FDA Steps Up Enforcement of cGMPs for OTC Drugs

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Pharmaceutical Technology, Pharmaceutical Technology-08-02-2019, Volume 43, Issue 8
Pages: 40–41

Senior managers of OTC drug companies are on a learning curve, as FDA warning letters cite insufficient understanding of cGMPs and inadequate responses to prior 483s.

Manufacturers of over-the-counter (OTC) drugs have always been subject to the US Code of Federal Regulations (CFR) Parts 210 and 211, but recently, FDA has begun to step up enforcement of cGMPs in this sector, says Nick Capman, CEO of The FDA Group. So far, 2019 has seen an increase in both FDA 483 notices (483s) and warning letters to OTC drug manufacturers.

For an area that had traditionally been less scrutinized than generic or name brand drugs, the new regulatory emphasis has signaled the need for a culture change, particularly for business owners and CEOs, who, in the past, may have been disconnected from day-to-day operations, says consultant Gary Ritchie. “This is an industry that has operated without much oversight in the past. Now they are being scrutinized, and change is proving difficult,” he says. 

OTC company managers must first develop compliance strategies, says Ritchie, and generally, the best way is first to apply the predicate rule to operations and then run everything under current good manufacturing practices (cGMPs), taking special care to ensure data integrity. Ritchie cites ABC Labs, a contract testing lab for OTCs, as an example. The company received a warning letter (1) from FDA based on inadequate response to a prior 483 in 2012, for failing to ensure that lab record data were complete, for inadequate access controls to computer systems as well as master production and control records, and for failing to validate its test methods for key assays. Based on previous inspection findings, FDA had asked the firm to suspend testing until it could ensure that its laboratory testing met cGMP requirements. The company had not provided that assurance, yet resumed testing services in 2016.

“Just about the worst thing any company can do is have a standard operating procedure (SOP) and fail to follow it, but even worse is doing something that FDA has expressly asked you not to do,” says Ritchie. “With heightened scrutiny, the fundamentals need to be practiced, and it is management’s responsibility to see that they are,” he says.  Recent FDA citations for OTC facilities have followed similar patterns, including everything from failing to have a quality department in place, to failing to act on problems mentioned in previous inspections and 483 notices (2,3). In one case, the Canadian firm, Petra Hygienic Systems International, showed violations that had originally been noted by FDA in 2012 and 2014. In addition, the firm had inadequate and unvalidated equipment cleaning methods and failed to follow requirements for finished product testing. Imports from the company were banned (4).

In a webinar (5), J. Lawrence Stevens, senior regulatory and quality consultant, and Alan Greathouse, senior director of quality and service assurance, both with The FDA Group, discussed trends that have resulted in OTC drug manufacturers receiving 483s and warning letters from FDA for cGMP violations.  The most frequent problems can be sorted into six categories, Stevens said during the program:

  • Inadequate understanding of CFR 210 and 211, and lack of understanding of “unwritten regulations” (e.g., the need for corrective and preventive action [CAPA] programs), which is never actually called out in CFR 210 or 211

  • Inadequate analytical and microbial testing

  • Inadequate nonconformance and CAPA management

  • Inadequate/nonexistent quality unit

  • Issues related to past inspections

  • Common quality management systems (QMS) problems.

Beware of cheat sheets

Even a cursory look at recent OTC warning letters and 483s reveals repetitions of all these issues. One problem that Stevens noted in the webcast is document control. “Beware of employees using cheat sheets to remind them of entire procedures. FDA will view these as showing that there is insufficient control over manufacturing documentation,” he said.

CAPA is another area often cited during FDA inspections because inspectors are applying a quality systems approach, and for CFR 211, in nonconformance, which is where CAPA fits in, Stevens told the audience.

Companies are also expected to perform internal audits, using their own people or external consultants, but all testing must be validated and documented, Stevens said. In addition, he noted, many companies are performing nonconformance testing, but once they find problems they simply reject product, but don’t investigate the root cause of the problems. FDA will expect such an investigation, he said.

Regulators often cite water systems as a problem area, Greathouse told webcast listeners. It is important to ensure that FDA and US Pharmacopeial Convention (USP) guidance are being followed for these systems, and that sufficient testing is validated and fully documented for total organic carbon and microbial testing. “If you use deionized water in product, you need to know requirements for the water in order to test it, and you procedures must be in place in case there are any deviations from requirements,” he said.


Respond adequately to 483s

Another recurring theme in FDA enforcement actions has been OTC companies failing to respond adequately to a 483 and having the same problems discovered by FDA inspectors during a subsequent inspection. Repeat problems will trigger a warning letter.“Respond to 483s as if they were warning letters,” Stevens suggested.

Another potential vulnerability is in finished product testing and validation, said Greathouse.  He suggested determining whether to perform microbial and other testing and validation studies inhouse or outsourcing it. “If you use an outside lab, you must ensure that the lab has validated its test methods and that they have demonstrated that to you,” he said. This requires formally auditing the contract lab to determine when and how they perform the tests, and what equipment and procedures are in place for those tests.

CAPA, the ‘unwritten regulation’

Another area where OTC manufacturers may stumble is in nonconformance management and CAPA, an “unwritten regulation” for OTC drug companies, said Stevens. “CAPA is a formal way to identify problems, investigate the root cause of problems, and implement corrective action.  You may already be doing this informally but will need to formalize procedures to comply with cGMPs,” he said.

Beware of inadequate, incomplete, or undocumented investigations, which will show up in warning letters. “Firms may fix problems but may not investigate the reasons for the problems in the first place to ensure that they don’t repeat. FDA expects you to use CAPA to remediate problems,” he said.

Root cause analysis techniques will be crucial, and your CAPA procedure must identify the tools that you will be using. Another point to remember is to define the product conditions that will trigger a product recall. Stevens also suggested that companies not dismiss out-of-specification (OOS) and other problems as “laboratory errors” in documentation without examining their cause.

As noted previously, another problem that FDA often finds, especially with small companies, is that there is no official quality department at the company. “A company’s quality unit has responsibility and authority from senior management. One way to tell how seriously a company’s management considers regulatory compliance and quality is how they budget for it, the kind of people they hire for it and what their authority is, who listens to them, as well as what kinds of quality decisions can and cannot be overturned,” said Stevens.

The company’s most senior executive is legally responsible for the quality unit, and problems may result in the CEO being charged with violation of the US Food Drug and Cosmetic Act, he said.  It also behooves OTC company staffers to be on top of all previous FDA inspection files. After all, said Greathouse, the FDA investigators visiting the facility will have pulled these documents out a week ago, and they will determine how today’s inspection will be run. “Repeated observations are a red flag,” he said.


1. FDA, Warning Letter to Advanced Botanical Consulting Testing, Inc., fda.gov, June 11, 2019.
2. B. Unger, “Week of March 10, 2019: FDA Sent These Warning Letters,” fdazilla.com, March 19, 2019.
3. B. Unger, “Week of June 23, 2019: FDA Sent These Warning Letters,” fdazilla.com, July 3, 2019.
4. A. Mulero, “Repeat Violations Spur FDA to Ban Canadian OTC Drugmaker Imports,” raps.org, May 14, 2019.
5. FDA Group Webcast, “cGMP and Quality Management for OTC Manufacturers: Six Critical Questions,” thefdagroup.com, May 2019.

Article Details

Pharmaceutical Technology
Vol. 43, No. 8
August 2019
Pages: 40–41


When referring to this article, please cite it as A. Shanley, “FDA Steps Up Enforcement of cGMPs for OTC Drugs," Pharmaceutical Technology 43 (8) 2019.