Do These Recent Drug GMP Warning Letters Signal A Shift In FDA Enforcement Focus?

The FDA’s posting of drug GMP warning letters citing product adulteration has substantially decreased in the past several months. Warning letters are generally issued approximately seven months after inspections. The decrease we are now seeing is due to the slowdown of on-site inspections with COVID travel limitations and concerns regarding investigator safety.

However, the FDA recently posted two unique warning letters that all pharmaceutical and API firms, regardless of their product category, should consider and evaluate. These first-of-a-kind warning letters often signal a new enforcement focus or process for the FDA. (For example, when the FDA issued a warning letter to McKesson Corp. in Feb. 2019, it was the first — and so far, the only — time the agency cited failure to comply with the requirements in the November 2013 Drug Supply Chain Security Act (DSCSA) amendments to the Food, Drug, and Cosmetic [FD&C] Act.) The two warning letters posted the week of Jan. 27, 2021 and addressed here, have broad applicability to pharma companies and represent the FDA’s renewed emphasis on both alternatives to on-site inspections and the importance of purchasing controls and supplier management.

Yuyao YiJia Daily Chemical Co., Ltd

The FDA posted a warning letter issued Jan. 22, 2021 to Yuyao YiJia Daily Chemical Co., Ltd., located in Ningbo, China. Products made at this location were placed on import alert on Sept. 23, 2020. The firm manufactures over-the-counter (OTC) drug products, including hand sanitizers. Unlike other warning letters issued for violations of GMPs, the letter does not identify an inspection date, nor is the firm currently listed in the FDA’s inspection database. The warning letter, however, does list an FDA Establishment Identifier (FEI) number. The second sentence of the opening paragraph states, “FDA has reviewed the records you submitted in response to our March 31, 2020 request for records and other information pursuant to section 704(a)(4) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) for your facility…”. Note in the discussion below a follow-up set of requests made on May 8, 2020. It would be interesting to know what precipitated the request for documents and whether a Form-482 was issued.

The warning letter identifies four deficiencies: one associated with final product testing, one associated with material controls, one addressing deficiencies in the stability program, and one that identifies lack of a functioning quality unit. Each deficiency ends with a comprehensive list of requested actions and information to be provided as part of the response to the warning letter. Let us go through each deficiency briefly and identify the specifics that the FDA found problematic. I will not address the substantial FDA follow-up requests; readers can peruse those separately.

1. Deficiency No. 1 addresses the firm’s failure to adequately test finished product shipped to the United States. Records submitted to the FDA by the company indicated identity and strength of the active ingredient were not tested prior to distribution. Further, the company did not provide test methods and only listed equipment. The FDA requested the missing information on May 8, 2020. In response, the firm “restated [their] original response” to indicate a third-party laboratory was used but again did not provide specifications or methods for testing of identity and strength. The FDA notes that after the request for documents, the firm shipped several lots of hand sanitizer for U.S. distribution.
2. Deficiency No. 2 addresses failure to test incoming raw materials, minimally to determine identity. When the FDA requested whether the firm tested purchased raw materials, the firm replied “…that the testing was done by their supplier.” The FDA then asked which identity test was performed by their supplier, and the firm provided the supplier CoA, which did not include a specification or results. Further, the company could not provide evidence that it qualified the supplier or verified the results on the CoA.
3. Deficiency No. 3 identified that the stability data did not include evaluation of the active ingredient nor did it include any microbiological data.
4. Deficiency No. 4 cited an inadequate quality unit because the firm failed to develop and implement adequate written procedures for the quality unit.

The FDA concludes the warning letter by suggesting the firm hire a qualified consultant and stating that “Based on FDA’s review of records and information provided in response to our request, your firm’s quality systems are inadequate.” It will be interesting to see if additional warning letters are issued based on this practice. This warning letter should serve as a wake-up call to all firms that have submitted documentation to FDA at its request that enforcement actions may be taken on the basis of those documents.

Professional Compounding Centers Of America

The second warning letter was issued to Professional Compounding Centers of America dba PCCA in Houston, Texas, on Jan. 27, 2021. The warning letter was based on the outcome of an inspection ending Oct. 29, 2019. The FDA notes that it replaces a warning letter dated Jan. 7, 2021. Considering the nature of the deficiencies, it is surprising it took almost 15 months to issue the warning letter. PCCA is not a total stranger to enforcement actions. The FDA inspection database identifies a 2009 inspection classified as OAI (official action indicated), though I’ve been unable to find a warning letter resulting from the inspection. Two inspections before this warning letter were classified NAI (no action indicated) and VAI (voluntary action indicated), respectively. In this warning letter, the FDA identifies four areas where the firm is in violation of the FD&C Act:

• The firm purchased APIs that were deemed adulterated; its supplier was placed on import alert and was issued a warning letter.
• At least 23 API suppliers in the PCCA supply chain have a history of GMP non-compliance.
• The firm’s glycerin USP product is adulterated and misbranded and four pain drugs manufactured by PCCA were deemed misbranded.
• Labeling of repackaged APIs did not accurately identify all manufacturers.

