27 January 2022

EMA/CHMP/QWP/545525/2017 Rev. 2
Committee for Medicinal Products for Human Use (CHMP)

Guideline on the requirements to the chemical and

pharmaceutical quality documentation concerning
investigational medicinal products in clinical trials

Draft agreed by Quality Working Party December 2015

Adopted by CHMP for release for consultation December 2015

Consultation of European Commission ad hoc group on clinical trials February 2016

Start of public consultation 12 April 2016

End of consultation (deadline for comments) 12 October 2016

Agreed by Quality Working Party May 2017

Consultation of European Commission ad hoc group on clinical trials June 2017

Rev. 1 Adopted by CHMP 14 September 2017

Date coming into effect 6 months after publication

Draft update of Chapter 9 agreed by Quality Working Party 6 June 2021

Draft Rev. 2 Adoption by Committee for Medicinal Products for Human 24 June 2021
Use for release for consultation

Start of public consultation 1 July 2021

End of consultation (deadline for comments) 31 August 2021

Update of Chapter 9 agreed by Quality Working Party November 2021

Rev. 2 Adopted by CHMP 27 January 2022

Date coming into effect (Rev. 2) 31 January 2022

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This guideline replaces the “Guideline on the requirements to the chemical and pharmaceutical quality

documentation concerning investigational medicinal products in clinical trials”

(CHMP/QWP/185401/2004 final)

Keywords Guideline, Clinical Trial, Quality

This guideline replaces the “Guideline on the requirements to the chemical and
pharmaceutical quality documentation concerning investigational medicinal products in
clinical trials” (CHMP/QWP/185401/2004 final)
EMA/CHMP/QWP/545525/2017 Rev. 2 Page 2/3
Guideline on the requirements for the chemical and
pharmaceutical quality documentation concerning
investigational medicinal products in clinical trials
Table of contents
1. Introduction ....................................................................................................................... 8
1.1. Objectives of the guideline .................................................................................. 8
1.2. Scope of the guideline ........................................................................................ 8
1.3. General points concerning all IMPs ........................................................................ 8
1.4. Submission of data ............................................................................................. 9
1.5. General considerations ........................................................................................ 9
2. Information on the chemical and pharmaceutical quality concerning investigational
medicinal products in clinical trials ........................................................................................ 9

2.2.1.S Drug substance ......................................................................................................... 9

2.2.1.S.1 General information ................................................................................. 10
2.2.1.S.1.1 Nomenclature ....................................................................................... 10
2.2.1.S.1.2 Structure ............................................................................................. 10
2.2.1.S.1.3 General properties................................................................................. 10
2.2.1.S.2 Manufacture ............................................................................................ 11
2.2.1.S.2.1 Manufacturer(s) .................................................................................... 11
2.2.1.S.2.2 Description of manufacturing process and process controls.......................... 11
2.2.1.S.2.3 Control of materials ............................................................................... 11
2.2.1.S.2.4 Control of critical steps and intermediates................................................. 12
2.2.1.S.2.5 Process validation and/or evaluation ........................................................ 12
2.2.1.S.2.6. Manufacturing process development ....................................................... 12
2.2.1.S.3 Characterisation ...................................................................................... 12
2.2.1.S.3.1 Elucidation of structure and other characteristics ....................................... 12
2.2.1.S.3.2 Impurities ............................................................................................ 12
2.2.1.S.4 Control of the Drug Substance ................................................................... 13
2.2.1.S.4.1 Specification(s) ..................................................................................... 13
Additional information for phase II and phase III clinical trials....................................... 13
2.2.1.S.4.2 Analytical procedures............................................................................. 13
2.2.1.S.4.3 Validation of analytical procedures ........................................................... 14
Information for phase I clinical trials ......................................................................... 14
Information for phase II and III clinical trials .............................................................. 14
2.2.1.S.4.4 Batch analyses ..................................................................................... 14
2.2.1.S.4.5 Justification of specification(s) ................................................................ 14
2.2.1.S.5 Reference standards or materials ............................................................... 14
2.2.1.S.6 Container closure system .......................................................................... 15
2.2.1.S.7 Stability.................................................................................................. 15
2.2.1.P Investigational medicinal product under test .......................................................... 15
2.2.1.P.1 Description and composition of the investigational medicinal product ............... 15

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2.2.1.P.2 Pharmaceutical development ..................................................................... 16
Additional information for phase II and phase III clinical trials....................................... 16
2.2.1.P.2.1 Manufacturing process development......................................................... 16
2.2.1.P.3 Manufacture ............................................................................................ 16
2.2.1.P.3.1 Manufacturer(s) .................................................................................... 16
2.2.1.P.3.2 Batch formula ....................................................................................... 17
2.2.1.P.3.3 Description of manufacturing process and process controls .......................... 17
2.2.1.P.3.4 Controls of critical steps and intermediates ............................................... 17
Additional information for phase III clinical trials ......................................................... 17
2.2.1.P.3.5 Process validation and/or evaluation ........................................................ 17
2.2.1.P.4 Control of excipients ................................................................................. 17
2.2.1.P.4.1 Specifications ....................................................................................... 17
2.2.1.P.4.2 Analytical procedures ............................................................................. 18
2.2.1.P.4.3 Validation of the analytical procedures...................................................... 18
2.2.1.P.4.4 Justification of specifications ................................................................... 18
2.2.1.P.4.5 Excipients of animal or human origin ........................................................ 18
2.2.1.P.4.6 Novel excipients .................................................................................... 18
2.2.1.P.5 Control of the investigational medicinal product ............................................ 18
2.2.1.P.5.1 Specifications ....................................................................................... 18
Additional information for phase II and phase III clinical trials....................................... 19
2.2.1.P.5.2 Analytical procedures ............................................................................. 19
2.2.1.P.5.3 Validation of analytical procedures ........................................................... 19
Additional information for phase II and III clinical trials ................................................ 19
2.2.1.P.5.4 Batch analyses ...................................................................................... 19
2.2.1.P.5.5 Characterisation of impurities .................................................................. 19
2.2.1.P.5.6 Justification of specification(s) ................................................................. 20
Additional information for phase II and phase III clinical trials....................................... 20
2.2.1.P.6 Reference standards or materials ............................................................... 20
2.2.1.P.7 Container closure system .......................................................................... 20
2.2.1.P.8 Stability .................................................................................................. 20
Information for phase I clinical trials ......................................................................... 21
Additional information for phase II and phase III clinical trials....................................... 22
3. Information on the chemical and pharmaceutical quality of authorised, non-modified test
and comparator products in clinical trials ............................................................................ 22

4. Information on the chemical and pharmaceutical quality of modified authorised test and
comparator products in clinical trials ................................................................................... 22

4.2.1.P Modified test/comparator product .......................................................................... 22

4.2.1.P.1 Description and composition ...................................................................... 22
4.2.1.P.2 Pharmaceutical development ..................................................................... 23
4.2.1.P.3 Manufacture ............................................................................................ 23
4.2.1.P.3.1 Manufacturer(s) related to the modification ............................................... 23
4.2.1.P.3.2 Batch formula ....................................................................................... 23
4.2.1.P.3.3 Description of manufacturing process and process controls .......................... 23
4.2.1.P.4 Control of excipients ................................................................................. 23

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4.2.1.P.4.1 Specifications ....................................................................................... 23
4.2.1.P.4.2 Analytical procedures ............................................................................. 24
4.2.1.P.4.3 Validation of analytical procedures ........................................................... 24
4.2.1.P.4.4 Justification of specifications ................................................................... 24
4.2.1.P.4.5 Excipients of animal or human origin ........................................................ 24
4.2.1.P.5 Control of the modified authorised product ................................................. 24
4.2.1.P.5.1 Specifications ....................................................................................... 24
4.2.1.P.5.2 Analytical procedures ............................................................................. 24
4.2.1.P.5.3 Validation of analytical procedures ........................................................... 24
4.2.1.P.5.4 Batch analyses ...................................................................................... 25
4.2.1.P.5.5 Characterisation of impurities .................................................................. 25
4.2.1.P.5.6 Justification of specification(s) ................................................................. 25
4.2.1.P.7 Container closure system .......................................................................... 25
4.2.1.P.8 Stability .................................................................................................. 25
5. Information on the chemical and pharmaceutical quality of investigational medicinal
products containing existing active substances used in bio-equivalence studies, e.g.
generics (chemical substances) ........................................................................................... 26

5.2.1.S Drug substance ....................................................................................................... 26

5.2.1.S.1 General information ................................................................................. 26
5.2.1.S.1.1 Nomenclature ....................................................................................... 26
5.2.1.S.1.2 Structure ............................................................................................. 26
5.2.1.S.1.3 General Properties................................................................................. 26
5.2.1.S.2 Manufacture ............................................................................................ 27
5.2.1.S.2.1 Manufacturer(s) .................................................................................... 27
5.2.1.S.2.2 Description of manufacturing process and process controls.......................... 27
5.2.1.S.3 Characterisation ...................................................................................... 27
5.2.1.S.3.2 Impurities ............................................................................................ 27
5.2.1.S.4 Control of the drug substance .................................................................... 27
5.2.1.S.4.1 Specifications ....................................................................................... 27
5.2.1.S.4.2 Analytical procedures............................................................................. 28
5.2.1.S.4.3 Validation of analytical procedures ........................................................... 28
5.2.1.S.4.4 Batch analyses ..................................................................................... 28
5.2.1.S.4.5 Justification of specifications ................................................................... 28
5.2.1.S.5 Reference Standards or materials ............................................................... 28
5.2.1.S.6 Container closure system .......................................................................... 28
5.2.1.S.7 Stability.................................................................................................. 28
5.2.1.P Investigational medicinal product under test .......................................................... 29
5.2.1.P.1 Description and composition ...................................................................... 29
5.2.1.P.2 Pharmaceutical development ..................................................................... 29
5.2.1.P.3 Manufacture ............................................................................................ 29
5.2.1.P.3.1 Manufacturer(s) .................................................................................... 29
5.2.1.P.3.2 Batch formula ....................................................................................... 29
5.2.1.P.3.3 Description of manufacturing process and process controls .......................... 29
5.2.1.P.3.4 Control of critical steps and intermediates ................................................. 29

