Investigational medicinal product dossier
<PRODUCT>, VERSION <xx.yy>
<date>
QUALITY
AUTHORS

		

		

Explanatory text: Depending on the nature of the IMP one of the following EU guidelines on quality documentation for clinical trial applications is applicable as expressed in the scope-section of each guideline:
-	Guideline on the requirements for the chemical and pharmaceutical quality documentation concerning investigational medicinal products in clinical trials - Revision 1  (EMA/CHMP/QWP/545525/2017) https://www.ema.europa.eu/en/requirements-chemical-pharmaceutical-quality-documentation-concerning-investigational-medicinal
-	Guideline on the requirements for quality documentation concerning biological investigational medicinal products in clinical trials – Revision 1 (EMA/CHMP/BWP/534898/2008 rev. 1 corrigendum) https://www.ema.europa.eu/en/requirements-quality-documentation-concerning-biological-investigational-medicinal-products-clinical
-	(Draft) guideline on quality, non-clinical and clinical requirements for investigational advanced therapy medicinal products in clinical trials (EMA/CAT/852602/2018) https://www.ema.europa.eu/en/guideline-quality-non-clinical-clinical-requirements-investigational-advanced-therapy-medicinal#current-version--section

Please note that for placebo products (as well as modified authorised test and comparator products) guidance is also laid down in the Guideline on the requirements for the chemical and pharmaceutical quality documentation concerning investigational medicinal products in clinical trials - Revision 1  (EMA/CHMP/QWP/545525/2017) https://www.ema.europa.eu/en/requirements-chemical-pharmaceutical-quality-documentation-concerning-investigational-medicinal

In general, the guidance as presented in the above guidelines should be followed for each section. Where additional information is requested, this is indicated below in that particular section. Please do not leave out any headings; in case there is no information indicate that the section is not applicable.
Depending on the development stage of the product the amount of information required is more or less extensive. For early phase trials less information is expected than for later phase trials. For some sections of the IMPD this is also indicated in the relevant guidance. 

			TABLE OF CONTENTS

Explanatory text: The table of contents for the pharmaceutical part follows the headings as given by the EU guidelines. 

1.	INTRODUCTION

2.1	CHEMICAL PHARMACEUTICAL DATA

2.1.S	ACTIVE SUBSTANCE

2.1.S.1	General Information:
2.1.S.1.1	Nomenclature
2.1.S.1.2	Structure
2.1.S.1.3	General Properties

2.1.S.2	Manufacture:
2.1.S.2.1	Manufacturer(s)
2.1.S.2.2	Description of Manufacturing Process and Process Controls
2.1.S.2.3	Control of Materials
2.1.S.2.4	Controls of Critical Steps and Intermediates
2.1.S.2.5	Process Validation and/or Evaluation
2.1.S.2.6	Manufacturing Process Development
 
2.1.S.3	Characterisation:
2.1.S.3.1	Elucidation of Structure and Other Characteristics
2.1.S.3.2	Impurities

2.1.S.4	Control of Active Substance:
2.1.S.4.1	Specification
2.1.S.4.2	Analytical Procedures
2.1.S.4.3	Validation of Analytical Procedures
2.1.S.4.4	Batch Analyses
2.1.S.4.5	Justification of specification

2.1.S.5	Reference Standards or Materials

2.1.S.6	Container Closure System

2.1.S.7	Stability

2.1.P	DRUG PRODUCT

2.1.P.1	Description and Composition of the Investigational Medicinal Product

2.1.P.2	Pharmaceutical Development:

2.1.P.3	Manufacture:
2.1.P.3.1	Manufacturer(s)
2.1.P.3.2	Batch Formula
2.1.P.3.3	Description of Manufacturing Process and Process Controls
2.1.P.3.4	Controls of Critical Steps and Intermediates
2.1.P.3.5	Process Validation and/or Evaluation 

