Experts say FDA enforcement focus unchanged, use of alternative tools to grow
Regulatory News | 01 June 2022 |
The US Food and Drug Administration (FDA) will continue to focus on data integrity practices and take a hard look at OTC firms’ testing programs either through onsite inspections or using alternative inspection tools in fiscal year 2022, according to experts who spoke to Regulatory Focus on near-term enforcement trends.
In addition, industry should expect to continue fielding requests for electronic records as the agency’s use of this alternative inspection tool is expected to grow. Pending user fee legislation would codify this tool and expand its use to device inspections, said a legal observer.
The experts discussed these trends amid the backdrop of a significant decrease in the number of FDA inspections, and a resulting drop in warning letters for good manufacturing practice (GMP) violations, and the agency’s increasing reliance on the use of alternative tools to conduct inspections.
Overall drop in enforcement letters
In March 2020, FDA announced it would be terminating all onsite domestic and foreign inspections, except for mission-critical inspections, as pandemic-prompted travel restrictions prevented staff travel to sites around the world. (RELATED: Coronavirus prompts FDA to cancel travel, postpone inspections and meetings, Regulatory Focus 10 March 2022).
Across all regulated products, the number of domestic inspections dropped from 14,725 in FY 2017 to about 4,500 so far in FY 2022, and the number of foreign inspections dropped from, 3,166 in FY 2017 to 135 thus far in FY 2022, according to FDA’s Inspections Data Dashboard.
This translated into a similar drop in warning letters. In FY 2021, FDA issued 42 drug GMP warning letters, a sizeable decrease from the 106 letters issued in FY 2020, according to an analysis of FDA drug GMP warning letters for FY 2021 and 2021 conducted by consultant Barbara Unger.
OTC focus will continue
Despite the downward shift in warning letters, FDA will continue to focus on data integrity violations and testing programs at OTC firms, either through onsite or remote inspections, the experts predicted.
Unger’s analysis found that in FY 2021, almost 80% of warning letters sent to drug manufacturers, excluding compounding pharmacies and outsourcing facilities, were issued to OTC firms. She predicted that going forward, OTC firms will continue receiving the bolus of warning letters.
“With over-the-counter drugs, everyone has a medicine cabinet full of them, so they touch everybody, it is not like prescription drugs, which has a narrow subset, so if you look at public health, they touch way more people. A couple of years ago, FDA inspected a few of those sites and it was like ‘oh my god they are out of control.’ My guess is that the profit margin for these drugs is pretty narrow. They don’t have a lot of the things prescription drugs have, such as a quality system, which would develop these requirements.”
Unger said the lack of testing on incoming raw materials, inadequate qualification of suppliers, and not establishing the validity of suppliers’ certificates of analysis are some of the main GMP violations cited in warning letter to OTC manufacturers. She said this is “fundamental stuff” and added that “prescription drugs were at this place 20 years or 30 years ago, and OTC manufacturers are just behind the game.”
Wolf not at the door
Robert Pollock, a consultant with Lachman Consultants, said that data integrity will be an area of continued focus for FDA.
“If you run down the issues, data integrity is going to be way up there. In my opinion, the natural course is that people get a little lax when the wolf is not at the door, and the wolf has not been at the door in a couple of years.” He added, “I don’t think it is intentional, as it may be related to a fall down in training and things of that nature.”
The number of warnings letters with data integrity problems has increased over the past three years, from 47% of the warning letters issued in FY 2019, to 51% in FY 2020 to 65% in FY 2021, according to Unger.
Attorney Anne Walsh of Hyman, Phelps and McNamara agreed that data integrity will continue to be a focus during inspections.
“I think that is certainly an area that we will see continued focus from FDA. They know what to look for now, data integrity concerns will continue to be raised.”
She added, “Even if there is not outright fraud happening, we will continue to see data integrity concerns … I do not see that going away, where you can see it on site you can see it on paper, the agency has been able to do both.”
“Gone are the days where you would see papers being thrown of the dumpster behind the facility, that stuff is probably not happening anymore as pharmaceutical companies are hopefully more trained in data integrity,” she said.
Cross contamination: A lingering problem
Another recurring theme being seen by Pollock in warning letters is cross contamination issues. “There have been sterility issues and cleanrooms not being as clean as they should be. This have been prominent themes in warning letters issued over the past couple of years.”
