Download Best practices for preparing the IMPD quality section

Best practices for
preparing the
IMPD quality
section
JUDITH JONES
REGULATORY AFFAIRS DIRECTOR, EU
20th April 2016
Disclaimer – This presentation is not intended to provide or
contain legal advice. Please consult your attorney or other
legal representative with any specific legal questions.
©2016 Catalent Pharma Solutions. All rights reserved.
Background
Currently applicable legislation:
•
EU Clinical Trials Directive (“EUCTD”; Directive 2001/20/EC)
•
EU Directive relating to medicinal products for human use
2001/83/EC
•
EU Good Clinical Practice (GCP) Directive 2005/28/EC
Future legislation:
•
EU Clinical Trials Regulation (EU regulation No 536/2014 on clinical
trials on medicinal product)
—
Published in Official Journal of the EU on 27th May 2014.
—
Likely to become applicable by October 2018 (EMA/760345/2015
Endorsed)
—
2001/20/EU no longer applicable from October 2021
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What is an Investigational Medicinal Product (IMP)?
The clinical trials directive 2001/20/EU defines an
investigational medicinal product as:
d) ‘investigational medicinal product’: a pharmaceutical form of
an active substance or placebo being tested or used as a reference
in a clinical trial, including products already with a marketing
authorisation but used or assembled (formulated or packaged) in
a way different from the authorised form, or when used for an
unauthorised indication, or when used to gain further information
about the authorised form;
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IMPD Guidance
• Guideline on the Requirements to the Chemical and
Pharmaceutical Quality Documentation Concerning
Investigational Medicinal Products in Clinical Trials
(CHMP/QWP/185401/2004 final)
• Guideline on the Requirements for Quality Documentation
Concerning Biological Investigational Medicinal Products in
Clinical Trials (EMA/CHMP/BWP/534898/2008)
• Guidance on Investigational Medicinal Products (IMPS) and
‘Non Investigational Medicinal Products' (NIMPS)
(SANCO/C/8/SF/cg/a.5.001(2011)332855)
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IMP or Non IMP (NIMP)?
NIMPs are medicinal products that fall within Article 3(3) of Directive
2001/83/EC, while not falling within the definition of IMP as defined in
Article 2(d) of Directive 2001/20/EC.
For example a trial may require the use of a concomitant or rescue
medication for preventive, diagnostic or therapeutic reasons
Types of NIMP include:
• Rescue/escape medication
• Challenge agent
• Medicinal products used to assess end-points in the clinical trial
• Concomitant medicinal products systematically prescribed to the study
patients
• Background treatment
Many NIMPs are generally already approved medicinal products, in these
cases limited additional quality data is required to be submitted.
However when NIMPs do not have an MA in EU the same level of quality
and safety should be ensured for the NIMPs as for the IMPs used in the
trials
5
IMPD Structure
The structure required for the Quality section of the IMPD largely follows
the standard CTD (common technical document) format for Module 3
Quality.
Sections are presented for:
•
Drug Substance: Module S
•
Investigational Medicinal Product: Module P
•
Appendices: Module A
•
Regional Information: Module R.
When the IMP already has an EU MAA (or MA in ICH territory) it is possible
to submit a simplified IMPD in the form of the SmPC (or equivalent) in
place of a complete IMPD.
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2.1 S Drug Substance
General considerations:
•
If more than one drug substance manufacturer will be used during
course of clinical trial supply, provide a separate 2.1.S for each
manufacturer.
•
Reference to an Active Substance Master File (ASMF) or EDQM
Certificate of Suitability is acceptable, usual procedures for commercial
product to be followed.
•
The suitability of the referenced pharmacopoeial monograph to
appropriately control the quality of the active substance (including
impurity profile) should be presented
•
Reference to USP or JP monograph is acceptable.
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2.1 S Drug Substance
2.1.S.1 – General Information
•
2.1.S.1.1 - Nomenclature – provide INN name, pharmacopoeial name,
internal code numbers, any other names/codes
•
2.1.S.1.2 - Structure – As much data as available should be presented,
including structural formula, molecular weight, chirality/stereochemistry
(as much is known)
•
2.1.S.1.3 - General properties – list of relevant physico-chemical
properties, particularly those that may affect pharmacological or
toxicological safety, such as solubility, pKa, polymorphism, isomerism,
permeability etc.
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2.1 S Drug Substance
2.1.S.2 – Manufacture
•
2.1.S.2.1 – Manufacturer(s)– name, address and responsibilities for ALL sites
involved in the manufacturing process
•
2.1.S.2.2 – Description of manufacturing process and controls – provide brief
summary of process and flow diagram. Process controls should be shown. Where
relevant for critical process controls, provide details. Include details of batch size
or range for material to be used in clinical trial.
