Changes from plenary report to adopted text

AddedControl of Excipients

Added— Specifications

Added— Analytical Procedures

Added— Validation of Analytical Procedures

Added— Justification of Specifications

Added— Excipients of Human or Animal Origin

Added— Novel Excipients

AddedControl of Finished Medicinal Product

Added— Specification(s)

Added— Analytical Procedures

Added— Validation of Analytical Procedures

Added— Batch Analyses

Added— Characterisation of Impurities

Added— Justification of Specification(s)

AddedReference Standards or Materials

AddedContainer Closure System

AddedStability

Added— Stability Summary and Conclusion

Added— Post-approval Stability Protocol and Stability Commitment

Added— Stability Data

Added— Appendices

Added— Facilities and Equipment (Biological Medicinal Products only)

Added— Adventitious Agents Safety Evaluation

Added— Excipients

Added— European Community Additional Information

Added— Process Validation Scheme for the Medicinal Product

Added— Medical Device

Added— Certificate(s) of Suitability

Added— Medicinal products containing or using in the manufacturing process materials of animal and/or human origin (TSE procedure)

Added— Literature References

Added3.2. Content: basic principles and requirements

Added(1) The chemical, pharmaceutical and biological data that shall be provided shall include for the active substance(s) and for the finished medicinal product all of relevant information on: the development, the manufacturing process, the characterisation and properties, the quality control operations and requirements, the stability as well as a description of the composition and presentation of the finished medicinal product.

Added(2) Two main sets of information shall be provided, dealing with the active substance(s) and with the finished medicinal product, respectively.

Added(3) This Module shall in addition supply detailed information on the starting and raw materials used during the manufacturing operations of the active substance(s) and on the excipients incorporated in the formulation of the finished medicinal product.

Added(4) All the procedures and methods used for manufacturing and controlling the active substance and the finished medicinal product shall be described in sufficient details to enable them to be repeated in control tests, carried out at the request of the competent authority. All test procedures shall correspond to the state of scientific progress at the time and shall be validated. Results of the validation studies shall be provided. In the case of test procedures included in the European Pharmacopoeia, this description shall be replaced by the appropriate detailed reference to the monograph(s) and general chapter(s).

Added(5) The monographs of the European Pharmacopoeia shall be applicable to all substances, preparations and pharmaceutical forms appearing in it. In respect of other substances, each Member State may require observance of its own national pharmacopoeia.

AddedHowever, where a material in the European Pharmacopoeia or in the pharmacopoeia of a Member State has been prepared by a method liable to leave impurities not controlled in the pharmacopoeia monograph, these impurities and their maximum tolerance limits must be declared and a suitable test procedure must be described. In cases where a specification contained in a monograph of the European Pharmacopoeia or in the national pharmacopoeia of a Member State might be insufficient to ensure the quality of the substance, the competent authorities may request more appropriate specifications from the marketing authorisation holder. The competent authorities shall inform the authorities responsible for the pharmacopoeia in question. The marketing authorisation holder shall provide the authorities of that pharmacopoeia with the details of the alleged insufficiency and the additional specifications applied.

AddedIn the case of analytical procedures included in the European Pharmacopoeia, this description shall be replaced in each relevant section by the appropriate detailed reference to the monograph(s) and general chapter(s).

Added(6) In case where starting and raw materials, active substance(s) or excipient(s) are described neither in the European Pharmacopoeia nor in the pharmacopoeia of a Member State, compliance with the monograph of a third country pharmacopoeia can be accepted. In such cases, the applicant shall submit a copy of the monograph accompanied by the validation of the analytical procedures contained in the monograph and by a translation where appropriate.

Added(7) Where the active substance and/or a raw and starting material or excipient(s) are the subject of a monograph of the European Pharmacopoeia, the applicant can apply for a certificate of suitability that, where granted by the European Directorate for the Quality of Medicines, shall be presented in the relevant section of this Module. Those certificates of suitability of the monograph of the European Pharmacopoeia are deemed to replace the relevant data of the corresponding sections described in this Module. The manufacturer shall give the assurance in writing to the applicant that the manufacturing process has not been modified since the granting of the certificate of suitability by the European Directorate for the Quality of Medicines.

