SPECIFICATIONS AND CONTROL TESTS ON THE …

1 83_____3AQ11a nSPECIFICATIONS AND CONTROL TESTS ON THEFINISHED PRODUCTG uideline TitleSpecifications and CONTROL TESTS on the finished ProductLegislative basisDirective 75/318/EEC as amendedDate of first adoptionDecember 1991 Date of entry intoforceJune 1992 StatusLast revised 1991 Previous titles/otherreferencesControl of the finished product / III/3324/89 Additional NotesThis note for guidance concerns the application of Part 2,section E of the Annex to Directive 75/318/EEC asamended, with a view to the granting of a marketingauthorisation for a new medicinal ANALYSISAPPENDIX85_____3AQ11a nSPECIFICATIONS AND CONTROL TESTS ON THEFINISHED PRODUCTNote for guidance concerning the application of Part 2, section E of the Annex to Directive75/318/EEC as amended, for the purposes of granting a marketing glossary of terms used is included in an appendix to this characteristics covered by the specificationsQuality characteristics cover the following area: general characteristics of the pharmaceutical form, particularly pharmacotechnical;that is to say those characteristics, determined in general by physical TESTS with limitsof acceptance, relating to the product performance or handling ( hardness, friabilityof a conventional tablet); identification of the active substance(s); assay of active substances (and also for herbal medicines, quantitative determinationof the constituents with known therapeutic activity).

2 If necessary, identification and assay of the excipients such as: identification of colorants used, identification and assay of antimicrobial agents or antioxidant preservatives (withacceptance limits); purity TESTS (if necessary, the investigation of breakdown products, residual solvents orother process related impurities, microbial contamination); pharmaceutical TESTS ( dissolution); safety TESTS including abnormal or specific toxicity TESTS , where applicable, i nparticular for biological order to determine the SPECIFICATIONS of the finished product , the quality characteristicsrelated to the manufacturing process should be taken into appropriate specification for each aspect of quality studied during the phase ofdevelopment and during the validation of the manufacturing process should be least those aspects considered to be critical should be the object of SPECIFICATIONS Relationship between dossier SPECIFICATIONS and thePharmacopoeiaThe general provisions of the European Pharmacopoeia describe and define the content andlegal weight of the various sections of its monographs and general 3AQ11a_____Directive 75/318/EEC as amended recapitulates those aspects of quality which must be theobject of appropriate SPECIFICATIONS by referring to the general monographs of the

3 EuropeanPharmacopoeia or, failing this, to pharmacopoeias of Member monographs on medicinal products, the European or national pharmacopoeiaedefine the reference quality level. In the marketing authorisation application, the applicantshould determine the most appropriate means for reaching the stated objective, and supply theappropriate analytical validation data. In all cases, routine TESTS on the finished product atrelease follow the stipulations of section addition, as a result of the fact that these monographs correspond to regulatoryspecifications, they represent the limit values of medicinal product at the end of their shelflife (except for those provisions referring to production). The SPECIFICATIONS for release of thefinished product must comply with the criteria defined by Directive 75/318/EEC as amended, 5% for the assay of active substance(s) except when otherwise Relationships between the specification of a finished product atthe end of shelf life and at manufacture (at release)a )The aim of the application dossier for a marketing authorisation is to set the qualitylevel of the medicinal product as intended for marketing.

4 It establishes SPECIFICATIONS , qualitative and quantitative characteristics, with test procedures and acceptancelimits, with which the medicinal product must comply during its intended shelf Part II F of the dossier, the applicant proposes a shelf life for the medicinal productmainly on the basis of the level of active constituents (efficacy) and the admissiblelevel of any breakdown products or impurities (safety) and consistentpharmacotechnical properties. From the behaviour of the medicinal product theapplicant deduces the appropriate storage conditions which will maintain compliancewith the SPECIFICATIONS of the medicinal )The specification limits of the finished product at the time of batch release are set by themarketing authorisation applicant such that the SPECIFICATIONS proposed at the end ofshelf life are guaranteed; they are established on the basis of a critical detailed reviewof the data gathered from the batches analysed.