2.1.P.4	Control of Excipients:
2.1.P.4.1	Specification
2.1.P.4.2	Analytical Procedures
2.1.P.4.3	Validation of Analytical Procedures
2.1.P.4.4	Justification of Specifications
2.1.P.4.5	Excipients of Human or Animal Origin
2.1.P.4.6	Novel Excipients

2.1.P.5	Control of the Investigational Medicinal Product:
2.1.P.5.1	Specification
2.1.P.5.2	Analytical Procedures
2.1.P.5.3	Validation of Analytical Procedures
2.1.P.5.4	Batch Analyses
2.1.P.5.5	Characterization of impurities
2.1.P.5.6	Justification of Specification

2.1.P.6	Reference Standards or Materials

2.1.P.7	Container Closure System

2.1.P.8	Stability

2.1.Q	PLACEBO PRODUCT

2.1.Q.1	Description and composition

2.1.Q.2	Pharmaceutical development

2.1.Q.3	Manufacture:
2.1.Q.3.1	Manufacturer(s)
2.1.Q.3.2	Batch Formula 
2.1.Q.3.3	Description of Manufacturing Process and Process Controls 
2.1.Q.3.4	Control of Critical Steps and Intermediates
2.1.Q.3.5	Process Validation and/or Evaluation

2.1.Q.4	Control of Excipients: 
2.1.Q.4.1	Specifications
2.1.Q.4.2	Analytical Procedures
2.1.Q.4.3	Validation of Analytical procedures
2.1.Q.4.4	Justification of Specifications
2.1.Q.4.5	Excipients of Human or Animal Origin
2.1.Q.4.6	Novel Excipients 

2.1.Q.5	Control of the Placebo Product: 
2.1.Q.5.1	Specifications
2.1.Q.5.2	Analytical Procedures 

2.1.Q.7	Container Closure System 

2.1.Q.8	Stability 

2.1.A	APPENDICES
2.1.A.1	Facilities and Equipment
2.1.A.2	Adventitious Agents Safety Evaluation
2.1.A.3	Novel Excipients
2.1.A.4	Solvents for Reconstitution and Diluents

LIST OF FIGURES

It is recommended to provide a list of figures with their titles and page numbers

LIST OF TABLES
It is recommended to provide a list of tables with their titles and page numbers

1	Introduction 
Explanatory text: This paragraph should give a short introduction to the compound and its level of pharmaceutical and clinical development. 

2.1	CHEMICAL PHARMACEUTICAL DATA
2.1.S	DRUG SUBSTANCE
2.1.S.1	General Information
2.1.S.1.1	Nomenclature 
Please refer to the relevant guideline depending on the nature of the IMP (provide information concerning the nomenclature of the active substance, e.g. INN, etc) 

2.1.S.1.2	Structure 
Please refer to the relevant guideline depending on the nature of the IMP.

2.1.S.1.3	General Properties 
Please refer to the relevant guideline depending on the nature of the IMP. Additional information can be provided in tabulated form 

2.1.S.2	Manufacture 
2.1.S.2.1	Manufacturer(s) 
Please refer to the relevant guideline depending on the nature of the IMP. In general, the name(s) and address(es) and responsibilities of each manufacturer, including contractors, and each proposed production site or facility involved in manufacture, testing, packaging and batch release should be provided.

2.1.S.2.2	Description of Manufacturing Process and Process Controls 
Please refer to the relevant guideline depending on the nature of the IMP. Please also include (safety-relevant) IPCs. 

2.1.S.2.3	Control of Materials 
Please refer to the relevant guideline depending on the nature of the IMP. For raw and starting materials of biological origin CoAs should be provided.

2.1.S.2.4	Control of Critical Steps and Intermediates 
Please refer to the relevant guideline depending on the nature of the IMP. In general, tests and acceptance criteria for the control of critical steps (if any) in the manufacturing process should be provided.

2.1.S.2.5	Process Validation and/or Evaluation 
Please refer to the relevant guideline depending on the nature of the IMP. Additionally, provide information on the status of validation. 
Typically more information is required in case of sterile drug substance (e.g. validation of aseptic process).

