Similarities and Differences of International Practices and Procedures for the Regulation for Active Substance Master Files/Drug Master Files of Human Use: Moving Toward Regulatory Convergence

Purpose. A gap analysis survey of international practices for Active Substance Master Files (ASMFs)/Drug Master Files (DMFs) of human use was conducted as a project of the ASMF/DMF working group of the International Generic Drug Regulators Pilot (IGDRP) to identify similarities and differences among ASMF/DMF procedures of 10 IGDRP members and 2 observers. Methods. We conducted a questionnaire survey and compared the following aspects: overall ASMF/DMF procedures, submission requirements for ASMFs/DMFs, assessment processes for ASMFs/DMFs, the technical requirements for active pharmaceutical ingredients (APIs), generation of assessment reports for ASMFs/DMFs, procedures for changing ASMF/DMF details, and Good Manufacturing Practice (GMP) inspection/certification of API manufacturers. Twelve organizations participated in this project: the Brazilian Health Surveillance Agency (Anvisa), the European Union (EU), Health Canada (HC), the Singapore Health Sciences Authority (HSA), the South African Medicines Control Council (MCC), the South Korean Ministry of Food and Drug Safety (MFDS), the Japanese Pharmaceuticals and Medical Devices Agency (PMDA), the Swiss Agency for Therapeutic Products (Swissmedic), the Taiwan Food and Drug Administration (TFDA), the Australian Therapeutic Goods Administration (TGA), the European Directorate for the Quality of Medicines & HealthCare (EDQM) (Observer) and the Prequalification Team (PQT) of the World Health Organization (WHO), which includes the PQT–Medicines (Observer). Results. Although there were many similarities among the participating agencies surveyed, there were also differences that should be discussed such as assessment processes of ASMFs/DMFs and Technical requirements for APIs. Conclusions. These differences revealed by this survey will be key considerations in order to facilitate the filing of ASMFs/DMFs globally and to establish a framework for sharing and utilizing information related to ASMFs/DMFs among IGDRP members in the future. This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.


INTRODUCTION
Active Pharmaceutical Ingredients (APIs) are indispensable for manufacturing drug products. Their manufacture utilizes significant technical know-how, much of which is the intellectual property of the API manufacturer. For example, synthetic processes, reaction and purification conditions. Often manufacturing information is registered as patents (1,2). It is important to API manufacturers to protect their intellectual property because it is directly linked to their business interests.
In the registration application for Marketing Authorizations (MA) of drug products, API quality data as well as drug product quality data are required. If an applicant of a drug product manufactures the API itself, the applicant is able to provide this API information directly to the regulatory agency together with other application data. However, APIs are generally manufactured by dedicated, third-party API manufacturers, not the drug product manufacturer. Thus, it is difficult for API manufacturers to provide their confidential information to the applicant in support of a drug product application.
To protect the API manufacturer's confidential information, an Active Substance Master File (ASMF)/Drug Master File (DMF) system has been developed.
This system enables API information, including confidential intellectual property, to be provided to a regulatory agency by API manufacturers directly without disclosing protected information to the applicant. Typically, the API manufacturer submits this data to the regulatory agency in the form of an ASMF/DMF. The applicant can then refer to the ASMF/DMF data by providing a letter of access, which is consent by the ASMF/DMF holder to permit the regulatory agency to access the ASMF/DMF data to support the applicant's drug product submission. ASMF/DMF systems are utilized in many organizations.
Increasingly API supply chains are globalized (3,4). API manufacturers export their APIs to various countries and applicants use multiple sources of APIs in order to secure a stable supply of generic drugs. Even when an API manufacturer supplies the same API to applicants in different countries, an assessment based on the regulations in each country is required. Therefore it is supposed that similar assessments are carried out by multiple regulatory agencies even when it is the same API, manufactured at the same manufacturing site, by the same manufacturing method. In order to avoid duplication of assessments, mutual collaboration procedures could be established under which one agency will assess the ASMF/DMF on behalf of other concerned agencies. Convergence of ASMF/DMF regulation will streamline the process of assessment and be beneficial for regulatory agencies, applicants and API manufacturers.
Against such a background, the International Generic Drug Regulators Pilot (IGDRP) was launched in 2012, and an ASMF/DMF working group has been established in the IGDRP. The scope of the ASMF/DMF working group is limited to APIs for human use that are the subject of master file assessments (5). This working group is working to establish a framework for information sharing and potential mutual reliance in the assessment of ASMFs/DMFs among the members. This activity will ultimately enable members to avoid unnecessary assessments and optimize the consistency of assessment outcomes.
In order to progress the IGDRP ASMF/DMF working group discussions, it was important to understand the similarities and differences of the ASMF/DMF regulation among the participating organizations. However, the survey that compared the ASMF/DMF system information of all 12 organizations has not been reported. Therefore, a gap analysis survey of the practices and procedures for ASMFs/DMFs was initiated in May 2014 by the Pharmaceuticals and Medical Devices Agency (PMDA), the regulatory agency in Japan. Twelve organizations participated in this project. In this article, we present the results of this survey as the first step toward understanding the current situation with a view to assist in guiding the work of the IGDRP ASMF/DMF working group for regulatory convergence in this area. Guidelines on active pharmaceutical ingredient master file procedure (16) Guidelines on submission of documentation for a multisource (generic) finished pharmaceutical product for the WHO Prequalification of Medicines Programme: quality part (17) 2008 2012 aThe EDQM and the PQT-WHO are observers to the IGDRP. bThe PQT is a unit within the WHO, which includes the Prequalification Team-Medicines. The primary function of the Prequalification Team-Medicines is to determine if essential medicines intended for international procurement meet WHO standards for quality, safety, and efficacy, and are produced under WHO GMP standards. IGDRP, International Generic Drug Regulators Pilot.

