IMPD. The Investigational Medicinal Product Dossier IMPD S+P Part Do s and Don't s

Transcription

1 IMPD The Investigational Medicinal Product Dossier IMPD S+P Part Do s and Don't s 1 Joachim Ahlert YES Pharmaceutical Development Services GmbH Oberaegeri - 4 May 2012

2 Presentation outline Table of contents: Regulatory requirements and guidelines General requirements on the quality documentation of test preparations for the clinical Phases I - III Changes/Variations to the pharmaceutical quality of fthe IMPD Typical dos and don'ts 2

3 The Investigational Medicinal Product Dossier The Investigational Medicinal Product Dossier Regulatory Requirements: Based on Directive 2001/20/EC ( Clinical Trials Directive ) request for conducting a clinical trial (Art. 9.2) details on formats to be determined by EU Commission and Member States (Art. 9.8) Directive 2005/28/EC laying down principles and detailed guidelines for good clinical practice as regards investigational medicinal products for human use 3

4 Regulatory Requirements and Guidelines Regulatory Requirements (continued): European Commission The rules governing medicinal products in the European Union Volume 10: Clinical trials 10/index_en.htmen 4

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6 Regulatory Requirements and Guidelines Regulatory Requirements ( direct relevance on quality documentation): ti - European Commission - EudraLex The Rules Governing Medicinal i Products in the European Union Volume 4: Good Manufacturing Practices Annex 13: Investigational Medicinal Products Feb 2010, Brussels, ENTR/F/2/AM/an D(2010) 3374 EMEA / EMA / CHMP Guideline on the requirements to the chemical and pharmaceutical quality documentation concerning investigational medicinal products in clinical trials London, 31 March 2006, CHMP/QWP/185401/2004 final 6

7 Regulatory Requirements and Guidelines Communication from the Commission - Detailed guidance on the request to the competent authorities for authorisation of a clinical trial on a medicinal product for human use, notification of substantial amendments and declaration of the end of the trial CT 1, (2010/C 82/01) a) the format and contents of the request as well as the documentation to be submitted to support that request, on the quality and manufacture of the investigational medicinal product, b) the presentation and content of the proposed amendment c) the declaration of the end of the clinical trial.' 7 replaces Revision 2 from October 2005

8 IMPD - Detailed guidance (Chapter 2.7) 60. The IMP dossier (IMPD) gives information related to the quality of any IMP (i.e. including reference product and placebo), manufacture and control of the IMP, and data from non-clinical studies and from its clinical use. However, in many cases where the IMP has a marketing authorisation, ti an IMPD is not required [ ] Quality data should be submitted in a logical structure, such as the headings of the [ ] Guideline on the requirements to the chemical and pharmaceutical quality documents concerning IMPs in clinical trials (CHMP/QWP/185401/2004). This document also contains guidance for quality of placebos.

9 IMPD - Detailed guidance (Chapter 2.7.3) Simplified IMPD by referring to other documentation Possibility to refer to the IB for the preclinical i l and clinical i l parts of the IMPD (with exceptions) Possibility to refer to the SmPC in another clinical trials application i SmPC (or equivalent within ICH region) if an IMP has a marketing authorisation in EU or in an ICH country (Table 1) Cross-reference to a previous submission of the IMPD to the same Member State concerned by the same applicant or another applicant (letter of authorisation ti necessary) IMPD in cases of placebo Information on a placebo may also be provided as a simplified IMPD 9

10 Non-Investigational Medicinal Products (NIMPs) Further clarification and definition necessary, therefore: 10 European Commission - Volume 10: Guidance on Investigational Medicinal Products (IMPs) and 'Non-investigational Medicinal Products' (NIMPs) (Rev. 1, March 2011): Some medicinal products do not fall within the definition of IMPs as defined d of Dir. 2001/20/EC... and can be referred to as "non-investigational medicinal products" (NIMPs). E.g., some CT protocols require the use of concomitant or rescue/escape medication for preventive, diagnostic, therapeutic reasons and/or to ensure that adequate medical care is provided or may also be used to induce a physiological response. It is recommended that a sponsor uses NIMPs with MAs valid in the Member State concerned. If this is not possible, it is recommended that a NIMP with a MA in another Member State is used.

