The Asia-Pacific (APAC) region is known to be a diverse area with respect to languages, religion, culture, and economics. It is also heterogeneous with respect to requirements for new drug approvals. Many countries have their own specific requirements. Understanding the product approval landscape and country-specific nuances can be challenging but is necessary to get drug products approved in APAC countries.

While developed countries in the region such as Japan and Australia have drug registration requirements similar to those in the United States and the European Union minus some nuances, smaller countries in the region have their own unique requirements. At the FDA/Xavier PharmaLink conference held virtually in March 2020, AbbVie Global Regulatory Affairs Director Debra Webb gave an overview of drug approval processes within the APAC region.

Part I of this two-part series covers the processes in place for approval of drugs by the various regulatory authorities in the region’s developing economies as well as challenges and opportunities. This part also includes current drug approval timelines by country. Part II focuses on Webb’s experience with various drug agencies during the drug approval process and provides a case study on a post-approval change in South Korea.

[RELATED: For information on the FDA Drug Review Process, check out our Checklist for interacting with FDA.]

Checklist: Interacting with FDA During Drug Review Process

Country-Specific Requirements

The APAC region varies in area depending on context, but it generally includes countries in or near the western Pacific Ocean—East Asia, South Asia, Southeast Asia, and Oceania.

For the purposes of this discussion, Webb excluded China, Japan, Australia, and New Zealand, and, instead, focused on smaller, less-known markets:

  • Hong King
  • India
  • Indonesia
  • Korea
  • Macau
  • Malaysia
  • Philippines
  • Singapore
  • Taiwan
  • Thailand
  • Vietnam

As a general overview, regulatory agencies in the APAC region request extensive ancillary or regional document requirements including raw data. Most markets require approval in major markets first, and even a detailed comparison to the dossier from that major market. 

“In so doing,” Webb commented, “the applicant negates its ability to be able to submit redacted or reduced content, which increases the burden post-approval.”

Some markets have presubmission or preclearance submission requirements prior to submission of the actual dossier. Additional summary documents may also be required, such as drug substance master files and lists of excipient suppliers. And for the manufacturing site, drug substance, and drug products, some markets require full Common Technical Document (CTD) sections 3.2.S and 3.2.P sections for each manufacturer.

In addition, many of these markets require full commercial supply chain stability data. 

“We do see some typical box-checking mentality seen in some markets in both the registration and post approval processes,” Webb said.

Ancillary/Regional Document Requirements

Webb shared a list of what she termed “regional or ancillary documents,” which she said are “some” of the requirements in the markets being discussed (Figure 1).

Figure 1 Regional or Ancillary Documents

Regarding ancillary documents, some markets require:

  • Full analytical methods
  • Company versions of compendial methods
  • Process validation protocols and reports
  • Drug substance and drug product certificates of analysis (CoAs)
  • Excipient packaging CoAs

Agencies may also ask for copies of excipient monographs, compendial methods/monographs, and copies of some guidances, such as ICH guidance documents or FDA Code of Federal Regulations (CFR) information.

In addition, patent information and extensive GMP information may also be requested, along with all the associated raw data such as chromatograms and example calculations. Other documents requested include site master files, material safety data sheets, and photos and samples of the company’s drug products.

Additional raw data such as spectra, executed batch records for manufacturing as well as packaging with COAs for all ingoing components, packaging drawings and specifications for cartons, and various declarations may be asked for.

South Korea

Webb proceeded to go through what her specific experiences have been with a few of the APAC markets, including South Korea, Malaysia, Taiwan, and Vietnam.

South Korea takes the standard European Union Marketing Authorization Application (EU MAA) content for module three, and requires QC release testing for each imported batch. A test method transfer needs to be documented for release testing.

This market also requires a drug master file (DMF) for small molecules. The DMF must be submitted prior to the dossier and the process can take up to eight to twelve months. As a result of the DMF submission, there may be a potential for an inspection.

Korea also has leachable test requirements, and a New Chemical Entity (NCE) requires demonstrated evidence of no impact to the drug product after packaging. Bulk test results on tablets are not sufficient. Companies also need to show comparability with test results after the tablets have been packaged. And on the biologic side, stability data after assembly is required—for example, for a needle-stick protector with prefilled syringe.

Korea is a market with extensive GMP submission requirements for both drug substances and drug products. They require site documentation information, such as what is found in the site master file, along with SOPs, drawings, and diagrams.