2.1.S.2.6	Manufacturing Process Development 
Please refer to the relevant guideline depending on the nature of the IMP. 

2.1.S.3	Characterisation 
2.1.S.3.1	Elucidation of Structure and Other Characteristics 
Please refer to the relevant guideline depending on the nature of the IMP.

2.1.S.3.2	Impurities 
Please refer to the relevant guideline depending on the nature of the IMP. For non-pharmacopeial drug substances process and product related impurities should be addressed. 

2.1.S.4	Control of Active Substance
2.1.S.4.1	Specification
Please refer to the relevant guideline depending on the nature of the IMP. This paragraph should provide the specification for the batch(es) of the active substance to be used in the clinical trial.  The specification should preferably be tabulated and include which methods are used for each test (including referral to international quality standards, where applicable) and the acceptance criteria. Example (chemical DS):
Table 1:	Specifications for <PRODUCT> drug substance
Attribute	Method	Acceptance criteria	
Appearance	Visual observation	Record results	
Identification
(1)
(2)
(3)	
UV Absorption
IR Absorption
X-ray powder diffraction method	
Conforms to the reference spectrum
Conforms to the reference spectrum
Conforms to the reference X-ray diffraction pattern	
Melting point	PhEur	141 to 145C	
Purity
(1) Heavy metals
(2) Related substances

(3) Methanol
Ethanol	
Ph.Eur., Method IV
HPLC

GC	
 20 ppm
Each:  0.5 %
Total:  2.0 %
Methanol:  0.3 %
Ethanol:  0.5 %	
Water	Ph.Eur., KF method
(coulometric titration)	 1.0 %	
Residue on ignition	PhEur	 0.10 %	
Assay	Titration	97.5 to 102.5 %	
N.B.: Contents of the table are for illustrative purposes only. Specifications used in routine testing are acceptable as well.

2.1.S.4.2	Analytical Procedures 
Please refer to the relevant guideline depending on the nature of the IMP. A brief description of all non-compendial analytical procedures should be provided. 

2.1.S.4.3	Validation of Analytical Procedures.
Please refer to the relevant guideline depending on the nature of the IMP. The suitability of the analytical methods used should be addressed. 
Depending on the stage of development of the product a tabulated summary of the results of the validation carried out should be provided. It is not necessary to provide full validation reports. 

2.1.S.4.4	Batch Analyses 
Please refer to the relevant guideline depending on the nature of the IMP. Batch number, batch size, manufacturing site, manufacturing date, control methods, acceptance criteria and the test results should be listed together with the use of the DS batches. Please also indicate the GMP status and manufacturing process used for each DS batch. 

2.1.S.4.5	Justification of specification
Please refer to the relevant guideline depending on the nature of the IMP. Provide justification of the acceptance criteria as laid down in the specification provided in section 2.1.S.4.1. 
Where possible refer to pharmacopeial monographs. 
In case acceptance criteria are based upon a calculation (e.g. endotoxin limit), please also provide the calculation itself. 

2.1.S.5	Reference Standards or Materials 
Please refer to the relevant guideline depending on the nature of the IMP. 
Stability of the reference standard should be monitored, however no data are necessary.

2.1.S.6	Container Closure System 
Please refer to the relevant guideline depending on the nature of the IMP. The immediate packaging material should be described and interaction between the active substance and the immediate packaging should be considered.

2.1.S.7	Stability 
Please refer to the relevant guideline depending on the nature of the IMP. This paragraph may be divided in a section indicating the stability summary and conclusions, a section on the post-approval stability protocol and commitment, and a section with the actual stability data/ results in tabulated form depending on the amount of information. Please indicate the retest period/ shelf-life of the drug substance.   

