Navigating regulatory landscapes can be daunting, especially when dealing with proprietary drug substance information. For pharmaceutical companies planning to register therapeutic products in Singapore, understanding the requirements of a Drug Master File (DMF) is essential. In August 2024, Singapore’s Health Sciences Authority (HSA) updated its DMF guideline as part of the broader “Guidance on Therapeutic Product Registration.” This blog post unpacks the purpose, structure, and lifecycle of the DMF submission process in Singapore and offers practical insights for applicants and DMF holders alike.
What is a Drug Master File (DMF)?
A DMF is a confidential, detailed document that provides information on the manufacturing, processing, and packaging of a drug substance. The DMF is typically used to support a product registration application without revealing proprietary details to the applicant of the final drug product.
The purpose of a DMF is to allow the drug substance manufacturer (also known as the DMF Holder) to protect trade secrets while still providing sufficient technical data for regulatory evaluation. In essence, it enables collaboration between different parties in the supply chain without compromising intellectual property.
The Structure of a DMF: Open vs Closed Parts
One of the most essential features of Singapore’s Drug Master File (DMF) system is its two-part structure, which allows for a careful balance between regulatory transparency and the protection of proprietary information. This design reflects a global best practice, enabling regulators to access all necessary technical information for product evaluation while simultaneously ensuring that sensitive manufacturing details are not shared beyond what is strictly necessary.
- Open Part of the DMF (Applicant’s Part)
The open part, sometimes referred to as the “applicant’s part,” contains information that is shared both with the product registration applicant and the Health Sciences Authority (HSA). This section includes details necessary to demonstrate the general acceptability and consistency of the drug substance, but it excludes confidential elements such as proprietary manufacturing processes.
According to the ICH Common Technical Document (CTD) structure adopted by HSA, the open part generally includes the following sections of Module 3.2.S (or Part II.S in the ASEAN CTD):
- S.1 – General Information: This section covers the drug substance name, manufacturer, chemical structure, molecular formula, and other identifiers like the CAS number.
- S.2.1 – Manufacturer(s): Identifies the name, address, and responsibilities of all manufacturers involved in the production and quality control of the substance.
- S.3 to S.7 – Additional Quality Information: These include characterisation (S.3), control of drug substance (S.4), reference standards (S.5), container closure system (S.6), and stability data (S.7).
- Closed Part of the DMF (Restricted or Confidential Part)
The closed part of the DMF is where the proprietary “know-how” lives. This section contains confidential, sensitive information related to the drug substance’s manufacturing process that the DMF Holder does not wish to share with the applicant or any other third party except the regulatory agency.
This portion corresponds to sections S.2.2 to S.2.6 of Module 3.2.S, which cover the following:
- S.2.2 – Description of Manufacturing Process and Process Controls: This section provides detailed step-by-step information on how the drug substance is synthesized or derived, including all in-process controls and critical steps.
- S.2.3 – Control of Materials: Details of raw materials, solvents, reagents, and intermediates used during synthesis. It may include information about the specifications and suppliers of starting materials, which can be highly proprietary.
- S.2.4 – Controls of Critical Steps and Intermediates: Identifies which steps in the manufacturing process are considered critical to quality and what tests or controls are applied at those stages.
- S.2.5 – Process Validation and/or Evaluation: Describes the evidence supporting that the process, as designed, consistently produces material of acceptable quality.
- S.2.6 – Manufacturing Process Development: A narrative of the history and rationale behind how the current manufacturing process was established. It may include discussion of alternative methods, scalability considerations, or lessons learned during development.
Submission Requirements: Who Submits What?
The DMF submission process involves two main stakeholders—the applicant and the DMF Holder—each with different responsibilities.
From the Applicant:
- Submit the open part of the DMF in PDF format as part of the application dossier.
- Include a Letter of Access, which authorizes the HSA to refer to the DMF.
- Provide a copy of the acknowledgment email from the HSA confirming receipt of the Letter of Access.
From the DMF Holder:
- Complete the Online DMF Submission Form (accessible via a government portal).
- Submit a cover letter referencing the Response ID from the form.
- Provide the complete DMF (both open and closed parts) in softcopy.
- Submit a copy of the Letter of Access.
All files must be provided electronically, either on CD/DVD or through cloud-based file sharing (EasiShare). The use of hard copies is discouraged and will not trigger assignment of a DMF number.