5 Nevertheless, acquired experience is afactor recognised to be very important in terms of good manufacturing practice. One ofthe basic requirements of GMP (see the Guide to GMP) is the systematic review of a l lmanufacturing processes in the light of experience. Thus, the applicant, in compliancewith Directive 65/65/EEC as amended, Article 9. a, shall adapt or refine thespecifications at release as a function of experience acquired by the manufacturer(s) ofthe medicinal )The SPECIFICATIONS of the finished product at manufacture may be different from thoseof the medicinal product at certain cases, for characteristics of the medicinal product which may change duringstorage under the approved conditions, the quality required at the end of shelf lifeshould be taken into account in determining appropriate SPECIFICATIONS at the time ofmanufacture, for example in the case of overages for reasons of is desirable that all SPECIFICATIONS (characteristics and acceptance limits)

6 Of themedicinal product and the finished product at the time of release be presented in the87_____3AQ11a nform of a summary table. In this table, the limits of any likely breakdown productswhich may form under the approved conditions of storage should be summary table could be presented as follows:SUMMARY PRESENTATION OF THE SPECIFICATIONS OF THE MEDICINALPRODUCT AND THE finished product (AT MANUFACTURE)Methods and Acceptance LimitsCharacteristicsof the medicinal product upto the end of shelf lifeof the finished product atrelease1. Characteristics of thepharmaceutical formIndicate with an asterisk the specification limits whichmay require updating in the light of experience acquiredafter the first n production batches2. Identification and assay ofactive constituents3.

7 Purity tests4. Excipient: Identificationfor example of colorants,preservatives, limit valuesof preservatives should be given of specification reference number and signature and date presentation of the complete series of SPECIFICATIONS does not affect the choice and thefrequency of the testing which will effectively be carried out on the finished product atmanufacture (or possibly on the bulk product or intermediate product ) (see ). SPECIFICATIONS and routine TESTS for the release of batches offinished product at the time of manufacture (at release) between validation of the manufacturing process, GMP andestablishment of specificationsThe compliance of each batch of finished product with its SPECIFICATIONS at manufactureshould be guaranteed by GMP (see Guide to GMP).

8 Nevertheless, those features of the batchdocumentation required by GMP may not be included in the marketing the marketing authorisation dossier, it must be shown that the manufacturing processused in compliance with GMP is capable of producing the finished product consistently i ncompliance with the SPECIFICATIONS chosen; these SPECIFICATIONS take into account: development studies described in Part II A 4 of the marketing authorisation dossier(see note for guidance Development Pharmaceutics and Process Validation ) which willhave led to the identification of the features of the formulation and the manufacturingprocess, which are essential for the quality of product ;88n 3AQ11a_____ the validation of critical steps in the manufacturing process described in Part III B 3 ofthe marketing authorisation dossier which enable scale up and batch reproducibility tobe TESTS and periodic testsDifferent types of TESTS may exist:a ) TESTS to be carried out batch by batch on the finished product or, possibly, on the bulkproduct;b) TESTS whose performance during a manufacturing step (intermediate products or in-process controls) will contribute a greater guarantee of finished product compliancethan their performance on the finished product or on the bulk product .

9 C )periodic TESTS (not carried out batch by batch on the finished product or, possibly on theintermediate product or bulk product ), where the frequency of performance is highlydependent on other parameters of GMP ( microbiological quality);d ) TESTS whose performance on the finished product or possibly on the bulk product atmanufacture can be replaced by the verification of another highly dependentspecification (for example replacement of the test for uniformity of mass with the testfor uniformity of content);e) TESTS which are not carried out routinely once the guarantees of compliance arefurnished by the manufacturer; these specific cases are exceptional ( identificationof colorants);f ) TESTS corresponding to critical points in the manufacturing process to be monitoredparticularly during the first n production batches and temporarily in the course ofany substantial modification (for example changing the manufacturing site,materials, etc.

10 Subsequently, as a function of acquired experience and especiallyvalidation of the production process, their batch by batch performance can be omitted( residual solvents).There may exist situations other than those described for verifying specificationsAs a function of the conclusions of parts II A 4 and II B 3, the dossier must clearly indicatethe individual TESTS to be carried out for the release of the finished product and state whetherthey are done routinely on each batch of finished product , or indicate the periodicity of testing(batch by batch, every n batches, the first n batches etc.).Two cases are possible depending upon whether or not the products are known and for whichthe manufacturer has available substantial production the first case, for example a new dosage strength of an already authorised product , or anew conventional formulation (solution, compressed tablet etc.)