the investigational medicinal product dossier - rpd · pdf filethe investigational medicinal...

IMPDThe Investigational Medicinal Product Dossier

“IMPD S+P P t D ’ d D 't ”“IMPD S+P Part Do’s and Don't s”

Joachim Ahlert

11

YES Pharmaceutical Development Services GmbHOberaegeri - 4 May 2012

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 f th IMPDof the IMPD

► Typical dos and don'ts

22

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)and Member States (Art. 9.8)

► Directive 2005/28/EClaying down principles and detailed guidelines for good clinical practice as regards investigational medicinal products for human use

3

medicinal products for human use

Regulatory Requirements and Guidelines

Regulatory Requirements (continued):

European CommissionThe rules governing medicinal products in the European UnionUnionVolume 10: Clinical trialshttp://ec.europa.eu/health/documents/eudralex/vol-10/index en htm10/index_en.htm

4


Regulatory Requirements (♦ direct relevance on quality d t ti )documentation):

- European Commission - EudraLexTh R l G i M di i l P d t i th EThe Rules Governing Medicinal Products in the European UnionVolume 4: Good Manufacturing PracticesAnnex 13: Investigational Medicinal ProductsFeb 2010, Brussels, ENTR/F/2/AM/an D(2010) 3374

♦ EMEA / EMA / CHMPGuideline on the requirements to the chemical and pharmaceutical quality documentation concerning investigational medicinal products in clinical trialsLondon, 31 March 2006, CHMP/QWP/185401/2004 final

6

, ,


Communication from the Commission -

Detailed guidance on the request to the competent authorities for authorisation of a clinical trial on a medicinal product for humanclinical 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)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 requestthe 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 b) e p ese a o a d co e o e p oposedamendment…

c) the declaration of the end of the clinical trial.'

7replaces Revision 2 from October 2005

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 studiescontrol of the IMP, and data from non clinical studiesand from its clinical use.However, in many cases where the IMP has a

k ti th i ti IMPD i t i d [ ]marketing authorisation, an IMPD is not required […].

► 68 Quality data should be submitted in a logical► 68. 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

8

This document also contains guidance for quality of placebos.

IMPD - Detailed guidance (Chapter 2.7.3)

2.7.3 Simplified IMPD by referring to other documentationP ibilit t f t th IB f th li i l d li i l► Possibility to refer to the IB for the preclinical and clinical parts of the IMPD (with exceptions)

► Possibility to refer to the SmPC in another clinical trials li iapplication

SmPC (or equivalent within ICH region) if an IMP has a marketing authorisation in EU or in an ICH country (Table 1)1)

► Cross-reference to a previous submission of the IMPD to the same Member State concerned by the same applicant

th li t (l tt f th i ti )or another applicant (letter of authorisation necessary)

2.8.3 IMPD in cases of placebop► Information on a placebo may also be provided as a

simplified IMPD

9

Non-Investigational Medicinal Products (NIMPs)

Further clarification and definition necessary, therefore:

European Commission - Volume 10:Guidance on Investigational Medicinal Products (IMPs) and 'Non-investigational Medicinal Products' (NIMPs)Non-investigational Medicinal Products (NIMPs)(Rev. 1, March 2011):Some medicinal products do not fall within the definition of IMP d fi d f Di 2001/20/EC d b f d tIMPs as defined 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.y p y g pIt 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

10

recommended that a NIMP with a MA in another Member State is used.

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► 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 2.7.3► NIMP dossier as set out in Section 2.8► Additional information as set out in Section 2 9► Additional information as set out in Section 2.9

- 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

IMPD - Quality Documentation - General

EMEA / EMA / CHMPG id li h i h h i lGuideline on the requirements to the chemical

and pharmaceutical quality documentation concerning investigational medicinal productsconcerning 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 g j y q yany 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 ofdata from non clinical studies and the previous clinical use of the IMP or justify in the application why information is not provided. ...

12


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. INTRODUCTION1.1 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 foraim of this guideline to define harmonised requirements for the documentation to be submitted throughout the European Community.

13

...


EMEA Guideline on the requirements to chem./pharm. lit (CHMP/QWP/185401/2004) ( t )quality ... (CHMP/QWP/185401/2004) (cont.)