Pollock said some of the warning letters in FY 2021 showed failures to prevent cross contamination, and issues that he has “not seen in a while,” such as companies not paying attention to facility maintenance, such as cleaning air ducts. FDA’s June 11 warning letter to Lupin subsidiary Novel Laboratories found inadequate equipment cleaning and maintenance procedures, including inspecting air ducts. (RELATED: FDA warns Lupin subsidiary, aesthetics firm, Regulatory Focus 29 June 2021).
FDA is also continuing to focus on compounding pharmacies said Pollock. “There have been a ton of warning letters” issued to compounding pharmacies. “There have been sterility issues and all kinds of things, such as cleanrooms not as clean as they should be.”
Of the 42 warning letters FDA issued in FY 2021, 12, or roughly 25%, went to compounding pharmacies, according to Unger’s analysis.
Remote assessments not going away
Walsh said industry should expect more inspections through electronic records requests, as the proposed House user fee reauthorization legislation would further codify FDA’s authority to request records or other information as part of remote
Walsh said under the legislation, “they are codifying their authority for this, this would be a permanent tool in FDA’s bag of tricks.”
The proposed legislation also directs FDA to issue guidance “designing circumstances in which the Secretary intends to issue requests for records or other information in advance of or in lieu of, an inspection under section 704(a)(4) of the Federal Food Drug and Cosmetic Act.” The legislation calls on FDA to issue this draft guidance on the matter within a year of its passage.
The guidance would address the processes for responding to requests either electronically or in physical form, and the factors used to evaluate “whether such records and other information are provided within a reasonable timeframe, withing reasonable limits, and in a reasonable manner, according for resources and other limitations that may exist, including for small businesses.”
Walsh said there are benefits to remote inspections, as it “gives [FDA] the ability to lay eyes on more sites, and for industry that is seeking approval of a drug, having inspectors remotely assess can get a drug approved sooner than if you have to wait for FDA to inspect on site.”
Walsh advises retraining
With FDA resuming onsite inspections, Walsh advised industry to brush up its training efforts on how to conduct internal audits and host inspections.
“Because the regulatory teams are a bit out of practice on inspections, they have been given a breather over the past couple of years. Retraining on how to conduct inspections and how to respond to FDA could be timely not only for FDA but for subject matter experts in the facility. This could be helpful to make sure they have their A game on when FDA inspectors come on site.”
In addition, industry should expect to continue fielding requests for electronic records as the agency’s use of this alternative inspection tool is expected to grow. Pending user fee legislation would codify this tool and expand its use to device inspections, said a legal observer.
The experts discussed these trends amid the backdrop of a significant decrease in the number of FDA inspections, and a resulting drop in warning letters for good manufacturing practice (GMP) violations, and the agency’s increasing reliance on the use of alternative tools to conduct inspections.
Overall drop in enforcement letters
In March 2020, FDA announced it would be terminating all onsite domestic and foreign inspections, except for mission-critical inspections, as pandemic-prompted travel restrictions prevented staff travel to sites around the world. (RELATED: Coronavirus prompts FDA to cancel travel, postpone inspections and meetings, Regulatory Focus 10 March 2022).
Across all regulated products, the number of domestic inspections dropped from 14,725 in FY 2017 to about 4,500 so far in FY 2022, and the number of foreign inspections dropped from, 3,166 in FY 2017 to 135 thus far in FY 2022, according to FDA’s Inspections Data Dashboard.
This translated into a similar drop in warning letters. In FY 2021, FDA issued 42 drug GMP warning letters, a sizeable decrease from the 106 letters issued in FY 2020, according to an analysis of FDA drug GMP warning letters for FY 2021 and 2021 conducted by consultant Barbara Unger.
OTC focus will continue
Despite the downward shift in warning letters, FDA will continue to focus on data integrity violations and testing programs at OTC firms, either through onsite or remote inspections, the experts predicted.
Unger’s analysis found that in FY 2021, almost 80% of warning letters sent to drug manufacturers, excluding compounding pharmacies and outsourcing facilities, were issued to OTC firms. She predicted that going forward, OTC firms will continue receiving the bolus of warning letters.
