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Writer's pictureSharan Murugan

UK MHRA Guidance: Orphan Medicinal Products, Reference Medicinal Products (RMPs), and Handling of Active Substance Master Files (ASMFs) and Certificates of Suitability (CEP)

The UK Medicines and Healthcare products Regulatory Agency (MHRA) on 18th october, 2024 updated multiple guidances such as "Orphan Medicinal Products, Reference Medicinal Products (RMPs), and the Handling of Active Substance Master Files (ASMFs) and Certificates of Suitability (CEPs)". These processes aim to ensure the safety, efficacy, and quality of medicines, particularly in specialised areas such as rare diseases, bioequivalence, and substance quality.


Orphan medicinal products are specifically developed for the treatment, diagnosis, or prevention of rare diseases—those that affect a small proportion of the population. The Orphan designation provides benefits such as market exclusivity, fee reductions, and regulatory support, aimed at encouraging the development of drugs for rare conditions.

In Great Britain, a medicinal product can receive an orphan designation if it meets the following criteria:

  1. It is intended to treat a life-threatening or chronically debilitating disease affecting no more than 5 in 10,000 people in the UK.

  2. The product provides a significant benefit over existing treatments, or there are no satisfactory treatment alternatives.

  3. The medicine is likely to bring substantial benefit to patients.


The designated product eligible for 10 years of market exclusivity after authorisation, Scientific advice from the MHRA to aid the development process and reduced regulatory fees for submissions and assessments. This designation is vital for supporting innovation and providing new treatment options for patients with rare diseases.


Reference Medicinal Products (RMPs) are established medicinal products that serve as a comparative standard in the approval process for generic and biosimilar drugs. The RMP is critical for demonstrating bioequivalence or similarity in terms of safety and efficacy for a new generic product seeking marketing authorisation. RMPs are required for new generic medicines and other abridged marketing authorisation applications. This guidance explains what an RMP is, and how it can be used to support UK marketing applications.

The MHRA provides detailed guidance on selecting an appropriate RMP, ensuring that the product chosen has been authorised for more than 8 years and can act as a valid point of reference for the purposes of bioequivalence studies. Manufacturers must provide evidence supporting their selection of an RMP, ensuring the regulatory assessment is accurate and transparent.


The Active Substance Master File (ASMF) procedure and Certificates of Suitability (CEP) are two mechanisms used to ensure the quality of active substances used in medicinal products. The MHRA accepts Active Substance Master Files (ASMFs) and Certificates of Suitability (CEPs). This document summarises the ASMF compilation and submission process.

  • The ASMF procedure allows active substance manufacturers to submit confidential information about the manufacturing process directly to the MHRA, ensuring the quality, purity, and consistency of the active substance used in the finished product. By using the ASMF, applicants can maintain the confidentiality of proprietary manufacturing data, while still ensuring compliance with regulatory standards for quality and safety.


  • The Certificate of Suitability (CEP), issued by the European Directorate for the Quality of Medicines & HealthCare (EDQM), demonstrates that a substance complies with the requirements of the European Pharmacopoeia. The CEP serves as evidence that the substance meets the necessary quality standards and can be used in pharmaceutical products.


This guidance details on how to properly manage these files during submission, ensuring that all regulatory obligations are met.

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