2.1.P	DRUG PRODUCT 
2.1.P.1	Description and Composition of the investigational medicinal Product 
Please refer to the relevant guideline depending on the nature of the IMP. The qualitative and quantitative composition of the IMP should be provided. Please also provide a physical description of the drug product.
The qualitative composition of the drug product should be provided in a table. Pharmaceutical Standards (e.g. Ph. Eur.) should be provided where applicable. Example (chemical DS)
The qualitative compositions of <PRODUCT> 50- and 100-mg tablets is listed in Table 3. The tablets are round (diameters 7.1 mm (50-mg) and 8.1 mm (100-mg)).
Table 3: 	Qualitative composition of <PRODUCT> 50- and 100-mg and placebo tablets
Component	Reference to standards	Function	
			
<PRODUCT>	In house	Active ingredient	
D-Mannitol	Ph.Eur.	Filler	
Low Substituted Hydroxypropylcellulose	Ph.Eur.	Disintegrant	
Hypromellose	Ph.Eur.	Binder	
Purified water 	Ph.Eur.	Solvent	
Magnesium Stearate	Ph.Eur.	Lubricant	
Purified water	Ph.Eur.	Solvent	

2.1.P.2	Pharmaceutical Development
Please refer to the relevant guideline depending on the nature of the IMP. For early development there may be only limited information to include in this section. A short description of formulation development, including justification of any new pharmaceutical form or excipient, should be provided.
Provide a qualitative description of the formulation used in the study. Mention if different formulations were used for earlier studies.

2.1.P.2.1	Components of the Medicinal Product
Additional relevant information with respect to drug substance and excipients should be provided here.

2.1.P.2.2	Medicinal product
Additional relevant information with respect to the formulation development can be provided here.

2.1.P.2.3	Manufacturing Process Development
Please refer to the relevant guideline depending on the nature of the IMP. Changes in the manufacturing process (if any) including changes in formulation and dosage form compared to previous clinical trials should be described. Comparability should be addressed.

2.1.P.2.4	Container Closure System
No development information needs to be provided.

2.1.P.2.5	Microbiological Attributes
Provide only relevant information.

2.1.P.2.6	Compatibility
Provide only relevant information.

2.1.P.3	Manufacture 
2.1.P.3.1	Manufacturer(s)
Please refer to the relevant guideline depending on the nature of the IMP. In general, the name(s) and address(es) and responsibilities of all manufacturers for each proposed production site in manufacture, testing and batch release should be provided. In case that multiple manufacturers contribute to the manufacture of the IMP, their respective responsibilities need to be clearly stated.

2.1.P.3.2	Batch Formula 
Please refer to the relevant guideline depending on the nature of the IMP. In general, the batch formula for the batch(es) to be used for the clinical trial should be presented. This should include a list of all components. The batch sizes or range of batch sizes should be given.

2.1.P.3.3	Description of Manufacturing Process and Process Controls 
Please refer to the relevant guideline depending on the nature of the IMP. This paragraph should include a flow-chart including relevant in-process controls (IPCs) as well as a brief process description. This should not be a detailed instruction for production, but details/precautions taken, relevant for the safety of the drug product for testing in human subjects should be provided. (Example: actions taken to ensure viral safety in a biotech product).

2.1.P.3.4	Control of Critical Steps and Intermediates
Please refer to the relevant guideline depending on the nature of the IMP. In general, tests and acceptance criteria for the control of critical steps (if any) in the manufacturing process should be provided. 

2.1.P.3.5	Process Validation and/or Evaluation
Please refer to the relevant guideline depending on the nature of the IMP. Additionally, provide information on the status of process validation. 

2.1.P.4	Control of Excipients 
2.1.P.4.1	Specifications
Please refer to the relevant guideline depending on the nature of the IMP. Refer to the Pharmacopoeias for the excipients used, where possible. For excipients not covered by the aforementioned standards, an in-house specification should be provided.

2.1.P.4.2	Analytical Procedures
Please refer to the relevant guideline depending on the nature of the IMP. In general, in cases where reference to a pharmacopoeial monograph cannot be made, the analytical methods used should be indicated. 

