INVESTIGATION OF

MEDICINAL PRODUCTS
DOSSIER
CONTENTS
•Overview: EMA
•Drug approval process
•Clinical trial application
•IMPD: Introduction
•What is IMPD
•Format of IMPD
•Contents of IMPD
•Objectives
•Scope
•Guidance & legal basis
 Overview: EMA
European Medical Agency (EMA) is decentralized agency in EU which is
responsible for scientif ic evaluation, supervision and safety monitoring of
medicines developed by pharmaceutical companies for use in EU.

EMA protect the public and animal health in 27 EU member states as well as
the countries of the European Economic Area, by ensuring that all medicines
available in EU market are safe effective and of high quality.
 DRUG APPROVAL PROCESS
There are two regulatory steps to go through before a drug is approved to be
marketed in EU.

These two steps are:

1) Clinical trial application:(approved at member state level)
2) Marketing authorization application:(approved at member state level as
well as centralized level)

Qualified person has to certify that the IMP are manufactured according to
GMP or not.

Competent authority has right to inspect:

a) Manufacturing facility (For GMP Compliance) ,
b) Preclinical facility (GLP Compliance) and
c) Clinical trial sites (GCP Compliance)
CLINICAL TRIAL APPLICATION (CTA)

• The sponsor submit clinical trial application to competent

authority in each member state in which clinical trials are to be
conducted.
• The competent authority has 60 days to review and approve or
reject the application.
• Application is in prescribed form & cover
• 1)The proposed clinical trial protocol.
• 2) Manufacturing and quality control of drug and
• 3)supporting documents such as: -
 Chemical, pharmacological and biological data.
 Non clinical pharmacological & toxicological data. (Module 4 of
CTD)
 Previous human experience and clinical data (If any).
• 4)The CMC (quality) information is presented in IMPD - is one
n. of the Core Documents of CTA
INVESTIGATIONAL MEDICAL PRODUCT DOSSIER (IMPD)
• IMPD is basis for approval of clinical trials by competent authorities in EU.
• The Clinical trial Directive came in force, harmonizing the laws, regulations
and administrative provisions of the member states relating to the
implementation of GCP in the conduct of clinical trials on medicinal
products for human use and harmonizing the procedure for authorization.
 It defines the documentation to be submitted to Ethics committee as well as
IMPD to be submitted to the competent authority for approval.
 The IMPD is one of several pieces of Investigational Medicinal Product (IMP)
related data required whenever the performance of a clinical trial is intended in
one or more European Union Member States.
 The IMPD includes summaries of information related to the quality,
manufacture and control of any IMP (including reference product and placebo),
and data from non-clinical and clinical studies.
Dossier – A collection of documents about a particular person, event or subject.
Medicinal product dossier – File containing detailed records about a particular
drug product.
WHAT IS IMPD ?

