Changes from plenary report to adopted text

Added3.2.2.3. M a n u f a c t u r i n g p r o c e s s o f t h e f i n i s h e d m e d i c i n a l p r o d u c t

Addeda) The description of the manufacturing method accompanying the application for Marketing Authorisation pursuant to Article 8 (3) (d), shall be drafted in such a way as to give an adequate synopsis of the nature of the operations employed.

AddedFor this purpose it shall include at least:

Added— mention of the various stages of manufacture including process controls and corresponding acceptance criteria, so that an assessment can be made of whether the processes employed in producing the pharmaceutical form might have produced an adverse change in the constituents,

Added— in the case of continuous manufacture, full details concerning precautions taken to ensure the homogeneity of the finished product,

Added— experimental studies validating the manufacturing process, where a non-standard method of manufacture is used or where it is critical for the product,

Added— for sterile medicinal products, details of the sterilisation processes and/or aseptic procedures used,

Added— a detailed batch formula.

AddedThe name, address, and responsibility of each manufacturer, including contractors, and each proposed production site or facility involved in manufacturing and testing shall be provided.

Addedb) Particulars relating to the product control tests that may be carried out at an intermediate stage of the manufacturing process, with a view to ensuring the consistency of the production process shall be included.

AddedThese tests are essential for checking the conformity of the medicinal product with the formula when, exceptionally, an applicant proposes an analytical method for testing the finished product which does not include the assay of all the active substances (or of all the excipient constituents subject to the same requirements as the active substances).

AddedThe same applies where the quality control of the finished product depends on in-process control tests, particularly if the medicinal product is essentially defined by its method of preparation.

Addedc) Description, documentation, and results of the validation studies for critical steps or critical assays used in the manufacturing process shall be provided.

Added3.2.2.4. C o n t r o l o f e x c i p i e n t s

Addeda) All the materials needed in order to manufacture the excipient(s) shall be listed identifying where each material is used in the process. Information on the quality and control of these materials shall be provided. Information demonstrating that materials meet standards appropriate for their intended use shall be provided.

AddedColouring matter shall, in all cases, satisfy the requirements of Directives 78/25/EEC and/or 94/36/EC. In addition, colouring matter shall meet purity criteria as laid down in Directive 95/45/EC, as amended.

Addedb) For each excipient, the specifications and their justifications shall be detailed. The analytical procedures shall be described and duly validated.

Addedc) Specific attention shall be paid to excipients of human or animal origin.

AddedRegarding the specific measures for the prevention of the Transmission of animal Spongiform Encephalopathies, the applicant must demonstrate also for excipients that the medicinal product is manufactured in accordance with the Note for Guidance on Minimising the Risk of Transmitting Animal Spongiform Encephalopathy Agents via Medicinal Products and its updates, published by the Commission in the Official Journal of the European Union.

AddedDemonstration of compliance with the aforementioned Note for Guidance can be done by submitting either preferably a certificate of suitability to the relevant monograph on Transmissible Spongiform Encephalopathies of the European Pharmacopoeia, or by the supply of scientific data to substantiate this compliance.

Addedd) Novel excipients:

AddedFor excipient(s) used for the first time in a medicinal product or by a new route of administration, full details of manufacture, characterisation, and controls, with cross references to supporting safety data, both non-clinical and clinical, shall be provided according to the active substance format previously described.

AddedA document containing the detailed chemical, pharmaceutical and biological information shall be presented. This information shall be formatted in the same order as the chapter devoted to Active Substance(s) of Module 3.

AddedInformation on novel excipient(s) may be presented as a stand-alone document following the format described in the former paragraphs. Where the applicant differs from the novel excipient manufacturer the said stand-alone document shall be made available to the applicant for submission to the competent authority.

AddedAdditional information on toxicity studies with the novel excipient shall be provided in Module 4 of the dossier.

AddedClinical studies shall be provided in Module 5.

Added3.2.2.5. C o n t r o l o f t h e f i n i s h e d m e d i c i n a l p r o d u c t

AddedFor the control of the finished medicinal product, a batch of a medicinal product is an entity which comprises all the units of a pharmaceutical form which are made from the same initial quantity of material and have undergone the same series of manufacturing and/or sterilisation operations or, in the case of a continuous production process, all the units manufactured in a given period of time.

AddedUnless there is appropriate justification, the maximum acceptable deviation in the active substance content of the finished product shall not exceed ± 5 % at the time of manufacture.

AddedDetailed information on the specifications, (release and shelf life) justification for their choice, methods of analysis and their validation shall be provided.

Added3.2.2.6. R e f e r e n c e s t a n d a r d s o r m a t e r i a l s

AddedReference preparations and standards used for testing of the finished medicinal product shall be identified and described in detail, if not previously provided in the section related to the active substance.

Added3.2.2.7. C o n t a i n e r a n d c l o s u r e o f t h e f i n i s h e d m e d i c i n a l p r o d u c t

AddedA description of the container and the closure system(s) including the identity of each immediate packaging material and their specifications shall be provided. The specifications shall include description and identification. Non-pharmacopoeial methods (with validation) shall be included where appropriate.

AddedFor non-functional outer packaging materials only a brief description shall be provided. For functional outer packaging materials additional information shall be provided.

Added3.2.2.8. S t a b i l i t y o f t h e f i n i s h e d m e d i c i n a l p r o d u c t

Addeda) The types of studies conducted, protocols used, and the results of the studies shall be summarised;

Addedb) Detailed results of the stability studies, including information on the analytical procedures used to generate the data and validation of these procedures shall be presented in an appropriate format; in case of vaccines, information on cumulative stability shall be provided where appropriate;

Addedc) The post authorisation stability protocol and stability commitment shall be provided.

Added4. MODULE 4: NON-CLINICAL REPORTS

Added4.1. Format and Presentation

AddedThe general outline of Module 4 is as follows:

Added— Table of contents

Added— Study reports

Added— Pharmacology

Added— Primary Pharmaco-dynamics

Added— Secondary Pharmaco-dynamics

Added— Safety Pharmacology

Added— Pharmaco-dynamic Interactions

Added— Pharmaco-kinetics

Added— Analytical Methods and Validation Reports

Added— Absorption

Added— Distribution

Added— Metabolism

Added— Excretion

Added— Pharmaco-kinetic Interactions (non-clinical)

Added— Other Pharmaco-kinetic Studies

Added— Toxicology

Added— Single-Dose Toxicity

Added— Repeat-Dose Toxicity