Navigating approval filings choppy international waters

Understanding regional differences, implementing best-practice documentation processes key to successful approval outcomes 

Drug Master Files 

A DMF is a procedure that is used globally to share information confidentially between the active substance manufacturer and the marketing authorisation applicant. API manufacturers are responsible for submitting this document to health authorities located in the intended market. The document includes detailed information on the CMC (chemistry, manufacturing and controls) of the API. Other pieces of information enclosed relate to facilities, processes, packaging and the storing of the drug substance. 

Despite being a global procedure, the way DMFs are applied can vary between different regions. For example, there are disparities in the way the US-DMF and EU-DMF are handled.


The European market divides the ASMF (Active Substance Master File) into two parts: the applicant’s part (AP) or open part and the RP (restricted part) or closed part. 


  • The information is regarded as non-confidential
  • The document will be disclosed to the applicant/ MA holder 
  • Written consent from the ASMF holder is required for the document to be submitted by individuals to third parties 


  • The information is regarded as confidential
  • Submitted by the ASMF holder to the National Competent Authorities/ MA holder
  • The document details the individual steps of the manufacturing method and the QC during the manufacture of the active substance 

The overarching aim of the ASMF procedure is to safeguard the valuable information provided on the manufacturing of an active substance, as well as enabling the marketing authorisation applicant (MAA) to be fully accountable for the quality of the active substance used in their product. 

Furthermore, National Competent Authorities receive access in order to evaluate the suitability of the API in the medicinal product. 

Challenges of regulatory documentation

Control strategy and impurities 
The control strategy of an API is determined by the CQA (critical quality attributes) and plays a vital role in the regulatory success of drug substance documentation. In order to gain successful regulatory approval of control strategy, a full understanding of the characteristics and manufacturing steps must be known. The approval is also subject to the availability of analytical methods to control any potential impurities, including degradation products. Impurities, such as chemicals that can be detrimental to the safety and efficacy of pharmaceutical products, can develop during manufacture or during the storage of a finished product. ICH guidelines provide a detailed framework on impurities, which are designed to support companies to produce drug products with reduced impurity content – particularly toxic impurities. 

Regulatory starting materials (RSM)

In addition to the tight regulations on impurities in drug substances, manufacturers must also pay attention to the starting materials used in drug substance synthesis. Regulatory and quality requirements necessitate the naming of starting material manufacturers in the dossier alongside the synthesis pathway. In order to clarify the formation of the structural core elements and origin of potential impurities, all steps in the synthesis pathway need to be outlined. Additionally, the selection of RSMs and justifications of their designation in the supply chain is now a primary focus in a bid to prevent regulatory risks. This also helps to avoid unexpected spikes in cost during the move from clinical to commercial supply chain.

Furthermore, it should not be presumed that the RSM used for the production of drug substance during clinical trial studies and applications will attain approval in the final marketing application without the involvement of further justification. Regulatory agencies want to mitigate impeding clinical development and so they are less likely to refuse the proposed RSM designations in the clinical trial application, unless the GMP portion of the API process fails to demonstrate bond-making reactions other than purification steps. These expectations differ in the transition from clinical to commercial manufacturing, meaning sponsors need to give strong reasoning and evidence that supports their RSM designation. 

Final thoughts

Regulatory approval processes are upheld worldwide in order to ensure the safety and efficacy of drug products. Due to APIs driving the activity and effectiveness of all medicines, stringent measures are in place when it comes to documentation. The procedures for filing information on APIs vary between regions, which can add layers of complexity that must be identified and understood. Only then, can drug developers and their contract partners effectively navigate the global regulatory requirements and achieve market approval. 

If you’re looking to find out more about regulatory affairs and requirements we can help