11 IMPD - Final overview of the documentation req. List of documentation to be provided to NCA Cover letter (Section 2.3) Clinical trial application form Protocol with the contents set out in Section 2.5 Investigator's Brochure (IB), or document replacing IB (as of Section 2.6) IMPD/simplified IMPD, as set out in Sections 2.7 and NIMP dossier as set out in Section 2.8 Additional information as set out in Section Copy of Ethics Committee opinion - Summary of scientific advice from Member State/Agency - Agency's Decision on the agreement on the PIP, if appl. - Content of the labelling of the IMP - Proof of payment for fees 11

12 IMPD - Quality Documentation - General EMEA / EMA / CHMP Guideline on the requirements to the chemical and pharmaceutical quality documentation concerning investigational medicinal products in clinical trials, CHMP/QWP/185401/2004 final London, 31 March 2006 The IMPD should give information to justify the quality of any IMP to be used in the clinical trial, including reference products and placebos. It should also provide data from non-clinical studies and the previous clinical use of the IMP or justify in the application why information is not provided

13 IMPD - Quality Documentation - General EMEA / CHMP Guideline on the requirements to the chemical and pharmaceutical quality documentation concerning investigational medicinal products in clinical trials London, 31 March 2006, CHMP/QWP/185401/2004 final 1. INTRODUCTION 1.1 Objectives of the Guideline... Since clinical trials will often be designed as multi-center studies, potentially involving different Member States, it is the aim of this guideline to define harmonised requirements for the documentation to be submitted throughout the European Community

14 IMPD - Quality Documentation - General EMEA Guideline on the requirements to chem./pharm. quality... (CHMP/QWP/185401/2004) (cont.) 1.2 Scope of the Guideline This guideline addresses the documentation on the chemical and pharmaceutical quality of IMPs containing chemically defined active substances, synthetic peptides, p herbal substances, herbal preparations and chemically defined radio-active/radio-labelled substances to be submitted to the competent authority for approval prior to beginning a clinical trial in humans. It includes the requirements for IMPs to be tested in phase I, phase II and phase III studies as well as the requirements for modified and unmodified comparator products and IMPs to be tested in generic bioequivalence studies [and placebo products] 14

15 IMPD (CHMP/QWP/185401/2004) The IMP dossier required will depend on many factors including: risk aspects nature of the product state of development patient population nature and severity of the illness type and duration of the clinical trial itself 15

16 IMPD - Quality Documentation - General General Remarks: - Structure similar to CTD structure of "Module 3 Quality", i.e. Module S (Drug Substance), P (Drug Product), A (Appendices) and R (?, Regional Information, e.g. Medical Device, CEP)? - A Quality Overall Summary (QOS, CTD Module 2.3) is not required. 16

17 IMPD - Quality Documentation - Contents EMEA Guideline on the requirements to chem./pharm. quality... (CHMP/QWP/185401/2004) (cont.) 2. Information on the Chemical and Pharmaceutical Quality Concerning Investigational Medicinal Products in Clinical Trials S DRUG SUBSTANCE 2.1.S.1 1 General Information P INVESTIGATIONAL MEDICINAL PRODUCT UNDER TEST 2.1.P.1 Description and Composition of the Investigational Medicinal Product... APPENDICES 2.1.A.1 Facilities and Equipment 2.1.A.2 2 Adventitious Agents Safety Evaluation... (CTD structure with identical wording of the headlines only deviation: "investigational medicinal product" instead of "drug product"

18 IMPD - Quality Documentation - Contents General Remarks: - Documentation on used API (according to "EMEA Guideline on the requirements...": - The suitability of the referenced pharmacopoeial monograph to adequately control the quality of the active substance (impurity profile) will have to be demonstrated. - Reference to an Active Substance Master File or a Certificate of Suitability (CEP) of the EDQM is acceptable. -For impurities in IMPs, a justification that the product is safe for its intended use, considering the anticipated exposure of volunteers and patients, respectively, will be required. - The difference between "analytical procedure" (refers to the way of performing the analysis) and "analytical method" (refers to the principles of the method used) should be kept in mind. 18

19 IMPD - Quality Documentation - Contents General Remarks (continued): For investigational medicinal products reference to a monograph of the Ph. Eur., another EU compendium, the USP or the JP is accepted. Exception: For test preparations in generic bioequivalence studies supporting an application within the EU, the Ph. Eur. requirements must be fulfilled. 19

20 IMPD - Quality Documentation - Contents General Requirements for Phase I - III test preparations: 2.1.S Drug Substance 2.1.S.1 General Information 2.1.S.1.1 Nomenclature (Proposed) INN, pharmacopoeial, IUPAC, lab code. 2.1.S.1.2 Structure As far as available: structural formula, molecular weight, chirality/ stereochemistry. 2.1.S.1.3 General Properties Physico-chemical chemical and other relevant properties, such as solubilities, pka, polymorphism, isomerism, log P, permeability etc. 20

