Regulatory Affairs CMC guidance documents to help prepare EU Clinical Trial IMPDs

At the very first time, if any company is planning to apply for an IND and start planning internally, it starts with the a basic target product profile to begin with the development products.

Companies/professionals greatly underestimate the time to prepare and submit well-designed, well-executed IMPD. From the time it is decided, responsible departments focus mainly on a genuine clinical candidate and typically plan on at least a one or two-year time frame to gather sufficient information to file an IMPD and submit it to relevant EU member states

Companies/Regulatory affairs (RA) professionals which devote methodical, systematic attention from day one would move far more efficiently toward clinical trials than companies who delay.

Ideally, even before the research phase, applicants/ RA professionals should start studying the relevant EMA requirements and form details for an IMPD submission to determine how best they can meet those requirements and achieve approval efficiently in less extent of time with least number of queries from HA.

For ease and quick reference to RA professionals, URRA CMC lists below the IMPD guidance with the complete details. The below guidance emphasizes mainly on CMC (Chemistry, manufacturing and controls) of the product to be filed.

CMC guidance documents to help prepare IMPDs

To prepare an Investigational Medicinal Product Dossier (IMPD) for a clinical trial in Europe, you will need to follow the relevant quality guidelines outlined by the European Medicines Agency (EMA) and other regulatory authorities. These guidelines focus on the CMC (Chemistry, Manufacturing, and Controls) aspects and other quality-related elements critical for the quality section of the IMPD.

Here are the key quality guidance documents relevant for preparing an IMPD:

1. ICH Guidelines

   - ICH Q1A(R2): Stability Testing of New Drug Substances and Products 

     Provides guidance on the stability data required for the active substance and the finished product.

   - ICH Q3A(R2): Impurities in New Drug Substances 

     Focuses on impurity limits and their control in drug substances.

   - ICH Q3B(R2): Impurities in New Drug Products 

     Provides guidelines on acceptable impurity levels in the drug product.

   - ICH Q5C: Stability Testing of Biotechnological/Biological Products 

     Specific to the stability testing of biological and biotechnological products used in clinical trials.

   - ICH Q6A: Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances 

     Guidance for the specification of drug substances and drug products, applicable to chemical entities.

   - ICH Q8(R2): Pharmaceutical Development 

     Guidance on the design and development of the drug product.

   - ICH Q9: Quality Risk Management 

     Provides principles of risk management related to the quality of the medicinal product.

   - ICH Q10: Pharmaceutical Quality System 

     Focuses on maintaining a quality system through the product lifecycle.

2. EMA Guidance

   - EMA/CHMP/QWP/545525/2017: Guideline on the Requirements for the Chemical and Pharmaceutical Quality Documentation Concerning Investigational Medicinal Products in Clinical Trials 

     Specifically designed for IMPD submissions, this guideline outlines the detailed requirements for quality documentation, including control of starting materials, drug substance, drug product, and specifications.

   - EMA/CHMP/BWP/534898/2008: Guideline on the Requirements for Quality Documentation Concerning Biological Investigational Medicinal Products in Clinical Trials 

     Focuses on quality documentation for biological investigational products.

   - EMA/CHMP/SWP/28367/07: Guideline on Non-clinical Requirements for Investigational Medicinal Products for Phase I Clinical Trials 

     Addresses the non-clinical aspects that intersect with quality for phase I trials.

### 3. EU GMP Guidelines (Good Manufacturing Practices)

   - EudraLex Volume 4 – Part I and II: 

     These are the foundational guidelines for ensuring GMP compliance in manufacturing investigational medicinal products. The Annex 13 is particularly relevant for IMP manufacturing.

   - Annex 13 to the EU GMP Guidelines: Manufacture of Investigational Medicinal Products 

     This is key for ensuring the proper quality control and packaging of investigational medicinal products used in clinical trials.

   - Annex 2: Manufacture of Biological Active Substances and Medicinal Products for Human Use 

     Provides guidelines specific to biologics used in investigational drugs.

### 4. Specific Guidance for Biologics

   - EMA/CHMP/BWP/187338/2005: Guideline on Development, Production, Characterisation and Specifications for Monoclonal Antibodies and Related Substances 

     Provides detailed guidelines for monoclonal antibodies used as investigational products.

   - EMA/CHMP/BWP/2458/03: Guideline on Virus Safety Evaluation of Biotechnological Investigational Medicinal Products 

     This focuses on ensuring virus safety for investigational biological products.

### 5. Other Relevant Guidelines

   - ICH Q7: Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients 

     This guideline helps ensure that APIs used in the IMP are manufactured under good practices.

   - EudraLex Volume 10: Clinical Trials 

     Specifically, this volume deals with guidance on clinical trials, including the preparation of the IMPD and addressing both quality and safety issues.

   - EMA/CHMP/QWP/180157/2011: Guideline on the Pharmaceutical Quality of Investigational Medicinal Products 

     This guideline provides information on the pharmaceutical quality requirements specific to investigational medicinal products in clinical trials.

### 6. Annexes and Templates

   - IMPD Quality Template: The EMA provides a quality template for the IMPD that specifies the sections you need to address for chemical and biological products. This template outlines the exact structure for Module 3 of the eCTD for investigational products.

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### Key Sections to Include in IMPD (Quality Part):

1. Drug Substance:

   - Information on the active substance (stability, impurities, characterization, manufacturing process).

2. Drug Product:

   - Detailed descriptions of the formulation, stability, control of excipients, and the drug product.

3. Manufacturing Process:

   - Detailed description of the manufacturing, quality control, and validation processes.

4. Specifications:

   - Specifications and analytical methods for both the drug substance and the drug product.

5. Stability Data:

   - Stability testing protocols and data.

6. Packaging and Labeling:

   - Compliance with Annex 13 (IMP labeling).

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### Conclusion:

When preparing an IMPD for a clinical trial in Europe, you must ensure that your submission meets the quality requirements set out by ICH, EMA, and EU GMP guidelines. The documents above provide the foundation for ensuring that your investigational product is properly manufactured, characterized, and controlled for clinical use, ensuring compliance with European regulations.