In this article, we focus primarily on supplier qualification and oversight activities at PCCA. Supplier qualification and ongoing oversight should include an evaluation of enforcement actions that may be in place against the supplier. This warning letter provides a unique perspective of the importance the FDA places on this assessment. Although previous warning letters have cited use of materials from a supplier on import alert, this enforcement action takes failures in this area to a new level based on the number of examples provided. The FDA states, “Your receipt in interstate commerce of adulterated drugs (i.e., those listed on an import alert) and the delivery or proffered delivery thereof, is a violation of section 301(c) of the FD&C Act, 21 U.S.C. 331(c).”

The FDA begins the warning letter by citing purchase of materials that were the subject of an import alert put in place on July 30, 2018. The firm in question refused an FDA inspection and destroyed batch records. It also received a warning letter, though the date of the letter was redacted. The FDA proceeds to identify that at least 23 other API suppliers to PCCA were under import alert and/or received warning letters. Some of the import alerts have been removed and some warning letters were closed out, though others remain in effect. “To understand whether PCCA has received or introduced additional adulterated drugs in interstate commerce, we are therefore requesting information regarding timing of receipt and distribution of drugs from the 23 facilities listed below.” Further, “FDA has evidence that the drugs listed in the import alert appear to be adulterated. You [PCCA] are responsible for ensuring that the drugs you distribute are manufactured in compliance with all relevant CGMP requirements for drugs.” Nine of the firms remain on import alert 99-32 for “…delaying, denying, limiting, or refusing an FDA Drug Inspection.” Six firms have been the subject of a warning letter.

Because the FDA identified a “pattern” of problematic manufacturers that supply PCCA, the firm is asked to “…provide the lot numbers and dates of distribution for all drugs received from each facility listed above” in response to this warning letter so the FDA can determine the extent of the adulterated drug products that PCCA introduced into interstate commerce. For those materials that were used during the period when the supplier was either under import alert or the subject of a warning letter, the FDA asks whether PCCA customers were notified that they were supplied adulterated drug products. For those who were not notified, the FDA asks that PCCA do so and provide the agency with a copy of the notification. The FDA enforcement report does not identify any product recalls from either PCCA or Professional Compounding Centers of America, though not all recalls may be included.

PCCA must provide the FDA an “evaluation of their supplier program including a plan to audit [their] suppliers.” It also was asked to perform a full reconciliation of drugs from the manufacturers identified in the warning letter. For firms and drugs that may be on import alert, PCCA must identify whether any adulterated drugs remain in its possession. The FDA also asked the firm to schedule a meeting to “discuss the adequacy of the corrective actions” that the firm proposed to prevent “continued introduction of adulterated and misbranded goods into interstate commerce.”

Switching to the topic of the firm’s adulterated glycerin, USP product, PCCA stated that each lot was tested by the supplier prior to receipt. Supplier qualification included testing for ethylene glycol (EG) and diethylene glycol (DEG), and PCCA is “confident” that the glycerin is free from EG or DEG impurities. PCCA does not believe it needs to test incoming glycerin for EG and DEG impurities because it is “superfluous, and simply not required.” As you might expect, the FDA deemed this response inadequate, stating, “You cannot ensure the quality and security of the supply chain with regard to DEG and EG adulteration given your current practice because you do not independently verify that the API manufacturer’s reports are reliable…”

And finally, four PCCA relabeled and repackaged APIs were deemed to be misbranded because other firms were involved in the production of four APIs, but the label identifies only PCCA and does not identify activities performed by the firm. Thus, the label is “false and misleading.”

Conclusions

Both warning letters are directly relevant to all prescription drug pharmaceutical manufacturers even though these enforcement actions were issued to an OTC drug manufacturer and a compounding pharmacy. All would be well served to evaluate the deficiencies and determine if their firms share any that are similar. Take-home lessons from these warning letters include but are not limited to:

• The FDA has taken GMP enforcement action against a company based on remote document review, without an on-site inspection. Firms should take requests for documents by the FDA seriously and ensure that correct and complete information is provided. Responses that are “revised” after additional requests are made for information may likely be problematic.
• Firms should closely monitor the enforcement status of their current and potential suppliers, including CMOs. The FDA posts and updates import alert actions and warning letters and status on its website.
• Firms, such as PCCA, that receive or introduce adulterated drugs, including APIs, into interstate commerce have and will face enforcement action. This includes extensive actions they must take at the FDA’s direction, such as those described in this warning letter.
• Supplier management and purchasing controls remain a focal point of the FDA’s inspection and enforcement activities.

About The Author:

Barbara Unger formed Unger Consulting, Inc. to provide GMP auditing and regulatory intelligence services to the pharmaceutical industry, including general GMP auditing and auditing and remediation in the area of data management and data integrity. Her auditing experience includes leadership of the Amgen corporate GMP audit group for APIs and quality systems. She also developed, implemented, and maintained the GMP regulatory intelligence program for eight years at Amgen. This included surveillance, analysis, and communication of GMP related legislation, regulations, guidance, and industry compliance enforcement trends. Unger was the first chairperson of the Rx-360 Monitoring and Reporting work group that summarized and published relevant GMP and supply chain related laws, regulations, and guidance. She was the co-lead of the Rx-360 Data Integrity Working Group. You can contact her at bwunger123@gmail.com.