21 IMPD - Quality Documentation - Contents General Requirements for Phase I - III test preparations (continued): S Drug Substance (continued) 2.1.S.2 Manufacture 2.1.S.2.1 Manufacturer(s) Name(s) and address(es) of all manufacturer(s), incl. contractors, site(s) of production involved in manufacture and testing. 2.1.S Description of Manufacturing Process and Process Controls Brief summary of synthesis process, flow chart incl. starting materials (stereochemistry), t intermediates, t solvents, catalysts, t critical reagents, relevant process controls, production scale, batch size. For substances complying with a monograph of the Ph. Eur., an EU Member State pharmacopoeia, the USP or JP, no further details are required.

22 IMPD - Quality Documentation - Contents General Requirements for Phase I - III test preparations (continued): 2.1.S Drug Substance (continued) 2.1.S.2 Manufacture (cont.) 2.1.S.2.3 Control of Materials Listing of materials used in the manufacture of the drug substance together with brief summary on the quality and control of any attributes anticipated to be critical e.g. where control is required to limit an impurity in the drug substance. 2.1.S.2.4 Control of Critical Steps and Intermediates In case of critical steps: brief summary of tests and acceptance criteria i for their control. 2.1.S.2.5 Process Validation and/or Evaluation Not applicable. 22

23 IMPD - Quality Documentation - Contents General Requirements for Phase I - III test preparations (continued): 2.1.S Drug Substance (continued) 2.1.S.2 Manufacture (cont.) 2.1.S.2.6 Manufacturing Process Development Documentation (flow chart) of significant differences in the manufacturing process of batches used in the non-clinical studies. 23

24 IMPD - Quality Documentation - Contents General Requirements for Phase I - III test preparations (continued): 2.1.S Drug Substance (continued) 2.1.S.3 Characterisation 2.1.S.3.1 Elucidation of Structure and other Characteristics The structure should be established with suitable methodology (e.g. NMR, MS, UV, IR), relevant data (such as spectra and interpretation) to be provided. 21S32Impurities 2.1.S.3.2 For substances which comply with a monograph of the Ph. Eur., the pharmacopoeia of an EU Member State, USP or JP, no further details are required. In cases where reference to a pharmacopoeial monograph cannot be made. 24

25 IMPD - Quality Documentation - Contents General Requirements for Phase I - III test preparations (continued): 2.1.S Drug Substance (continued) 2.1.S.3 Characterisation (continued) 2.1.S.3.2 Impurities (continued) Impurities, degradation products, residual solvents relevant to the drug substance used for the clinical trial should be stated. 25

26 IMPD - Quality Documentation - Contents General Requirements for Phase I - III test preparations (continued): 2.1.S Drug Substance (continued) 2.1.S.4 Control of the Drug Substance 2.1.S.4.1 Specification(s) Specifications, tests used, acceptance criteria; mandatory: identity, assay; (preliminary) upper limits should be set for impurities; for drug substances used in aseptically manufactured products: microbiological quality. For substances which comply with a monograph of the Ph. Eur., the pharmacopoeia of an EU Member State, USP or JP, reference to the relevant monograph is sufficient i (suitability must have been demonstrated and limits for any relevant residual solvent or catalyst should be included). 26

27 IMPD - Quality Documentation - Contents General Requirements for Phase I - III test preparations (continued): 2.1.S Drug Substance (continued) 2.1.S.4 Control of the Drug Substance (continued) 2.1.S.4.1 Specification(s) (cont.) Specifications set for previous phase I or phase II trials should be reviewed and adjusted, where appropriate. 2.1.S.4.2 Analytical Procedures The analytical methods used should be described (e.g. reversephase HPLC, potentiometric titration, etc.). It is not necessary to provide a detailed description of the analytical procedures. For substances which h comply with a monograph of the Ph. Eur., the pharmacopoeia of an EU Member State, USP or JP, reference to the relevant monograph is sufficient. 27

28 IMPD - Quality Documentation - Contents General Requirements for Phase I - III test preparations (continued): 2.1.S Drug Substance (continued) 2.1.S.4 Control of the Drug Substance (continued) 2.1.S.4.3 Validation of Analytical Procedures - Phase I trials: Confirmation of suitability of analytical methods, tabular presentation of acceptance limits and parameters (specificity, linearity etc.) for performing validation. - Phase II and III trials: Demonstration of suitability of analytical methods, tabular presentation ti of summary of the results of the validation carried out (results or values found for specificity, linearity etc.), provision of full validation report is not necessary. 28