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5.2.1.P.3.5 Process validation and/or evaluation ........................................................ 30
5.2.1.P.4 Control of excipients ................................................................................. 30
5.2.1.P.4.1 Specifications ....................................................................................... 30
5.2.1.P.4.2 Analytical procedures ............................................................................ 30
5.2.1.P.4.3 Validation of analytical procedures ........................................................... 30
5.2.1.P.4.4 Justification of specifications ................................................................... 30
5.2.1.P.4.5 Excipients of animal or human origin ........................................................ 30
5.2.1.P.4.6 Novel excipients .................................................................................... 30
5.2.1.P.5 Control of the investigational medicinal product ............................................ 30
5.2.1.P.5.1 Specifications ....................................................................................... 30
5.2.1.P.5.2 Analytical procedures ............................................................................. 31
5.2.1.P.5.3 Validation of analytical procedures ........................................................... 31
5.2.1.P.5.4 Batch analyses ...................................................................................... 31
5.2.1.P.5.5 Characterisation of impurities .................................................................. 31
5.2.1.P.5.6 Justification of specification(s) ................................................................. 31
5.2.1.P.6 Reference standards or materials ............................................................... 31
5.2.1.P.7 Container closure system .......................................................................... 31
5.2.1.P.8 Stability .................................................................................................. 32
6. Information on the chemical and pharmaceutical quality concerning placebo products in
clinical trials ........................................................................................................................ 32

6.2.1.P Placebo product in clinical trials.............................................................................. 32

6.2.1.P.1 Description and composition ...................................................................... 32
6.2.1.P.2 Pharmaceutical development ..................................................................... 32
6.2.1.P.3 Manufacture ............................................................................................ 32
6.2.1.P.3.1 Manufacturer(s) .................................................................................... 32
6.2.1.P.3.2 Batch formula ....................................................................................... 33
6.2.1.P.3.3 Description of manufacturing process and process controls .......................... 33
6.2.1.P.3.4 Control of critical steps and intermediates ................................................. 33
6.2.1.P.3.5 Process validation and/or evaluation ........................................................ 33
6.2.1.P.4 Control of excipients ................................................................................. 33
6.2.1.P.4.1 Specifications ....................................................................................... 33
6.2.1.P.4.2 Analytical procedures ............................................................................. 33
6.2.1.P.4.3 Validation of analytical procedures ........................................................... 33
6.2.1.P.4.4 Justification of specifications ................................................................... 33
6.2.1.P.4.5 Excipients of animal or human origin ........................................................ 33
6.2.1.P.4.6 Novel excipients .................................................................................... 34
6.2.1.P.5 Control of the placebo product ................................................................... 34
6.2.1.P.5.1 Specifications ....................................................................................... 34
6.2.1.P.5.2 Analytical procedures ............................................................................. 34
6.2.1.P.7 Container closure system .......................................................................... 34
6.2.1.P.8 Stability .................................................................................................. 34

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7. Appendices ...................................................................................................................... 34

7.2.1.A.1 Facilities and equipment ...................................................................................... 34

7.2.1.A.2 Adventitious agents safety evaluation ................................................................. 34

TSE agents ............................................................................................................ 35
Viral safety ............................................................................................................ 35
Other adventitious agents ........................................................................................ 35
7.2.1.A.3 Novel excipients................................................................................................... 35

7.2.1.A.4 Solvents for reconstitution and diluents .............................................................. 35

8. Auxiliary medicinal products ............................................................................................ 35

9. Changes to the investigational medicinal product and auxiliary medicinal product with a
need to request a substantial modification to the IMPD....................................................... 35

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1. Introduction
1.1. Objectives of the guideline

The following guideline is to be seen in connection with Regulation (EU) No. 536/2014 on clinical trials
on medicinal products for human use, and repealing Directive 2001/20/EC, which came into force on
June 20, 2014.

Since clinical trials will often be designed as multi -centre 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 Union.

It should be clearly differentiated between the requirements for a dossier for a clinical trial and a
marketing authorisation dossier. Whilst the latter ones have to ensure a state-of-the-art quality of a
product for wide use in patients, information to be provided for investigational medicinal products
(IMPs) should focus on the risk aspects and should consider the nature of the product, the state of
development/clinical phase, patient population, nature and severity of the illness as well as type and
duration of the clinical trial itself. As a consequence, it will not be possible to define very detailed
requirements applicable to all sorts of different products. However, guidance on standard information
which should normally be presented in the quality part of an IMPD is provided in this guideline.

1.2. Scope of the guideline

This guideline addresses the documentation on the chemical and pharmaceutical quality of IMPs and
Auxiliary Medicinal Products containing chemically defined drug substances, synthetic peptides,
synthetic oligonucleotides, 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 and Auxiliary Medicinal
Products to be tested in phase I, phase II, phase III and phase IV studies as well as the requirements
for modified and unmodified comparator products and IMPs to be tested in generic bioequivalence
studies.

When compiling the quality part of the IMPD for phase II and phase III clinical studies, the larger and
longer exposure of patients to the product have to be taken into account compared to phase I clinical
studies. Based on the diversity of products to be used in the different phases of clinical trials, the
requirements defined in this guideline can only be of an illustrative nature and cannot be expected to
present an exhaustive list. IMPs based on innovative and/or complex technologies may need more
detailed data to be submitted. For certain situations, e.g. where the drug substance from the specific
source to be used for an IMP is already included in a medicinal product authorised within the EU, not
all the documentation outlined in the following chapters need to be submitted in the IMPD, but a
simplified IMPD will suffice.

1.3. General points concerning all IMPs

IMPs should be produced in accordance with the principles and the detailed guidelines of Good
Manufacturing Practices for Medicinal Products.

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1.4. Submission of data

The IMPD should be provided in a clearly structured format following the numbering system as given in
the chapters 2 to 8 of this Guideline. However, the first Arabic number being introduced only to
facilitate the Guideline’s use should be omitted.

The IMPD should include the most up-to-date information relevant to the clinical trial available at time
of submission of the clinical trial application.

1.5. General considerations

For drug substances or IMPs to be used in clinical trials as described in chapters 2 to 8, reference to
either the European Pharmacopoeia (Ph. Eur.), the Pharmacopoeia of an EU Member State, the United
States Pharmacopoeia (USP) or the Japanese Pharmacopoeia (JP) is acceptable. For active substances,
the suitability of the referenced monograph to adequately control the quality of the active substance
(impurity profile) will have to be demonstrated by the applicant/sponsor. Suitability of monographs of
the European Pharmacopoeia (Ph. Eur.) can be demonstrated with certificates of suitability (CEP)
issued by the European Directorate for the Quality of Medicines (EDQM). In other cases, information on
the synthesis of the drug substance, including reagents, solvents, catalysts and processing aids, should
be provided.

For generic bioequivalence studies as described in chapter 5 which will support a Marketing
Authorisation Application (MAA) in the EU, applicants/sponsors are advised that reference to the Ph.
Eur. will facilitate future licensing activities in the EU.

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.

When compiling the documentation, the difference between “analytical procedure” and “analytical
method” should be kept in mind. The term “analytical procedure” is defined in ICH Q 2 (A) and refers
to the way of performing the analysis. The term “analytical method” refers to the principles of the
method used.

2. Information on the chemical and pharmaceutical quality

concerning investigational medicinal products in clinical trials

2.2.1.S Drug substance

Reference to an Active Substance Master File or a Certificate of Suitability of the European Directorate
for the Quality of Medicines is acceptable. The procedure as described in the “Guideline on Active
Substance Master File Procedure – CPMP/QWP/227/02 Rev 3 corr” and the “Guideline on Summary of
Requirements for Active Substances in the Quality Part of the Dossier – CHMP/QWP/297/97 Rev 1” in
their current version should be followed, even though no specific reference to clinical trials application
is included.

For reference to pharmacopoeial monographs, see chapter 1.5 General Considerations.

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If the Active substance used is already authorised in a drug product within the EU/EEA or in one of the
ICH-regions, reference can be made to the valid marketing authorisation. A statement from Marketing
Authorisation Holder or drug substance manufacturer should be provided that the active substance has
the same quality as in the approved product.

Name of the drug product, marketing authorisation number or its equivalent, marketing authorisation
holder and the country that granted the marketing authorisation should be given.

2.2.1.S.1 General information

2.2.1.S.1.1 Nomenclature

Information concerning the nomenclature of the drug substance (e.g. INN-name (if approved),
pharmacopoeial name, chemical name (IUPAC, CAS-RN), laboratory code, other names or codes, if
any) should be given. In the case of radio-nuclides or radio-labelled substances which are used in
phase I studies in humans to develop a non-radioactive medicinal product, the radio-nuclide or the
radio-labelled substance should be stated additionally.

For radio-nuclides, the isotope type should be stated (IUPAC-nomenclature).

In the case of radio-nuclide generators, both parent radio-nuclide and daughter radio-nuclide are
considered as drug substances. For kits, which are to be radio-labelled, the part of the formulation
which will carry or bind the radio-nuclide should be stated as well as the radio-labelled product. For
organic-chemical precursors, the same information should be provided as for drug substances.

For herbal substances the binominal scientific name of the plant (genus, species, variety and author)
and the chemotype as well as the parts of the plant, the definition of the herbal substance, other
names (synonyms mentioned in other Pharmacopoeias) and the laboratory code should be provided.

In addition, for herbal preparations the ratio of the herbal substance to the herbal preparation as well
as the extraction solvent(s) used for extraction should be stated.

