The FDA's Best Tips For Avoiding Drug Master File Setbacks

Impurity assessment and starting materials justification are the top reasons for deficiencies related to Type II drug master files in first-cycle DMF reviews while the US FDA continues to see "hidden facilities" that are listed in DMFs but not the ANDAs they are linked with.

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facilities listed in dmfs hidden from andas

Inadequate impurity testing of active pharmaceutical ingredients is by far the most common deficiency in Type II drug master files that the US Food and Drug Adminstration cites in first-cycle reviews of DMFs, an agency official recently said.

The second most common reason: inadequate justification of the starting material.

In addition, the agency continues to see a problem with “hidden facilities,” or those facilities that are listed in DMFs but not in the associated generic drug applications, said Wei Liu, a reviewer with the Office of Pharmaceutical Quality in the FDA’s Center for Drug Evaluation and Research.

Liu shared her insights about key deficiencies in Type II DMFs during a “Midnight Madness” meeting on pharmaceutical quality issues sponsored by OPQ on 23 July. The meeting ran from 12 am to 5 am Eastern Daylight Time so it could be during the workday in Asia.

DMFs are submissions to the FDA that provide confidential information about facilities, processes or drug substances used in manufacturing drug products and are referenced in new drug applications, ANDAs and investigational new drug applications. Under the Generic Drug User Fee Amendments of 2012, the FDA cannot begin an ANDA review until it determines the relevant DMFs are “available for reference.”

She said that 83% of the DMF deficiencies cited in the first cycle of ANDAs reviews stem from inadequate assessment of an API impurity with most of these problems in the area of assessing potential genotoxic impurities (PGI).

Liu recommended that manufacturers consult the following International Council on Harmonization and FDA guidance document to better understand how to control impurities:

• ICH Q3A Impurities in New Drug Substances;

• ICH M7 Assessment and control of DNA reactive (mutagenic) impurities in pharmaceuticals to limit potential carcinogenic risk;

• ICH Q3C Impurities: Residual Solvents; and

• FDA’s Guidance for Industry ANDAs: Impurities in Drug Substances.

Another 12% of DMF deficiencies stemmed from inadequate justification of starting materials. Liu advised manufacturers to consult the ICH Q11 guideline and the ICH Q11 question-and-answer guide to get more information on qualifying starting materials.

The Continuing Problem With Hidden Facilities

Liu said that another problem is the presence of “hidden facilities” listed in the DMF but not the ANDA. Of the 2,405 ANDAs received from October 2017 to May 2020, 15%, or 363 had this problem.

A consequence of having a new facility discovered late in the ANDA assessment cycle is that it “does not allow sufficient time for evaluation or inspection and may prevent an approval.”

The hidden facilities issue has not improved much since last year when an FDA official observed that 16% of ANDAs had an issue with facilities that are listed in DMFs but not the associated ANDAs.  (Also see "ANDA Sponsors Urged To Ask DMF Holders About 'Hidden Facilities'" - Pink Sheet, 13 Nov, 2019.)

To avoid this problem, Liu said that ANDA sponsors should ensure that all facilities that come into contact with the API are listed in Section S.2.1 of the DMF. This includes all final API manufacturing and testing sites such as all API manufacturers that perform routine commercial release and stability tests, including microbial tests; facilities that micronize the API; facilities that sterilize the API; facilities that store or warehouse the API prior to a disposition decision including facilities that store the stability sample; and facilities that perform crude extractions prior to purifying the API.

The FDA issued a final guidance aimed to address the hidden facilities issue by naming the types of manufacturing facilities that firms must list as part of submissions for new drug applications, ANDAs, biologics license applications and supplements.  (Also see "US FDA Details Facilities That NDAs, ANDAs Should Note" - Pink Sheet, 25 Oct, 2019.)

In addition, sponsors should communicate early and interact frequently with DMF holders.

She said that “this high number is indicative of poor communication between applicants and DMF holders regarding the DMF-related facilities that support their ANDAs.”