29 IMPD - Quality Documentation - Contents General Requirements for Phase I - III test preparations (continued): P Investigational Medicinal Product Under Test 2.1.P.1 Description and Composition Qualitative and quantitative composition of the IMP incl. description of the dosage form and function of each excipient. 2.1.P.2 Pharmaceutical Development Short description of formulation development, incl. justification of any new pharmaceutical form or excipient. For early development, there may be no or only limited information to include in this section. The compatibility with solvents used for reconstitution, diluents and admixtures should be demonstrated, t d where applicable. Additional information for phase II and III clinical trials: If changes in the formulation or dosage form compared to the IMP used in earlier clinical trials have been made: Relevance of the earlier material to be discussed.

30 IMPD - Quality Documentation - Contents General Requirements for Phase I - III test preparations (continued): P Investigational Medicinal Product Under Test (continued) 2.1.P.3 Manufacture 2.1.P Manufacturer(s) Name(s) and address(es) of all manufacturer(s), contractors, site(s) of production involved in manufacture and testing. Respective responsibilities need to be stated. t 2.1.P.3.2 Batch Formula Presentation of batch formula for the batch to be used for the clinical trial (where relevant, appropriate range may be given). 2.1.P.3.3 Description of Manufacturing Process and Process Controls Flow chart indicating each step and including any relevant inprocess controls, brief narrative description.

31 IMPD - Quality Documentation - Contents General Requirements for Phase I - III test preparations (continued): 2.1.P Investigational Medicinal Product Under Test (continued) 2.1.P.3 Manufacture 2.1.P.3.4 Control of Critical Steps and Intermediates No data are required for phase I and II trials, except for - non-standard manufacturing processes [ CPMP/QWP/2054/03*] - manufacturing processes for sterile products. Additional information for phase III clinical trials: For critical manufacturing steps their control and possible intermediates should be documented. Should intermediates be stored, it should be assured that duration and conditions of storage are appropriately p controlled. *: Annex II to NfG on Process Validation: Non Standard Processes 31

32 IMPD - Quality Documentation - Contents General Requirements for Phase I - III test preparations (continued): 2.1.P Investigational Medicinal Product Under Test (continued) 2.1.P.3 Manufacture 2.1.P.3.5 Process Validation and/or Evaluation Data are not required, except for - non-standard sterilisation processes not described in Ph. Eur., USP or JP and - non-standard manufacturing processes. In these cases, the critical manufacturing steps, the validation of the manufacturing process as well as the applied in process controls should be described. 32

33 IMPD - Quality Documentation - Contents General Requirements for Phase I - III test preparations (continued): P Investigational Medicinal Product Under Test (continued) 2.1.P.4 Control of Excipients 2.1.P Specifications References to Ph. Eur., a Member State pharmacopoeia, the USP or JP should be indicated. For excipients i not tdescribed din one of fthe mentioned pharmacopoeias, reference to the relevant food-chemical regulations (e.g. FCC) can be made. For excipient mixtures composed of pharmacopoeial substances (e.g. pre-fabricated dry mix for film-coating) a general specification of the mixture is sufficient. For excipients not covered by any of the afore-mentioned standards, an in-house monograph should be provided.

34 IMPD - Quality Documentation - Contents General Requirements for Phase I - III test preparations (continued): P Investigational Medicinal Product Under Test (continued) 2.1.P.5 Control of the Investigational Medicinal Product 2.1.P Specifications Release and shelf-life specifications, incl. test methods and acceptance criteria. Upper limits it may be set for both individual id degradation d products and the sum of degradation products. Safety considerations should be taken into account. The specifications should be reviewed and adjusted during further development. Specifications set for previous phase I or phase II trials should be reviewed and adjusted, where appropriate. p 2.1.P.5.2 Analytical Procedures The analytical methods should be described for all tests.

35 IMPD - Quality Documentation - Contents General Requirements for Phase I - III test preparations (continued): P Investigational Medicinal Product Under Test (continued) 2.1.P.5 Control of the Investigational Medicinal Product 2.1.P.5.3 Validation of Analytical Procedures - Phase I trials: Confirmation of suitability of analytical methods, tabular presentation ti of acceptance limits it and parameters (specificity, it linearity etc.) for performing validation. - Phase II and III trials: Demonstration of suitability of analytical methods, tabular presentation of summary of the results of the validation carried out (results or values found for specificity, linearity etc.), provision of full validation report is not necessary.

