Guideline on the requirements for quality …

1 See websites for contact detailsEuropean Commission Directorate-General for Health & Consumers Medicines Agency European Union, 2012. Reproduction is authorised provided the source is March 2012 EMA/CHMP/BWP/534898/ 2008 Committee for Medicinal Products for Human Use (CHMP) Guideline on the requirements for quality documentation concerning biological investigational medicinal products in clinical trialsDraft Agreed by Biologic Working PartyJanuary 2010 Adoption by Committee for Medicinal Products for Human Use for release for consultation18 February 2010 Start of public consultation28 February 2010 End of consultation (deadline for comments)31 August 2010 Agreed by Biologic Working Party7 March 2012 Adoption by Committee for Medicinal Products for Human Use15 March 2012 Date for coming into effect15 April 2012 KeywordsBiological product, investigational medicinal product (IMP)

2 , clinical trial, qualityGuidelineon the requirementsfor qualitydocumentationconcerningbiological investigationalmedicinalproductsin clinicaltrialsEMA/CHMP/BWP/534898/ 2008 Page 2/17 Guideline on the requirements for quality documentation concerning biological investigational medicinal products in clinical trialsTable of contents1. Introduction (background)..32. Information on the biological, chemical and pharmaceutical quality concerning biological investigational medicinal products in clinical Active of the active standards or closure Investigational medicinal product under and composition of the investigational medicinal of of the investigational medicinal standards or closure and agents safety for reconstitution and Substantial the requirementsfor qualitydocumentationconcerningbiological investigationalmedicinalproductsin clinicaltrialsEMA/CHMP/BWP/534898/ 2008 Page 3/171.

3 Introduction (background)The "Detailed guidance on the request to the competent authorities for authorisation of a clinical trial on a medicinal product for human use, the notification of substantial amendments and the declaration of the end of the trial 1 ('detailed guidance CT-1 ) sets out the requirements as regards data related to an investigational medicinal product (IMP) to be submitted with the request for a clinical trial authorisation in the IMP Dossier (IMPD).This Guideline addresses the specific documentation requirements on the biological, chemical and pharmaceutical quality of IMP containing biological / biotechnology derived substances in cases where no 'simplified IMPD' is submitted (see section of the detailed guidance CT-1).Moreover, this Guideline lists, as regards documentation on the biological, chemical and pharmaceutical quality of the IMP, examples of amendments which are typically considered as 'substantial' (see section 3 of the detailed guidance CT-1).

4 The guidance outlined in this document applies to proteins and polypeptides, their derivatives, and products of which they are components ( conjugates). These proteins and polypeptides are produced from recombinant or non-recombinant cell-culture expression systems and can be highly purified and characterised using an appropriate set of analytical procedures. The principles may also apply to other product types such as proteins and polypeptides isolated from tissues and body fluids. 2. Information on the biological, chemical and pharmaceutical quality concerning biological investigational medicinal products in clinical trialsSActive substanceReference to an Active Substance Master File or a Certificate of Suitability (CEP) of the European Directorate for the quality of Medicines is neither acceptable nor applicable for biological / biotechnological active concerning the nomenclature of the active substance ( proposed INN-name, pharmacopoeial name, proprietary name, company code, other names or codes, if any) should be brief description of the predicted structure should be provided.

5 Higher order structure, schematic amino acid sequence indicating glycosylation sites or other post-translational modifications and relative molecular mass should be included, as appropriate. 1 OJ C82, , p. the requirementsfor qualitydocumentationconcerningbiological investigationalmedicinalproductsin clinicaltrialsEMA/CHMP/BWP/534898/ 2008 Page 4 General propertiesA list of physico-chemical and other relevant properties of the active substance should be provided including biological activity ( the specific ability or capacity of a product to achieve a defined biological effect). The proposed mechanism of action should be (s)The name(s) and address(es) and responsibilities of each manufacturer, including contractors, and each proposed production site or facility involved in manufacture, testing and batch release should be of manufacturing process and process controlsThe manufacturing process and process controls should be adequately described.