1.2 Scope of the GuidelineThis guideline addresses the documentation on the chemical and pharmaceutical quality of IMPs containing chemically defined active substances, synthetic peptides, herbal , y p p ,substances, herbal preparations and chemically defined radio-active/radio-labelled substances to be submitted to the competent authority for approval prior to beginning a clinicalcompetent 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 comparatorthe requirements for modified and unmodified comparator products and IMPs to be tested in generic bioequivalence studies [and placebo products]

14

IMPD (CHMP/QWP/185401/2004)

► The IMP dossier required will depend on many factors including:

► risk aspects► nature of the product► nature of the product► state of development► patient populationpatient population► nature and severity of the illness► type and duration of the clinical trial itselfyp

15


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(Appendices) and R (?, Regional Information, e.g. Medical Device, CEP)?

- A Quality Overall Summary (QOS, CTD Module 2.3) is not required.

16

IMPD - Quality Documentation - Contents

EMEA Guideline on the requirements to chem./pharm. lit (CHMP/QWP/185401/2004) ( t )quality... (CHMP/QWP/185401/2004) (cont.)

2. Information on the Chemical and Pharmaceutical Quality Concerning Investigational Medicinal Products in Clinical Trials

2.1.S DRUG SUBSTANCE2 1 S 1 General Information2.1.S.1 General Information...2.1.P INVESTIGATIONAL MEDICINAL PRODUCT UNDER TEST2.1.P.1 Description and Composition of the Investigational Medicinal Product...APPENDICES2.1.A.1 Facilities and Equipment2 1 A 2 Adventitious Agents Safety Evaluation2.1.A.2 Adventitious Agents Safety Evaluation...(CTD structure with identical wording of the headlinesonly deviation: "investigational medicinal product" instead of

17

only deviation: investigational medicinal product instead of "drug product"


General Remarks:

- Documentation on used API (according to "EMEA Guideline on the requirements ...":

- The suitability of the referenced pharmacopoeial monograph toThe 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 ofperforming the analysis) and "analytical method" (refers to theprinciples of the method used) should be kept in mind.

18


General Remarks (continued):

►For investigational medicinal products reference to a monograph of the Ph. Eur., another EU compendium, the USP or the JP is acceptedUSP or the JP is accepted.

Exception:►For test preparations in generic bioequivalence studies►For test preparations in generic bioequivalence studies

supporting an application within the EU, the Ph. Eur. requirements must be fulfilled.

19


General Requirements for Phase I - III test preparations:

2.1.S Drug Substance

2.1.S.1 General Information2.1.S.1.1 Nomenclature(Proposed) INN pharmacopoeial IUPAC lab code(Proposed) INN, pharmacopoeial, IUPAC, lab code.2.1.S.1.2 StructureAs far as available: structural formula, molecular weight, , g ,chirality/ stereochemistry.2.1.S.1.3 General PropertiesPhysico-chemical and other relevant properties, such asPhysico chemical and other relevant properties, such as solubilities, pKa, polymorphism, isomerism, log P, permeability etc.

20


General Requirements for Phase I - III test preparations ( ti d)(continued):

2.1.S Drug Substance (continued)2.1.S.2 Manufacture2.1.S.2.1 Manufacturer(s)Name(s) and address(es) of all manufacturer(s) inclName(s) and address(es) of all manufacturer(s), incl. contractors, site(s) of production involved in manufacture and testing.2 1 S 2 2 Description of Manufacturing Process and Process2.1.S.2.2 Description of Manufacturing Process and Process ControlsBrief summary of synthesis process, flow chart incl. starting

t i l ( t h i t ) i t di t l t t l tmaterials (stereochemistry), intermediates, solvents, catalysts, critical reagents, relevant process controls, production scale, batch size. For substances complying with a monograph of the

21

Ph. Eur., an EU Member State pharmacopoeia, the USP or JP, no further details are required.



2.1.S Drug Substance (continued)2.1.S.2 Manufacture (cont.)2.1.S.2.3 Control of MaterialsListing of materials used in the manufacture of the drugListing 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 substancecontrol is required to limit an impurity in the drug substance.2.1.S.2.4 Control of Critical Steps and IntermediatesIn case of critical steps: brief summary of tests and acceptance

it i f th i t lcriteria for their control.2.1.S.2.5 Process Validation and/or EvaluationNot applicable.

22



2.1.S Drug Substance (continued)2.1.S.2 Manufacture (cont.)2.1.S.2.6 Manufacturing Process DevelopmentDocumentation (flow chart) of significant differences in theDocumentation (flow chart) of significant differences in the manufacturing process of batches used in the non-clinical studies.

