Are there high-risk drugs on the market that do not require an FDA drug application submission, approval, or a facility inspection to be marketed? Yes.

We know that FDA can issue warning letters based on website reviews – for example, for obviously false claims or claims not substantiated by data that has been submitted to the agency.

However, drug manufacturers are primarily interested in analyzing warning letters issued for violations of Good Manufacturing Practices (GMPs). Thus, the interest in drug GMP warning letters issued when GMPs have been allegedly violated. Can those violations be determined without an inspection of the facility where manufacturing is taking place? Yes, under certain circumstances.

At the PDA-FDA Joint Regulatory Conference in late September 2023, in Washington, DC, FDA Center for Drug Evaluation and Research (CDER) Office of Manufacturing Quality (OMQ) Office of Compliance (OC) director Francis Godwin discussed “non-application drugs,” his agency’s concerns around them, and regulatory actions that have been taken for some drugs in that class.

What is a Non-Application Drug?

In the U.S. regulatory framework, application drugs – those subject to a New Drug Application (NDA), generic drug application (ANDA), biologics (BLA), or biosimilar (SBLA) drug application – go through a review process to look at manufacturing controls, and they are inspected as part of the application approval process.

If a firm has never been inspected before, it will be inspected as part of the application review process. Even if it has been inspected before, the FDA may do a product-specific preapproval inspection to review the manufacturing of a new product.

That framework exists for application products, but it does not exist for drugs that do not require an approved application, the so-called “non-application” drugs. Non-application drugs include, for example, over-the-counter (OTC) drugs that must only comply with USP monographs to be marketed and homeopathic products.

Godwin commented, “Because there is no review or inspection prior to marketing, we tend to see a higher GMP non-compliance rate when we go out on inspection” at facilities where the non-application products are manufactured.

Although “a lot” of the non-application drugs are lower-risk dosage forms, he said, “there is a heightened concern when we have high-risk dosage forms in this non-application space, particularly from a microbiological standpoint.”

The three dosage forms “that we tend to be nervous about” are otic (put in the ear), nasal (sprayed up the nose), and ophthalmic (put in the eye),” Godwin said.

When FDA’s Office of Manufacturing Quality (OMQ) becomes aware of a non-application drug on the market with a profile that “causes us a bit of concern,” Godwin told attendees, “we will contact our colleagues in the Office of Testing and Research at CDER (FDA’s Center for Drug Evaluation and Research) and we will contact the folks in the ORA (Office of Regulatory Affairs) ORS (Office of Regulatory Science) to get samples to the micro labs to see what is going on and see if there is a concern. Sadly, sometimes we have seen problems, and multiple compliance actions have resulted, including warning letters, import alerts, and recalls.”

Working with ORS

Godwin outlined how CDER has been working with agency colleagues in the ORS, the Office of Regulatory Science, on the sampling of some high risk non-application drugs. What is ORS?

Figure 1 | ORA Locations
ORA’s Office of Regulatory Science is a nationwide network of laboratories that performs chemical and microbiological analysis on samples provided to it by colleagues in other parts of FDA.It consists of 15 ISO:IEC 17205 accredited laboratories located strategically across the United States that are an important part of FDA’s mission to protect the public health by analyzing samples to support regulatory actions. More information on the ORA is available here.

Case Study 1: Nasal Spray

From a warning letter (see Figure 2) issued at the end of 2022, “FDA laboratory testing of SnoreStop NasoSpray, homeopathic Anti-Snoring Nasal Spray drug product lot 2373/21222 found gross microbial contamination. The individual sample results varied between 420 and up to 6200 colony forming units (CFU)/mL for total aerobic microbial count of and between 30 and up to 3800 CFU/mL for total yeast and mold counts.”

Figure 2 | Screenshot of Green Pharmaceuticals Warning Letter in the Redica Systems Platform
“Not what you want to put up your nose,” Godwin commented.

Because the analysis showed contamination, the agency deemed it adulterated and used this citation in the warning letter: “Therefore, this homeopathic drug product is adulterated under section 501(a)(1) of the FD&C Act, in that it has been contaminated with filth, and has been rendered injurious to health…”

The company instituted a recall. FDA further pointed out in the warning letter, “Your firm released finished drug products without adequate testing for critical microbial attributes (i.e., testing to ensure absence of objectionable microorganisms). Without appropriate testing of each batch of drug product required to be free of objectionable microorganisms prior to release, as required under 21 CFR 211.165(b), you did not have scientific evidence regarding the potential presence of microbial contamination that is objectionable in view of its intended use. Particularly for a drug product that is intended for use as a nasal spray, it is essential that your drug products are tested for microbial contamination.”