The IMPD is a document divided in four distinct sections. It provides

information on
(i) the quality, manufacture and control of the IMP,
(ii) the non-clinical studies conducted with the IMP,
(iii) the clinical use of the IMP, and
(iv) the overall risk / benefit assessment of the IMP in the proposed trial.
• IMPDs are submitted as part of clinical trial application (CTA) dossier, as
the basis for approval of clinical trials by competent regulatory authorities (Cas)
within EU.
FORMAT OF IMPD: IMPD follow the structure of CTD module (3).
IMPD CONTENTS:
Table of content for full IMPD follows the headings given by guidelines.
1) Drug Substance
2) Investigational Medical Product(IMP) Under Test.
3) Appendices
 Imp under test-
Drug Substance 1) Description and Composition of the Medicinal Product
2)Pharmaceutical Development –
1) General information
3)Manufacture –
-Nomenclature - Manufacturer(s) -name(s), address,responsibilities
-Structure -Control of critical steps and intermediates
-Process validation
-Generak properties
+Batch formula
2) Manufacture +Description of manufacturing process and process
- Manufacture's name,address, responsiblilty controls
-Control of critical steps and intermediates -3)Control of excipients –
-Specification
-Process validation and evaluation -Justification of specification
Manufacturing process development -Analytical procedures
3) characterization -validation of analytical procedures
+Excipients of human or animal origin
-Elucidation of structure +Novel excipients
-Impurities 4) Control of the investigational medicinal product
-Description of Manufacturing Process -Specification
-Justification of specification
-Controls of material -Batch analysis
4)Control of drug substance -Analytical procedures
-Specification -validation of analytical procedures
-Reference standard or materials
-Justification of specification
-Container-Closure system
-Batch analysis -Stabilit
-Analytical procedures Appendices
Adventitious agents safety evaluation -
-validation of analytical procedures
- TSE agents
-Reference standard or materials -Viral safety
-Container-Closure system -Other adventitious agents
-Stability -Excipients
-Solvents
 1) Drug Substance
1) General Information
i) Nomenclature - Information concerning the nomenclature of the drug
substance, pharmacopoeial name, chemical name (IUPAC),laboratory code,
other names or codes, if any) should be given.
ii) Structure - They should include the structural formula, molecular weight,
chirality/stereochemistry as far as elucidated.
iii) General Properties - A list of physico-chemical and other relevant
properties of the active substance should be provided, in particular physico-
chemical properties that could affect pharmacological or toxicological
safety, such as solubilities, pKa, polymorphism, isomerism, log P,
permeability etc.
2) Manufacture:
i) Manufacturer(s) - The name(s) and address(es) and responsibilities of all
manufacturer(s), including contractors, and each proposed site involved in
manufacture and testing should be provided.
iv) Controls of Critical Steps and Intermediates - In case of critical steps in the synthesis,
tests and acceptance criteria for their control should be briefly summarised.

v) Process validation and/or evaluation - Not applicable for drug substances to be used
in clinical trials.

vi) Manufacturing Process Development - It should be documented if the manufacturing

process significantly differs from that used for the production of the batches used in the
non-clinical studies. In this case, a flow chart of the manufacturing process used for the
drug substance used in the non-clinical studies should be presented.

3) Characterization:
i) Elucidation of Structure and Other Characteristics – The structure of chemically
defined substances should be established with suitable methodology; relevant data
should be provided.
ii) Impurities - In cases where reference to a pharmacopoeial monograph listed above
cannot be made, impurities (e.g. degradation products, residual solvents) deriving
from the manufacturing process or starting materials relevant to the drug substance
used for the clinical trial, should be stated.
ii) Description of Manufacturing Process and Process - A brief summary of the
synthesis process, a flow chart of the successive steps including, for each
step, the starting materials, intermediates, solvents, catalysts and critical
reagents used should be provided.