36 IMPD - Quality Documentation - Contents General Requirements for Phase I - III test preparations (continued): 2.1.P Investigational Medicinal Product Under Test (continued) 2.1.P.5 Control of the Investigational Medicinal Product (cont.) 2.1.P.5.6 Justification of Specification(s) For phase I clinical trials, brief justification of specifications for degradation products and any other parameters that may be relevant to the performance of the drug product is sufficient. i Toxicological justification should be given, where appropriate. Additional information for phase II and III clinical trials: Brief justification of the choice of specifications which may affect efficacy or safety. 36

37 IMPD - Quality Documentation - Contents General Requirements for Phase I - III test preparations (continued): P Investigational Medicinal Product Under Test (continued) 2.1.P.7 Container Closure System The intended immediate packaging and, where relevant for the quality of the drug product, the outer packaging to be used for the IMP in the clinical trial should be stated. Reference to a pharmacopoeial monograph, if appropriate. For non-compendial materials description and specifications should be provided. For dosage forms that have a higher potential for interaction between filling and container (e.g. parenterals, ophthalmic products, oral solutions) more details may be needed. Where an interaction ti is unlikely l (e.g. solid oral dosage forms), a justification for not providing any information may suffice.

38 IMPD - Quality Documentation - Contents General Requirements for Phase I - III test preparations (continued): P Investigational Medicinal Product Under Test (continued) 2.1.P.8 Stability The shelf-lifelife of the IMP should be based on the stability profile of the active substance and the available data on the IMP. Extrapolation may be used, provided that stability studies are conducted in parallel to the clinical studies and throughout its entire duration. This should include the proposal for shelf-life extension, defining the criteria based on which the sponsor will extend the shelf-life life during an ongoing study. stability commitment should be provided. The batches of drug product must meet the specification requirements throughout h t the period of use. In-use stability data should be presented, where relevant.

39 IMPD - Quality Documentation - Contents General Requirements for Phase I - III test preparations (continued): P Investigational Medicinal Product Under Test (continued) 2.1.P.8 Stability - Phase I trials: Confirmation that an ongoing stability program will be carried out with the relevant batch(es) and that, prior to the start of the clinical trial, at least studies under accelerated and longterm storage conditions will have been initiated, tabular presentation of summary of available results (incl. supportive data from development studies), evaluation of available data and justification of the proposed shelf-life. - Additional information for phase II and III clinical trials: Tabular presentation ti of available results, evaluation of available data and justification of the proposed shelf-life.

40 IMPD - Quality Documentation - Contents General Requirements for Phase I - III test preparations (continued): 2.1.A Appendices 2.1.A.1 Facilities and Equipment Not applicable. 2.1.A.2 Adventitious Agents Safety Evaluation Identification of all materials of human or animal origin used in the manufacturing process of both drug substance and drug product. TSE agents in this section. Viral safety in this section. Other adventitious agents such as bacteria, mycoplasma, and fungi in appropriate sections within the core dossier. 40

41 IMPD - Quality Documentation - General General Requirements for Phase I - III test preparations (continued): Increasing requirements depending on the product development Clin. Phase I Clin. Phase II Clin. Phase III registration 41 Formulation preliminary preliminary represen- tative final Manufacture lab scale lab scale pilot scale production scale Specification oriented preliminary preliminary final Validation of acceptance presentation availability of presentation analytical criteria of parameter validation of validation procedures report reports Stability studies Initiation of studies >> increased availability of stability data >> >> Increasing knowledge on drug substance and investigational medicinal product >>

42 IMPD - Requirements for special test preparations Requirements on the Quality Documentation for special test t preparations (CHMP/QWP/185401/2004): Authorised, non-modified test and comparator products in clinical trials Modified authorised comparator products in clinical trials Investigational Medicinal Products containing existing active substances in bio-equivalence e studies, e.g. generics e (chemical substances) Placebo products in clinical trials following slides 42

43 IMPD - Requirements for special test preparations Requirements on the Quality Documentation for special test t preparations (continued): - Authorised, non-modified Test and Comparator Products in Clinical Trials If these have already been authorised in the EU/EEA, in the ICH-regions or one of the Mutual Recognition Agreement (MRA)-partner countries*, only the name of the MA-holder and the MA-number need to be provided. *: Australia/New Zealand, Japan, Canada, Switzerland 43

