The clinical trials sector continues experiencing substantial growth, with investigational medicinal products (IMPs) serving as the cornerstone of pharmaceutical innovation and drug development.
As regulatory frameworks evolve and breakthrough therapies advance through development pipelines, understanding the intricacies of IMP development, manufacturing, and compliance has become increasingly critical for industry professionals.
An investigational medicinal product represents any pharmaceutical preparation—whether a novel compound, existing drug, or placebo—that undergoes testing or serves as a reference standard in clinical trials. This encompasses everything from groundbreaking gene therapies to established medicines being evaluated for new indications or patient populations.
What is an Investigational Medicinal Product (IMP)?
According to the ICH E6(R2) Good Clinical Practice guidelines, an investigational medicinal product is defined as “a pharmaceutical form of an active ingredient or placebo being tested or used as a reference in a clinical trial.”
This definition extends beyond newly developed compounds to include:
- Licensed medicines tested for unapproved indications
- Approved drugs used in different formulations or packaging
- Existing treatments being evaluated in new patient populations
- Combination therapies involving approved medicines in novel configurations
- Reference products and placebos used for comparative studies
The regulatory distinction is crucial: even a well-established medicine becomes an IMP when used outside its marketing authorisation parameters or when additional data collection is required for approved uses.
IMP Classification and Types
Primary Classifications
Novel IMPs represent completely new molecular entities with no prior regulatory approval. These require comprehensive dossiers covering preclinical toxicology, pharmacokinetics, and manufacturing data.
Repurposed IMPs involve existing medicines being investigated for new therapeutic applications. Whilst some safety data may already exist, additional studies are typically required for the new indication.
Modified IMPs include approved medicines with alterations to:
- Dosage form or strength
- Route of administration
- Target patient population
- Combination with other active substances
Regulatory Categories
Full IMPD Requirements: Applied when limited regulatory data exists, requiring comprehensive documentation across all dossier sections.
Simplified IMPD Approach: Permitted when substantial regulatory evaluation has already occurred within EU Member States, allowing cross-referencing to existing marketing authorisations.
The Investigational Medicinal Product Dossier (IMPD)
The IMPD serves as the primary regulatory document supporting clinical trial applications across the European Union. This comprehensive dossier provides regulatory authorities with essential information to assess the IMP’s suitability for human testing.
IMPD Structure and Components
Quality Section
- Active substance characterisation and specifications
- Finished product composition and manufacturing process
- Analytical methods and validation data
- Stability studies and storage conditions
- Reference standards and impurity profiles
Non-Clinical Section
- Pharmacology and toxicology data
- ADME (Absorption, Distribution, Metabolism, Excretion) studies
- Safety pharmacology assessments
- Genotoxicity and carcinogenicity evaluations
- Reproductive and developmental toxicity data
Clinical Information
- Previous clinical experience
- Investigator’s brochure cross-references
- Risk-benefit assessment
- Clinical pharmacology data from prior studies
IMPD vs Clinical Trial Application (CTA)
Whilst the CTA represents the complete submission to regulatory authorities for clinical trial authorisation, the IMPD forms the technical core of this application. The CTA encompasses additional elements including:
- Protocol summaries
- Investigator qualifications
- Ethics committee approvals
- Insurance documentation
- Regulatory compliance statements
IMP Manufacturing and Good Manufacturing Practice (GMP)
IMP manufacturing must adhere to GMP standards specifically adapted for investigational products. These requirements recognise the unique challenges of clinical trial manufacturing whilst maintaining essential quality controls.
Key Manufacturing Considerations
Batch Size Flexibility: IMP manufacturing often involves smaller batch sizes compared to commercial production, requiring scalable processes and appropriate validation approaches.
Documentation Requirements: Enhanced documentation traceability is essential, with clear batch records linking specific product lots to individual clinical trial subjects.
Stability Considerations: Limited stability data may necessitate conservative storage conditions and shortened shelf-lives during early development phases.
Supply Chain Management: Complex logistics involving multiple clinical sites, varying storage requirements, and precise inventory tracking across global trials.
Quality Person (QP) Responsibilities
The Qualified Person holds ultimate responsibility for IMP release, ensuring each batch meets specified quality standards before clinical use. Key responsibilities include:
- Batch record review and approval
- Deviation assessment and impact evaluation
- Storage and transport condition verification
- Regulatory compliance confirmation
- Change control oversight
Clinical Trial Phases and IMP Requirements
Phase I: First-in-Human Studies
Primary Objectives: Safety assessment, dosage range determination, preliminary pharmacokinetic evaluation
IMP Considerations:
- Limited manufacturing batches with enhanced analytical characterisation
- Conservative stability specifications
- Rigorous safety monitoring protocols
- Flexible dosing formulations for escalation studies
Phase II: Proof-of-Concept Trials
Primary Objectives: Efficacy evaluation, optimal dosing determination, expanded safety assessment
IMP Requirements:
- Consistent manufacturing processes
- Comparative reference products
- Patient-friendly formulations
- Supply chain optimisation for multi-site trials
Phase III: Pivotal Efficacy Studies
Primary Objectives: Large-scale efficacy confirmation, comprehensive safety evaluation, regulatory submission preparation
Manufacturing Focus:
- Process validation and scale-up preparation
- Commercial manufacturing method development
- Global supply chain establishment
- Regulatory compliance across multiple jurisdictions
Regulatory Framework and Compliance
European Union Regulations
Regulation (EU) No 536/2014 harmonises clinical trial conduct across EU Member States, establishing standardised IMPD requirements and streamlined approval processes.