2.2.1.S.1.2 Structure

The data available at the respective stage of clinical development should be presented. They should
include the structural formula, molecular weight, chirality/stereochemistry as far as elucidated.

In the case of radio-nuclides or radio-labelled substances which are used in phase I studies in humans
to develop a non-radioactive medicinal product, the structural formula before and – if known – after
the radio-labelling should be given. For kits for radiopharmaceutical preparations, the ligand's
structural formula before and, if known, after the radio-labelling should be given.

In addition, the physical state, the extract type, if known the constituent(s) relevant for the
therapeutic activity or the analytical marker substance(s) used should be stated for herbal substances
and herbal preparations. Information about excipients in the final herbal preparations should be
provided.

2.2.1.S.1.3 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.

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For radio-nuclides, the nuclear and radiophysical properties should be stated. Their source should be
also specified, i.e. whether fission or non-fission.

2.2.1.S.2 Manufacture

2.2.1.S.2.1 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.

In the case of radio-nuclides or radio-labelled substances which are used in phase I studies in humans
to develop a non-radioactive medicinal product, the manufacturer should be stated. For
radiopharmaceuticals, the manufacturer of the radiopharmaceutical precursors and of non-radioactive
precursors should be stated, as well as the source of any cyclotron irradiation target materials and
production site(s) at which irradiation occurs.

2.2.1.S.2.2 Description of manufacturing process and process controls

For chemical substances: 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. Drug substance manufacturing process should be described in the
IMPD in such extent so it is understood how impurities are introduced in the process, and why the
proposed control strategy is suitable. This will typically include a description of multiple chemical
transformation steps. Any relevant process controls should be indicated. Where critical steps in the
synthesis have been identified, a more detailed description may be appropriate. The stereo-chemical
properties of starting materials should be discussed, where applicable. For substances which comply to
the European Pharmacopoeia (Ph. Eur.), the Pharmacopoeia of an EU Member State, the United States
Pharmacopoeia (USP) or the Japanese Pharmacopoeia (JP) reference to the monographs is acceptable,
but suitability of the referenced monograph to adequately control the quality of the active substance
(impurity profile) should be discussed by submission of sufficient information on the manufacturing
process of the active substance (see chapter 1.5 General Considerations).

For radio-nuclides, the manufacturing process, as well as nuclear reactions should be described,
including possible undesired nuclear reactions. The conditions for irradiation should be given. The
cleaning and segregation processes for the radiopharmaceutical preparation and the organo-chemical
precursors should be stated.

For herbal substances or herbal preparations, a brief summary of the manufacturing process and a flow
chart of the successive steps, starting with the plant cultivation or the plant collection, should be
provided. The in-process controls carried out should be documented. The main production steps should
be indicated.

2.2.1.S.2.3 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
genotoxic impurity. For radio-nuclides, details on the target material should be given.

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2.2.1.S.2.4 Control of critical steps and intermediates

In case of critical steps in the synthesis, tests and acceptance criteria for their control should be briefly
summarised.

2.2.1.S.2.5 Process validation and/or evaluation

Not applicable for drug substances to be used in clinical trials.

2.2.1.S.2.6. 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.

Significant changes in the manufacturing process, which may impact on quality, should be discussed
(e.g. change of route of synthesis).

2.2.1.S.3 Characterisation

2.2.1.S.3.1 Elucidation of structure and other characteristics

The structure of chemically defined substances should be established with suitable methodology;
relevant data should be provided.

For radiopharmaceutical substances, the analogous non-radioactive substances should be used to

determine the structure. For radiopharmaceutical kits the structure of the radiolabelled compound
should be described where possible.

For herbal substances, information should be given on the botanical, macroscopic and microscopic and
phytochemical characterisation. Where applicable, details should be given on the biological activity. For
herbal preparations, details should be provided on the physical and phytochemical characterisation.
Where applicable, details should be given on the biological activity.

2.2.1.S.3.2 Impurities

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, provided its suitability to adequately control the
quality of the active substance from the specific source has been discussed.

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.

Discussion on (potential) mutagenic impurities according to ICH M7 should be provided (structure,

origin, limit justification). The level of detail necessary depends on the phase of the clinical trial.

Absence of routine control for solvents/catalysts used in the manufacturing process should be justified.

In the case of radio-nuclides or radio-labelled substances which are used in phase I studies in humans
to develop a non-radioactive medicinal product, the radiochemical purity and the chemical purity
should be indicated describing any assumptions made, e.g. as a consequence of the determination

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being made prior to dilution with cold material. For radiopharmaceutical substances, the radio-nuclidic
purity, the radiochemical purity and the chemical purity should be stated and discussed.

For herbal substances or herbal preparations, data on potential contamination by micro-organisms,

products of micro-organisms, aflatoxins, pesticides, toxic metals, radioactive contamination, fumigants,
etc. should be stated. The general requirements of the Ph. Eur. should be fulfilled.

2.2.1.S.4 Control of the Drug Substance

2.2.1.S.4.1 Specification(s)

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. Upper limits, taking safety considerations into account, should be set for the impurities.
They may need to be reviewed and adjusted during further development. The limits should be
supported by the impurity profiles of batches of active substance used in non-clinical and clinical
studies. If ICH or Ph.Eur. requirements are met, no further limit justification is expected.

Where specifications are set for (potential) mutagenic impurities, the guidance given in relevant
guidelines should be taken into consideration.

The microbiological quality for drug substances used in aseptically manufactured products should be
specified.

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 will be sufficient, provided its suitability to
adequately control the quality of the active substance from the specific source has been demonstrated.
The specification should, however, include acceptance criteria for any relevant residual solvent or
catalyst.

For radiopharmaceutical drug substances, the level of radio-nuclidic impurities, radiochemical

impurities as well as the chemical impurities should be addressed.

Additional information for phase II and phase III clinical trials

Specifications and acceptance criteria set for previous phase I or phase II trials should be reviewed
and, where appropriate, adjusted to the current stage of development.

2.2.1.S.4.2 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 (see definition of analytical
methods vs. analytical procedures in chapter 1.5 General Considerations).

For radiopharmaceutical substances, the method used for the measurement of radioactivity should be
described.

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 will be sufficient.

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2.2.1.S.4.3 Validation of analytical procedures

Information for phase I clinical trials

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.

Information for phase II and III clinical trials

The suitability of the analytical methods used should be demonstrated. A tabulated summary of the
results of the validation carried out should be provided (e.g. results or values found for specificity,
linearity, range, accuracy, precision, quantification and detection limit, as appropriate). It is not
necessary to provide a full validation report.

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 will be sufficient.

In case of major changes in analytical methods, cross-validation data should be presented especially
for specified unknown impurities identified by their relative retention time (RRT) unless otherwise
justified. A re-analysis of preclinical batch with the new method should also be considered, where
relevant.

2.2.1.S.4.4 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 (e.g. in case the comparable quality of batches manufactured by previous
processes has to be demonstrated), should be supplied. If data are not available for the batches to be
used in the current clinical trial, data for representative batches for each drug substance manufacturer
may be submitted instead. The batch number, batch size, manufacturing site, manufacturing date,
control methods, and the test results should be listed.

The manufacturing process used for each batch should be assigned as stated under 2.2.1.S.2.2.

2.2.1.S.4.5 Justification of specification(s)

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.

2.2.1.S.5 Reference standards or materials

The parameters characterising the batch of drug substance established as reference standard should
be presented, where applicable.

For radiopharmaceuticals, data on the standards used for calibration and the non-radioactive (cold)
standards should be provided.

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For herbal preparations, the parameters characterising the primary reference standards should be
given. In cases where the herbal substance is not described in a monograph of the Ph. Eur. or a
monograph in the pharmacopoeia of an EU Member State, a characterised herbarium sample should be
available.

2.2.1.S.6 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.

2.2.1.S.7 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. Alternatively, for active
substances covered by a pharmacopoeial monograph, confirmation that the active substance will meet
specifications at time of use will be acceptable.

The retest period should be defined based on the available stability data and should be clearly stated.
For drug substances covered by a Certificate of Suitability (CEP) which does not include a retest date,
supporting stability data and a retest period should be provided. In case no retest period is defined,
statement should be included that the drug substance is tested immediately before the drug product
manufacture.

The retest period can be extended without a substantial modification submission, if a stability protocol,
retest period extension plan and a statement that in case of any significant negative trend the Sponsor
will inform the competent authority are provided. The stability protocol should cover the maximum
planned re-test period.

For herbal preparations, results of stress testing may be omitted, where justified.

2.2.1.P Investigational medicinal product under test

2.2.1.P.1 Description and composition of the investigational medicinal product

The complete qualitative and quantitative composition of the IMP should be stated. For proprietary
prefabricated components (e.g. capsule shells), flavours and excipient mixtures (e.g. film-coating
mixtures), a qualitative composition is sufficient. A short statement or a tabulation of the dosage form
and the function of each excipient should be included. Standard terminology from the EDQM standard
terms database should be preferably used for dosage forms, where applicable.

In addition, the radioactivity per unit should be specified for radiopharmaceuticals. Radioactivity should
only be expressed in Becquerel at a given date, and time if appropriate. If a calibration time is stated,
the time zone used should be stated (e.g. GMT/CET).

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2.2.1.P.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. For products to be reconstituted or diluted prior to their use, the method of
preparation should be summarised and reference made to a full description in the clinical protocol or
associated handling instructions which will be available at the clinical site should be provided.

For kits for radiopharmaceutical preparations, the suitability of the method used for the radio-labelling
for the intended use should be demonstrated (including results on the physiological distribution after
radio-labelling in rats/rodents). For radio-nuclide generators, the suitability of the elution medium
should be proven. For radiopharmaceuticals, the effect of radiolysis on the purity should be addressed.