6 The manufacturing process typically starts with a vial(s) of the cell bank and includes cell culture, harvest(s), purification, modification reactions and filling. Storage and shipping conditions should be flow chart of all successive steps including in-process-testing should be given. The results of in-process testing may be recorded as action limits or reported as preliminary acceptance criteria. During development, as process knowledge is gained, further detail of in-process testing and the criteria should be provided and acceptance criteria reviewed. Batch(es) and scale should be defined, including information on any pooling of harvests or reprocessing during manufacture of the active substance ( filter integrity test failure) should be described and of materialsRaw and starting materialsMaterials used in the manufacture of the active substance ( raw materials, starting materials, cell culture media, growth factors, column resins, solvents, reagents) should be listed identifying where each material is used in the process.

7 Reference to quality standards ( compendial monographs or manufacturer's in-house specifications) should be made. Information on the quality and control of non-compendial materials should be provided. Information demonstrating that materials (including biologically-sourced materials, media components, monoclonal antibodies, enzymes) meet standards applicable for their intended use should be provided, as all raw materials of biological origin (including those used in the cell bank generation), the source and the respective stage of the manufacturing process where the material is used should be indicated. Summaries of adventitious agents safety information for biologically-sourced materials should be provided in Appendix the requirementsfor qualitydocumentationconcerningbiological investigationalmedicinalproductsin clinicaltrialsEMA/CHMP/BWP/534898/ 2008 Page 5/17 Source, history and generation of the cell substrateA summarised description of the source and generation (flow chart of the successive steps) of the cell substrate, analysis of the expression vector used to genetically modify the cells and incorporated in the parental / host cell used to develop the Master Cell Bank (MCB)

8 , and the strategy by which the expression of the relevant gene is promoted and controlled in production should be provided, following the principles of CPMP/ICH Guideline bank system, characterisation and testingA MCB should be established prior to the initiation of phase I trials. It is acknowledged that a Working Cell Bank (WCB) may not always be on the generation, qualification and storage of the cell banks is required. The MCB and/or WCB should be characterised and results of tests performed should be provided. The generation and characterisation of the cell banks should be performed in accordance with principles of CPMP/ICH Guideline banks should be characterised for relevant phenotypic and genotypic markers so that the identity, viability, and purity of cells used for the production are ensured. Nucleic acid sequence of the expression cassette including sequence of the coding region should be confirmed prior to the initiation of clinical safety assessment for adventitious agents and qualification of the cell banks used for the production of the active substance should be provided in , if substrate stabilityAny available data on cell substrate stability should be of critical steps and intermediatesTests and acceptance criteria for the control of critical steps in the manufacturing process should be provided.

9 It is acknowledged that due to limited data at an early stage of development (phase I/II) complete information may not be available. Hold times and storage conditions for process intermediates should be justified and supported by data, as validation and /or evaluationProcess validation / evaluation data should be collected throughout the development, although they are not required to be submitted in the manufacturing steps intended to remove or inactivate viral contaminants, the relevant information should be provided in the section A2, Adventitious agents safety the requirementsfor qualitydocumentationconcerningbiological investigationalmedicinalproductsin clinicaltrialsEMA/CHMP/BWP/534898/ 2008 Page 6 process developmentProcess improvement Manufacturing processes and their control strategies are continuously being improved and optimised,especially during the development phase and early phases of clinical trials.

10 These improvements and optimisations are considered as normal development work, and should be appropriately described in the submitted dossier. Changes to the manufacturing process and controls should be summarized and the rationale for changes should be presented. This description should allow a clear identification of the process versions used to produce each batch used in non-clinical and clinical studies, in order to establish an appropriate link between pre-change and post-change batches. Comparative flow charts and/or list of process changes may be used to present the process evolution. Process modifications may require adaptation of in-process and release tests, and thus these tests and corresponding acceptance criteria should be reconsidered when changes are introduced. Comparability exerciseDepending on the consequences of the change introduced and the stage of development, a comparability exercise may be necessary to ensure that the change would not have an adverse impact on clinical characteristics of the product.