“With over-the-counter drugs, everyone has a medicine cabinet full of them, so they touch everybody, it is not like prescription drugs, which has a narrow subset, so if you look at public health, they touch way more people. A couple of years ago, FDA inspected a few of those sites and it was like ‘oh my god they are out of control.’ My guess is that the profit margin for these drugs is pretty narrow. They don’t have a lot of the things prescription drugs have, such as a quality system, which would develop these requirements.”
Unger said the lack of testing on incoming raw materials, inadequate qualification of suppliers, and not establishing the validity of suppliers’ certificates of analysis are some of the main GMP violations cited in warning letter to OTC manufacturers. She said this is “fundamental stuff” and added that “prescription drugs were at this place 20 years or 30 years ago, and OTC manufacturers are just behind the game.”
Wolf not at the door
Robert Pollock, a consultant with Lachman Consultants, said that data integrity will be an area of continued focus for FDA.
“If you run down the issues, data integrity is going to be way up there. In my opinion, the natural course is that people get a little lax when the wolf is not at the door, and the wolf has not been at the door in a couple of years.” He added, “I don’t think it is intentional, as it may be related to a fall down in training and things of that nature.”
The number of warnings letters with data integrity problems has increased over the past three years, from 47% of the warning letters issued in FY 2019, to 51% in FY 2020 to 65% in FY 2021, according to Unger.
Attorney Anne Walsh of Hyman, Phelps and McNamara agreed that data integrity will continue to be a focus during inspections.
“I think that is certainly an area that we will see continued focus from FDA. They know what to look for now, data integrity concerns will continue to be raised.”
She added, “Even if there is not outright fraud happening, we will continue to see data integrity concerns … I do not see that going away, where you can see it on site you can see it on paper, the agency has been able to do both.”
“Gone are the days where you would see papers being thrown of the dumpster behind the facility, that stuff is probably not happening anymore as pharmaceutical companies are hopefully more trained in data integrity,” she said.
Cross contamination: A lingering problem
Another recurring theme being seen by Pollock in warning letters is cross contamination issues. “There have been sterility issues and cleanrooms not being as clean as they should be. This have been prominent themes in warning letters issued over the past couple of years.”
Pollock said some of the warning letters in FY 2021 showed failures to prevent cross contamination, and issues that he has “not seen in a while,” such as companies not paying attention to facility maintenance, such as cleaning air ducts. FDA’s June 11 warning letter to Lupin subsidiary Novel Laboratories found inadequate equipment cleaning and maintenance procedures, including inspecting air ducts. (RELATED: FDA warns Lupin subsidiary, aesthetics firm, Regulatory Focus 29 June 2021).
FDA is also continuing to focus on compounding pharmacies said Pollock. “There have been a ton of warning letters” issued to compounding pharmacies. “There have been sterility issues and all kinds of things, such as cleanrooms not as clean as they should be.”
Of the 42 warning letters FDA issued in FY 2021, 12, or roughly 25%, went to compounding pharmacies, according to Unger’s analysis.
Remote assessments not going away
Walsh said industry should expect more inspections through electronic records requests, as the proposed House user fee reauthorization legislation would further codify FDA’s authority to request records or other information as part of remote
Walsh said under the legislation, “they are codifying their authority for this, this would be a permanent tool in FDA’s bag of tricks.”
The proposed legislation also directs FDA to issue guidance “designing circumstances in which the Secretary intends to issue requests for records or other information in advance of or in lieu of, an inspection under section 704(a)(4) of the Federal Food Drug and Cosmetic Act.” The legislation calls on FDA to issue this draft guidance on the matter within a year of its passage.
The guidance would address the processes for responding to requests either electronically or in physical form, and the factors used to evaluate “whether such records and other information are provided within a reasonable timeframe, withing reasonable limits, and in a reasonable manner, according for resources and other limitations that may exist, including for small businesses.”
Walsh said there are benefits to remote inspections, as it “gives [FDA] the ability to lay eyes on more sites, and for industry that is seeking approval of a drug, having inspectors remotely assess can get a drug approved sooner than if you have to wait for FDA to inspect on site.”
Walsh advises retraining
With FDA resuming onsite inspections, Walsh advised industry to brush up its training efforts on how to conduct internal audits and host inspections.
“Because the regulatory teams are a bit out of practice on inspections, they have been given a breather over the past couple of years. Retraining on how to conduct inspections and how to respond to FDA could be timely not only for FDA but for subject matter experts in the facility. This could be helpful to make sure they have their A game on when FDA inspectors come on site.”
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