Additional information for phase II and phase III clinical trials

If changes in the formulation or dosage form compared to the IMP used in earlier clinical trials have
been made, the relevance of the earlier material compared to the product under testing should be
described. Special consideration should be given to dosage form specific changes in quality parameters
with potential clinical relevance, e.g. in vitro dissolution rate.

2.2.1.P.2.1 Manufacturing process development

Changes in the current manufacturing process compared to the ones used in earlier clinical trials are to
be explained. Special consideration should be given to dosage form specific changes in quality
parameters with potential clinical relevance, e.g. in vitro dissolution rate.

2.2.1.P.3 Manufacture

2.2.1.P.3.1 Manufacturer(s)

The name(s) and address(es) and responsibilities of all manufacturer(s), including contractors, and
each proposed site involved in manufacture, packaging/assembly and testing should be provided. In
case that multiple manufacturers contribute to the manufacture of the IMP, their respective
responsibilities need to be clearly stated. Site(s) responsible for QP release in the EEA should be also
stated.

When re-packaging and or re-labelling is carried out at a hospital, health centre or clinic where the
investigational medicinal product is to be used for the trial exclusively at those institutions, and where
an exemption from the need to hold a manufacturing authorisation, as provided for in article 61 (5) of
the Regulation (EU) No. 536/2014 applies, it is not necessary to provide the names and addresses of
those institutions in this section. If relevant, it is sufficient to indicate that these activities will take
place.

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2.2.1.P.3.2 Batch formula

The batch formula for the batch to be used for the clinical trial should be presented. Where relevant,
an appropriate range of batch sizes may be given.

2.2.1.P.3.3 Description of manufacturing process and process controls

A flow chart of the successive steps, indicating the components used for each step and including any
relevant in-process controls, should be provided. In addition, a brief narrative description of the
manufacturing process should be included.

Non-standard manufacturing processes or new technologies and new packaging processes should be
described in more detail (c.f. Annex II to Note for Guidance on Process Validation: Non-Standard
Processes (CPMP/QWP/2054/03)).

2.2.1.P.3.4 Controls of critical steps and intermediates

Information is not required for phase I and II clinical trials, with the exception of:

 Non-standard manufacturing processes; and

 Manufacturing processes for sterile products.

For sterilisation by filtration the maximum acceptable bioburden prior to the filtration must be stated in
the application. In most situations NMT 10 CFU/100 ml will be acceptable, depending on the volume to
be filtered in relation to the diameter of the filter. If this requirement is not met, a pre-filtration
through a bacteria-retaining filter should be carried out in order to obtain a sufficiently low bioburden.
If availability of the formulated medicinal product is limited, a prefiltration/filtration volume of less than
100 ml may be tested if justified.

Statement that aseptic processing operations were validated using media fill runs should be provided.

Additional information for phase III clinical trials

If critical manufacturing steps have been identified; their control as well as possible intermediates
should be documented.

Should intermediates be stored, assurance should be provided that duration and conditions of storage
are appropriately controlled.

2.2.1.P.3.5 Process validation and/or evaluation

Data are not required during the development phases, i.e. clinical phases I to III, except for non-
standard sterilisation processes not described in the Ph. Eur., USP or JP. In this case, the critical
manufacturing steps, the validation of the manufacturing process as well as the applied in process
controls should be described.

2.2.1.P.4 Control of excipients

2.2.1.P.4.1 Specifications

References to the Ph. Eur., the pharmacopoeia of an EU Member State, USP or JP should be indicated.
For 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

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substances, e.g. pre-fabricated dry mix for film- coating, a general specification of the mixture will
suffice. For excipients not covered by any of the afore-mentioned standards, an in-house monograph
should be provided. Specification for capsule shells should be provided.

2.2.1.P.4.2 Analytical procedures

In cases where reference to a pharmacopoeial monograph listed under 2.2.1.P.4.1 cannot be made,
the analytical methods used should be indicated.

2.2.1.P.4.3 Validation of the analytical procedures

Not applicable.

2.2.1.P.4.4 Justification of specifications

Not applicable.

2.2.1.P.4.5 Excipients of animal or human origin

Cf. section 7.2.1.A.2.

2.2.1.P.4.6 Novel excipients

For novel excipients, details are to be given on their manufacturing process, characterisation and
control in relevance to product safety. Information as indicated in section 3.2.S of the CTD should be
provided in annex 2.1.A.3 consistent with the respective clinical phase (c.f. section 7.2.1.A.3), details
are to be included on e.g. their manufacturing process, characterisation and stability.

2.2.1.P.5 Control of the investigational medicinal product

2.2.1.P.5.1 Specifications

The chosen release and shelf-life specifications should be submitted, including test methods and
acceptance criteria. At least, tests on identity, assay and degradation products should be included for
any pharmaceutical form.

Upper limits may be set for both individual degradation products and the sum of degradation products.
Safety considerations should be taken into account. The limits should be supported by the impurity
profiles of batches of active substance used in non-clinical/clinical studies. The specifications and
acceptance criteria should be reviewed and adjusted during further development.

Drug product specific tests and acceptance criteria should be included in the specifications in line with
the pharmaceutical form used (e.g. dissolution/disintegration for oral solid dosage forms; uniformity of
dosage units; or pH, bacterial endotoxins and sterility for parenteral dosage forms).

The omission of drug product specific tests should be justified.

For radiopharmaceuticals, it should be specified which tests are carried out prior to batch release and
which tests are carried out retrospectively. For kits for radiopharmaceutical preparations, appropriate
tests after radioactive radio-labelling should be stated.

For medicinal products to be reconstituted or diluted prior to their use, the acceptable quality standard
after preparation should be stated and documented by development testing.

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Additional information for phase II and phase III clinical trials

Specifications and acceptance criteria set for previous phase I or phase II trials should be reviewed
and, where appropriate, adjusted to the current stage of development.

2.2.1.P.5.2 Analytical procedures

The analytical methods should be described for all tests included in the specification (e.g. dissolution
test method). It is not necessary to provide a detailed description of the analytical procedures (see
definition of analytical methods vs. analytical procedures in chapter 1.5 General considerations).

For complex or innovative pharmaceutical forms, a higher level of detail may be required.

2.2.1.P.5.3 Validation of analytical procedures

For phase I clinical trials, 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.

Additional information for phase II and III clinical trials

The suitability of the analytical methods used should be demonstrated. A tabulated summary of the
results of the validation should be provided (e.g. results or values found for specificity, linearity, range,
accuracy, precision, quantification and detection limit, as appropriate). It is not necessary to provide a
full validation report.

2.2.1.P.5.4 Batch analyses

Batch results in a tabulated form or certificates of analysis for representative batches (same
manufacturing site, same manufacturing process, same composition, and comparable batch size,
unless otherwise justified,) to be used in the clinical trial should be provided. The results should cover
the relevant strengths to be used in the trial.

The batch number, batch size, manufacturing site, manufacturing date, control methods, and the test
results should be listed.

In case of more than one bulk manufacturing sites, it is necessary to provide results for batches which
have been produced by each of the bulk manufacturing sites relevant for the current trial unless
otherwise justified, (e.g. where one legal entity has multiple sites (in the same country), then batch
analysis data from one site only would be sufficient).

Results for batches controlled according to previous, wider specifications are acceptable if the results
comply with the specifications for the planned clinical trial.

2.2.1.P.5.5 Characterisation of impurities

Additional impurities/degradants observed in the IMP, but not covered by section 2.2.1.S.3.2, should
be stated.

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2.2.1.P.5.6 Justification of specification(s)

For IMPs in phase I clinical trials, it will be sufficient to briefly justify the specifications and acceptance
criteria for degradation products and any other parameters that may be relevant to the performance of
the drug product. Toxicological justification should be given, where appropriate.

Additional information for phase II and phase III clinical trials

The choice of specifications and acceptance criteria for parameters which may affect efficacy or safety
should be briefly justified.

2.2.1.P.6 Reference standards or materials

The parameters for characterisation of the reference standard should be submitted, where applicable.
Section 2.2.1.S.5 - Reference Standards or Materials - may be referred to, where applicable. For
radiopharmaceuticals, information should be provided on radioactive standards used in the calibration
of radioactivity measurement equipment.

2.2.1.P.7 Container closure system

The intended immediate packaging and additionally, 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. 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, a description and
specifications should be provided. For dosage forms that have a higher potential for interaction
between filling and container closure system (e.g. parenterals, ophthalmic products, oral solutions),
more details may be needed for phase III studies (e.g. extractables, leachables). For dosage forms
where an interaction is unlikely, e.g. solid oral dosage forms, a justification for not providing any
information may suffice.

If a medical device is to be used for administration its regulatory status should be explicitly stated
(e.g. whether it is CE marked for its intended purpose or not). In the absence of certification for its
intended purpose, a statement of compliance of the medical device with relevant legal requirements
for safety and performance is required. Where a medicinal product is combined with an integral
medical device and the principal mechanism of action is that of the medicinal product, the combined
product is governed by the medicines legislation and a CE mark is not required during development.
However, at the time of MAA the requirements of article 117 of Regulation (EU) 2017/745 should be
taken into account.

2.2.1.P.8 Stability

The shelf-life and storage conditions of the IMP should be defined based on the stability profile of the
active substance and the available data on the IMP. Stability data for representative batch(es) should
be provided in a tabulated form. Extrapolation may be used, provided that stability studies are
conducted in parallel to the clinical studies and throughout its entire duration. Shelf life extrapolation
can be made under the following conditions:

 Results at long-term as well as at accelerated storage conditions are available;

 No significant changes in stability behaviour are observed. If any observed, justification should be
provided;

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 Stability protocol covering the proposed extrapolated shelf life should be provided;

 Criteria used to extrapolate data should be clearly defined; and

 Depending on the data available:

‐ A fourfold extrapolation of accelerated stability data may be acceptable up to a shelf life of

12 months

‐ An extrapolation of + max 12 months to long-term stability data available (at least 6-

months) may be acceptable for a shelf life of more than 12 months

‐ Other schemes may be possible but should be justified.