Added(8) For a well-defined active substance, the active substance manufacturer or the applicant may arrange for the

Added(i) detailed description of the manufacturing process,

Added(ii) quality control during manufacture, and

Added(iii) process validation

Addedto be supplied in a separate document directly to the competent authorities by the manufacturer of the active substance as an Active Substance Master File.

AddedIn this case, the manufacturer shall, however, provide the applicant with all of the data, which may be necessary for the latter to take responsibility for the medicinal product. The manufacturer shall confirm in writing to the applicant that he shall ensure batch to batch consistency and not modify the manufacturing process or specifications without informing the applicant. Documents and particulars supporting the application for such a change shall be supplied to the competent authorities; these documents and particulars will be also supplied to the applicant when they concern the open part of the active substance master file.

Added(9) Specific measures concerning the prevention of the transmission of animal spongiform encephalopathies (materials from ruminant origin): at each step of the manufacturing process, the applicant must demonstrate the compliance of the materials used 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. Demonstration of compliance with the said Note for Guidance can be done by submitting either, preferably a certificate of suitability to the relevant monograph of the European Pharmacopoeia that has been granted by the European Directorate for the Quality of Medicines or by the supply of scientific data to substantiate this compliance.

Added(10) For adventitious agents, information assessing the risk with respect to potential contamination with adventitious agents, whether they are non-viral or viral, as laid down in relevant guidelines as well as in relevant general monograph and general chapter of the European Pharmacopoeia, shall be provided.

Added(11) Any special apparatus and equipment, which may be used at any stage of the manufacturing process and control operations of the medicinal product, shall be described in adequate details.

Added(12) Where, in accordance with the second subparagraph of Article 1(8) or the second subparagraph of Article 1(9) of Regulation (EU) 2017/745 of the European Parliament and of the Council (), a product is governed by this Directive, the marketing authorisation dossier shall include, where available, the results of the assessment of the conformity of the device part with the relevant general safety and performance requirements set out in Annex I to that Regulation contained in the manufacturer's EU declaration of conformity or the relevant certificate issued by a notified body allowing the manufacturer to affix a CE marking to the medical device.

AddedIf the dossier does not include the results of the conformity assessment referred to in the first subparagraph and where for the conformity assessment of the device, if used separately, the involvement of a notified body is required in accordance with Regulation (EU) 2017/745, the authority shall require the applicant to provide an opinion on the conformity of the device part with the relevant general safety and performance requirements set out in Annex I to that Regulation issued by a notified body designated in accordance with that Regulation for the type of device in question.

Added3.2.1 Active substance(s)

Added3.2.1.1. G e n e r a l i n f o r m a t i o n a n d i n f o r m a t i o n r e l a t e d t o t h e

Addeds t a r t i n g a n d r a w m a t e r i a l s

Addeda) Information on the nomenclature of the active substance shall be provided, including recommended International Non-proprietary Name (INN), European Pharmacopoeia name if relevant, chemical name(s).

AddedThe structural formula, including relative and absolute stereo-chemistry, the molecular formula, and the relative molecular mass shall be provided. For biotechnological medicinal products if appropriate, the schematic amino acid sequence and relative molecular mass shall be provided.

AddedA list shall be provided of physicochemical and other relevant properties of the active substance, including biological activity for biological medicinal products.

Addedb) For the purposes of this Annex, starting materials shall mean all the materials from which the active substance is manufactured or extracted.

AddedFor biological medicinal products, starting materials shall mean any substance of biological origin such as micro-organisms, organs and tissues of either plant or animal origin, cells or fluids (including blood or plasma) of human or animal origin, and biotechnological cell constructs (cell substrates, whether they are recombinant or not, including primary cells).

AddedA biological medicinal product is a product, the active substance of which is a biological substance. A biological substance is a substance that is produced by or extracted from a biological source and that needs for its characterisation and the determination of its quality a combination of physico-chemical-biological testing, together with the production process and its control. The following shall be considered as biological medicinal products: immunological medicinal products and medicinal products derived from human blood and human plasma as defined, respectively in paragraphs (4) and (10) of Article 1; medicinal products falling within the scope of Part A of the Annex to Regulation (EEC) No 2309/93; advanced therapy medicinal products as defined in Part IV of this Annex.