44 IMPD - Requirements for special test preparations Requirements on the Quality Documentation for special test t preparations (continued): - Authorised, non-modified Test and Comparator Products in Clinical Trials For IMPs sourced from outside of the EU/EEA, MRApartner countries or ICH regions, a full documentation according to the requirements stated in chapter 2 of this guideline, should be submitted. 44

45 IMPD - Requirements for special test preparations Requirements on the Quality Documentation for special test t preparations (continued): - Authorised, modified reference preparations p in clinical trials 21PM 2.1.P Modified dcomparator Product Information especially with view to the modification. 45

46 IMPD - Requirements for special test preparations Requirements on the Quality Documentation for special test t preparations (continued): - Authorised, modified reference preparations p in clinical trials (continued) Stability - Reworking (breaking, halves, encapsulation) usually stability investigation necessary - Repackaging: comparable tight or tighter packaging material Risik analysis: PIL, storage advice, other literature stable usually no stability testing, initial shelf life sensitive secondary yp pack medium (e.g. light, humidity) check and define short tests (light, humidity) Any influence be switched off? Stab testing / no stability testing 46

47 IMPD - Requirements for special test preparations Requirements on the Quality Documentation for special test t preparations (continued): - Clinical test preparations in generic bioequivalence studies The requirements are especially valid for test preparations in bioequivalence studies in order to prove the efficacy of the test preparation for generic use against a registered reference preparation). 2.1.S Drug Substance for APIs, whose quality is controlled sufficiently by a Ph. Eur. monograph or another EU compendial monograph, or, if not available, by the USP or JP, there are only limited data necessary. 2.1.P Investigational Medicinal Product Under Test Similar il to the "General Requirements" for test t preparations. 47

48 Changes and Amendments to the IMPD Subsequent Changes to the provisions of the pharmaceutical quality Amendments to the trial are regarded as 'substantial' if they have a significant impact on: - Safety - Physical/mental l integrityi of participants i - The scientific value of the trial. - It is up to the sponsor to assess whether an amendment is to be regarded as 'substantial'. - Case-by-case decision 48

49 Changes and Amendments to the IMPD Changes to the pharmaceutical quality (continued) Examples of changes to IMP: - Importation of the medicinal product - Primary packaging material - API manufacturer - Manufacturing process of the drug substance - Specifications of active substance - Manufacture of the medicinal product - Release and shelf-life specification of the medicinal product - Specification of excipients i affecting product performance - Shelf-life including after fist opening and reconstitution - Major change of formulation - Test procedures of the active substance - Test procedures of the medicinal product -Test procedures of non-pharmacopoeial p excipients 49

50 Changes and Amendments to the IMPD Changes to the pharmaceutical quality (continued) Cave: Shelf-life of investigational medicinal product Does an extension of the shelf-life lif of test t preparations require explicit approval?) No approval necessary if -anextension of shelf-life or -a widening of storage conditions based on additional data with unchanged shelf-life specification. Approval necessary for - a tightening of shelf-life life or -a tightening of storage conditions 50

51 Major deficiencies in IMPDs - the don'ts Major formal deficiencies in the IMPD : - Reference to documents submitted in another European procedure - Letter of Access and/or Closed Part of the ASMF missing - ASMF procedure not acceptable for biotechnological test preparations - Excipient Master Files need to be submitted 51 source: Dr. A. Aylin Mende, BfArM

52 Major deficiencies in IMPDs - the don'ts Major quality related concerns in the IMPD: - Only the last step of API synthesis presented - Unreadable or insufficient spectra - TSE confirmations missing - Test parameter and specification limits missing - Stability extrapolation missing 52 Source:Dr. A. Aylin Mende, BfArM

53 Quality documentation of the IMPD - and the dos? Recommendation on the IMPD preparation: - An IMPD has the same composition as the CTD dossier - Less detailed d - Contents increases with increased knowledge and Clinical Phase - Development of sections: pharmaceutical development, validations, justification, stability - Often slightly wider limits in IMPD than acceptable in registration dossier 53

54 Link between IMPD and CTD Identity/similarities between IMPD and CTD structure Level of detail differs IMPD: limited and growing during development CTD: complete Both have a kind of life cycle (both require updates/ variations over time) For new developments it is sensible to consider a kind of "rolling submission", i.e. derive the application for MA file from the "growing IMPD file" Ensure completeness of information in MA file by using a predefined CTD/eCTD backbone already for the IMPD generation 54

55 YES Pharmaceutical Development Services GmbH Dr. Joachim Ahlert Bahnstrasse Friedrichsdorf Germany Telephone: Telefax: