L 214 of 24.8.1993, p. 22).
3 O.J. L 20321.7.1998 p. 14.
I III
“Guide to the Preparation, Use and Quality Assurance of Blood Com-ponents”, Council of Europe Press) and the World Health Organization (see report by the WHO Expert Committee on Biological Standardisation, WHO Technical Report Series 840, 1994).
This annex should also be read in conjunction with the guidelines adopted by the CPMP, in particular “Note for guidance on plasma-derived medicinal products (CPMP/BWP/269/95 rev.2)”, “Virus validation studies:
the design, contribution and interpretation of studies validating the inacti-vation and removal of viruses” published in Volume 3A of the series “The Rules Governing Medicinal Products in the European Community”) and
“Contribution to part II of the structure of the dossier for applications for marketing authorisation-control of starting materials for the production of blood derivatives”(III/5272/94).
These documents are regularly revised and reference should be made to the latest revisions for current guidance.
The provisions of this annex apply to medicinal products derived from human blood and plasma. They do not cover blood components used in transfusion medicine, since these are presently not covered by EC directives.
However many of these provisions may be applicable to such components and competent authorities may require compliance with them.