Investigational Medicinal Product (IMP): GMP, Manufacturing, and Regulatory Guide for 2026

A single missing signature on a batch record can stop a clinical trial in its tracks. That signature belongs to the Qualified Person releasing the investigational medicinal product, the drug, biologic, or placebo at the center of every clinical study.

This guide covers what an IMP is, how IMP GMP and manufacturing requirements work under EU and US law, how IMP testing, distribution, and management fit together across the clinical supply chain, and what changed in the regulatory landscape in 2025 and 2026.

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 a clinical trial. This encompasses everything from 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 vs. Non-Investigational Medicinal Product (NIMP)

Not every drug used in a clinical trial is an IMP. A Non-Investigational Medicinal Product (NIMP), sometimes called an auxiliary medicinal product, is a medicine used for supportive, rescue, or standard-of-care purposes within a trial rather than as the object of study itself. Background therapy that all patients receive regardless of study arm, or rescue medication for adverse events, typically falls under the NIMP category rather than the IMP category, which affects how it is documented, labeled, and sourced. The EUPATI Toolbox glossary and clinical protocols filed with regulators both draw this distinction explicitly, and it is worth stating clearly since sponsors and CROs frequently need to classify a given product correctly for regulatory and supply chain purposes.

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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 authorizations, per EMA guidance CHMP/QWP/185401/2004

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 recognize the unique challenges of clinical trial manufacturing while maintaining essential quality controls.

Annex 13 and the Two-Step Release Procedure

The specific EU GMP standard governing IMP manufacture is Annex 13 of the EU GMP Guidelines (EudraLex Volume 4), which was substantially revised in 2022. That revision removed content on the two-step release procedure and sponsor-manufacturer contractual arrangements from the annex itself, since those obligations are not unique to IMP manufacturers; this material now sits in a separate sponsor-responsibilities guideline in EudraLex Volume 10. Labeling requirements for IMPs also moved out of Annex 13 into Annex VI of the Clinical Trials Regulation (CTR).

More recently, the Detailed Commission Guideline on GMP for IMPs required under Commission Delegated Regulation (EU) 2017/1569 has been finalized within Annex 13, alongside a parallel version and an IMP batch-release template published in EudraLex Volume 10. This guidance formalizes a two-step release procedure:

1. QP certification: the Qualified Person of the manufacturer or importer certifies each batch under CTR Article 62(1), confirming the requirements of Article 63(1) and (3) and Article 12 of Commission Delegated Regulation (EU) 2017/1569 have been met.
2. Sponsor regulatory release: the sponsor performs the regulatory release for use in the clinical trial, only after QP certification is complete.

An IMP cannot be used in a clinical trial in an EU Member State until both steps are complete.

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 in IMP Testing and ReleaseThe Qualified Person holds ultimate responsibility for IMP release, ensuring each batch meets specified quality standards before clinical use. Before certifying a batch, a QP typically reviews:

• Batch manufacturing and packaging records
• Results of any analyses or tests performed after importation
• Stability reports
• Source and verification of storage and shipment conditions
• Audit reports on the quality systems of manufacturers in the supply chain
• Records of retain and reference sample storage
• Documentation certifying export authorization from the country of manufacture, where applicable
• Any other factor relevant to the quality of the batch

Source: ProPharma Group, A Roadmap for Clinical Trials: QP Certification of IMP

Where an IMP is manufactured and packaged at different sites under different QPs, Annex 16 of EudraLex Volume 4 governs how responsibilities are divided.

Other QP responsibilities include:

• Deviation assessment and impact evaluation
• Regulatory compliance confirmation
• Change control oversight

IMP Distribution and Clinical Supply Chain Management

Getting an IMP from a GMP-certified manufacturing site to a patient, correctly blinded, within validated storage conditions, and with a documented chain of custody the entire way, is a discipline in its own right that sits at the intersection of GMP, clinical operations, logistics, and regulatory recordkeeping. A failure anywhere in this chain, such as a temperature excursion or a reconciliation discrepancy, can compromise data integrity independent of how well the trial itself was designed. Source: CASRAI, Clinical Trial Supply Management

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: CTR, CTIS, and Annex VI Labeling Rules

Regulation (EU) No 536/2014 (the Clinical Trials Regulation, or CTR) harmonizes clinical trial conduct across EU Member States, establishing standardized IMPD requirements and streamlined approval processes. As of January 31, 2025, the transition period for moving all clinical trial applications onto the Clinical Trials Information System (CTIS) has ended; every EU/EEA trial application must now go through CTIS, with no remaining legacy national pathway

In April 2025, CTIS was designated a World Health Organization (WHO) Primary Registry, meaning trials registered in CTIS now meet WHO’s international trial registration and reporting standards without requiring a separate registration submission.

IMP-specific GMP requirements are set out in Annex 13 of the EU GMP Guidelines (manufacturing) and Annex VI of the CTR (labeling), with active substances for clinical trials separately addressed under EU GMP Guidelines Part II, Chapter 19.

United States: IND and 21 CFR Parts 210 and 211

The Investigational New Drug (IND) application serves as the US equivalent to the EU CTA, with similar but distinct requirements for product characterization and clinical protocols. Manufacturing of investigational drugs for Phase 1 trials is governed by 21 CFR Parts 210 and 211, and the FDA’s guidance on current good manufacturing practice for Phase 1 investigational drugs provides the agency’s expectations for how those requirements apply to early-phase clinical material. [Citation added]

Other Jurisdictions: ICH and TGA

International Council for Harmonisation (ICH): ICH guidelines provide globally recognized standards for IMP development, with particular emphasis on quality (Q series) and safety (S series) requirements.

Australia’s Therapeutic Goods Administration (TGA) applies its own IMP-specific GMP framework under PE009-16 Annex 13, which closely parallels the EU approach but is administered separately; the TGA has also been developing an interpretive guide to this framework. Source: TGA, Investigational Medicinal Products: Expectations and Effective Risk Mitigation.

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, including current EU CTR/CTIS obligations
• Robust manufacturing processes scalable from clinical to commercial phases
• Proactive quality systems ensuring patient safety and data integrity
• A well-managed distribution and chain-of-custody process from GMP release through to the patient
• Cross-functional collaboration between regulatory, quality, manufacturing, and clinical supply teams
• Adaptive approaches accommodating evolving scientific and regulatory landscapes

As the pharmaceutical industry continues advancing toward personalized 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.