METHODS
Taiwan Food and Drug Administration (TFDA), and the Australian Therapeutic Goods Administration (TGA).
The API master file (APIMF) procedure and API prequalification procedure of the PQT-WHO correspond to an ASMF/DMF system. API prequalification is a comprehensive evaluation that includes assessment of the APIMF to verify with WHO norms and standards, and assessment of sites of API manufacture to verify compliance with WHO GMP requirements (18). In the EDQM, the Certificate(s) of Suitability to the Monographs of the European Pharmacopoeia (CEPs) procedure also corresponds to an ASMF/DMF system. There is no ASMF/DMF system used by the MCC of the South African Medicines Control Council (MCC), but the MCC is currently developing an ASMF/DMF system.
All organizations permit the submission of master files for APIs. In addition, HC, the HSA, the PMDA and the TGA accept master files for API intermediates. Other than APIs and intermediates, master files for excipients can be submitted to the EDQM, HC, and the PMDA. Materials for medical devices are also the subject of master files within the PMDA.
The acceptance criteria for ASMFs/DMFs are different among the organizations. For example, HC accepts different polymorphic forms of an API in the same ASMF/DMF, whereas the other organizations do not. Additionally, in the case of differing synthetic routes (e.g., enzymatic versus synthetic only), the MFDS and the TFDA accepts differing synthetic routes as long as the final API specification is the same. The EDQM and HC do not recommend the inclusion of differing synthetic routes in the same ASMF/DMF, while the remaining organizations do not accept such situations. Knowledge of the acceptance criteria of the practices of other regulatory agencies is important (e.g., different forms of the API in the same ASMF/DMF) when comparing ASMFs/DMFs between agencies and when attempting to utilize assessment reports from other regulatory agencies.
In each organization, there is a coding system for ASMFs/DMFs to distinguish other ASMFs/DMFs. For example, the EDQM and HC apply a chronological coding 'YYYY-XXX' to received ASMFs/DMFs, where Y is the received year and X is the number of ASMF/DMFs received so far for that year). Swissmedic applies the code 'DXXXXX (X is a serial number)' to received ASMF/DMFs. The TGA has no internal coding system, TGA uses the code provided by the ASMF/DMF holder but gives the ASMF/DMF a TGA file number XXXX/yyyyy, where XXXX is the year when the ASMF/DMF was first submitted and any subsequent changes to the ASMF/DMF (updates), and yyyyy is a number given by the TGA. In all regulatory agencies, such internal codes do not change when the ASMF/DMF version is updated.
The use of an ASMF/DMF procedure is not mandatory except by the Anvisa and the MFDS. Anvisa requires the submission of an ASMF/DMF for 30 listed APIs, and the remaining APIs are evaluated with the drug product application. Anvisa expectation is to increase the number of APIs that must undergo the ASMF/DMF procedure in the following years. Similarly, the MFDS also requires registration on 206 APIs listed including their salts and hydrates and new chemical entities (NCEs) authorized by the MFDS after 1 July 2002 and updates on the list. Though the use of an ASMF/DMF procedure is not mandatory in TFDA, TFDA requires API registration of only NCEs and 10 other listed APIs. All organizations permit an unlimited number of ASMFs/DMFs to be submitted for the same API.
In some organizations, additional conditions are imposed when foreign companies submit ASMFs/DMFs, although the ASMFs/DMFs are submitted to regulatory agencies directly by the API manufacturers. Anvisa requires that a legal entity making a submission to the regulatory agency must be based in Brazil. The MFDS, PMDA, and TFDA require the appointment of an in-country caretaker or agent if the ASMF/DMF holder is a foreign company. In Japan and South Korea, in-country caretakers play important roles in administration procedures because ASMF/DMF application forms, notifications and other related documents have to be written in the native language (19). HC recommends that a North American agent is used in order to expedite communications if an ASMF/DMF Holder is not based in North America.

