Guest Column | May 15, 2020

Should You List All Manufacturing Facilities In Your Drug Application? A Question Of Regulatory Ethics

By Ketan Agravat, rK3 Solutions


This two-part article addresses the importance of listing of drug substance manufacturing facilities in a drug application and discusses the role of regulatory professionals in ensuring the security and integrity of the drug supply chain. Part 1 discussed importance of supply chain security and integrity for pharmaceutical products.

Here in Part 2, we will review the importance of listing all appropriate manufacturing facilities in the drug substance section of a drug application and discuss the role of regulatory professionals in ensuring that the necessary information is included in the application.

To begin, we will look at the definitions of various components of drug development, which will help in the evaluation of the facilities involved in the manufacturing of drug substance.

Active Pharmaceutical Ingredient/Drug Substance

According to ICH Q7: API (or drug substance) is “any substance or mixture of substances intended to be used in the manufacture of a drug (medicinal) product and that, when used in the production of a drug, becomes an active ingredient of the drug product. Such substances are intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease or to affect the structure and function of the body.”1

According to Drug Master Files Guidance for Industry: API is “any substance intended for incorporation into a finished drug product and intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment or prevention of disease, or to affect the structure or any function of the body.”2

API is a core ingredient of any medicine; without it, the medicine does not have its intended therapeutic effect, i.e., the medicine is not a medicine.

API is developed and synthesized in a laboratory and manufactured at commercial scale in a factory that is required to follow regulatory standards and good practice guidelines — good manufacturing practice (GMP), good clinical practice (GCP), good laboratory practice (GLP), good distribution practice (GDP), etc., collectively known as GxP — laid out by various regulatory agencies/health authorities like the FDA, the European Medicines Agency (EMA), etc. The synthesis and manufacturing data should be submitted to the appropriate agency for review in the drug application for approval of marketing. Regulatory submissions are one of the ways to comply with GDP, by listing all the necessary facilities appropriately in the respective sections.

This data can be submitted as an individual application known as a drug master file (DMF), or simply master file (MF) — or a certificate of suitability (CEP or COS) for the European Directorate for the Quality of Medicines (EDQM) — or it can be included as part of a drug application, new drug application (NDA), or abbreviated NDA (ANDA) or marketing authorization application (MAA). Applications for API use various nomenclatures depending on the regional health authority to which they are being submitted.

The format of a drug application (including the data required for API in the DMF) is standardized by ICH via the common technical document (CTD), which is now mandated to be submitted in electronic format (eCTD).

What Is A Drug Master File?

In the U.S., a Type 2 drug master file (DMF) is used for drug substance, drug substance intermediate, and material used in their preparation, or drug product. Drug master files are submissions to the FDA that may be used to provide confidential, detailed information about facilities, processes, or articles used in the manufacturing, processing, packaging, and storing of human drug products.

The EU uses active substance master files, which include documentation providing detailed information on the manufacturing of the active substance of a medicine.

In both definitions, the complete information on the manufacturing of API should be provided, beginning with the selected/justified starting material (key starting material [KSM], per ICH Q11).

DMFs are voluntary submissions used to protect the confidentiality of an API manufacturing process and other related proprietary information. It gives flexibility to API manufacturers to provide access to multiple customers for their drug applications. DMFs should be submitted directly to regulatory authorities, except for the ASMF, as the open part of the ASMF shall be included simultaneously in the MAA.

The ICH CTD has defined following format for a DMF:

Table 1: Table of Contents for DMF* Module 3 – Quality

3.2 Drug Substance

3.2.S.1   General Information

3.2.S.1.1               Nomenclature

3.2.S.1.2               Structure

3.2.S.1.3               General Properties

3.2.S.2   Manufacture

3.2.S.2.1               Manufacturer(s)

3.2.S.2.2               Description of Process and Process Controls

3.2.S.2.3               Control of Materials

3.2.S.2.4               Control of Critical Steps and Intermediates

3.2.S.2.5               Process Validation and/or Evaluation

3.2.S.3   Characterization

3.2.S.3.1               Elucidation of Structure and Other Characteristics

3.2.S.3.2               Impurities

3.2.S.4   Control of Drug Substance

3.2.S.4.1               Specifications

3.2.S.4.2               Analytical Procedures

3.2.S.4.3               Validation of Analytical Procedures

3.2.S.4.4               Batch Analyses

3.2.S.4.5               Justification of Specification

3.2.S.5   Reference Standards or Materials

3.2.S.6   Container/Closure Systems

3.2.S.7   Stability

3.2.S.7.1               Stability Summary and Conclusions

3.2.S.7.2               Post-approval Stability Protocol and Commitment

3.2.S.7.3               Stability Data


       * Type 2 DMF in the U.S.

Each of the above sections has to have all the necessary information related to the quality of the API.

DMFs should have current information as per the ongoing manufacturing practices for the particular API.