•
2.1.S.2.3 – Control of materials– materials used (starting materials, reagents,
catalysts, etc.) should be detailed including brief summary of control of critical
attributes.
•
2.1.S.2.4 – Control of critical steps– For any critical steps identified in S.2.3,
provide brief details of the test method/s and acceptance criteria
•
2.1.S.2.5 – Process validation and/or evaluation– not required for IMPD.
•
2.1.S.2.6 – Manufacturing process development– detail if process differs
significantly from process used for manufacture of non clinical batches.
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2.1 S Drug Substance
2.1.S.3 – Characterisation
•
2.1.S.3.1 – Elucidation of structure – Structure of chemically defined
substances should be demonstrated via appropriate means.
•
2.1.S.3.2 – Impurities – For pharmacopoeial materials (Ph Eur, EU MS
pharmacopoeia, USP or JP) no further details required. Impurities,
degradation products, residual solvents or catalysts relating to the
manufacturing process or starting materials should be stated.
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2.1 S Drug Substance
2.1.S.4 – Control of the Drug Substance
•
2.1.S.4.1 – Specification – provide the specification, tests and
acceptance criteria used by drug product manufacturer for testing of
drug substance used in clinical trials.
•
2.1.S.4.2 – Analytical procedures – describe nature of all tests used in
the specification, e.g. HPLC, GC….
•
2.1.S.4.3 – Validation of analytical procedures – for phase I the
suitability of the methods should be discussed. Present in tabular
format the parameters for performing validation
•
2.1.S.4.4 – Batch analysis – provide C of A for batch/es used in current
trial, or if not available representative batch analysis may be provided.
•
2.1.S.4.5 – Justification of specification – for non pharmacopoeial
materials, provide brief justification for impurities and parameters
relevant to performance of drug product.
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2.1 S Drug Substance
2.1.S.5 – Reference Standards or materials – the parameters used to
characterise the lot of drug substance as reference standard should be
presented. Provide C of As for any commercially purchased reference
standards
2.1.S.6 – Container Closure System – provide details of the primary
packaging material used for the drug substance
2.1.S.7 – Stability – available stability data should be summarised in
tabular format. Parameters critical to drug substance stability should be
detailed and potential degradation pathways should be highlighted. A
retest period based on available data should be proposed, extrapolation is
accepted. When the proposed retest period is matched by acceptable real
time data, non substantial amendment is needed to extend retest period.
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2.1 P Investigational Medicinal Product Under Test
2.1.P.1 – Description and Composition – provide a tabular summary of the
qualitative and quantitative composition of the IMP, including function of
each excipient.
2.1.P.2 – Pharmaceutical Development – provide a short summary of
formulation development. For early development there may be little or no
information to include here. For Phase II and III trials, detail if any
changes have been made to formulation since Phase I and discuss
relevance of earlier material.
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2.1 P Investigational Medicinal Product Under Test
2.1.P.3 – Manufacture
•
2.1.P.3.1 – Manufacturer(s) - name, address and responsibilities for ALL
sites involved in the manufacturing process.
•
2.1.P.3.2 – Batch formula – provide the batch formula for the batch to
be used in the clinical trial, if appropriate, a batch size range can be
given.
•
2.1.P.3.3 – Description of process and controls – provide brief narrative
summary of entire process and accompany with a flow diagram. Inprocess controls should be shown. For non standard or new processes
or technologies, describe in more thorough detail.
•
2.1.P.3.4 – Control of critical steps and intermediates – for Phase I and
II not required to present information unless sterile product or nonstandard process.
•
2.1.P.3.5 – Process validation – For development phases (Ph I to III)
not required to be presented.
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2.1 P Investigational Medicinal Product Under Test
2.1.P.4 – Control of Excipients
•
2.1.P.4.1 – Specifications – refer to relevant pharmacopoeia, if no
pharmacopoeia monograph, refer to relevant food or chemical
standards. Otherwise provide copy of in-house specification.
•
2.1.P.4.2 – Analytical procedures – for any non-pharmacopoeial
methods, analytical methods should be indicated.
•
2.1.P.4.3 – Validation of analytical procedures – not required for IMPDs.
•
2.1.P.4.4 – Justification of specification – not required for IMPDs.
•
2.1.P.4.5 – Excipients of animal or human origin – refer to section A.2.
•
2.1.P.4.6 – Novel excipients – if novel excipient is used need to provide
full details on manufacture, characterisation and control, using as
example 2.1.S section format and level of detail
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2.1 P Investigational Medicinal Product Under Test
2.1.P.5 – Control of Investigational Medicinal Product
•
2.1.P.5.1 – Specifications – release and shelf life specifications should be
provided detailing methods and acceptance criteria. Set upper limits for
degradation products (individual and total) based on available data and results
observed in non-clinical batches
•
2.1.P.5.2 – Analytical procedures –analytical methods for all tests should be
indicated.