Submission Requirements for ASMFs/DMFs
All organizations require the submission of an administrative submission form with the ASMF/DMF. In addition, letters of access, GMP certification, bovine spongiform encephalopathy (BSE)/transmissible spongiform encephalopathy (TSE) certification, and fees are required in some organizations. A letter of access generally means a letter written by the ASMF/DMF holder permitting a regulatory agency to reference information in the ASMF/DMF on behalf of the applicant (8).
Most organizations have adopted the International Conference on Harmonization (ICH) of Technical Requirements for Registration of Pharmaceuticals for Human Use Common Technical Document (CTD) format as the structure for the technical document (with the exception of Anvisa). The MFDS and PMDA accept not only the CTD but also other formats. The CTD format is provided by the International Conference on Harmonization as a common format for the technical documentation (20). Table 2 shows the contents of CTD sections. In addition, the EDQM, the EU, HC, the PQT-WHO, and Swissmedic require submission of Module 2 of the CTD (quality overall summary (QOS)) for APIs. The EU, HC, the HSA, the MFDS, the PMDA, the PQT-WHO (APIMF procedure), Swissmedic, and the TGA have adopted the division of ASMFs/DMFs into an Applicant's Part and a Restricted Part.
For example, the EU guideline states that "the Applicant's Part contains the information that the ASMF holder regards as non-confidential to the applicant, whereas the Restricted Part contains the information that the ASMF holder regards as confidential" (7). The terms "Applicant's Part" and "Restricted Part" are interchangeable with the terms "Open Part" and "Closed Part", respectively, in some other organizations. The CTD subsections 3.2.S.2.2-3.2.S.2.6 (see Table 2) are the main components of the Restricted Part, with the remaining sections forming the Applicant's Part. The EU, HC and the PMDA prescribe the division of information between the Applicant's Part and the Restricted Part in their guidelines.

