Compliance Efforts — Where to Put One’s Priorities?

by Eric Foxman, Pharm. (Ret.)

FDA Compliance

Being in compliance and being prepared for an inspection are time and resource- consuming activities. Yet both are necessary and required of every company involved with making or marketing drug products. With the broad array of compliance requirements, where should a firm prioritize its efforts? Perhaps FDA itself can provide an initial answer — one that is available to every firm all the time.

FDA issued just short of 600 warning letters in 2023. Of those, about 180 were related to drugs, of which — with a caveat — 19 (more than 10%!) were for homeopathic drug products. Of the rest: about 225 were for tobacco/smoking/vaping products; and the balance mostly for foods, with a smaller number for medical devices and a handful for miscellaneous categories.

The caveat is that FDA had a sharp focus in 2023 on ophthalmic products of all types, not just homeopathic products. While FDA issued seven warning letters regarding homeopathic ophthalmic products, it also issued at least as many to non-homeopathic products. Put aside those seven and 12 of 180 (7%) warning letters were issued to manufacturers of homeopathic drugs.

However, we can learn much more by looking closely at the details in the warning letters. The 180 drug warning letters cover almost 460 citations, averaging 2.5 cited issues per warning letter. Reviewing the individual citations, and how frequently each arises, sheds light on FDA’s enforcement focus. Which are the ones that FDA has cited most often? Put another way, can we learn which areas should be a priority for our attention by seeing what FDA has focused upon?

FDA Issued Citations

Of the total number of citations, 82% are for GMP deviations and failures. Three areas of failure stand out, detailed below.

Common Area of Failure One

While it is only the seventh most frequently common cited issue (5.7%) in the 180 warning letters, it is disappointingly frequent (26.3%) in warning letters to homeopathic firms: Your firm failed to conduct microbiological testing before use of each lot of a component with potential for objectionable microbiological contamination in light of its intended use. (21 CFR 211.84(d)(6)).

In language fairly common in many letters, FDA goes on the state, “Your firm produces … water that is used as a component in the production of many of your OTC drug products. Your firm failed to adequately monitor the microbiological quality of the water you use …. [Y]ou only test your … water for microbiological attributes and total organic carbon (TOC) …. Water for pharmaceutical must be suitable for its intended use and routinely tested to ensure ongoing conformance with appropriate chemical and microbiological attributes.” [emphasis added]

The agency provides information on what is expected and what each firm should already have in place: qualifying and overseeing contract facilities that test water a firm produces; microbiological testing of the water system until a qualification of the system is complete and an appropriate monitoring procedure is established; and developing a procedure governing a firm’s program for ongoing control, maintenance, and monitoring that ensures the system consistently produces water that meets USP monograph specifications and appropriate microbial limits for water.

Common Area of Failure Two

For both overall pharma warning letters and those specific to homeopathic firms, the second most common citation is, “Your firm failed to conduct at least one test to verify the identity of each component of a drug product (21 CFR 211.84(d)(1)).” FDA expects firms to have already worked through the following:

• How to test each component lot for conformity with all appropriate specifications for identity, strength, quality, and purity;
• Accepting any results from supplier’s COA instead of testing each component lot for strength, quality, and purity, requires robustly establishing the reliability of supplier’s results through initial qualification as well as periodic requalification of the supplier’s test results;
• To have performed a comprehensive, independent review of its materials supply system to determine whether all suppliers of components, containers, and closures are each qualified and the materials are assigned appropriate expiration or retest dates.

In addition, the agency is laser focused on incoming shipments of ethyl alcohol due to potential diethylene glycol (DEG) or ethylene glycol (EG) contamination, which has been observed in many shipments around the world. Test results for DEG and EG for every incoming shipment are expected and should be retained through final product expiry. FDA requires these tests to be performed in addition to any ID testing of incoming shipments.