Furthermore, bracketing and matrixing designs of appropriate IMPs may be acceptable, where justified.
The batches of drug product must meet specification requirements throughout the period of use. If
issues arise, then the Competent Authorities should be informed of the situation, including any
corrective action proposed.

In case the drug product is stored in a bulk for a significant time period, relevant stability data should
be provided as well as shelf life, storage conditions and packaging material for the bulk. In case the
final drug product shelf life is calculated not from the first mixing of the drug substance with excipients
but from the time of packaging into the primary package, this should be clearly stated and justified.

Any proposal for a future shelf life extension without substantial modification submission should be
stated in the IMPD. Stability protocol, shelf life extension plan and a statement that in case of any
significant negative trend the Sponsor will inform the competent authority should be provided. The
stability protocol should cover the maximum planned shelf life.

For preparations intended for applications after reconstitution, dilution or mixing, and products in
multi-dose containers, excluding oral solid dosage forms, in-use stability data should be presented. In-
use stability studies should cover the practice described in the clinical protocol. Relevant parameters
should be monitored within the in-use stability studies (e.g. appearance, assay, impurities, visible and
sub-visible particles, microbial contamination). Shelf life and storage conditions after first opening
and/or after reconstitution and/or dilution should be defined. These studies are not required if the
preparation is to be used immediately after opening or reconstitution and if it can be justified that no
negative influence on the quality of the preparation through instabilities is to be expected.

For radiopharmaceuticals, the time of calibration should be specified, since the stability also depends
on the half-life of the radioactive isotope.

Information for phase I clinical trials

For phase I clinical trials, it should be confirmed 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-term storage conditions will have been initiated. Where available, the results
from these studies should be summarised in a tabulated form. Supportive data from development
studies should be summarised in a tabular overview. An evaluation of the available data and
justification of the proposed shelf-life to be assigned to the IMP in the clinical trial should be provided.

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Additional information for phase II and phase III clinical trials

The available stability data should be presented in a tabulated form. An evaluation of the available
data and justification of the proposed shelf- life to be assigned to the IMP in the clinical trial should be
provided. Data should include results from studies under accelerated and long-term storage conditions.

For radiopharmaceuticals, the time of calibration should be specified. The general stability guidelines
are not fully applicable for ready-for-use radiopharmaceuticals, radio-nuclide generators and
radioactive precursors. However, the aspects reflected in the Guideline on Radiopharmaceuticals
(EMEA/CHMP/QWP/306970/2007) should be taken into consideration.

3. Information on the chemical and pharmaceutical quality of

authorised, non-modified test and comparator products in
clinical trials
For test and comparator products to be used in clinical trials which have already been authorised in the
EU/EEA or in one of the ICH-regions (and are sourced from these countries), it will be sufficient to
provide the name of the MA-holder and the MA-number as proof for the existence of a MA, incl. copy of
the SmPC/Summary of Product Characteristics or its equivalent e.g. Prescribing information. For
repackaged/modified authorised products, see following chapter.

The applicant or sponsor of the clinical trial has to ensure that the IMP is stable at least for the
anticipated duration of the clinical trial in which it will be used. For authorised, not modified products,
it will be sufficient to state that the respective expiry date assigned by the manufacturer will be used.

For IMPs sourced from outside of the EU/EEA or ICH regions, a full documentation, according to the
requirements stated in chapter 2 of this guideline, should be submitted.

4. Information on the chemical and pharmaceutical quality of

modified authorised test and comparator products in clinical
trials
In preparing supplies for clinical trials, applicants often modify or process medicinal products which
have already been authorised in order to use them as test/comparator products in blinded studies.

As the marketing authorisation holder (MAH) of a authorised product is only responsible for the un-
changed product in its designated and authorised packaging, there is a need to ensure that the quality
of the product is not negatively affected by the modifications performed by the applicant or sponsor of
the clinical trial, with special emphasis on the biopharmaceutical properties.

4.2.1.P Modified test/comparator product

4.2.1.P.1 Description and composition

In the case of any modification of the authorised product other than repackaging, the complete
quantitative composition of the preparation should be specified. All additional substances/materials
added to the authorised product should be listed with reference to pharmacopoeial or in-house
monographs. For the authorised product itself, reference to the name and marketing authorisation
(MA) number will suffice, including a copy of the SPC/PIL in Module 1.

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4.2.1.P.2 Pharmaceutical development

The modifications carried out on the authorised product should be described and their influence on the
quality of the product discussed. Special focus should be assigned to all parameters relevant for the
function, stability and efficacy of the medicinal product, such as in vitro-dissolution and pH-value. It
should be demonstrated that these parameters remain comparable to those of the unmodified product.

Compatibility with other solvents (that are not stated in the original SmPC) used for drug product
reconstitution and dilution should be demonstrated. Compatibility studies reflecting the practice
described in the clinical protocol (e.g. dispersion of a tablet or content of the hard capsule in
water/juice/food) should be performed in case of unstable products and/or in case of preparation in
advance.

In case of solid oral dosage forms, comparative dissolution profiles of both original and modified
product should be provided to ensure unchanged bio-pharmaceutical properties. In those cases where
comparability cannot be established in vitro, additional clinical data to support equivalence may be
necessary.

4.2.1.P.3 Manufacture

4.2.1.P.3.1 Manufacturer(s) related to the modification

The name(s) and address(es) and responsibilities of all manufacturer(s), including contractors, and
each proposed site involved in the modification, packaging/assembly and testing of the modified
product should be provided. In case that multiple manufacturers contribute to the manufacture of the
IMP, their respective responsibilities need to be clearly stated. Sites responsible for import or/and QP
release in the EEA should be also stated.

When re-packaging and or re-labelling is carried out at a hospital, health centre or clinic where the
investigational medicinal product is to be used for the trial exclusively at those institutions, and where
an exemption from the need to hold a manufacturing authorisation, as provided for in article 61 (5) of
the Regulation (EU) No. 536/2014 applies, it is not necessary to provide the names and addresses of
those institutions in this section. If relevant, it is sufficient to indicate that these activities will take
place.

4.2.1.P.3.2 Batch formula

The batch formula for the batch intended to be used during the clinical trial should be presented. This
does not apply to authorised products which are only re-packaged.

4.2.1.P.3.3 Description of manufacturing process and process controls

All steps of the modification of the authorised medicinal product should be described, including in-
process controls that are carried out. For details, reference is made to section. 2.2.1.P.3.3).

4.2.1.P.4 Control of excipients

4.2.1.P.4.1 Specifications

References to the Ph. Eur., the pharmacopoeia of an EU Member State, USP or JP should be indicated.
For 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

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substances, e.g. pre-fabricated dry mix for film-coating, a general specification of the mixture will
suffice. For excipients not covered by any of the afore-mentioned standards, an in-house monograph
should be provided. Specification for capsule shells should be provided.

4.2.1.P.4.2 Analytical procedures

In cases where reference to a pharmacopoeial monograph listed under 4.2.1.P.4.1 cannot be made,
the analytical methods used should be indicated.

4.2.1.P.4.3 Validation of analytical procedures

Not applicable.

4.2.1.P.4.4 Justification of specifications

Not applicable.

4.2.1.P.4.5 Excipients of animal or human origin

Cf. Appendix 7.2.1.A.2.

4.2.1.P.5 Control of the modified authorised product

4.2.1.P.5.1 Specifications

The chosen release and shelf-life specifications of the modified authorised product should be
submitted, including test methods and acceptance criteria. Generally, they should include description
and identification of the drug substance as well as the control of important pharmaceutical and
technological properties, such as dissolution. Where an intact solid oral dosage form that is easily
identifiable by its colour, shape and marking is encapsulated, identification of the active substance may
not be necessary, and visual examination may suffice for identification. Depending on the degree of
modification of the authorised product, additional quality criteria, e.g. determination of the drug
substance(s) and impurities/degradants, may need to be specified and tested.

4.2.1.P.5.2 Analytical procedures

For parameters relevant to the performance of the modified authorised product, e.g. dissolution, the
methods should be described. It is not necessary to provide a detailed description of the analytical
procedures (see definition of analytical methods vs. analytical procedures in chapter 1.5 General
considerations).

4.2.1.P.5.3 Validation of analytical procedures

The suitability of the analytical methods used should be demonstrated. A tabulated summary of the
results of validation of the analytical methods should be provided (e.g. results or values found for
specificity, linearity, range, accuracy, precision, quantification and detection limit, as appropriate). It is
not necessary to provide a full validation report.

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4.2.1.P.5.4 Batch analyses

Results or certificates of analysis for the batch of modified authorised product to be used in the clinical
trial or of a representative batch should be provided.

In case of more than one bulk manufacturing sites, it is necessary to provide results for batches which
have been produced by each of the bulk manufacturing sites relevant for the current trial unless
otherwise justified, (e.g. where one legal entity has multiple sites (in the same country), then batch
analysis data from one site only would be sufficient).

The batch number, batch size, manufacturing site, manufacturing date, control methods, acceptance
criteria and the test results should be listed.

4.2.1.P.5.5 Characterisation of impurities

In those cases, where the authorised product has undergone significant modification by the sponsor,
e.g. has been processed with an excipient hitherto not present in the formulation with a likely impact
on product stability, and the original product is not known to be stable under normal conditions, special
emphasis should be given to demonstrating that the impurity profile has not changed compared to the
original product. For stable authorised products, where a small degree of modification has been
undertaken by the sponsor, e.g. where an intact tablet is encapsulated using the ingredients already
present in the tablet, justification for not quantifying impurities will suffice (for definition of “stable” cf.
Note for Guidance on Stability Testing of New Drug Substances and Products (CPMP/QWP/2736/99),
section 2.2.7 “Storage conditions”). This is not required for authorised products which are only re-
packaged.