The Assessment Process for ASMFs/DMFs
Based on the ASMFs/DMFs' relationship to a related drug product assessment process, ASMF/DMF assessment processes can be classified as follows:  Group 1 (assessment process is in conjunction with a drug product assessment process): the EU, HC, the HSA, the PMDA, the PQT-WHO (APIMF procedure), Swissmedic, and the TGA  Group 2 (assessment process is independent of a drug product assessment process): Anvisa, the EDQM, the MFDS, the PQT-WHO (API Prequalification), and the TFDA The Group 1 organizations undertake the ASMF/DMF assessment process in conjunction with the drug product assessment process (i.e., the ASMF/DMF has been referenced in an application for a drug product). The drug product applicant, the ASMF/DMF holder and the regulatory agency are involved in the ASMF/DMF assessment process. All organizations in Group 1 adopt the Applicant's Part/Restricted Part structure. By adopting this structure, a regulatory agency is able to discuss with an applicant the nonproprietary information contained in the Applicant's Part, because the Applicant's Part is itself shared with the applicant. Table 3 shows the relationship among the ASMF/DMF holder, the regulatory agency, and the drug product applicant in the assessment process of the Applicant's Part. As shown in the Table 3, EU, HC, the HSA, the PQT-WHO (APIMF procedure), and Swissmedic are provided not only both parts by the ASMF/DMF Holder, but also a copy of Applicant's Part by the drug product applicant. When deficiencies are found in the Applicant's Part, the EU, HC, the HSA and the TGA send deficiency letters to both the ASMF/DMF holder and the drug product applicant. On the other hand, the PMDA and Swissmedic send deficiency letters found in the Applicant's Part only to the applicant, and PQT-WHO (APIMF procedure) send letters only to the ASMF/DMF holder. All regulatory agencies receive responses from the ASMF/DMF holder. In addition, the EU, HC, the HSA, and Swissmedic receive responses from the drug product applicant. When the ASMF/DMF is accepted, it is accepted in connection with the MA of the drug product. At least in the EU, it is stipulated in guidelines that the marketing authorization holder (MAH) takes full responsibility for the quality and quality control of the API (7) and this may be the reason that an applicant is involved in all steps in the assessment process. It is supposed that the degree of involvement of an applicant in the assessment process for the ASMF/DMF is based on the concept of residence of responsibility for APIs in each organization.
EDQM, MFDS, PQT-WHO (API prequalification), and TFDA are not listed because they assess ASMF/DMF independent of a drug product.
The Group 2 organizations undertake the ASMF/DMF assessment process independent of the drug product assessment process. All assessment processes are completed between the ASMF/DMF holder or in-country caretaker and the regulatory agency, except for Anvisa where the assessment process is undertaken between the applicant (e.g. the drug product applicant or the legal entity) which is responsible for the ASMF/DMF application and the regulatory agency. For example, the ASMF/DMF holder submits an ASMF/DMF to the regulatory agency, receives deficiency letters from the regulatory agency and responds to the regulatory agency. After these processes, the ASMF/DMF is accepted on its own. Table 4 shows information about the application fee and assessment period of the ASMF/DMF. Within the Group 1 organizations discussed above, an application fee for the assessments of ASMFs/DMFs is not charged because it is part of the drug product application fee. HC has an additional nominal fee for the administration of ASMFs/DMFs. In the Group 2, an application fee for the ASMF/DMF is charged, except for Anvisa. Table 4 also summarizes the assessment timelines for the new ASMFs/DMFs application, excluding the time to submit responses. The EDQM, the MFDS, and the TFDA have assessment periods for the ASMF/DMF itself. The EU, HC, the HSA, the PMDA, Swissmedic, and the TGA have assessment periods for the ASMF/DMF that are determined by the timeline for the drug product assessment period. Anvisa has no limit for the ASMF/DMF assessment period.
When a drug product application (that is linked to the ASMF/DMF) is rejected or withdrawn before acceptance of the ASMF/DMF, the EU, HC, the HSA, the PMDA, the PQT-WHO, and Swissmedic suspend assessment of the ASMF/DMF. On the other hand, Anvisa, the TFDA, and the TGA continue assessment of the ASMF/DMF. Table 5 shows the pharmacopeias officially recognized and the acceptance of the EDQM's CEPs by various agencies. The European Pharmacopoeia (Ph. Eur.) is the most widely accepted pharmacopeia within the participating agencies. Table 6 shows the reference guidelines to control the quality of APIs in each organization. ICH guidelines (23) are widely referred to by participating agencies with respect to starting materials, impurities, and stability testing. In addition, the Committee for Medicinal Products for Human Use (CHMP) guidelines (24) are referred to by some agencies regarding starting materials and impurities.

The Technical Requirements for APIs
All organizations require the stability testing of APIs. According to the EU guidelines for stability of existing substances, an API that is covered by a Ph. Eur. monograph (where degradation products are listed), the EU does not require stability testing as long as the API is tested immediately before use. The PMDA does not require to submit results of stability testing of API as document of approval application of generic drug products in general. If the stability of an API cannot be assumed from the originator (e.g., polymorphic form difference, hydrate difference), the PMDA requires to submit results of stability testing of API in the assessment process in the case of approval application of generic drug. For the EDQM CEP procedure, a retest period is optional (according to EU rules), but in practice stability data are generally submitted and many CEPs carry a retest period.
Several organizations require specific stability study conditions (e.g., due to climatic zone conditions). For example, Anvisa requires studies to be conducted under the conditions indicated by the domestic guideline (25). Although the MCC refers to the ICH guideline as the primary requirement (26), they also require specific conditions if the API is temperature sensitive. Similarly, although the PQT-WHO follows the ICH guideline, PQT-WHO has its own guideline (17) and stipulates a first preference for long-term stability testing at Zone IVb conditions. Table 7 shows the similarities and differences of the procedures related to ASMF/DMF assessment reports. All organizations generate assessment reports for ASMFs/DMFs. However, the PMDA doesn't generate assessment reports for ASMFs/DMFs submitted in support of generic drug products. Though PMDA generates reports only in the case of new drug products, the PMDA is considering generating assessment reports for ASMFs/DMFs supporting generic drug products. All members adopt a descriptive assessment report style.  bOnly in the case of submission as an ASMF/DMF. The suitability of the Ph. Eur. and USP monograph as specification is evaluated during assessment. When a monograph is listed in JP, the specification should be conformance to the JP monograph before it is used for manufacturing drug products. BP, British Pharmacopoeia; JP, Japanese Pharmacopoeia; Ph. Eur., European Pharmacopoeia; Ph. Int., International Pharmacopoeia; USP, United States Pharmacopeia. Except for Anvisa, the MFDS, and the PMDA, assessment reports for ASMFs/DMFs are in English.