The Role of the Letter of Access
The Letter of Access is a pivotal document that links the therapeutic product application to the DMF. It serves multiple purposes:
- Authorizes HSA to reference the DMF during evaluation.
- Identifies the specific product (name, dosage form, and strength) it supports.
- Declares the local applicant responsible for registration.
- Confirms the obligation to notify HSA and the applicant of any DMF changes that may affect product safety or quality.
A sample format of the Letter of Access is available in the HSA’s Appendix 11B to ensure consistency and completeness.
Confidentiality Assurance for DMF Holders
To safeguard proprietary information, the closed part of the DMF is treated as confidential and accessed solely by HSA for evaluation purposes. It will not be disclosed to the applicant or any third party unless explicitly authorized by the DMF Holder in writing.
This approach balances regulatory transparency with business confidentiality, promoting trust between stakeholders in the drug supply chain.
Assignment of DMF Numbers
Once the required documents are submitted in the correct format, the HSA assigns a unique DMF number and issues an acknowledgment email. It’s important to note that:
- The DMF number does not imply approval or rejection. It merely indicates receipt.
- All future communications with HSA should reference the assigned DMF number.
DMF Lifecycle and Evaluation
The DMF undergoes two key phases during product registration:
- Screening Phase
- The DMF is checked for completeness alongside the drug application (NDA, GDA, or MIV-1).
- Any deficiencies in the open or closed parts are communicated:
- Closed part queries go directly to the DMF Holder.
- Open part queries are sent to both the DMF Holder and the applicant.
- Evaluation Phase
- The DMF is evaluated in conjunction with the drug application.
- Evaluation queries follow the same distribution pattern as screening queries.
- The DMF Holder is responsible for addressing all issues and submitting complete responses to HSA.
If an existing DMF is referenced, a new Letter of Access specific to the current application must be submitted.
DMF Updates and Maintenance
Both DMF Holders and applicants are responsible for ensuring that the DMF remains current. If any changes are made to the DMF:
- A Table of Summary of Changes must be provided, detailing the section modified, the current and proposed version, and the rationale for the revision.
- The Online DMF Submission Form must be resubmitted with updated documents.
- Any changes impacting drug substance or product specifications may trigger the need for a post-approval variation to be submitted by the product registrant.
For example, adding a new manufacturer to section S.2.1 would require:
- Notifying HSA through an updated submission.
- Updating the Letter of Access and application dossier as needed.
- Ensuring compliance with the broader post-approval process outlined in Chapter F of the HSA guidance.
Cancelling a DMF
If a DMF is no longer required to support a therapeutic product, the DMF Holder can request cancellation. Once processed, the DMF is considered closed. Any future application referencing this cancelled DMF would be treated as a new DMF, and all relevant documentation would need to be resubmitted.
Practical Takeaways
- Plan Early: Initiate DMF coordination well in advance of the product registration timeline.
- Ensure Completeness: Submissions lacking required documents or formatting will delay the assignment of a DMF number.
- Maintain Confidentiality: Use the correct channels (e.g., EasiShare) for submission of proprietary information.
- Coordinate Closely: Communication between the applicant and DMF Holder is vital for timely response to queries and updates.
- Stay Compliant: Regularly review the DMF to ensure it reflects current manufacturing practices and notify HSA of any changes promptly.
Conclusion
The DMF guideline issued by Singapore’s Health Sciences Authority provides a clear, structured framework for protecting proprietary drug substance information while facilitating regulatory review. For pharmaceutical companies and contract manufacturers looking to enter or maintain a presence in the Singapore market, adhering to these guidelines is not just a compliance requirement—it’s a strategic necessity.
By understanding the lifecycle of the DMF, the roles of each stakeholder, and the expectations around submission and maintenance, companies can ensure a smoother regulatory journey and contribute to a more transparent and trustworthy drug approval process in Singapore.
For the latest forms and submission tools, visit HSA’s website and access the Online DMF Submission Form.
Written by: Ames Gross – President and Founder, Pacific Bridge Medical (PBM)
Mr. Gross founded PBM in 1988 and has helped hundreds of medical companies with regulatory and business development issues in Asia. He is recognized nationally and internationally as a leader in the Asian medical markets. Mr. Gross has a BA degree, Phi Beta Kappa, from the University of Pennsylvania and an MBA from Columbia University.