Three executed batch records each for drug substance and drug product must be submitted along with supporting information such as:

  • COAs for all excipients going into executed batch records
  • Chromatograms and raw data for executed batch record
  • Any site-specific stability batches where primary stability batches were not made at the commercial site
  • Stability data from the commercial site where the batches were executed

South Korea requires EU GMP certificates and manufacturing authorizations. The drug product batch release data after assembly or after packaging and the process validation report, which also includes packaging validation and cleaning validation, must be submitted.

Malaysia

Malaysia allows only one drug product manufacturing batch release site per product registration. A second site requires a new registration. While there is no limit to the number of drug substance manufacturing sites a company can have in the country, a CTD full 3.2.S section, will need to be submitted for each manufacturing site.

Valid GMP certificates are required for all drug substance manufacturers and manufacturers of drug substance intermediates if different from the final drug substance site.

This market requires full commercial supply chain stability data, three batches with 12 months of stability data, for every combination of drug substance and drug product site that is registered.

Malaysia also has what is known as a Quest 3 portal for uploading the new product application dossier. This upload can take up to two weeks. Any uploaded attachments or documents that are greater than five megabytes must be divided into files no greater than five megabytes each. Some of the drug product sections only allow one document per session, so if you have multiple documents, you must concatenate those together first.

Excipients and manufacturers are selected from a drop-down list. If the site you are trying to register is not on the list, you will have to request that it be added, which can take several days.

Also required are drug substance and drug product COAs and the drug product process validation report. Notably, there is a dossier screening process. If any deficiencies are found, the dossier is rejected. There are three health authority departments that are screening the submissions. If any one of them rejects, the entire submission is rejected and resubmission is required.

“We also found that Malaysia presented us with multiple sets of extensive queries,” Webb pointed out. “I will show that in my case study.” [Editor’s Note: This case study will be provided in Part II of this article.]

Taiwan

Taiwan requires submission of all compendial test methods for drug substance, excipients, and drug products. This market also requires full commercial supply chain stability. Six months stability data on three batches is required at the time of submission, with 12 month data submitted during the review process. Also required are executed batch records for one of the commercial supply chain batches.

On the biologic side, an executed batch record for the drug substance must be submitted, as well as COAs for the drug substance, packaging components, excipients, and the drug product.

Only one drug product manufacturing or packaging site is allowed, although there is no limit on the biologics side. For both drug substance and drug products, a process validation report is required. If required reports are not provided initially, they will request the reports during the review. A GMP inspection will be required if the manufacturing site is not in a country with a mutual recognition agreement (MRA) with Taiwan or Pharmaceutical Inspection Cooperation Scheme (PIC/S) membership.

Vietnam

Vietnam requires the drug product process validation report as well as site master files. This market also requires commercial supply chain stability data, conducted on three batches with 12 month data. It also requests packaging component drawings and specifications for cartons. Vietnam only allows one product per product manufacturing site, while there is no limit on the drug substance side.

Opportunities in the Asia-Pacific Region

Several countries in the APAC region are now ICH members, including Singapore, Korea, China, and Taiwan, with India, Malaysia, and Australia as observers. They have product reviewers Webb characterized as “highly technical.” Review timelines can be comparable to that that we see in the Asian markets.

Hong Kong and Macau have lesser review requirements.

Singapore allows a verification route of approval. In addition, Singapore does not require a Certificate of Pharmaceutical Product (CPP), so there could be an opportunity to submit there first and use their CPP for the other APAC countries.

Put in place in 2007 was the Asia-Canada-Singapore-Switzerland (ACSS) Consortium, which is a collaborative initiative of like-minded, medium-sized regulatory authorities between Australia’s Therapeutic Goods Administration (TGA), Health Canada (HC), Singapore’s Health Sciences Authority (HSA) and the Swiss Agency for Therapeutic Products (Swissmedic) of Switzerland. These agencies share a product review process.

The dossier review timelines that AbbVie has seen in this market are shown below (Figure 2).

Figure 2 Review Timelines

“Some of them are close to what we see in major markets, especially in a few of the markets that have fast track or expedited pathways, which gives them shorter approval timelines,” Webb commented.

In part II, learn more about Webb’s experience with various regulatory agencies in the Asia-Pacific region on drug approvals. She also provides a case study on a post-approval in South Korea.

[Editor’s Note: For additional content on drug approval processes in the Latin American region, please consider the following articles.]

CMC Challenges and Opportunities in Latin America

How To Get New Drugs Approved In Brazil

Getting Drugs Approved In Mexico, Argentina, Colombia, And Peru

[RELATED: For information on the FDA Drug Review Process, check out our Checklist for interacting with FDA.]

Checklist: Interacting with FDA During Drug Review Process

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