The Generation of Assessment Reports for ASMFs/DMFs
No member publishes their ASMF/DMF assessment reports, except in the case of new drugs by the PMDA and the TFDA. The EU includes an evaluation of the API in their public assessment reports of the drug product.
The EU, and Swissmedic (on request only for applications filed after 1 July 2015) provide copies of the ASMF/DMF assessment reports on the Applicant's Part to Applicants/MAHs. The EU also provides copies of the full ASMF/DMF assessment report (the Applicant's Part and the Restricted Part) to the ASMF/DMF holder.

Procedures for Changing ASMF/DMF Details
When changes occur to the details of an ASMF/DMF, all organizations require for the ASMF/DMF holder to inform the regulatory authority of these changes. Like the initial assessment process, the timing of changeassessments can be classified into two patterns. One of the patterns is at the time of the filing of the updated information to the ASMF/DMF, another pattern is at the time the updated information is referenced in conjunction with a drug product application.
There are often different categories assigned to changes in the ASMF/DMF procedures of agencies (typically based on risk principles). For example, the EU has three types of change categories: Type IA (notification), Type IB (minor variations), and Type II (major variations). The MFDS and the PMDA have two types: partial change approval application and minor change notification. The PQT-WHO has four types: major amendments, minor amendments, immediate notification, and annual notification. The EDQM has three types: major change, minor change, and notifications. Anvisa is under discussion on the procedure. In addition, Anvisa, HC, the MFDS, the TFDA, and the PQT-WHO require periodic updates of ASMFs/DMFs. The MFDS requires it every year. HC and the PQT-WHO require this every 2 years. Anvisa and the TFDA require updates every 5 years. The EDQM requires one renewal after 5 years. Because the reporting categories are different among each organization, further investigations of their details such as documentation would be of value.

GMP Inspection/Certification of API Manufacturers
The TGA, Anvisa, the PMDA, the MFDS, and the PQT-WHO require the GMP certification of APIs manufacturers. HC has recently implemented this condition and is also moving toward this requirement. The timing of the demonstration of GMP certification varies in each organization. For example, Anvisa requires GMP evidence at the time of ASMF/DMF submission. The MFDS and the PQT-WHO require GMP to be established by the completion of ASMF/DMF assessment. The TGA and the PMDA require GMP to be established by the time of the drug product authorization. An application requesting GMP inspection is submitted by API manufacturers in HC and PQT-WHO, but by the drug product applicant in the TGA and the PMDA. Anvisa requires that the applicant of the ASMF/DMF requests GMP inspection of the API manufacturer.
Although GMP certification is not mandatory in the EU, the HSA, the MCC, Swissmedic, the TFDA and the EDQM, the EU and Swissmedic do require a GMP statement by a qualified person. In the EDQM, the API manufacturer has to declare compliance with the EU GMP Part II, inspections are carried out by the EDQM based on risk. The TFDA will require GMP certification for ASMF/DMF authorizations by 2016.

CONCLUSION
ASMF/DMF systems are widespread internationally and ASMFs/DMFs are assessed in many organizations. We conducted a gap analysis survey of ASMF/DMF procedures among IGDRP members and observers and identified similarities and differences between agencies participating in this survey.
First, the general acceptance criteria of different forms of an API in the same ASMF/DMF are largely the same, but there are differences in how agencies treat intermediates and these different forms (see 1. Outline of ASMF/DMF Systems). Second, the assessment processes of ASMFs/DMFs can be classified into two groups based on their relationship to the assessment process of an associated drug product (see 3. The Assessment Processes for ASMFs/DMFs). If the ASMF/DMF assessment process is conducted in conjunction with a drug product application, the Applicant's Part/Restricted Part structure is adopted for the technical document. Third, there are differences in the number and type of officially recognized pharmacopeias and guidelines for API quality among agencies (see 4. The Technical Requirements for APIs). Finally, there are various procedures to deal with ASMF/DMF changes in each organization (see 6. Procedures for Changing ASMF/DMF Details).
In order to progress to greater information sharing, regulatory convergence of technical requirements, and potentially mutual reliance of ASMF/DMF assessments, these differences will be key considerations. This survey is the first article to present and compare ASMF/DMF systems and ASMF/DMF assessment worldwide. We expect that further discussion will be undertaken to understand more deeply the current situation of ASMF/DMF systems and ASMF/DMF assessments worldwide.

DISCLAIMER
The views expressed in this article are those of the authors and do not necessarily reflect the official views of the Pharmaceuticals and Medical Devices Agency.