•
2.1.P.5.3 – Validation of analytical procedures – – for phase I the suitability of
the methods should be discussed. Present in tabular format the parameters for
performing validation.
•
2.1.P.5.4 – Batch analysis - provide C of A for batch/es used in current trial, or if
not available representative batch analysis may be provided.
•
2.1.P.5.5 – Characterisation of impurities – impurities or degradation products
not already discussed in 2.1.S.3.2 should be detailed here
•
2.1.P.5.6 – Justification of specification – for phase I briefly justify specification
and limits for degradation products and other key parameters.
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2.1 P Investigational Medicinal Product Under Test
2.1.P.6 – Reference standards
If additional reference standards are used in addition to those already
mentioned in 2.1.S.5, the characterisation of them should be submitted
here.
2.1.P.7 – Container closure system
•
Details of the primary packaging to be used for the IMP in the trial
should be detailed. If applicable refer to relevant pharmacopoeia.
•
If non standard administration device or non-compendial material,
description and specifications should be provided.
•
Where likelihood of interaction between product and container more
details are required.
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2.1 P Investigational Medicinal Product Under Test
2.1.P.8 – Stability
•
Define shelf life of IMP based on active substance data and that
available for IMP.
•
Extrapolation allowable as long as studies continue in parallel
throughout clinical trial.
•
Include details of any planned shelf life extension during course of
study. Stability commitment should be included.
•
Where justified and appropriate, bracketing and/or matrix study design
may be used.
•
For products where multiple administration occurs after dilution or
reconstitution step, in-use stability data should be presented.
•
For phase I need to include confirmation that accelerated and real time
studies have been initiated prior to start of trial.
•
Provide evaluation of available data and justification for proposed shelf
life.
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2.1 A Appendices
2.1.A.1 – Facilities and Equipment
•
Not applicable for IMPDs, including biological products.
2.1.A.2 – Adventitious Agents Safety Evaluation
•
All materials of human or animal origin used in the entire manufacturing
process (drug substance and drug product) should be identified.
•
TSE – current Note for Guidance must be applied
•
Where relevant a viral safety statement should be provided
•
Include information regarding other adventitious agents in appropriate
section of IMPD.
2.1.A.3 – Novel Excipients
•
Provide complete information, consist with clinical phase as per 3.2.S of
CTD
2.1.A.4 – Solvent for Reconstitution and Diluents
•
Provide relevant information as per 3.2.P of CTD
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IMPD for Placebo
2.1.P.1 – as per requirements for investigational medicinal product
2.1.P.2 – Discuss how differences compared to IMP in terms of taste, smell
and look are masked.
2.1.P.3 - as per requirements for investigational medicinal product
2.1.P.4 - as per requirements for investigational medicinal product
2.1.P.5 – specification should include a test to differentiate between test
and placebo products.
2.1.P.7 - as per requirements for investigational medicinal product
2.1.P.8 – shelf life should cover duration of trial. Stability studies only
needed when reason to expect placebo will undergo degradation or
changes to key characteristics.
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IMPD for Modified Comparator/Reference Product
2.1.P.1 – any additional substances added to authorised product must be detailed
and reference to relevant pharmacopoeia or in-house monograph provided.
2.1.P.2 – modifications and influence on quality of product should be described with
a focus on parameters key to function, safety and efficacy, and demonstration that
they remain comparable. For solid oral dosage forms comparative dissolution
profiles should be provided.
2.1.P.3 – detail all manufacturing sites, proposed batch formula and modification
steps including IPCs
2.1.P.4 - as per requirements for investigational medicinal product
2.1.P.5 – specification and methods should include description, ID of API and any
other control parameters relevant to pharmaceutical or technological properties.
Include batch analysis as for IMP. If significant modification need to consider impact
to impurities etc and ensure suitable control.
2.1.P.7 - as per requirements for investigational medicinal product
2.1.P.8 – shelf life should cover duration of trial. Stability studies needed when
significant modification to comparator.
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Changes to an IMPD
Changes to the IMP quality data are only considered “significant” where
they are likely to have an impact on:
•
Safety or physical mentality of the patients,
•
Scientific values of the trial
•
Conduct or management of the trial
•
Quality or safety of any IMP used in the trial.
An amendment to the IMPD is only considered “substantial” when one or
more of above are met.
Examples of substantial amendment:
•
Change to a new manufacturer of API (new company)
•
Deletion of test(s) from finished product specification
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