2.1.P.4.3	Validation of Analytical procedures
Please refer to the relevant guideline depending on the nature of the IMP.

2.1.P.4.4	Justification of Specifications
Please refer to the relevant guideline depending on the nature of the IMP.  Only when different from internationally accepted pharmaceutical standards.

2.1.P.4.5	Excipients of Human or Animal Origin
Please refer to the relevant guideline depending on the nature of the IMP. 

2.1.P.4.6	Novel Excipients 
Please refer to the relevant guideline depending on the nature of the IMP.

2.1.P.5	Control of the investigational medicinal Product 
2.1.P.5.1	Specifications
Please refer to the relevant guideline depending on the nature of the IMP. The same principles as described for setting the active substance specification should be applied for the medicinal product. This paragraph should provide the specification for the batch(es) of the IMP to be used in the clinical trial.  The specification should preferably be tabulated and include which methods are used for each test (including referral to international quality standards, where applicable) and the acceptance criteria.
Please note that drug product specific tests and acceptance criteria should be included in the specifications in line with the pharmaceutical form used. The omission of drug product specific tests should be justified.
Provide release and shelf life specifications in tabulated form.
Example (chemical DS):
Clinical trial batches of the <PRODUCT> 50-mg and 100-mg will meet the following specifications.
Table 4:	Release and shelf-life specifications for <PRODUCT> 50-mg and 100-mg tablets
Test Item	Method	Acceptance Criteria	
Description	Visual observation	Light yellow film-coated tablet 	
Identification	HPLC/UV spectrum	The <PRODUCT> retention time and UV spectrum are the same as those of reference standard.	
Related Substances	HPLC	Each: NMT 0.5%
Total: NMT 2.0%	
Content Uniformity*	HPLC	Conforms to Ph. Eur.	
Assay	HPLC	Release:
NLT 95.0% and NMT 105.0%
Shelf-life
NLT 93.0% and NMT 107.0%	
Dissolution Test	USP apparatus 2, 
50 rpm, 900 mL of simulated gastric fluid without pepsin (USP), 
UV spectrophotometry	Q = 75% at 30 minutes
Conforms to USP	
*: Only applied at release; NMT: Not more than; NLT: Not less than

2.1.P.5.2	Analytical Procedures 
Please refer to the relevant guideline depending on the nature of the IMP. A brief description of all analytical procedures should be provided. 

2.1.P.5.3	Validation of Analytical Procedures 
Please refer to the relevant guideline depending on the nature of the IMP. The suitability of the analytical methods used should be addressed. 
Depending on the stage of development of the product a tabulated summary of the results of the validation carried out should be provided. It is not necessary to provide full validation reports.

2.1.P.5.4	Batch Analyses 
Please refer to the relevant guideline depending on the nature of the IMP. Batch number, batch size, manufacturing site, manufacturing date, control methods, acceptance criteria and the test results should be listed together with the use of the DP batches. It should be indicated which batches will be used in the clinical trial and whether additional batches not yet manufactured might be used.

2.1.P.5.5	Characterization of Impurities 
Please refer to the relevant guideline depending on the nature of the IMP. In general, additional impurities and degradation products observed in the IMP, but not covered by section 2.1.S.3.2 should be identified and quantified as necessary.

2.1.P.5.6	Justification of Specification(s)
Please refer to the relevant guideline depending on the nature of the IMP. In general, the proposed acceptance criteria should be justified. 
Where possible refer to pharmacopeial monographs. 
In case acceptance criteria are based upon a calculation (e.g. endotoxin limit), please also provide the calculation itself. 

2.1.P.6	Reference standards
Please refer to the relevant guideline depending on the nature of the IMP. The parameters for characterisation of the reference standard should be submitted, where applicable. Section 2.1.S.5 may be referred to, where applicable.