iii) Control of Materials - Materials used in the manufacture of the drug

substance (e.g. raw materials, starting materials, solvents, reagents,
catalysts) should be listed together with a brief summary on the quality and
control of any attributes anticipated to be critical, for example, where
control is required to limit an impurity in the drug substance, e.g. chiral
control, metal catalyst control or control of a precursor to a potential geno-
toxic impurity. For radio-nuclides, details on the target material should be
given.
4) Control of Drug Substance
i) Specification - The specifications, the tests used as well as their acceptance criteria
should be specified for the batch(es) of drug substance(s) used in the clinical trial.
Tests for identity, impurities and assay are mandatory.
ii) Analytical Procedures - The analytical methods used for the drug substance should be
described for all tests included in the specification (e.g. reverse-phase-HPLC-UV,
potentiometric titration, head-space-GC-FID, etc.). It is not necessary to provide a
detailed description of the analytical procedures.
iii) Validation of Analytical Procedures - The suitability of the analytical methods used
should be confirmed. The acceptance limits (e.g. acceptance limits for the
determination of the content of impurities, where relevant) and the parameters
(specificity, linearity, range, accuracy, precision, quantification and detection limit, as
appropriate) for performing validation of the analytical methods should be presented
in a tabulated form.
iv) Batch Analyses - Batch results in a tabulated form or certificate of analysis for batches
to be used in the current clinical trial, for batches used in the non-clinical studies and,
where needed, for representative batches used in previous clinical trials should be
supplied.
v) Justification of specification – For substances for which reference to a
pharmacopoeial monograph listed under 2.2.1.S.4.1 cannot be made, a brief
justification of the specifications and acceptance criteria for impurities and any other
parameters which may be relevant to the performance of the drug product should be
provided based on safety and toxicity data, as well as the methods used for the
control of impurities. The solvents and catalysts used in the synthesis should be
taken into consideration.
vi) Reference Standards or Materials – The parameters characterizing the batch of drug
substance established as reference standard should be presented, where applicable.
vii) Container Closure System – The immediate packaging material used for the drug
substance should be stated. If non-compendial materials are used, a description and
specifications should be provided.
vii) Stability - The stability data available at the respective stage of development should
be summarised in tables. Stability data should be provided for batch(es)
manufactured according to the representative process (the same/very similar
synthesis, comparable batch size) and can be supported by data from batch(es)
manufactured by previous processes. The parameters known to be critical for the
stability of the drug substance need to be presented, i.e. chemical and physical
sensitivity, e.g. photosensitivity, hygroscopicity. Potential degradation pathways
should be described.
2) INVESTIGATIONAL MEDICINAL PRODUCT UNDER TEST

1) Description and Composition of the Medicinal Product –

The qualitative and quantitative composition of the IMP should be stated. The
information provided should include:
• a short statement or a tabulation of the dosage form
• composition, i.e. list of all components of the dosage form and their amount on a
per-unit basis (including overages, if any), the function of the components, and a
reference to their quality standards (e.g. compendial monographs or manufacturer’s
specifications)
• description of accompanying diluents(s)
2) Pharmaceutical Development –
A short description of formulation development, including justification of any new
pharmaceutical form or excipient, should be provided. For early development, there may
be no or only limited information to include in this section. The medicinal product
components, the dosage form and the administration device if any should be safe and
suitable for the patient population. Where applicable, the compatibility with solvents used
for reconstitution, diluents and admixtures should be demonstrated.
 Manufacturing process development - Changes in the manufacturing process including
changes in formulation and dosage form compared to previous clinical trials should be
described. An appropriate comparability exercise should support significant changes.
This data should be sufficiently detailed to allow an appropriate understanding of the
changes and assessment of possible consequences to the safety of the patient. Any
changes in the formulation during the clinical phases should be documented and justified
with respect to their impact on quality, safety, clinical properties, dosing and stability of
the medicinal product.
3) Manufacture –
i) Manufacturer(s) - The name(s), address(es) and responsibilities of all manufacturer(s)
and each proposed production site involved in manufacture, testing and batch
release should be provided. .
ii) Batch formula - The batch formula for the batch(es) to be used for the clinical trial
should be presented. This should include a list of all components. The batch sizes or
range of batch sizes should be given.
iii) Description of manufacturing process and process controls - A flow chart showing all
steps of the manufacturing process, including relevant IPCs (process parameters and
in-process-tests), should be provided accompanied by a brief process description.
The IPCs may be recorded as action limits or reported as preliminary acceptance
criteria and the focus should be on safety relevant attributes.
 iv) Control of critical steps and intermediates - Tests and acceptance criteria
for the control of critical steps in the manufacturing process should be
provided.
v) Process validation - The state of validation of aseptic processing and
lyophilisation should be briefly described, if applicable. The dossier should
particularly include information directly relating to the product safety, i.e. on
bioburden and media fill runs.
4) Control of excipients –
i) Specification – References of the pharmacopoeia of an EU Member State, USP or JP
may be made. For excipients not covered by any of the aforementioned standards,
an in-house specification should be provided.
ii) Analytical procedures - In cases where reference to a pharmacopoeial monograph
listed under cannot be made, the analytical methods used should be indicated.
iii) Validation of the analytical procedures - Not applicable.
iv) Justification of specification - For non-compendial excipients as listed above the in-
house specification should be justified.
v) Excipients of human or animal origin - For excipients of human or animal origin,
information should be provided regarding adventitious agents safety evaluation (e.g.
sources, specifications, description of the testing performed) and viral safety data
according to the Guideline on virus safety evaluation of biotechnological
investigational medicinal.
 vi) Novel excipients - For excipients used for the first time in a medicinal
product or by a new route of administration, full details of manufacture,
characterisation and controls, with cross references to supporting safety
data (non-clinical and/or clinical), should be provided according to the active
substance format .
5) Control of the investigational medicinal product –
i) Specification - The same principles as described for setting the active substance
specification should be applied to the medicinal product. In the specification, the
tests used as well as their acceptance criteria should be defined for the batch(es) of
the product to be used in the clinical trial to enable sufficient control of quality of the
product. Tests for content, identity and purity are mandatory.
ii) Analytical procedures - The analytical methods for all tests included in the
specification should be described. For some proteins and complex or innovative
pharmaceutical forms, a higher level of detail may be required.
iii) Validation of analytical procedures –
iv) Batch analysis - As specifications may initially be very wide, actual batch data are
important for quality assessment. For quantitative parameters, actual numerical
values should be presented.
v) Characterisation of impurities - Additional impurities and degradation products
observed in the IMP should be identified and quantified as necessary.
vi) Justification of specification - A justification for the quality attributes included in the
product specification should be provided mainly based on the active substance
specification. Stability indicating quality attributes should be considered. The proposed
acceptance criteria should be justified.
6) Reference standards or materials -The parameters for characterisation
of the reference standard should be submitted, where applicable.