23



2.1.S Drug Substance (continued)2.1.S.3 Characterisation2.1.S.3.1 Elucidation of Structure and other CharacteristicsThe structure should be established with suitable methodologyThe structure should be established with suitable methodology (e.g. NMR, MS, UV, IR), relevant data (such as spectra and interpretation) to be provided.2 1 S 3 2 Impurities2.1.S.3.2 ImpuritiesFor substances which comply with a monograph of the Ph. Eur., the pharmacopoeia of an EU Member State, USP or JP, no f th d t il i dfurther details are required.In cases where reference to a pharmacopoeial monograph cannot be made….

24



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 toImpurities, degradation products, residual solvents relevant to the drug substance used for the clinical trial should be stated.

25



2.1.S Drug Substance (continued)2.1.S.4 Control of the Drug Substance2.1.S.4.1 Specification(s)Specifications tests used acceptance criteria; mandatory: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 qualitymanufactured products: microbiological quality.For substances which comply with a monograph of the Ph. Eur., the pharmacopoeia of an EU Member State, USP or JP,

f t th l t h i ffi i t ( it bilitreference to the relevant monograph is sufficient (suitability must have been demonstrated and limits for any relevant residual solvent or catalyst should be included).

26



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 trialsSpecifications set for previous phase I or phase II trials should be reviewed and adjusted, where appropriate.2.1.S.4.2 Analytical ProceduresThe analytical methods used should be described (e g reverseThe analytical methods used should be described (e.g. reverse-phase HPLC, potentiometric titration, etc.). It is not necessary to provide a detailed description of the analytical procedures.F b t hi h l ith h f th Ph EFor 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.

27



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:- Phase I trials:Confirmation of suitability of analytical methods, tabular presentation of acceptance limits and parameters (specificity, linearity etc ) for performing validationlinearity etc.) for performing validation.- Phase II and III trials:Demonstration of suitability of analytical methods, tabular

t ti f f th lt f th lid ti i dpresentation 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



2.1.P Investigational Medicinal Product Under Test2.1.P.1 Description and CompositionQualitative and quantitative composition of the IMP incl. description of the dosage form and function of each excipient.2.1.P.2 Pharmaceutical DevelopmentShort 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

d i t h ld b d t t d h li bladmixtures should be demonstrated, 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:

29

clinical trials have been made:→ Relevance of the earlier material to be discussed.



2.1.P Investigational Medicinal Product Under Test (continued)(continued)2.1.P.3 Manufacture2 1 P 3 1 Manufacturer(s)2.1.P.3.1 Manufacturer(s)Name(s) and address(es) of all manufacturer(s), contractors, site(s) of production involved in manufacture and testing. R ti ibiliti d t b t t dRespective responsibilities need to be stated.2.1.P.3.2 Batch FormulaPresentation 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

30

Flow chart indicating each step and including any relevant in-process controls, brief narrative description.



2.1.P Investigational Medicinal Product Under Test (continued)(continued)2.1.P.3 Manufacture2 1 P 3 4 Control of Critical Steps and Intermediates2.1.P.3.4 Control of Critical Steps and IntermediatesNo data are required for phase I and II trials, except for - non-standard manufacturing processes [→ CPMP/QWP/2054/03*]

f t i f t il d t- 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 controlled.

31

g pp p y*: Annex II to NfG on Process Validation: Non Standard Processes



2.1.P Investigational Medicinal Product Under Test (continued)(continued)2.1.P.3 Manufacture2 1 P 3 5 Process Validation and/or Evaluation2.1.P.3.5 Process Validation and/or EvaluationData are not required, except for- non-standard sterilisation processes not described in Ph. Eur., USP JP dUSP 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 processcontrols should be described.

32



2.1.P Investigational Medicinal Product Under Test (continued)(continued)2.1.P.4 Control of Excipients2 1 P 4 1 Specifications2.1.P.4.1 SpecificationsReferences to Ph. Eur., a Member State pharmacopoeia, theUSP or JP should be indicated.F i i t t d ib d i f th ti dFor excipients not described in one of the 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.

33

g pFor excipients not covered by any of the afore-mentionedstandards, an in-house monograph should be provided.



