With Warning Letters (WLs) and significant FDA 483 observations continuing to confront the compounding pharmacy space, FDA is entering into rounds two and three of inspections to determine if corrective actions have been adequately and timely completed and if the compounding pharmacies understand compliance in this space. (See previous posts here and here).
Over 40% of compounders (503B and 503A) inspected have received Warning Letters (45 issued to date) and nearly 100% have received critical observations. Why hasn’t a single WL been lifted? Is the Industry responding adequately to the Drug Quality and Safety Act (DQSA) and FDA expectations, or do they think they are in the first few rounds of a prize fight?
FDA Investigators are well trained in GMP compliance and in the pharmacy compounding space and firms can be assured that they do their homework in preparation for an inspection. Investigators will prepare for inspections by reviewing and analyzing previous inspectional results (of the compounder being inspected and from other inspections) and responses of the compounder they are inspecting and will follow up on the adequacy and timeliness of corrective actions taken.
The triggers for FDA to take heavy-handed enforcement actions continue to be: facilities design (inadequate separation of unit operations, inadequate room classification, pressure differential monitoring, cleanability, etc.); sterility assurance, inadequate media challenges (not worst case), aseptic practices, sterility and pyrogen testing, environmental monitoring, training, filter validation, etc.; lack of or inadequate investigations especially into sterility failures/events; inadequate cleaning and sanitization/disinfecting processes; inadequate environmental monitoring of people and facilities; lack of appropriate specifications and test methods; lack of data to support beyond use dating; not sampling and testing every batch for sterility, pyrogens, particulate matter, identity and potency; inadequate analytical methods validation and others.
FDA is diving deeper and deeper in the round two and three inspections of other compounding pharmacies. A very recent FDA 483 (see October 9, 2015 FDA 483 (see here) contained 14 observations, with 5 cited as repeats from an inspection conducted 13 months earlier (September 2014). In a September 2014 letter, FDA had requested this firm to recall all of its sterile products form the market and FDA had notified health care professionals and consumers not to use products from this firm during September 2014. Despite this, the firm did not recall any products until October 10, 2015 after receipt of the recent FDA 483.
The FDA 483 cited the firm for a repeat observation for inadequate investigations into failing sterility test results, used six examples and noted “that in all cases, the investigations were either absent, incomplete or inadequate”. The firm was also cited for inadequate investigations into three failed media fills, failures for sub-visible particulate matter and failed potency tests (repeat observation). Other repeat observations included: media fills not simulating worst case processing conditions; review and investigation of OOS results for chemical and physical related tests; failure to test each batch of compounded preparation for pyrogens; no written program to assess stability characteristics of compounded products and data to support BUDs; and lack of process validation for lyophilized preparations. Other significant observations included but were not limited to: deficient cleaning and sanitization of rooms and equipment; inadequate aseptic practices; deficient environmental monitoring; lack of data to support pre-sterilization hold times and no pre—sterilization bioburden or endotoxin testing conducted; no finished product testing for impurities and no test specifications for non-sterile products; and labeling no containing required information per 503B(a)(10)(A) and (B).
Of special note is the following observations which demonstrates that FDA is diving deeper and deeper:
- “There is no assurance that test methods used for potency testing of your drug products for release and stability are accurate, sensitive, specific, and reproducible as no product and formulation specific method validation activities have been performed.” Maybe FDA is defining the validation requirements here for analytical methods for compounded drugs? The citation goes on to state that “the contract laboratory states that the results were generated using a proprietary method and that the method cannot be considered validated unless specificity of the formulation has been performed per USP/ICH guidelines”. How many compounding firms have this statement in their CoAs from their contract laboratory?
- “Your Outsourcing facility has not submitted a report to FDA identifying all products compounded during the six months prior to registration as required by section 503B(b)(2)(A).”
- “[D]rug substances used by your facility to compound drug products are not each manufactured by an establishment that is registered under section 510.”
Why is the Compounding Industry continuing to struggle to meet FDA requirements and expectations? Is it due to the lack of experience, knowledge, and training in the FDA-regulated world of the Food and Drug Cosmetic Act, a lack of adequate advice from third party consultants and legal advisers or a combination of the above? The industry and FDA are sort of learning as they go along an,d until all sides settle down and understand each other and the requirements of the DQSA and FDA expectations, we are likely going to continue to see this friction.
In order not to be knocked out in round two or three, what should the Compounding Industry do? It is recommended that they: train in the regulations; spar with the right internal and external people; study FDA expectations and review observations and responses from competitors for the entire industry; improve facilities and operating procedures and processes; strive to be the best: and be compliant with the rules and regulations.