7) Container closure system – The intended primary packaging to be used for

the IMP in the clinical trial should be described. Where appropriate, reference should be
made to the relevant pharmacopoeial monograph. If the product is packed in a non-
standard administration device, or if non-compendial materials are used, description and
specifications should be provided.
8) Stability – The same requirements as for the active substance are applied to
the medicinal product, including the stability protocol, stability results, shelf-life
determination, including extension of shelf-life beyond the period covered by real-time
stability data, stability commitment and post-approval extension. Stability studies should
provide sufficient assurance that the IMP will be stable during its intended storage period.
The presented data should justify the proposed shelf life of the product from its release
to its administration to patients. The stability protocol for the IMP should take into
account the knowledge acquired on the stability profile of the active substance.
 3) APPENDICES
Facilities and equipment –
Adventitious agents safety evaluation - All materials of human or animal origin use
in the manufacturing process of both the active substance and the medicinal product, or
such materials coming into contact with active substance or medicinal product during th
manufacturing process, should be identified. Information assessing the risk with respect
to potential contamination with adventitious agents of human or animal origin should be
provided.
TSE agents - Detailed information should be provided on the avoidance and control of
Transmissible Spongiform Encephalopathy agents. This information can include, for
example, certification & control of the production process, as appropriate for the materia
process & agent.
Viral safety - Where applicable, an assessment of the risk with respect to potential viral
contamination should be provided in this section. The documentation should comply wit
the requirements outlined in the guideline on virus safety evaluation of biotechnological
investigational medicinal products.
Other adventitious agents - Detailed information regarding other adventitious agents,
such as bacteria, mycoplasma, & fungi should be provided in appropriate sections within
the core dossier.
Excipients – For novel excipients, information as indicated in section S should be
provided in line with the respective clinical phase.
Solvents –For reconstitution and diluents For solvents for reconstitution and diluents,
th l ti f ti i di t di ti P h ld b id d
 Manufacturing authorization & reconstitution