GMP Guidelines for IMPs provide specific manufacturing standards addressing the unique aspects of investigational product preparation, labelling, and distribution.
Global Regulatory Considerations
United States: The Investigational New Drug (IND) application serves as the US equivalent to the EU CTA, with similar but distinct requirements for product characterisation and clinical protocols.
International Council for Harmonisation (ICH): ICH guidelines provide globally recognised standards for IMP development, with particular emphasis on quality (Q series) and safety (S series) requirements.
Common Challenges and Risk Mitigation
Manufacturing Challenges
Scale-Up Considerations: Early-phase manufacturing processes may not translate directly to commercial scale, requiring careful process development and validation strategies.
Supply Continuity: Clinical trial timelines can extend over several years, necessitating robust stability programmes and backup manufacturing arrangements.
Regulatory Changes: Evolving regulatory requirements may impact ongoing studies, requiring proactive monitoring and adaptive compliance strategies.
Quality Assurance Pitfalls
Inadequate Characterisation: Insufficient analytical development can lead to regulatory delays and potential safety concerns during clinical development.
Documentation Gaps: Incomplete batch records or missing quality documentation can compromise regulatory submissions and clinical trial integrity.
Change Control Failures: Poorly managed manufacturing changes can impact product comparability across clinical phases, potentially invalidating study data.
Technology and Innovation in IMP Development
Advanced Manufacturing Technologies
Continuous Manufacturing: Emerging technologies enable more efficient IMP production with enhanced quality control and reduced manufacturing timelines.
Personalised Medicine Approaches: Patient-specific therapies require novel manufacturing and supply chain strategies, particularly for cell and gene therapy products.
Digital Quality Systems: Electronic batch records, real-time monitoring, and data integrity solutions are transforming IMP manufacturing oversight.
Artificial Intelligence Applications
Predictive Analytics: AI-driven approaches to stability assessment, formulation optimisation, and supply planning are reducing development timelines and costs.
Quality Risk Assessment: Machine learning algorithms help identify potential quality issues and optimise manufacturing processes throughout clinical development.
Future Trends and Industry Evolution
The IMP landscape continues evolving with several key trends shaping the industry:
Decentralised Clinical Trials: Remote patient monitoring and direct-to-patient drug delivery are changing traditional IMP supply and monitoring approaches.
Advanced Therapy Medicinal Products (ATMPs): Cell, gene, and tissue-engineered therapies present unique manufacturing and regulatory challenges requiring specialised expertise.
Global Harmonisation: Continued regulatory alignment across jurisdictions is streamlining international clinical development and reducing duplicative requirements.
Key Takeaways
Investigational medicinal products represent the foundation of pharmaceutical innovation, requiring sophisticated understanding of regulatory requirements, manufacturing principles, and quality systems. Success in IMP development demands:
- Comprehensive regulatory strategy aligned with global requirements
- Robust manufacturing processes scalable from clinical to commercial phases
- Proactive quality systems ensuring patient safety and data integrity
- Cross-functional collaboration between regulatory, quality, and manufacturing teams
- Adaptive approaches accommodating evolving scientific and regulatory landscapes
As the pharmaceutical industry continues advancing towards personalised medicine and breakthrough therapies, mastering IMP development principles becomes increasingly critical for sustained competitive advantage.
Frequently Asked Questions (FAQs)
What is the difference between an IMP and a regular medicinal product?
An IMP is any pharmaceutical preparation used in clinical trials, including new drugs, existing medicines tested for new uses, or products in different formulations than their approved form. Regular medicinal products have marketing authorisation for specific approved uses.
What is an IMPD and why is it required?
The Investigational Medicinal Product Dossier (IMPD) is a comprehensive document containing quality, safety, and efficacy data for IMPs used in clinical trials. It’s required for regulatory approval of clinical trials in the EU and supports the Clinical Trial Application (CTA).
What is the difference between a CTA and IMPD?
A Clinical Trial Application (CTA) is the complete regulatory submission for clinical trial approval, whilst the IMPD is the technical dossier within the CTA that specifically covers the investigational medicinal product’s quality, manufacturing, and safety data.
Do licensed medicines become IMPs in clinical trials?
Yes, even licensed medicines become IMPs when used outside their marketing authorisation (different indication, formulation, or population) or when additional data collection is required for approved uses.
What GMP standards apply to IMP manufacturing?
IMPs must be manufactured according to Good Manufacturing Practice (GMP) standards specifically adapted for investigational products, which account for smaller batch sizes, enhanced documentation requirements, and flexible manufacturing processes whilst maintaining essential quality controls.
Who is responsible for IMP quality in clinical trials?
The trial sponsor holds ultimate responsibility for IMP quality, with the Qualified Person (QP) responsible for batch release. The sponsor must ensure appropriate manufacturing, storage, transport, and site suitability throughout the clinical trial.
What are the main phases of IMP clinical development?
IMP development typically progresses through Phase I (safety assessment), Phase II (efficacy evaluation), and Phase III (large-scale confirmation), each with specific manufacturing and regulatory requirements before potential market approval.
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