What are the GMP Requirements for Drug Development?

The information and data obtained from pharmaceutical development provide the basis for establishing the specifications and manufacturing processes, including controls for an active substance or a medicinal product. Changes to the composition and manufacturing processes during development and lifecycle management can provide additional insights and further support the establishment of specifications and process parameters ('design space'). The level of GMP in R&D should increase (based on a risk assessment) as the process progresses from early research work through to the final stages of development and formulation, stability testing, and process and cleaning validation (see WHO 'Good practices for research and development facilities of pharmaceutical products').

ICH Q8 - Pharmaceutical Development

According to the ICH Q8 Guideline, the scope and extent of qualification and validation should be determined on the basis of a risk-based approach. The "validation" of R&D processes is also referred to as "process design". This should normally include "design of experiments" (DoE), process development, the manufacture of products for use in clinical trials, pilot-scale batches and transfer. Analytical R&D procedures (including methods used for stability testing and cleaning validation) should be adequately described and validated (see also ICH Q14 Guideline 'Analytical Procedure Development' and ICH Q2 Guideline 'Validation of Analytical Procedures'). As the procedures are generally intended to be transferred to quality control (QC) units at production sites for commercial batches, the procedures and records should be sufficiently detailed to ensure that the transfer is successful. A control strategy should also ensure that a product of the required quality is manufactured consistently (i.e. reproducibly) throughout its entire lifecycle (see also ICH Q12 Guideline 'Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle Management'). These controls should be based on knowledge of the product, the formulation and the process, and should include at least the control of critical process parameters and material properties. At a minimum, those aspects of active substances, excipients, packaging materials and manufacturing processes that are critical to product quality should be identified, and the control strategies should be justified.

ICH Q11 - Development and Manufacture of Drug Substances (Chemical Entities and Biotechnological/Biological Entities)

As described in the ICH Q8 Guideline for medicinal products, a better understanding of the active substance and its manufacturing process can provide the basis for more flexible regulatory approaches. The degree of regulatory flexibility generally depends on the extent of the relevant scientific data submitted in the marketing authorisation application. In a 'traditional' development approach ('Traditional Approach'), target values and operating ranges for process parameters are established, and the control strategy is usually based on demonstrating process reproducibility as well as on testing to ensure compliance with defined acceptance criteria (see also EU GMP Guidelines Annex 15: 'Qualification and Validation' and 'FDA Guidance for Industry: Process Validation: General Principles and Practices'). In a "more modern" approach ("enhanced approach"), risk management and scientific evidence are utilised to a greater extent. Critical Process Parameters (CPPs) and process steps that may affect Critical Quality Attributes (CQAs) are used to develop suitable control strategies. The CPPs and CQAs can also support the definition of "design spaces". However, according to the ICH Q11 Guideline (and also EU GMP Annex 15), traditional and modern development approaches are not mutually exclusive. A company may use either a traditional or an enhanced approach to drug development, or a combination of both ("hybrid approach").

EMA Guidelines

The European Medicines Agency (EMA) has published two guidelines (in EudraLex Volume 10 Clinical Trials Guidelines) on the quality requirements for investigational medicinal products (IMPs):

• Guideline on the requirements for the chemical and pharmaceutical quality documentation concerning investigational medicinal products in clinical trials
• Guideline on the requirements for quality documentation concerning biological investigational medicinal products in clinical trials

These documents contain, amongst other things, details of the information required in the Investigational Medicinal Product Dossier (IMPD) for the validation of manufacturing processes and analytical methods (including stability testing) for active substances and investigational medicinal products for use in phases 1-3 of clinical trials. During the development phases, i.e. clinical phases I to III, complete process validation data may not be required, except, for example, in the case of non-standardised sterilisation procedures not described in the pharmacopoeias (e.g. Ph. Eur., USP or JP). In this case, the critical manufacturing steps, the validation of the manufacturing process and the process controls applied should be described. For dosage forms where there is a higher potential for interactions between the product and packaging materials (e.g. parenteral preparations, ophthalmic preparations, oral solutions), information on extractables and leachables, for example, may be required for Phase III studies. For dosage forms where an interaction is unlikely, e.g. solid oral dosage forms, a justification for not providing such information may suffice. The shelf life and storage conditions should be determined on the basis of the stability profile and the available data on the investigational product. Extrapolation (for chemical entities) is possible (i.e. conclusions regarding future data can be drawn from a known data set; see ICH Q1E Guideline 'Evaluation of Stability Data'), provided that the stability studies are conducted in parallel with the clinical trials and throughout their entire duration. In justified cases, bracketing and matrixing may be permissible (i.e. the use of a reduced test plan; see ICH Q1D Guideline). In Phase I, it should be confirmed that an ongoing stability programme is being conducted for the batch(es) in question, and that, prior to the start of the clinical trial, at least studies under accelerated and long-term storage conditions have been initiated.

The EMA's 'Guideline on quality documentation for medicinal products when used with a medical device' requires that the marketing authorisation dossier for "combination products" (integral medicinal products) contain specific information on manufacturing process development. In particular, the development of the control strategy for the medicinal product's manufacturing process must be described. In addition, suitable data must be submitted to demonstrate and justify the consistent performance of the medical device during the clinical development phases of the medicinal product. This should also include an assessment of the potential impact of changes to the medical device on relevant performance parameters. These parameters may include, for example, the delivered dose, the needle penetration force for subcutaneous or intramuscular injection, and usability factors. This also places specific demands on the development process. The ISO 13485 standard, which has also been adopted by the FDA since February 2026, describes so-called 'design controls' in this context, which should be applied to the combination product as a whole. These design controls describe a systematic set of procedures for managing the development process ("design process"), intended to ensure that the combination product meets user requirements, the intended use, and the specified specifications.

Useful links

• FDA Guidance for Industry: Process Validation: General Principles and Practices
• Annex 15 EU GMP Guidance 'Qualification and Validation'
• EMA Guideline on quality documentation for medicinal products when used with a medical device
• ICH Quality Guidelines
• EudraLex Volume 10 (EU Clinical Trials Guidelines)
• EudraLex Volume 4 (EU GMP)
• TRS 1044 - Annex 6: WHO good practices for research and development facilities of pharmaceutical products