2.1.P Investigational Medicinal Product Under Test (continued)(continued)2.1.P.5 Control of the Investigational Medicinal Product2 1 P 5 1 Specifications2.1.P.5.1 SpecificationsRelease and shelf-life specifications, incl. test methods andacceptance criteria.U li it b t f b th i di id l d d ti d tUpper limits may be set for both individual degradation products and the sum of degradation products. Safety considerationsshould be taken into account. The specifications should bereviewed and adjusted during further development.Specifications set for previous phase I or phase II trialsshould be reviewed and adjusted, where appropriate.

34

j pp p2.1.P.5.2 Analytical ProceduresThe analytical methods should be described for all tests.



2.1.P Investigational Medicinal Product Under Test (continued)(continued)2.1.P.5 Control of the Investigational Medicinal Product2 1 P 5 3 Validation of Analytical Procedures2.1.P.5.3 Validation of Analytical Procedures- Phase I trials:Confirmation of suitability of analytical methods, tabular

t ti f t li it d t ( ifi itpresentation of acceptance limits and parameters (specificity, 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.),

35

( p y y )provision of full validation report is not necessary.



2.1.P Investigational Medicinal Product Under Test (continued)(continued)2.1.P.5 Control of the Investigational Medicinal Product (cont.)2 1 P 5 6 Justification of Specification(s)2.1.P.5.6 Justification of Specification(s)For phase I clinical trials, brief justification of specifications fordegradation products and any other parameters that may be

l t t th f f th d d t i ffi i trelevant to the performance of the drug product is sufficient. 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



2.1.P Investigational Medicinal Product Under Test (continued)(continued)2.1.P.7 Container Closure SystemThe intended immediate packaging and, where relevant forThe 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 appropriateReference 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 interactionFor 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

i t ti i lik l ( lid l d f )

37

an interaction is unlikely (e.g. solid oral dosage forms), a justification for not providing any information may suffice.



2.1.P Investigational Medicinal Product Under Test (continued)(continued)2.1.P.8 StabilityThe shelf-life of the IMP should be based on the stability profileThe shelf life 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 areconducted in parallel to the clinical studies and throughout itsconducted in parallel to the clinical studies and throughout its entire duration. This should include the proposal for shelf-lifeextension, defining the criteria based on which the sponsorwill extend the shelf life during an ongoing studywill extend the shelf-life during an ongoing study.→ stability commitment should be provided.The batches of drug product must meet the specification

i t th h t th i d f

38

requirements throughout the period of use.In-use stability data should be presented, where relevant.



2.1.P Investigational Medicinal Product Under Test (continued)(continued)2.1.P.8 Stability- Phase I trials: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 long-of the clinical trial, at least studies under accelerated and long-term storage conditions will have been initiated, tabular presentation of summary of available results (incl. supportive data from development studies) evaluation of available datadata from development studies), evaluation of available data and justification of the proposed shelf-life.- Additional information for phase II and III clinical trials:T b l t ti f il bl lt l ti f

39

Tabular presentation of available results, evaluation of available data and justification of the proposed shelf-life.



2.1.A Appendices2.1.A.1 Facilities and EquipmentNot applicable.2.1.A.2 Adventitious Agents Safety Evaluationg yIdentification of all materials of human or animal origin used in the manufacturing process of both drug substance and drug productproduct.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



Increasing requirements depending on the product development

Clin. Phase I Clin. Phase II Clin. Phase III registration

Formulation preliminary preliminary represen-tative

finaltative

Manufacture lab scale lab scale pilot scale production scale

Specification oriented preliminary preliminary final

Validation of analytical

acceptance criteria

presentation of parameter

availability of validation

presentation of validation

procedures report reports

Stability studies

Initiation of studies

>> increased availability of stability data >>

41

>> Increasing knowledge on drug substance and investigational medicinal product >>

IMPD - Requirements for special test preparations

Requirements on the Quality Documentation for specialt t ti (CHMP/QWP/185401/2004)test preparations (CHMP/QWP/185401/2004):

• Authorised, non-modified test and comparator products in clinical trialsclinical trials

• Modified authorised comparator products in clinical trials

• Investigational Medicinal Products containing existing active substances in bio-equivalence studies, e.g. generics act e substa ces b o equ a e ce stud es, e g ge e cs(chemical substances)

• Placebo products in clinical trials• Placebo products in clinical trials

following slides

42


Requirements on the Quality Documentation for specialt t ti ( ti d)test preparations (continued):

- Authorised, non-modified Test and Comparator Products , pin Clinical Trials

If these have already been authorised in the EU/EEA in theIf 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 providedand the MA-number need to be provided.*: Australia/New Zealand, Japan, Canada, Switzerland

43



- Authorised, non-modified Test and Comparator Products , pin Clinical Trials

F IMP d f t id f th EU/EEA MRAFor IMPs sourced from outside of the EU/EEA, MRA-partner countries or ICH regions, a full documentationaccording to the requirements stated in chapter 2 of this guideline, should be submitted.

