An active substance is a substance or mixture of substances intended for use in the manufacture of a medicinal product and which, through its use as an active substance, becomes the medicinally active component of the finished medicinal product. Active substances are subject to specific quality and GMP requirements because their identity, purity, strength and impurity profile substantially influence the quality of the subsequent medicinal product.
Active substance as a starting material
In regulatory terminology, the active substance is often referred to as the Active Pharmaceutical Ingredient, API. ICH Q7 covers Good Manufacturing Practice for active substances under an appropriate quality management system and aims to ensure that they meet the requirements for quality and purity. EudraLex Volume 4 Part II contains the basic GMP requirements for active substances used as starting materials.
Quality control begins with raw materials, manufacturing steps and intermediates and extends through the release, storage and transport of the active substance. Specifications, suitable test methods, deviation management and change control ensure that the intended quality is achieved reproducibly. Quality risk management is decisive when selecting the scope of controls: scientific knowledge and the protection of patients are the primary considerations.
Documentation and Active Substance Master File
The quality of an active substance is described in the marketing authorisation dossier with information on manufacture, control, characterisation, impurities, reference standards, packaging and stability. An Active Substance Master File, or ASMF, enables confidential information from an active substance manufacturer to be submitted to the authorities separately from the applicant’s open documentation. The active substance manufacturer provides an open part for the applicant and a restricted part directly for the authority.
However, an ASMF does not constitute a transfer of overall regulatory responsibility. The marketing authorisation holder or applicant remains responsible for adequately substantiating the quality and quality control of the active substance in the context of its medicinal product. Changes to the active substance, manufacturing site or specifications must therefore be managed through appropriate agreements, change notifications and regulatory control of the marketing authorisation.
Distinction from excipient, medicinal product and investigational medicinal product
An excipient is a constituent of a medicinal product that is not the active substance. Excipients may be important for manufacture, stability, dosage form or use, but are not the medicinally active component in the sense described here. The finished medicinal product contains the active substance together with excipients and is provided in its respective dosage form.
An investigational medicinal product is the medicinal product used in a clinical trial, including an investigational or comparator treatment. It must not be equated with the active substance: an investigational medicinal product may comprise one or more active substances, excipients, a dosage form, labelling and study-specific packaging. Regulation (EU) No 536/2014 and Delegated Regulation (EU) 2017/1569 govern clinical trials and GMP principles for investigational medicinal products, respectively.
Active substance manufacturing must be controlled in such a way as to prevent contamination, mix-ups, unacceptable variability and uncontrolled impurities. ICH Q7 contains requirements for quality management, personnel, premises and equipment, documentation, materials management, production and laboratory testing in this regard. Clear responsibilities, supplier assessment and traceable quality agreements also remain essential for outsourced activities.
The supply chain does not end with manufacture. Storage and transport must maintain the specified conditions and enable traceability. In the EU, active substances are also subject to Good Distribution Practice principles. During the development of a medicinal product, it should be assessed at an early stage whether active substance quality and stability are compatible with the intended dosage form, clinical use and subsequent marketing authorisation documentation.
Active substance quality cannot be assessed solely on the basis of an end result. The manufacturing process and control strategy must be sufficiently understood and documented so that critical quality attributes are achieved consistently. Impurities may arise from starting materials, reagents, process aids, by-products or degradation and must be assessed accordingly. Stability is also relevant because quality may change during storage and transport. The active substance manufacturer therefore needs a system that brings together data from manufacturing, the laboratory and quality management. In the event of supplier changes or process changes, the possible impact on quality, specifications and suitability for the subsequent medicinal product must be assessed before implementation.
For each active substance batch, manufacturing documentation, certificate of analysis, specification assessment and traceability of the starting materials used must support release. In the event of process, manufacturing site or specification changes, the change assessment demonstrates that identity, purity, strength and impurity profile remain under control.
Relevance for clinical trials
In clinical trials, active substance quality directly influences the suitability of an investigational medicinal product and the interpretability of the results. Changes to the manufacturing process, test method or specification may affect the comparability of clinical batches. Sponsors, manufacturers and service providers must therefore coordinate active substance information, releases, stability data and the supply chain with the GMP requirements for investigational medicinal products and trial planning.
Full-service CROs such as Mediconomics support the coordination of regulatory documentation, the interface between the active substance manufacturer and the investigational medicinal product, the tracking of quality documents and the planning of study-related supply chains. Together with Regulatory Affairs, project management and quality management, they can structure the evidence required for trial sites, batch documentation and clinical conduct.
Frequently Asked Questions (FAQ)
Is an active substance already a medicinal product?
No. The active substance is the medicinally active component. The medicinal product is the finished product in its dosage form with the active substance and other constituents.
What is the purpose of an ASMF?
It enables confidential active substance information from the manufacturer to be submitted separately and supports the assessment by the authorities as part of a marketing authorisation dossier.
Is an investigational medicinal product the same as an active substance?
No. An investigational medicinal product is a medicinal product provided for a clinical trial and comprises more than its active substance.
Regulatory references
- ICH Q7 Good Manufacturing Practice for Active Pharmaceutical Ingredients – contains GMP principles for active substances.
- Directive 2001/83/EC – defines active substance and medicinal product in Union law.
- EudraLex Volume 4, Part II – contains basic GMP requirements for active substances as starting materials.
- Delegated Regulation (EU) 2017/1569 – lays down GMP principles for investigational medicinal products for human use.