Common Area of Failure Three

Again and again, FDA has cited companies for failures of their Quality Assurance Department, ranging from a lack of independent authority to a failure to establish or utilize test procedures. This is the third leading area for citations given to homeopathic companies. The actual words from warning letters are uniform:

• “Your firm’s quality control unit failed to exercise its responsibility to ensure drug products manufactured are in compliance with CGMP, and meet established specifications for identity, strength, quality, and purity. (21 CFR 211.22).”
• “Your firm failed to have, for each batch of drug product, appropriate laboratory determination of satisfactory conformance to final specifications for the drug product, including the identity and strength of each active ingredient, prior to release (21 CFR 211.165(a)).”
• “Your firm failed to establish and follow an adequate written testing program designed to assess the stability characteristics of drug products and to use results of stability testing to determine appropriate storage conditions and expiration dates (21 CFR 211.166(a)).” [Reminder: “drug product” includes the container, closure, and label, all of which need to assessed for stability in relation to storage and expiration.]

Additional reading reveals what FDA requires in response to the warning letters. This provides incredibly helpful insights into what action the agency presumes firms take prior to inspections — actions that if taken would have prevented the issuance of a warning letter.  For instance, in relation to the first bullet above, FDA requires: assurance a firm’s Quality Unit (QU) is given the authority and resources to effectively function; written determination whether procedures are robust and appropriate; providing the QU oversight throughout all the company’s operations to evaluate adherence to appropriate practices; complete and final review of each batch and its related information before the QU disposition decision; and more.

The agency goes further and provides information necessary to ensure one’s quality systems are adequate. “For guidance on establishing and maintaining CGMP-compliant quality systems, see FDA’s guidances: Q8(R2) Pharmaceutical Development ¹; Q9 Quality Risk Management ²; and/or Q10 Pharmaceutical Quality System ³.” [Reminder: this is not an exhaustive list.]

Surprisingly, only homeopathic companies were cited for the following GMP failure, one that should have been easy to avoid: “Your firm failed to prepare batch production and control records that include documentation of the accomplishment of each significant step in the manufacture, processing, packing, or holding of the batch, for each batch of drug product (21 CFR 211.188(b)).”

Four other areas were cited often enough to warrant attention so as to ensure these are not deficient areas which the agency will uncover in the course of an inspection:

• “Failure to establish written procedures for production and process control designed to assure that the drug products you manufacture have the identity, strength, quality, and purity they purport or are represented to possess (21 CFR 211.100(a)).”
• “Failure to establish and follow written procedures for investigating critical deviations or the failure of intermediates and API lots to meet specifications.”
• “Failure to clean, maintain, and sanitize and/or sterilize equipment and utensils at appropriate intervals to prevent malfunctions or contamination that would alter the safety, identity, strength, quality, or purity of the drug product beyond the official or other established requirements, and failure to establish and follow adequate written procedures for cleaning and maintenance of equipment (21 CFR 211.67(a) and (b)).”
• “Failure to use equipment in the manufacture, processing, packing, or holding of drug products that is of appropriate design, adequate size, and suitably located to facilitate operations for its intended use and for its cleaning and maintenance (21 CFR 211.63).” [Note: this is frequently cited in relation to water treatment system design and installation.]

Final Thoughts and Insights

For almost every citation, a careful reading of what FDA expects in response is a key to what firms should be doing now to avoid being cited for similar failures. As many companies can attest from unfortunate experience, inspectors do not necessarily cite all issues during a single visit. It is likely there may be slight shifts in which particular matters receive priority from the Agency; thus a subsequent inspection may cite concerns that seemed to be of no previous interest.

Above are eight of the most common deficiencies noted in last year’s warning letters. There is no reason to assume a wholesale change in the agency’s priorities from one year to the next. Use these examples as an initial check-list for your firm’s compliance efforts. And take these efforts an easy step further.

It is well worth a periodic review of FDA’s warning letters to drug facilities, whether homeopathic or not. Almost every warning letter contains a wealth of information regarding what must be done, and what to avoid. It may be necessary to ‘read between the lines’, yet all can be a helpful part of a company’s due diligence and compliance efforts. Warning letters can be found here. At the bottom of FDA’s Warning Letters webpage, one can sign up to receive a free email (usually weekly) when a new set of warning letters is posted. It only takes 5-10 minutes to scan each group (zero in on drug related warning letters) for tidbits that will minimize your firm’s risks and maximize its compliance success.

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¹ https://www.fda.gov/regulatory-information/search-fda-guidance-documents/q8r2-pharmaceutical-development

² https://www.fda.gov/regulatory-information/search-fda-guidance-documents/q9-quality-risk-management

³ https://www.fda.gov/regulatory-information/search-fda-guidance-documents/q10-pharmaceutical-quality-system