44



- Authorised, modified reference preparations in clinical, p ptrials

2 1 P M difi d C t P d t2.1.P Modified Comparator ProductInformation especially with view to the modification.

45



- Authorised, modified reference preparations in clinical , p ptrials (continued)Stability- Reworking (breaking halves encapsulation)Reworking (breaking, halves, encapsulation) usually stability investigation necessary

- Repackaging:• comparable tight or tighter packaging materialcomparable tight or tighter packaging material• Risik analysis: PIL, storage advice, other literature→ stable usually no stability testing, initial shelf life→ sensitive secondary pack medium (e.g. light, humidity)y p ( g g , y)

check and define short tests (light, humidity)

→ Any influence be switched off?

46

Stab testing / no stability testing



- Clinical test preparations in generic bioequivalence studiesstudiesThe requirements are especially valid for test preparations in bioequivalence studies in order to prove the efficacy of thebioequivalence studies in order to prove the efficacy of the test preparation for generic use against a registered reference preparation).2 1 S Drug Substance2.1.S Drug Substancefor 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 dataavailable, by the USP or JP, there are only limited data necessary.2.1.P Investigational Medicinal Product Under TestSi il t th "G l R i t " f t t ti

47

Similar to the "General Requirements" for test preparations.

Changes and Amendments to the IMPD

Subsequent Changes to the provisions of the h ti l litpharmaceutical quality

Amendments to the trial are regarded as 'substantial' if they have a significant impact on:have a significant impact on:

- SafetyPh i l/ l i i f i i- Physical/mental integrity of participants

- 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 decisionCase by case decision

48


Changes to the pharmaceutical quality (continued)

Examples of changes to IMP:- Importation of the medicinal product- Primary packaging material- Primary packaging material- API manufacturer- Manufacturing process of the drug substance

Specifications of active substance- Specifications of active substance- Manufacture of the medicinal product- Release and shelf-life specification of the medicinal product

S ifi ti f i i t ff ti d t f- Specification of excipients 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 excipients

49

p p p p


Changes to the pharmaceutical quality (continued)

Cave: Shelf-life of investigational medicinal product

D t i f th h lf lif f t t ti iDoes an extension of the shelf-life of test preparations require explicit approval?)

No approval necessary if- an extension of shelf-life or- a widening of storage conditions based on additionalg gdata with unchanged shelf-life specification.Approval necessary for

a tightening of shelf life or- a tightening of shelf-life or- a tightening of storage conditions

50

Major deficiencies in IMPDs - the don'ts

Major formal deficiencies in the IMPD :

- Reference to documents submitted in another European procedureLetter of Access and/or Closed Part of the ASMF missing- 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

51source: Dr. A. Aylin Mende, BfArM

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

52Source:Dr. A. Aylin Mende, BfArM

Quality documentation of the IMPD - and the dos?

Recommendation on the IMPD preparation:

- An IMPD has the same composition as the CTD dossierL d t il d- Less detailed

- Contents increases with increased knowledge and Clinical PhaseClinical Phase

- Development of sections: pharmaceutical development, validations, justification, stabilityvalidations, justification, stability

- Often slightly wider limits in IMPD than acceptable in registration dossier

53

Link between IMPD and CTD

► Identity/similarities between IMPD and CTD structurestructure

► Level of detail differs ► IMPD: limited and “growing” during developmentIMPD: limited and growing during development► CTD: “complete”

► Both have a kind of life cycle (b th i d t / i ti ti )(both require updates/ variations over time)

► For new developments it is sensible to consider a kind of "rolling submission", i.e. derive thekind 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

for the IMPD generation

YES Pharmaceutical Development Services GmbHDr. Joachim Ahlert

Bahnstrasse 42 - 4661381 Friedrichsdorf61381 Friedrichsdorf

GermanyTelephone: +49 6172 76 46 4-0p

Telefax: +49 6172 77 74 [email protected]

www.yes-services.eu

55

the investigational medicinal product dossier - rpd · pdf filethe investigational medicinal...

Documents