4.2.1.P.5.6 Justification of specification(s)

A justification of specification(s) will only be required in cases where a significant modification of the
authorised product may affect the product’s performance or safety.

4.2.1.P.7 Container closure system

The type of immediate packaging, material and package size(s) should be specified. If materials other
than those authorised are used, a description and specifications should be provided. Where
appropriate, reference should be made to the relevant pharmacopoeial monograph. If the
test/comparator product is packed in a non-standard administration device, or if non-compendial
materials are used, a description and specifications should be provided.

4.2.1.P.8 Stability

The applicant or sponsor of the clinical trial has to ensure that the modified test/comparator product is
stable for at least the anticipated duration of the clinical trial in which it will be used.

In the case of any modification with a likely significant impact on product stability, a minimum of
stability data on the modified authorised product should be available, depending on the length of the
planned clinical trial, prior to the start of the clinical trial in order to allow an assessment of the impact
of the modifications on product safety and stability. The available stability data should be presented in
a tabulated form. An evaluation of the available data and justification of the proposed shelf-life to be
assigned to the IMP in the clinical trial should be provided. Any degree of extrapolation may not exceed
the shelf-life originally assigned to the specific batch of authorised product by its MAH.

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Shelf life extension without a substantial modification submission can be approved under the same
conditions as described in the section 2.2.1.P.8.

In the case of only minor modifications, a justification of the stability over the intended trial period
may be acceptable.

In-use stability studies should be performed in case of use of the comparator product in different
conditions as those described in the SPC (according to the clinical protocol), if not otherwise justified
(the same requirements as defined in section 2.2.1.P.8 apply).

5. Information on the chemical and pharmaceutical quality of

investigational medicinal products containing existing active
substances used in bio-equivalence studies, e.g. generics
(chemical substances)
This section of the guideline is only relevant for the test product. Information on the
comparator/innovator product to be provided in the IMPD should meet the requirements as outlined in
sections 3 and 4, respectively.

5.2.1.S Drug substance

Reference to an Active Substance Master File or a Certificate of Suitability of the European Directorate
for the Quality of Medicines is acceptable. The procedure as described in the “Guideline on Active
Substance Master File Procedure – CPMP/QWP/227/02 Rev 3 corr” and the “Guideline on Summary of
Requirements for Active Substances in the Quality Part of the Dossier – CHMP/QWP/297/97 Rev 1” in
their current version should be followed, even though no specific reference to clinical trials application
is included.

For reference to pharmacopoeial monographs, see chapter 1.5 General Considerations.

If the Active substance used is already authorised in a drug product within the EU/EEA or in one of the
ICH-regions, reference can be made to the valid marketing authorisation. A statement should be
provided that the active substance has the same quality as in the approved product.

Name of the drug product, marketing authorisation number or its equivalent, marketing authorisation
holder and the country that granted the marketing authorisation should be given.

5.2.1.S.1 General information

5.2.1.S.1.1 Nomenclature

Information concerning the nomenclature of the drug substance (e.g. (proposed) INN-name,
pharmacopoeial name, chemical name, code, and other names, if any) should be given.

5.2.1.S.1.2 Structure

The structural formula should be presented.

5.2.1.S.1.3 General Properties

The main physicochemical and other relevant properties of the drug substance should be indicated.

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5.2.1.S.2 Manufacture

5.2.1.S.2.1 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.

5.2.1.S.2.2 Description of manufacturing process and process controls

For substances which comply to the European Pharmacopoeia (Ph. Eur.), the Pharmacopoeia of an EU
Member State, the United States Pharmacopoeia (USP) or the Japanese Pharmacopoeia (JP) reference
to the monographs is acceptable, but suitability of the referenced monograph to adequately control the
quality of the active substance (impurity profile) should be discussed by submission of sufficient
information on the manufacturing process of the active substance (see section 1.5).

In cases where reference to a pharmacopoeial monograph listed above cannot be made, 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 reagents used should be provided. The
stereo-chemical properties of starting materials should be discussed, where applicable.

5.2.1.S.3 Characterisation

5.2.1.S.3.2 Impurities

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, provided its suitability to adequately control the
quality of the active substance from the specific source has been discussed.

Discussion on (potential) mutagenic impurities should be provided (structure, origin, limit justification),
if relevant.

In cases where reference to a pharmacopoeial monograph listed above cannot be made, impurities
(e.g. possible degradation products and residual solvents), deriving from the manufacturing process or
starting materials relevant to the drug substance used for the bio-equivalence study should be stated.

Absence of routine control for solvents/catalysts used in the manufacturing process should be justified.

5.2.1.S.4 Control of the drug substance

5.2.1.S.4.1 Specifications

The microbiological quality of drug substances used in aseptically manufactured products should be
specified.

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, provided its suitability to adequately control the
quality of the active substance from the specific source has been demonstrated. The specification
should, however, include acceptance criteria for any relevant residual solvents and catalysts.

In cases where reference to a pharmacopoeial monograph listed above cannot be made, specifications,
tests used as well as the acceptance criteria should be provided for the batch(es) of the drug
substance(s) intended for use in the bio-equivalence study. Tests for identity and assay are
mandatory. Upper limits, taking safety considerations into account, should be set for the impurities.

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Where specifications are set for (potential) mutagenic impurities, the guidance given in relevant
guidelines should be taken into consideration.

5.2.1.S.4.2 Analytical procedures

For substances for which reference to a pharmacopoeial monograph listed under 5.2.1.S.4.1 of this
chapter cannot be made, the analytical methods used for the drug substance (e.g. reverse- phase-
HPLC-UV, potentiometric titration, head-space-GC-FID, etc.) should be provided. It is not necessary to
provide a detailed description of the analytical procedures (see definition of analytical methods vs.
analytical procedures in chapter 1.5 General Considerations).

5.2.1.S.4.3 Validation of analytical procedures

For substances for which reference to a pharmacopoeial monograph listed under 5.2.1.S.4.1 of this
chapter cannot be made, the suitability of the analytical methods used should be demonstrated. A
tabulated summary of the results of validation of the analytical methods should be provided (e.g.
values found for repeatability, limit of quantification etc.). It is not necessary to provide a full
validation report.

5.2.1.S.4.4 Batch analyses

Certificates of analyses or batch analysis data for the batch(es) intended for use in the planned bio-
equivalence study or, in their absence, for representative batches, should be supplied. The batch
number, batch size, manufacturing site, manufacturing date, control methods, acceptance criteria and
test results should be listed.

5.2.1.S.4.5 Justification of specifications

For substances for which reference to a pharmacopoeial monograph listed under 5.2.1.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.

5.2.1.S.5 Reference Standards or materials

For substances for which reference to a pharmacopoeial monograph listed under 5.2.1.S.4.1 cannot be
made, the parameters characterising the batch of drug substance established as reference standards
should be presented.

5.2.1.S.6 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.

5.2.1.S.7 Stability

The available stability data should be provided in a tabulated form. The retest period should be defined
based on the available stability data and should be clearly stated. For drug substances covered by a
Certificate of Suitability (CEP) which does not include a retest date, supporting stability data and a

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retest period should be provided. In case no retest period is defined, statement should be included that
the drug substance is tested immediately before the drug product manufacture.

5.2.1.P Investigational medicinal product under test

5.2.1.P.1 Description and composition

The complete qualitative and quantitative composition of the IMP should be stated. For proprietary
prefabricated components (e.g. capsule shells), flavours and excipient mixtures (e.g. film-coating
mixtures), a qualitative composition is sufficient. Standard terminology from the EDQM standard terms
database should be preferably used for dosage forms, where applicable.

5.2.1.P.2 Pharmaceutical development

A brief narrative description of the dosage form should be provided.

5.2.1.P.3 Manufacture

5.2.1.P.3.1 Manufacturer(s)

The name(s) and address(es) and responsibilities of all manufacturer(s), including contractors, and
each proposed site involved in manufacture, packaging/assembly and testing should be provided. In
case multiple manufacturers contribute to the manufacture of the IMP, their respective responsibilities
in the manufacturing chain should be clearly indicated. Site(s) responsible for import or/and QP release
in the EEA should be also stated.

When re-packaging and or re-labelling is carried out at a hospital, health centre or clinic where the
investigational medicinal product is to be used for the trial exclusively at those institutions, and where
an exemption from the need to hold a manufacturing authorisation, as provided for in article 61 (5) of
the Regulation (EU) No. 536/2014, it is not necessary to provide the names and addresses of those
institutions in this section. If relevant, it is sufficient to indicate that these activities will take place.

5.2.1.P.3.2 Batch formula

The batch formula for the batch to be used in the planned bio-equivalence study should be presented.
Where relevant, an appropriate range of batch sizes may be given.

5.2.1.P.3.3 Description of manufacturing process and process controls

A flow chart of the successive steps, including the components used for each step and including any
relevant in process controls, should be provided. In addition, a brief narrative description of the
manufacturing process should be included.

5.2.1.P.3.4 Control of critical steps and intermediates

If critical manufacturing steps have been identified; their control as well as possible intermediates
should be documented.

Should intermediates be stored, assurance should be provided that duration and conditions of storage
are appropriately controlled.

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5.2.1.P.3.5 Process validation and/or evaluation

Data are not required, except for non-standard sterilisation processes not described in the Ph. Eur.,
USP or JP. In this case, the critical manufacturing steps, the validation of the manufacturing process as
well as the applied in process controls should be described.

5.2.1.P.4 Control of excipients

5.2.1.P.4.1 Specifications

References to the Ph. Eur., the pharmacopoeia of an EU Member State, USP or JP should be indicated.
For 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 will
suffice. For excipients not covered by any of the afore-mentioned standards, an in-house monograph
should be provided. Specification for capsule shells should be provided.

5.2.1.P.4.2 Analytical procedures

In cases where reference to a pharmacopoeial monograph listed under 5.2.1.P.4.1 cannot be made,
the analytical methods used should be indicated.

