When it comes to drug approvals and post-approval changes in Asia-Pacific (APAC) markets, are you aware of the various requirements? In this article, originally published on October 15, 2020, Redica Systems Senior GMP Quality Expert Jerry Chapman examines these requirements and includes a small case study involving a post-approval change in South Korea.
AbbVie Global Regulatory Affairs Director Debra Webb has extensive experience with the drug product approval process in APAC markets. At the FDA/Xavier PharmaLink conference held virtually in March 2020, she shared her experiences and provided expert advice on navigating the various processes in several APAC markets.
In Part I of this article, she covered the processes in place for approval of drugs by the various regulatory authorities in developing economies within the APAC region. She also discussed challenges and opportunities in the region and current drug approval timelines by country. In Part II below, Webb shared her experiences with queries from various agencies during the drug approval process and provides a case study on a post-approval change in South Korea.
Queries During the Drug Approval Process
During the drug approval process in various APAC markets, agencies formally contact drug product applicants as their review progress with questions—known as queries—for the applicant to respond to. The number and extent of queries vary widely by country.
FIGURE 1 below depicts AbbVie’s experience with an application for the same product in four different APAC countries. Note that most of the queries regarded drug substances, and Malaysia far outpaced the other markets in the number of queries that AbbVie received.
Post-Approval Changes in South Korea
Moving from product approvals, Webb also gave a case study on a post-approval change in South Korea for the addition of a second drug substance manufacturing site.
“To begin with,” Webb said, “we had to update the drug substance Drug Master File (DMF) and we needed that approved prior to submitting the Module 3 update. In the DMF, an elemental impurity assessment was required, also batch analyses and COAs for three batches from the new site, and three months’ stability on one of those batches.”
The number and extent of queries vary widely by country
When it came time to submit Module 3, the updated drug substance section had been completed. The company submitted a test method transfer report for the alternate drug substance site. Also, comparative dissolution for the drug product made from the drug substance from the new site was needed.
Multiple Queries on Module 3 Info
For the test and reference batches in the comparative dissolution, AbbVie was required to provide executed batch records for both of those batches, also chromatograms and other raw data, and a test method transfer report for the drug product manufacturing site.
The comparative dissolution came from a commercial testing laboratory for drug product. “That was accepted by the agency without any comment,” Webb emphasized.
“Our Korean affiliate was very persistent that we needed to perform the comparative dissolution in a Korean laboratory. We went back and forth on that for several weeks.” She noted performing the testing in a lab in Korea would have required a method transfer and AbbVie QA agreement to re-test an already released drug product batch in an outside laboratory, both of which she characterized as “difficult.”
Once it was submitted there were multiple rounds of queries for Module 3 information, many of which had to do with the comparative dissolution. The company needed to confirm that the test had referenced drug product batches that were manufactured with identical parameters and processes.
“This led us to compile a tabular summary using the executed batch record with page numbering from the batch records showing where the identical equipment and in-process controls were,” Webb said. 12 dissolution batches were required. However, the lab had only one dissolution bath with six vessels, so the company needed to justify to the reviewer that two sets of tests on two different days were acceptable, as the agency would have expected it to all have been done on the same day.
The reviewers challenged the use of a single working standard for linearity “that was done per the approved method,” Webb emphasized. “But they still challenged it and said that the company should have had a calibration curve.”
“We had to re-provide our dissolution method validation information in support of that query,” she explained. “They also challenged our linearity validation using five concentrations of single injections, which was done per the approved method. Reviewers said we should have had three injections. And then for this product which has an extended dissolution profile, we successfully answered the question of why we did not have five-minute and 10-minute data.”
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