The following definitions, from various guidelines, will guide a regulatory professional as to what should be considered under manufacturing facilities:

Manufacture: All operations of receipt of materials, production, packaging, repackaging, labeling, relabeling, quality control, release, storage, and distribution of APIs and related controls. (ICH Q7)

The World Health Organization (WHO), in its guideline Good trade and distribution practices for pharmaceutical starting materials, notes that “It is important to note that any party that engages in repackaging or blending of an API is considered to be a manufacturer and must submit appropriate registration documents for such manufacturing. He or she must also comply with the GMP for APIs as stated in WHO Technical Report Series, No. 957, Annex 2, 2010 (4).”3

Contract Manufacturer: A manufacturer performing some aspect of manufacturing on behalf of the original manufacturer. (ICH Q7)

Quality Unit(s): An organizational unit independent of production which fulfills both quality assurance and quality control responsibilities. This can be in the form of separate QA and QC units or a single individual or group, depending upon the size and structure of the organization. (ICH Q7)

Outsourced Activities: Activities conducted by a contract acceptor under a written agreement with a contract giver. (ICH Q10)

It is very much evident from the above definitions that the “manufacturer” section of the DMF should include a listing of all the facilities involved in the manufacturing of API, either internal or external.

Requirements For Manufacturers

Regulatory professionals are critical in preparing the list of all the facilities involved in the drug manufacturing that should be included in drug application, since they can envisage the importance of a facility to the security of the drug supply chain and lay down a broader picture. This is achieved by providing factual, correct, and current information in the drug substance section of the drug application.

The ICH CTD requires regulatory professionals to list all the sites used for development, manufacture, release, stability study, and quality control of the API, including the name, address(es), and current contact information for each location.

Development site(s) include (related to the process development report in the CTD 3.2.S.2.5):

  • Research and development centers (in-house or outsourced) where API is developed
  • Scale-up facilities
  • Analytical laboratories
    • Product release
    • Stability study
    • Analytical method validation

Manufacturing site(s) used for API, intermediates, and designated key starting materials

  • Manufacturing
  • Reprocessing
  • Recycling
  • Recovering
  • Physical processing (like blending, micronisation, milling, etc.)
  • Warehouse
  • Packing/repacking

Release site(s), including laboratories used for specific testing, i.e., part of product release, such as:

  • Particle size analysis
  • Tests for polymorph
  • Tests for elemental impurities
  • Tests for genotoxic impurities
  • Microbial testing
  • Stability testing
  • Laboratories used for IPQC (in-process quality control)
  • Laboratories used for raw material analysis (e.g. analysis of potable/purified water),

Site(s) used for any specific study

  • Toxicology evaluation study for genotoxic impurity

All information should be current and should be updated from time to time. Any changes should be provided through appropriate amendments.

Role Of Regulatory Professionals

Regulatory compliance and integrity are key factors in the completion of drug applications. Any gaps in reporting will jeopardize the approval of the application. Ethics in the healthcare regulatory profession are crucial, as defined in the Code of Ethics by the Regulatory Affairs Professionals Society (RAPS). Ethical conduct plays a vital role in delivering safe and effective medicine to patients and helps individuals make positive contributions to public health.

The Code of Ethics defines the following eight characteristics for any regulatory professional:

  • Regulatory compliance
  • Competency
  • Objectivity
  • Integrity
  • Honesty/credibility
  • Accountability
  • Equitability
  • Dignity and respect

Regulatory professionals should provide accurate and current information on all the facilities involved in the above-described operations. This will ensure compliance with the cGxP, the security and integrity of the drug supply chain, and the provision of safe and effective medicine to patients.

The most important job for a regulatory professional is:

To ensure the organization’s activities are conducted in compliance with the current laws and regulations of the authorities under which it operates, consistent with advancing, preserving, and protecting public health.


The drug substance section of the DMF plays an important role in ensuring drug supply chain security by listing all the manufacturing partners, as described above, in the appropriate section. This enables the regulatory authority to look at each manufacturer’s information for its genuineness and access its compliance status by way of inspection or by shared information from other regulatory agencies.

It is the duty of healthcare regulatory professionals to maintain and report the complete and accurate components of manufacturers in the drug substance section of a drug application and update them in a timely manner as necessary. Doing so helps secure critical components of the drug supply chain and, ultimately, provide safe medications to patients.



About The Author:

Ketan Agravat is founder of rK3 Solutions, a regulatory consulting firm based in India. He has more than 25 years of experience in regulatory and quality functions related to active pharmaceutical ingredients. Having worked for multiple manufacturing companies over 20 years, he now serves small pharmaceutical manufacturers with the goal of helping them provide the best quality APIs/intermediates, including the supply of clinical trial materials to innovator companies. He is also engaged with educational institutions in guiding students on regulatory functions in the pharmaceutical industry. He can be contacted at