5.2.1.P.4.3 Validation of analytical procedures

Not applicable.

5.2.1.P.4.4 Justification of specifications

Not applicable.

5.2.1.P.4.5 Excipients of animal or human origin

Cf. Appendix 7.2.1.A.2.

5.2.1.P.4.6 Novel excipients

For novel excipients, details are to be given on their manufacturing process, characterisation and
control in relevance to product safety. Information as indicated in section 3.2.S of the CTD should be
provided in annex 2.1.A.3 consistent with the respective clinical phase (c.f. section 7.2.1.A.3), details
are to be included on e.g. their manufacturing process, characterisation and stability.

5.2.1.P.5 Control of the investigational medicinal product

5.2.1.P.5.1 Specifications

The chosen release and shelf-life specifications should be submitted, including test methods and
acceptance criteria. At least, tests on identity, assay and degradation products should be included for
any pharmaceutical form. Drug product specific tests defined in the Ph.Eur. monographs for dosage
forms (see chapter 1.5 General Considerations) and acceptance criteria should be included in the
specifications in line with the pharmaceutical form used (e.g. dissolution/disintegration for oral solid
dosage forms; uniformity of dosage units; or pH, bacterial endotoxins and sterility for parenteral
dosage forms).

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The omission of drug product specific tests should be justified.

5.2.1.P.5.2 Analytical procedures

The analytical methods should be described for all tests included in the specification (e.g. dissolution
test method). It is not necessary to provide a detailed description of the analytical procedures (see
definition of analytical methods vs. analytical procedures in chapter 1.5 General considerations).

For complex or innovative pharmaceutical forms, a higher level of detail may be required.

5.2.1.P.5.3 Validation of analytical procedures

The suitability of the analytical methods used should be demonstrated. A tabulated summary of the
validation results should be provided (e.g. results or values found for specificity, linearity, range,
accuracy, precision, quantification and detection limit, as appropriate). It is not necessary to provide a
full validation report.

5.2.1.P.5.4 Batch analyses

Certificates of analysis or batch analysis data for the batch(es) intended to be used in the planned bio-
equivalence study or, in their absence, representative batches, should be provided.

The batch number, batch size, manufacturing site, manufacturing date, control methods, acceptance
criteria and the test results should be listed.

5.2.1.P.5.5 Characterisation of impurities

Additional impurities/degradants observed in the IMP, but not covered by section 5.2.1.S.3.2, should
be stated.

5.2.1.P.5.6 Justification of specification(s)

It will be sufficient to briefly justify the specifications and acceptance criteria for degradation products
and any other parameters that may be relevant to the performance of the drug product. Toxicological
justification should be given, where appropriate.

5.2.1.P.6 Reference standards or materials

The parameters for characterisation of the reference standard should be submitted, if no compendial
reference standard is available.

Section 5.2.1.S.5 – Reference Standards or Materials – may be referred to, where applicable.

5.2.1.P.7 Container closure system

The intended immediate packaging and additionally, 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. 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, a description and
specifications should be provided. For dosage forms that have a higher potential for interaction
between filling and container closure system (e.g. parenterals, ophthalmic products, oral solutions),

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more details may be needed. For dosage forms where an interaction is unlikely, e.g. solid oral dosage
forms, a justification for not providing any information may suffice.

5.2.1.P.8 Stability

For bioequivalence studies, it should be confirmed 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-term storage conditions will have been initiated. The results from at least one
month accelerated studies or the results of the initial phase of studies under long-term storage
conditions should be summarised in a tabulated form. Supporting data from development studies
should also be summarised in a tabular overview. An evaluation of the available data and justification
of the proposed shelf-life and storage conditions to be assigned to the IMP in the bio-equivalence study
should be provided. Extrapolation may be used, provided a commitment is included to perform an
ongoing stability study in parallel to the bioequivalence study.

6. Information on the chemical and pharmaceutical quality

concerning placebo products in clinical trials
The quality documentation to be submitted for placebos is limited to the following sections of the
product part.

6.2.1.P Placebo product in clinical trials

6.2.1.P.1 Description and composition

The complete qualitative and quantitative composition of the placebo should be stated. For proprietary
prefabricated components (e.g. capsule shells), flavours and excipient mixtures (e.g. film-coating
mixtures), a qualitative composition is sufficient. A short statement or a tabulation of the dosage form
and the function of each excipient should be included.

6.2.1.P.2 Pharmaceutical development

It should be described how possible differences of the placebo preparation in relation to the
investigational medicinal product regarding taste, appearance and smell are masked, where applicable.

6.2.1.P.3 Manufacture

6.2.1.P.3.1 Manufacturer(s)

The name(s) and address(es) and responsibilities of all manufacturer(s), including contractors, and
each proposed site involved in manufacture, packaging/assembly and testing should be provided. In
case that multiple manufacturers contribute to the manufacture of the placebo, their respective
responsibilities need to be clearly stated.

When re-packaging and or re-labelling is carried out at a hospital, health centre or clinic where the
investigational medicinal product is to be used for the trial exclusively at those institutions, and where
an exemption from the need to hold a manufacturing authorisation, as provided for in article 61 (5) of
the Regulation (EU) No. 536/2014, it is not necessary to provide the names and addresses of those
institutions in this section. If relevant, it is sufficient to indicate that these activities will take place.

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6.2.1.P.3.2 Batch formula

The batch formula for the batch to be used for the clinical trial should be presented. Where relevant,
an appropriate range of batch sizes may be given.

6.2.1.P.3.3 Description of manufacturing process and process controls

A flow chart of the successive steps, indicating the components used for each step and including in-
process controls should be provided. In addition, a brief narrative description of the manufacturing
process should be included.

6.2.1.P.3.4 Control of critical steps and intermediates

Information is not required with the exception of manufacturing processes for sterile products (the
same requirements as defined in section 2.2.1.P.3.4 apply).

6.2.1.P.3.5 Process validation and/or evaluation

Data are not required, except for non-standard sterilisation processes not described in the Ph. Eur.,
USP or JP. In this case, the critical manufacturing steps, the validation of the manufacturing process as
well as the applied in process controls should be described.

6.2.1.P.4 Control of excipients

6.2.1.P.4.1 Specifications

References to the Ph. Eur., the pharmacopoeia of an EU Member State, USP or JP should be indicated.
For excipients not described in one on 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 will suffice. For excipients not covered by any of the afore-mentioned standards, an in-house
monograph should be provided. Specification for capsule shells should be provided.

6.2.1.P.4.2 Analytical procedures

In cases where reference to a pharmacopoeial monograph listed under 6.2.1.P.4.1 cannot be made,
the analytical methods used should be indicated.

6.2.1.P.4.3 Validation of analytical procedures

Not applicable.

6.2.1.P.4.4 Justification of specifications

Not applicable.

6.2.1.P.4.5 Excipients of animal or human origin

Cf. Appendix 7.2.1. A.2.

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6.2.1.P.4.6 Novel excipients

For novel excipients, details are to be given on their manufacturing process, characterisation and
control in relevance to product safety. Information as indicated in section 3.2.S of the CTD should be
provided in annex 2.1.A.3 (c.f. section 7.2.1.A.3) consistent with the respective clinical phase, details
are to be included on e.g. their manufacturing process, characterisation and stability. If the same novel
excipient is already described in the IMPD for the respective test product, cross-reference to the
relevant section will suffice.

6.2.1.P.5 Control of the placebo product

6.2.1.P.5.1 Specifications

The chosen release and shelf-life specifications should be submitted, including test methods and
acceptance criteria. The specifications should at minimum include a test which enables to clearly
differentiate between the respective investigational medicinal product and the placebo.

6.2.1.P.5.2 Analytical procedures

The analytical methods should be described for all tests included in the specification. It is not
necessary to provide a detailed description of the analytical procedures (see definition of analytical
methods vs. analytical procedures in chapter 1.5 General considerations).

6.2.1.P.7 Container closure system

The intended immediate packaging and additionally, where relevant for the quality of the drug product,
the outer packaging to be used for the placebo in the clinical trial, should be stated.

6.2.1.P.8 Stability

The shelf-life and storage conditions of the placebo should be defined. The shelf life of the placebo
product should preferably cover the anticipated duration of the clinical trial. Stability studies are only
required in cases where there is reason to suspect that the placebo product will undergo changes in its
physical characteristics or degradation, respectively, e.g. microbial purity of multi-dose containers,
hardness or appearance. In all other cases, a short justification of the assigned shelf-life will suffice.

7. Appendices

7.2.1.A.1 Facilities and equipment

Not applicable.

7.2.1.A.2 Adventitious agents safety evaluation

All materials of human or animal origin used in the manufacturing process of both drug substance and
drug product, or such materials coming into contact with drug substance or drug product during the
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 in this section.

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TSE agents

Detailed information should be provided on the avoidance and control of transmissible spongiform
encephalopathy agents. This information can include, for example, certification and control of the
production process, as appropriate for the material, process and agent.

The “Note for Guidance on Minimising the Risk of Transmitting Animal Spongiform Encephalopathy
Agents via Human and Veterinary Medicinal Products, EMEA/410/01”in its current version is to be
applied.

Viral safety

Where applicable, information assessing the risk with respect to potential viral contamination should be
provided in this section. The risk of introducing viruses into the product and the capacity of the
manufacturing process to remove or inactivate viruses should be evaluated.

Other adventitious agents

Detailed information regarding the other adventitious agents, such as bacteria, mycoplasma, and fungi
should be provided in appropriate sections within the core dossier.

7.2.1.A.3 Novel excipients

For novel excipients, information as indicated in section.3.2.S of the CTD should be provided,
consistent with the respective clinical phase.

7.2.1.A.4 Solvents for reconstitution and diluents

For solvents for reconstitution and diluents, the relevant information as indicated in section 3.2.P of the
CTD should be provided as applicable.

