Drug RA丨第12章 活性物质注册的全球监管程序

Chapter 12 The Global Regulatory Process for the Registration of Active Substances

There are two key objectives when introducing a new drug. One is obtaining marketing approval with a successful application in a drug’s lifecycle. The application process

encompasses marketing authorization applications (MAAs), New Drug Applications (NDAs), or Biologic License Applications (BLA), along with the registration of active substances detailing how the product is manufactured and controlled, summarizing years of testing. The second is creating unique value by developing and obtaining intellectual property in the country or countries where the drug will be marketed.

The active pharmaceutical ingredient (API)—central to developing a medicinal product—is the drug substance that delivers the intended health benefit. API developers and manufacturers invest many hours at high costs to characterize the API and define the manufacturing process, whether chemical drugs or biologics. Registration of active substances provides comprehensive information about the drug, enabling regulatory agencies and healthcare practitioners to ensure that therapeutic benefits outweigh the risks. Regulators assess quality, safety, and efficacy, and evaluate the ability of the future marketing license holder to ensure and monitor a sustainable benefit-risk ratio. In addition to summarizing quality, nonclinical and clinical data, marketing application submissions also lay bare how the safety reporting system transitions from development to the postapproval phase.

When companies are looking to establish a global regulatory strategy, they need to define which countries or economic blocks to register the proposed active substances. In 2020, 10 countries were identified as top pharmaceutical markets, as shown in Figure 11-1.2 Nowadays, the global market is grouped into economic blocks. Therefore, the top pharmaceutical countries can be grouped into the following blocks (Figure 11-2):

• North America: US;

• EU: France, Germany, Italy, and Spain;

• BRIC: Brazil and China;

• Trans-Pacific Partnership: Japan; and

• Commonwealth: Canada and UK.

Raw materials used to manufacture APIs and the API manufacturing process itself are subject to tight controls, and global regulations including current good manufacturing practices (cGMPs) to manufacture a quality ingredient that can be formulated into a medicinal product and used safely. The Chemistry, Manufacturing and Controls (CMC) described in a regulatory dossier to support clinical investigation or marketing authorization must provide a full description of the API, among other essential information described in Chapters 11, 12, 13, and 14.

The regulatory requirement for filing Drug Master File (DMF) and review process for API producers to get approved can vary from country to country. Table 11-1 shows the requirements for countries such as the US, EU, Japan, and China. Information in this chapter reflects the situation in the US, Canada, the UK, Brazil, China, and Japan.

Global Regulatory Requirements 

US

The provision for the submission of a DMF is codified in 21 CFR Part 314.420. In October 2019 the Food and Drug Administration (FDA) issued Revision 1 of the Drug Master Files Guidance for Industry updated from the agency’s September 1989 guidance document.3 This guidance describes the FDA’s current thinking on DMFs and does not establish legally enforceable requirements.

The guidance defines DMFs as “submissions to FDA that may be used to provide confidential, detailed information about facilities, processes or articles used in the manufacture, processing, packaging, and storing of human drug products.” DMFs are not typically submitted for nonproprietary information.

There are four types of DMFs defined in the guidance:

1.Type II includes information for the drug substance, drug substance intermediate, and materials used in their manufacture;

2.Type III for packaging material;

3.Type IV for excipient, colorant, flavor, essence, or material used in their preparation; and

4.Type V for FDA-accepted reference information. 

DMFs are required to be an accurate and complete English translation; a certified translation is not required. In general, the FDA expects the DMF holder to be the manufacturer of the material covered by the DMF. If the DMF holder is not the manufacturer, the DMF should include a statement that the DMF holder assumes full responsibility for the manufacturing of the material. The manufacturer of any material can decide to submit the information necessary for review directly to a customer for submission the investigational new drug (IND), the NDA, the Abbreviated New Drug Application (ANDA), another DMF, and amendments and supplements to regulatory applications. The FDA allows for cross-reference to the DMF or most of Module 32S, except forModules 1, 2.1, Module 4.1, and Module 6.4 Also, data require- ments are the same regardless of submission via DMF or direct inclusion in the market application.

The FDA’s guidance provides detailed information to prepare and submit DMFs, the information expected in DMFs, and the agency’s review process. Additional information is provided on the FDA’s DMF webpage.5 The agency updates its DMF list on a quarterly basis. There were more than 35,000 DMFs listed as of June 2022. The list includes a small number (490) of Type I DMFs; however, Type I’s were discontinued in 2000 but the numbering of the other DMF types did not change. Of the number of DMFs on the FDA’s list, the largest number of DMFs are Type II (roughly 24,800). The next largest number of DMFs are Type III with approximately 6,500. Type II DMFs are the most widely used DMF type. When considering a Type III DMF for your API or referencing a Type III DMF as the sponsor/applicant of your regulatory submission, the following are important elements from the guidance.