• Both the total and partial manufacture of investigational medicinal products, as well
as the various processes of dividing up, packaging or presentation, is subject to the
authorization referred to in Article 13(1) Directive 2001/20/EC, cf. Article 9(1) Directive
2005/28/EC. This authorization, however, shall not be required for reconstitution
under the conditions set out in Article 9(2) Directive 2005/28/EC. For the purpose of
this provision, reconstitution shall be understood as a simple process of:
• dissolving or dispersing the investigational medicinal product for administration of the
product to a trial subject,
• or, diluting or mixing the investigational medicinal product(s) with some other
substance(s) used as a vehicle for the purposes of administering it,
• Reconstitution is not mixing several ingredients, including the active substance,
together to produce the investigational medicinal product.
• An investigational medicinal product must exist before a process can be defined as
reconstitution.
• The process of reconstitution has to be undertaken as soon as practicable before
administration.”
• “The reconstitution is understood as the simple process of dissolving or dispersing the
investigational medicinal product for administration of the product to a trial subject, or
diluting or mixing the investigation medicinal product with some other substance(s)
used as a vehicle for the purpose of administering it to a trial subject.
• Reconstitution is not mixing several ingredients, including the active substance,
together to produce the investigational medicinal product. An investigational
medicinal product must exist before a process can be defined as reconstitution
 CLINICAL TRIALS –OBJECTIVES
Clinical trial often to be designed as multi-center studies potentially involve in different
member states. Aim of these guidelines to defines harmonized requirement of
documentation to be submitted throughout the European community.

SCOPE -Guidelines addressed to IMPs containing chemically defined active substances,

synthetic peptides, herbal substance, herbal preparation and chemically defined radio
active/radio labelled substance. It include requirements of IMPs to be tested in phase I,
phase II and phase III clinical studies. Guidelines addresses the documentation on the
chemical and pharmaceutical quality of IMPS containing chemically defined active
substances, synthetic peptides, herbal substance, herbal preparation and chemically
defined radio active/radio labeled substances to be submitted to the competent authority
for approval prior to beginning a clinical trial in humans. It include requirements of IMPS
to be tested in phase I, phase II and phase III clinical studies.

GUIDANCE AND LEGAL BASIS: The guidance is based on Regulation (EU) No 536/2014
on Clinical Trials on Medicinal Products for Human Use (Repealing Directive 2001/20/EC)
on the approximation of laws, regulations and administrative provisions of the Member
States. The Regulation comes into force in 2016, harmonizing the laws, regulations and
administrative provisions of the Member States relating to the implementation of Good
Clinical Practice (GCP) in the conduct of clinical trials on medicinal products for human
use. European Member States have transformed the requirements outlined in the
Directive into the respective national laws.
 DIFFERENCE BETWEEN IB & IMPD
IB IMPD
IB is a document for trial Regulatory document for CT approval,
investigators, summarizing the non- containing comprehensive data on the
clinical and clinical data to inform product quality, manufacturing, and risk
them about the product’s properties, benefit analysis, primarily for EU
rationale, and safety
Primary Clinical investigators & other key trial Regulatory authorities (EU)
Audienc personnel
e
Purpose To provide investigators with To serve as the basis for regulatory
information to understand the about approval of the clinical trial
the investigational product’s
rationale, risk and safety for
conducting the trial
content A compilation of clinical and non- A comprehensive dossier of data,
clinical data relevant to the study in including quality manufacturing, non-
human. Includes summaries of non- clinical and clinical information. It is
clinical and clinical data, adverse more detailed and can be full or
reactions and guidance for simplified
investigators
f Cli i l t i l d t d th P d td l t f t i
 GUIDANCE AND LEGAL BASIS -
The guidance is based on Regulation (EU) No 536/2014 on Clinical Trials on Medicinal
Products for Human Use (Repealing Directive 2001/20/EC) on the approximation of laws,
regulations and administrative provisions of member states relating to implementation of
GCP in clinical trials.

The Regulation comes into force in 2016, harmonizing the laws, regulations and
administrative provisions of the Member States relating to the implementation of Good
Clinical Practice (GCP) in the conduct of clinical trials on medicinal products for human
use.

European Member States have transformed the requirements outlined in the Directive
into the respective national laws.

The IMPD includes summaries of information related to the quality, manufacture and
control of the investigational medicinal product , data from non- clinical studies and from
its clinical use.