FDA Warning Letter Missing Ongoing Stability Studies for APIs

Company Antaria Pty. Ltd, Australia

Synopsis 

1.Inadequate Investigation 

2.Own Analytal Methods used but proved to equivalent to USP methods

3.Annual Stability missed

1.Failure to adequately investigate and document out-of-specification results and implement appropriate corrective actions.

Your firm manufactures API (b)(4) USP, labeled in part to be the active ingredient used in (b)(4). You failed to adequately investigate out-of-specification (OOS) test results. Specifically, your firm lacked adequate investigations and corrective actions for numerous OOS results obtained during laboratory testing of your API, including assay and loss on ignition (LOI) testing. The root causes were not clearly defined nor adequately documented, and lots with OOS results were released by your quality unit (QU).

In your response, you state that staff turnover and insufficient staff training attributes to the lack of competency in good laboratory practices. Additionally, you state that you will revise your OOS procedures. You also state that you will review historical LOI OOS to identify a root cause and retrain your laboratory staff. Your response is inadequate because you failed to describe a holistic review of all investigations’ root cause analyses and corrective actions for adequacy. In addition, you did not inform your customers who received OOS lots for assay nor perform a retrospective assessment of retain samples.

Inadequate investigations can lead to unidentified root causes, ineffective corrective action and preventive action (CAPA), and recurring problems that compromise the ability to manufacture safe and effective drugs.

Own Analytal Methods used but proved to equivalent to USP methods

2.Failure to ensure that, for each batch of API, appropriate laboratory tests are conducted to determine conformance to specifications.

Based on review of your laboratory results, you failed to appropriately perform analytical testing (assay and LOI) of your (b)(4) USP in accordance to the current version of United States Pharmacopeia (USP) monograph, nor did you have data to support that your test method was equivalent or better than the USP method. In your response, you state that you will revise your (b)(4) USP assay and LOI test methods to better align with the USP.

Without adequate testing, there is no scientific evidence to assure that your APIs conform to appropriate specifications before release.

Annual Stability missed

3.Failure to design an adequate documented, on-going stability testing program to monitor the stability characteristics of API and to use the results to confirm appropriate storage conditions and retest or expiry dates.

Your firm’s stability program is inadequate. Your firm failed to place at least one lot of your API manufactured in 2019, 2020, or 2021 on stability annually.

In your response, you acknowledge that your stability procedure lacks specificity regarding appropriate testing. Additionally, you acknowledge that your stability study only consists of lots manufactured in 2015 and that you only establish your annual, ongoing stability program in 2022. Your response is inadequate because you did not discuss a retrospective review of API lots in distribution that were manufactured without appropriate stability testing.

Without an adequate stability program, you cannot ensure that your APIs meet established specifications and all pre-determined quality criteria throughout the APIs’ assigned shelf-life.

In response to this letter provide:

A comprehensive, independent assessment and CAPA plan to ensure the adequacy of your stability program. Your remediated program should include, but not be limited to:

    o Stability-indicating methods.

    o Stability studies for each drug product in its marketed container-closure system before distribution is permitted.

    o An ongoing program in which representative batches of each product are added each year to the program to determine if the shelf-life claim remains valid.

    o Detailed definition of the specific attributes to be tested at each station (timepoint).

All procedures that describe these and other elements of your remediated stability program.