A Type II DMF must be submitted in the standard electronic common technical document (eCTD) format in accordance with the Guidance for Industry Providing Regulatory Submissions in Electronic Format-Certain Human Pharmaceutical Product Applications and Related Submissions using the eCTD Specifications (Rev. 6). The FDA’s eCTD submission standards with a complete list of eCTD section headings is provided on the agency’s website.6 Additional information and ICH guidelines for

the CTD are also available. A DMF of 10 GB or smaller must be submitted through the FDA’s Electronic Submission Gateway (ESG). The majority of DMFs fall into this category. Submissions of more than 10 gigabytes can also be submitted through the ESG or can be delivered prepaid on physical media, such as a CD or thumb drive. The FDA announced in June 2019 a proposed rule (84 FR 30968) related to Biologics License Applications (BLA) and Master Files.7 The proposed rule, when final, codifies three specific aspects:

It allows certain biological products, originally approved in a New Drug Application (NDA) under the Federal Food, Drug, and Cosmetic (FD&C) Act, to continue relying on a DMF for information on a drug substance (DS), drug substance intermediate (DSI), or drug product (DP) after the NDA is deemed to be a license for a biological product under the Public Health Service (PHS) Act.8 A BLA under the PHS Act may rely on a Master

File except for information on DS, and DSI defined as material produced during the steps of API manufacturing that undergo further molecular change or purification after it becomes an API or DP (finished dosage form, e.g., tablet, capsule). The PHS Act also codified the FDA’s practice of permitting investigational new drug applications to incorporate by reference any information contained in a Master File for products subject to licensure. The agency generally expects drug substance information to be submitted to the BLA in the relevant sections of the application.

Because DMFs are not approved or disapproved, an environmental assessment is not required to be submitted in a DMF (eCTD Section 1.12.14).3 However, DMF holders should include a commitment in the DMF to operate their facilities in compliance with applicable environmental laws. This statement can also be included in the applicants/sponsors regulatory submission as part of Appendix A.2.1.

Before submitting the original Type II DMF in eCTD format, the DMF holder must request a pre-assigned number from the FDA’s Center for Drug Evaluation and Research (CDER).10 Original submissions must include a cover letter and complete administrative and technical information in the appropriate eCTD modules. For a Type II DMF, Module 3 is the most relevant section, with Module 3 information summarized in Module 2,Quality Overall Summary. Module 4, Nonclinical, is not typically necessary for a Type II DMF unless nonclinical evaluations to support safety were conducted, such as for impurities.

In the cover letter, it is critical to include a statement of commitment signed by the DMF holder that the DMF is current, and the holder will comply with the statements made in the DMF.Only one company should be listed as the DMF holder; joint submissions are not accepted. Detailed information of the contact person and responsible official, if different from the contact person, should be provided including a name, title, phone numbers, fax numbers (if available), a secure email address, and a description of specific responsibilities. The FDA recommends using the cover letter template found on the CDER’s webpage for original and subsequent submissions.3 To facilitate communication with the FDA, it is important for foreign DMF holders to appoint an agent, preferably in the US, who is familiar with agency regulations, guidance, and procedures.

Agents are not responsible for the contents of the DMF; this responsibility cannot and should not be delegated to the agent. The agent can submit on behalf of the DMF holder and can sign DMF submissions with the following exceptions:

• Agent appointment letters

• Statement of commitment

• Name changes

• Holder transfers

• New holder acceptance letters

• DMF closure requests

The guidance further clarifies that the agent for a DMF is not the same as the agent for the purposes of the Drug Listing and Registration System (DRLS); this person should not be listing for registration purposes in the DMF unless they are also the agent for the DMF and DRLS. DMF holders can have different agents for different DMFs.

In earlier years, DMFs were submitted to the FDA in advance of being referenced in a sponsor/applicant application.

More recently, DMFs are submitted closer to or in parallel with applications to support clinical evaluation or product approvals. When a DMF is submitted, the FDA will review the file for administrative information and send an acknowledgement letter to the DMF holder (and agent, if applicable), listing the DMF number, subject (title), type (I, II, III, or IV), and holder’s name, as specified in the DMF cover letter. If administrative information is incomplete, the FDA contacts the holder (and agent, if applicable) to request the missing info. Until all administrative information filing issues are adequately addressed and the DMF is referenced in an application or another DMF, the DMF is not available for technical review. A key document in the administrative information is the debarment certification. DMF holders are included in the category of “Persons whose services were used in any capacity in connection with the application” required under Section 306(k)(1) of the FD&C Act. DMF holders can submit their own debarment certifications in eCTD Section 1.3.3.9 More information on debarment certifications is included in the FDA’s draft Guidance for Industry Submitting Debarment Certification Statements.11

The most critical document to the successful use of the DMF is the Letter of Authorization (LoA). It is key to a complete review of the referenced technical information in the DMF. Until an LoA is submitted to the DMF for a specific application or other DMF (21 CFR Part 314.420[d]),12 the FDA will not review the DMF for technical information. The LoA permits the FDA to review the DMF and permits the authorized party (i.e., the company or individual who applies, or another DMF)to incorporate information into an application or another DMF by reference (eCTD Section 1.4.1). Reviewers may find that additional information is needed to continue a review, or that the DMF cannot be used to support approval of an ANDA or NDA, or in the case of an IND, allow clinical trials to proceed.