8. Auxiliary medicinal products

For auxiliary medicinal products the same requirements and principles apply as for investigational
medicinal products. The requirements depend on the type of the product (authorised / not authorised /
modified / non-modified medicinal product).

9. Changes to the investigational medicinal product and

auxiliary medicinal product with a need to request a
substantial modification to the IMPD
In accordance with Good Manufacturing Practice, a Product Specification File should be maintained for
each IMP/auxiliary medicinal product at the respective site and be continually updated as the
development of the product proceeds, ensuring appropriate traceability to the previous versions.

In compliance with the Clinical Trial Regulation (CTR), a change to IMP/auxiliary medicinal product
quality data is either:
- a substantial modification (art 2.2.13)
- a change relevant to the supervision of the trial (art 81.9)

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- a non-substantial modification (changes outside the scope of substantial modifications and changes
irrelevant to the supervision of the trial)

Substantial modification means any change which is likely to have a substantial impact on the safety
and rights of the subjects or on the reliability and robustness of the data generated in the clinical trial.

Assessment of an IMPD should be focussed on patient safety. Therefore, any modification involving a
potential new risk has to be considered a substantial modification. This may be especially the case for
changes in impurities profile, microbial contamination, viral safety, TSE and in some particular cases to
stability when toxic degradation products may be generated.

Non-substantial changes relevant to the supervision of the trial (Art 81.9 change) are a concept
introduced under the CTR, which aims to update information in the CTIS without the need for a
substantial modification application, when this information is necessary for oversight but does not have
a substantial impact on patients safety and rights and/or data robustness. Art 81.9 states “The sponsor
shall permanently update in the EU database information on any changes to the clinical trial which are
not substantial modifications but are relevant for the supervision of the clinical trial by the Member
states concerned”. Art 81.9 changes can be submitted only if the change does not trigger additional
changes, which are expected to be submitted as an substantial modification application.

For non-substantial modifications documentation should not be proactively submitted, but the relevant
internal and study documentation supporting the change should be recorded within the company and if
appropriate, at investigator site. At the time of an overall IMPD update or submission of a substantial
modification the non-substantial changes should be incorporated into the updated documentation.
However, when submitting a modified IMPD, the sponsor should clearly identify which changes are
substantial and which are not.

When any quality modification will become effective with the start of a new clinical trial (e.g. change of
name of the IMP, new manufacturing process), the notification will take place with the application for
the new trial. Submissions of substantial modifications are only necessary for changes to ongoing
clinical trials (i.e. after time of approval).

In the following table, examples are given for changes in IMPs, containing chemically defined or herbal
drug substances, and their classification. This list does not claim to be exhaustive. The sponsor should
decide on a case by case basis how to classify the change. In case of doubt, the sponsor should consult
the Reporting Member State.

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 Changes to IMPD Substantial Modification (SM) Art. 81.9 non-substantial Non-substantial Modification (NSM)
Modification (NSM)
Manufacturer(s) of drug  Addition of or a change to a new  Alternate sites of manufacture within
substance manufacturer (outside the company or one company with unchanged
within the company but in a different manufacturing process and
country) specifications
 Deletion of manufacturing or testing site  Name or address change of drug
(for quality/safety reason, GMP non- substance manufacturer provided that
compliance) the manufacturing site and all
manufacturing operations must remain
the same
 Deletion of a manufacturing or testing
site (no quiality/safety reason)
 Replacement or addition of a testing
site provided that the same analytical
methods are used, and method transfer
has been demonstrated

Manufacturing process of  Different route of synthesis  Modifications of the process parameters

drug substance  Widening of the process parameters or and widening of in-process acceptance
IPC acceptance criteria with impact on criteria such that there is no impact to
product quality and safety product quality (same process and
 Changes in the physicochemical synthetic route, albeit with possible
properties with influence on the quality slight modifications in solvents,
of the IMP (e.g., particle size reagents, catalysts, temperature,
distribution, polymorphism in case of pressure, reaction time, or
solid dosage forms etc.) stoichiometry that do not impact the
 Change in the manufacturing process of physicochemical properties or the
an herbal substance or herbal impurity profile of the active substance)
preparation  Scale-up not impacting the
physicochemical properties or the
impurity profile
 Changes in the physiochemical
properties without influence on the
quality of the IMP (e.g., particle size
distribution for highly soluble drug,
particle size distribution and/or
polymorphism for a drug product that
contains a spray dried dispersion)

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 Changes to IMPD Substantial Modification (SM) Art. 81.9 non-substantial Non-substantial Modification (NSM)
Modification (NSM)
 Addition or tightening of IPC if not due
to safety reasons
 Addition of a reprocessing not described
in the IMPD (e.g., repetition of a
purification step)

Specification of drug  Widening of acceptance criteria  Tightening of acceptance criteria (no

substance  Deletion of specification parameter safety reason)
 Addition of specification parameter(s)  Addition of specification parameter(s)
for safety/quality reasons, e.g. addition with no safety reason
of mutagenic impurity control  Addition, deletion or replacement of a
specification parameter due to
compendial change

Test methods of drug  New or different test method (e.g. NIR  Improvement of the same analytical
substance/ drug product instead of HPLC) or method changes method (e.g., greater sensitivity,
requiring new validation providing precision, accuracy) provided
results that are not better or equivalent 1)the acceptance criteria are similar or
to the approved method, and/or impact tighter
the control strategy or specification 2)the improved method is suitable for
use or validated according to the stage
of development, and lead to comparable
or better validation results
 Update of the test procedure to comply
with revised PhEur, USP, or JP
monograph

Reference standard  Introduction of new RS, provided

equivalence has been established to the
previous RS

Retest period of drug  Reduction of retest period and/or  Extension of retest period based on the
substance restriction of the storage conditions due currently approved stability protocol or
to safety and/or quality concern scheme
 Extension of retest period not based on  Reduction of retest period and/or
the currently approved stability protocol change to more restrictive storage
or without prior commitment conditions provided that the change

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Modification (NSM)
 Extension of stability protocol duration should not be the result of unexpected
through additional timepoints to extend events arising during manufacture or
retest period because of stability concerns
 Additional intermediate stability
timepoint (e.g., additional pull point at
42 months) without changing the
conditions for the extrapolation, leading
to corresponding interim retest period
extension

Change to the formulation  Change in the qualitative or quantitative  Qualitatively identical but quantitatively
of medicinal product composition in one or more excipients different composition of non-functional
that may have a significant impact on tablet coating if there is no impact on
the quality or safety of the IMP blinding
(including exchange of excipients to  Different shape of an IR-tablet, e.g.
excipients with same functional round to capsule shaped, with no
characteristics, e.g., disintegrant) clinical impact (e.g. dissolution profile of
 Change and/or addition of drug product the new shape is comparable to the old
strength one) and if there is no impact on
blinding
 Change of imprint/embossing/other
markings provided it has no impact on
blinding

Manufacturer(s) of the  Addition or replacement of  Deletion of manufacturing, packaging,

investigational medicinal manufacturing, packaging, or testing or testing site (no safety reason)
product site  Name change of the manufacturer
 Deletion of manufacturing, packaging,  Addition or replacement of an
or testing site (for safety reason, GMP importation site that is not a QP
non-compliance) certification site, with a valid GMP
 Addition or replacement of batch status
release certification site (QP
certification)

Manufacturing process of  Significant changes to the  Modifications of the process parameters

the investigational medicinal manufacturing process (e.g., dry (same process) where no effect on
product compacting vs. wet granulation, product quality is expected.

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Modification (NSM)
conventional granulation vs. fluid-bed-  Scale-up (such as that the multiplication
granulation) and critical process factor for the scale-up does not exceed
controls (e.g. bioburden limit) 10) for standard manufacturing
 Scale-up for non-standard processes or processes
large scale-ups such as that the
multiplication factor for the scale-up
exceeds 10 for standard manufacturing
processes

Specification of excipients  Changes in the particle size distribution

where these may affect with influence on in-vitro dissolution
product performance

Test methods of non-  New or different test method (e.g. NIR  Minor changes of the analytical method
pharmacopoeial excipients instead of HPLC) already covered by the IMPD
 Update of the test procedure to comply
with PhEur, USP, or JP

Specification (release or  Widening of acceptance criteria with  Tightening of acceptance criteria (no
shelf-life) of the clinical relevance, e.g. change in the safety reason)
investigational medicinal hardness with influence on the  Addition of specification parameter(s)
product disintegration time and/or the in vitro- (no safety reason, control of mutagenic
dissolution, or widening of acceptance impurities excluded)
criteria for impurities
 Deletion of specification parameter(s)
 Addition of specification parameter(s)
with clinical relevance or for
quality/safety reasons (e.g., to control
polymorphs in the drug product that
have the potential to change during
manufacture or on stability, to monitor
unqualified impurities , or to control
mutagenic impurities)

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 Changes to IMPD Substantial Modification (SM) Art. 81.9 non-substantial Non-substantial Modification (NSM)
Modification (NSM)
Container closure system  New container closure system is
introduced (e.g., less protective
material, different container/material
for liquid product)

Medical devices  Addition of, changes to, or replacement  Changes to, or replacement of, a
of, a medical device in the IMPD that medical device in the IMPD which is not
potentially impacts the quality, safety considered to impact the quality, safety
and/or efficacy. and/or efficacy.

Stability of the  Reduction of shelf-life and/or restriction  Extension of shelf-life based on the
investigational medicinal of the storage conditions due to safety currently approved stability protocol or
product and/or quality concern scheme
 Any extension of the shelf life not based  Additional intermediate stability
on the currently approved stability timepoint (e.g., additional pull point at
protocol or without prior commitment 42 months) without changing the
 Extension of stability protocol duration conditions for the extrapolation, leading
through additional timepoints to extend to corresponding interim shelf life
shelf-life extension

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