2.1.P.7	Container Closure System 
Please refer to the relevant guideline depending on the nature of the IMP. In general, the intended primary packaging of the IMP in the clinical trial should be described and compatibility with the drug product addressed.. Where appropriate, reference should be made to the relevant pharmacopoeial monograph.

2.1.P.8	Stability 
Please refer to the relevant guideline depending on the nature of the IMP. In general, the same requirements as for the active substance are applied to the medicinal product. 
This paragraph may be divided in a section indicating the stability summary and conclusions, a section on the post-approval stability protocol and commitment, and a section with the actual stability data/ results in tabulated form depending on the amount of information. 
Please indicate the shelf-life of the drug product.

2.1.Q	PLACEBO PRODUCT
The quality documentation to be submitted for placebos is limited to the following sections of the product part.

2.1.Q.1	Description and composition
Please refer to the guidance on placebo. In general, the complete qualitative and quantitative composition of the placebo should be stated. 

2.1.Q.2	Pharmaceutical development
Please refer to the guidance on placebo. It should be described how possible differences of the placebo preparation in relation to the IMP regarding taste, appearance and smell are masked, where applicable.

2.1.Q.3	Manufacture

2.1.Q.3.1	Manufacturer(s)
Please refer to the guidance on placebo. In general, 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.

2.1.Q.3.2	Batch Formula 
Please refer to the guidance on placebo. In general, the batch formula for the batch to be used for the clinical trial should be presented.

2.1.Q.3.3	Description of Manufacturing Process and Process Controls 
Please refer to the guidance on placebo. In general, a flow chart and brief narrative description of the manufacturing process should be included.

2.1.Q.3.4	Control of Critical Steps and Intermediates
Please refer to the guidance on placebo.  

2.1.Q.3.5	Process Validation and/or Evaluation
Please refer to guidance on placebo.

2.1.Q.4	Control of Excipients 
2.1.Q.4.1	Specifications
Please refer to the guidance on placebo. Refer to the Pharmacopoeias for the excipients used, where possible. For excipients not covered by the aforementioned standards, an in-house specification should be provided.

2.1.Q.4.2	Analytical Procedures
Please refer to the guidance on placebo. In cases where reference to a pharmacopoeial monograph cannot be made, the analytical methods used should be indicated. 

2.1.Q.4.3	Validation of Analytical procedures
Please refer to the guidance on placebo. In general, not applicable.

2.1.Q.4.4	Justification of Specifications
Please refer to the guidance on placebo. In general, not applicable.

2.1.Q.4.5	Excipients of Human or Animal Origin
Please refer to the guidance on placebo. 

2.1.Q.4.6	Novel Excipients 
Please refer to the guidance on placebo. 

2.1.Q.5	Control of the Placebo Product 
2.1.Q.5.1	Specifications
Please refer to the guidance on placebo. Of note, the specifications should at minimum include a test which enables to clearly differentiate between the respective investigational medicinal product and the placebo.

2.1.Q.5.2	Analytical Procedures 
Please refer to the guidance on placebo. A brief description of all analytical procedures should be provided.

2.1.Q.7	Container Closure System 
Please refer to the guidance on placebo.

2.1.Q.8	Stability 
Please refer to the guidance on placebo. In general, the shelf-life and storage conditions of the placebo should be defined.

2.1.A	APPENDICES 
2.1.A.1	Facilities and Equipment
Not applicable.

2.1.A.2	Adventitious Agents Safety Evaluation
See the relevant guideline depending on the nature of the IMP. In general, all materials of human or animal origin used in the manufacturing process of both the active substance and the medicinal product, or such materials coming into contact with active substance or medicinal product during 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.

Reference to the relevant guidance for avoidance of TSE agents and potential viral contamination is indicated in the relevant guideline. 

2.1.A.3	Novel Excipients
For novel excipients, information as indicated in section 2.1.S should be provided in line with the respective clinical phase.

2.1.A.4	Solvents for Reconstitution and Diluents
For solvents for reconstitution and diluents, the relevant information as indicated in section 2.1. P should be provided.