In these cases, the FDA will contact the DMF holder and the agent, if applicable, regarding the concerns. This situation may pose a challenge to applicants/sponsors if the DMF holder does not share the request or comments. It is critical that the Quality Agreement with the DMF holder include open and specified communication timelines regarding comments and requests from regulatory authorities from a DMF review so any impact or delays to approval or clinical trial start can be addressed, mitigated,and communicated internally by the applicant/sponsor. Further, it is important for the applicant/sponsor to be aware of any commitments made by the DMF holder that may impact the medicinal product.

DMF holders can authorize one or more applicants/sponsors to incorporate by reference the information contained in the DMF. An LOA is submitted even if the authorized party and the DMF holder are the same company. However, an applicant does not need to create a new DMF when referencing its own material and can include the information directly in its own application.

The DMF holder sends a copy of the LoA to the authorized party, and the authorized party must include a copy of the LoA in the application (21 CFR Part 314.50[a][1])13 or DMF (eCTD Section 1.4.2).9 The FDA recommends the use of its LoA template on the CDER’s webpage.14 Importantly, an LoA does not give an authorized party permission to view, review, or access a DMF. In eCTD Section 1.4.3,9 a list of parties currently authorized to incorporate by reference any information in the DMF must be included, and revised and submitted when additional parties are authorized or withdrawn.

The above information is applicable to all four DMF types. For Type II DMFs, specifically DS, DSIs, and materials used in their preparation and storage, a copy of the shipping label to the site or sites(s) for forward processing should be provided in the eCTD Section 1.149 on labeling.

Each Type II DMF should be submitted for a single drug substance, drug substance intermediate, and type of material used in their preparation, and include a statement that the material covered by the DMF is manufactured under cGMPs. Separate DMFs should also be submitted for drug substances manufactured using different processes.

The definition and criteria for designating starting materials and intermediates are discussed in ICH guidance for industry Q7 Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients (Rev. 1)15 and Q11 Development and Manufacture of Drug Substances16 and ICH Q7 and Q11’s corresponding Questions and Answers guidance.17,18 Drug substance manufacturers should collect stability data according to their stability protocol and should continue to submit data from ongoing studies in a quality/stability amendment to the DMF, see guidance for industry, Q1A(R2) Stability Testing of New Drug Substances and Products,19 from ICH, the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use.

For sterilization of drug substances to be used in sterile products, the same sterility assurance information should be submitted as for sterile drug products in accordance with guidance for industry, Submission Documentation for Sterilization Process Validation in Applications for Human and Veterinary Drug Products,20 and other supporting documents included on the CDER’s DMF webpage. Building and facility information, including floor plans, can be submitted in a Type II DMF if a Type V DMF is not cross-referenced for the information. If material used in the preparation of a drug substance or drug substance intermediate requires FDA review of CMC information (e.g., defined artificial cell growth media), the information should be submitted in the Type II DMF.

As with a regulatory submission, whether supporting clinical evaluation or an approved market application, annual reports are submitted for DMFs. These reports help assure the FDA that the statement of commitment is current. Failure to submit the report annually may result in closure of the DMF by the agency. Further, this report should not be used to report changes to the DMF. In some cases, it may be necessary to submit an amendment to the DMF and an annual report under eCTD sequence numbers.

There are three differences in Type II DMF requirements for generic products that do not apply to nongeneric products. For Type II DMFs referenced in ANDAs, under the Generic Drug User Fee Amendments of 2012,21 commonly referred to as GDUFA, DMF holders are required to pay a fee when first authorizing the reference of their DMF in a generic application. Type II Drug Substance DMFs must undergo an FDA completeness assessment (CA). The October 2017 Rev 1 guidance makes recommendations about the information that should be included in the DMF to facilitate a GDUFA CA. The guidance does not apply to Type II Drug Substance DMFs used for NDAs or other submissions that are not generic drug submissions, or any other types of DMFs.

Also, for Type II DMFs referenced in ANDAs or a prior approval supplement (PAS) to an ANDA, as part of negotiations to reauthorize GDUFA,21 the FDA agreed to a program enhancement that allows for instances when an early review,“DMF prior assessment,” could be requested by a DMF holder. The early assessment for a Type II DMF would start six months prior to an ANDA or PAS submission referencing the DMF. The early assessment does not apply to Type II API DMFs used to support NDAs, submissions related to ANDAs not described in the guidance, or any other type of DMF.

Another important program enhancement under GDUFA that only applies to ANDAs is the provision that for holders of Type II DS DMFs referenced in ANDAs can request teleconferences in response to first cycle DMF deficiency letters.

Conclusion

Registering active substances allows the holder to disclose valuable confidential or proprietary information and “know-how” to the regulatory authorities related to facilities, processes, or materials used to manufacture, package, and store product without disclosing confidential information from the applicants/sponsors. One additional component, the holder must also evaluate the financial impact/ value

when registering substances to the corporation. Therefore, these applications are solely at the discretion of the holder.