“Basically, it was a homeopathic manufacturer making nasal spray that wasn’t doing testing. “There was contamination, we found it, they didn’t, and a warning letter ensued,” Godwin summarized.

Case Study 2: Ear Drops

The second case study of an issue with a non-application product that Godwin provided also involved a homeopathic product. In this case, no warning letter was issued, but a recall took place.

This description of the product involved was taken from FDA’s Enforcement Report, which is published online on the agency’s website and details recalls of products regulated by FDA: Homeopathic EarAche Ear Drops, 0.33 FL OZ (10 mL) bottles, Distributed by: CVS Pharmacy, Inc., One CVS Drive, Woonsocket, RI 02895. NDC 59779-568-15.

The product was tested and found to be contaminated. The reason for the voluntary recall by the company was microbial contamination of a non-sterile product. Although products administered in the ear (otic products) are not required to be sterile, microbial controls still need to be in place at a certain level for those products. Such controls were not part of the manufacturing or testing processes.

The product was recalled as a Class II recall. According to FDA, “Class II is a situation in which use of, or exposure to, a violative product may cause temporary or medically reversible adverse health consequences or where the probability of serious adverse health consequences is remote.” 50,640 bottles were recalled nationwide. Recall initiation date was 05-24-2022; termination date was 06-08-2023.

Case Study 3: Ophthalmic Drops

The third case study Godwin provided involved ophthalmic drops.

“Probably the most concerning trend we have seen in the non-application space is related to ophthalmics,” he stressed. “There have been multiple ophthalmic cases we have taken on this year in which there have been recalls, warning letters, etc. Ophthalmic products are required to be sterile. The regulation is 21 CFR 200.50, which goes into sterility and preservatives for ophthalmic products. We take sterile drugs very seriously.”

21 CFR 200.50(a)(1) states, “Informed medical opinion is in agreement that all preparations offered or intended for ophthalmic use, including preparations for cleansing the eyes, should be sterile. It is further evident that such preparations purport to be of such purity and quality as to be suitable for safe use in the eye.” There are additional detailed requirements.

On August 22, 2023, FDA warned consumers not to purchase and to immediately stop using Dr. Berne’s MSM Drops 5% Solution and LightEyez MSM Eye Drops – Eye Repair due to bacterial contamination, fungal contamination, or both.

“Basically, our labs found that these solutions were just teeming with stuff,” the Office of Compliance director revealed.

In FDA’s alert to the public, it noted that the agency conducted sampling and testing based on these products intended use in the eyes, due to the industry’s recent manufacturing issues with eye drops. Results of the testing showed the products were contaminated with microbes and were not sterile. Under the Federal Food, Drug and Cosmetic Act, eye drops must be sterile to be safe for use.

Figure 3 | FDA announcement for Berne’s Whole Health Products
The manufacturer, Dr. Berne’s Whole Health Products, voluntarily recalled its MSM Drops 5% and 15% Solution Eye Drops due to bacterial and fungal contamination on August 26, 2023.

Godwin told the audience that FDA “has a heightened presence in the ophthalmic space right now.”

Recent Developments

Godwin’s presentation at the PDA/FDA meeting in September 2023 served as a harbinger of continued issues with ophthalmic products. On November 3, 2023, the agency published a warning to consumers regarding non-application ophthalmic products, part of which is reproduced here to show the scope of the issues Godwin discussed at the conference:

[11/3/2023] Cardinal Health Inc. has initiated a voluntarily recall for all lots of six Leader brand ophthalmic products. The list FDA provided on October 27 included five products branded as Leader. The list has been updated to include the sixth product.

Additionally, Harvard Drug Group LLC also initiated a voluntary nationwide recall for all lots of two Rugby Laboratories brand eye drops.

The agency has updated the list of products to include the national drug codes (NDCs) that have been confirmed. FDA will provide additional information as it becomes available.

[10/30/2023] FDA is updating the list of over-the-counter eye drop products consumers should not purchase or use to include Equate Hydration PF Lubricant Eye Drop 10 mL sold by Walmart in stores and online. Walmart is removing the product from their store shelves and website.

[10/27/2023] FDA is warning consumers not to purchase and to immediately stop using 26 over-the-counter eye drop products due to the potential risk of eye infections that could result in partial vision loss or blindness. Patients who have signs or symptoms of an eye infection after using these products should talk to their health care provider or seek medical care immediately. These products are marketed under the following brands:

CVS Health
Leader (Cardinal Health)
Rugby (Cardinal Health)
Rite Aid
Target Up & Up
Velocity Pharma

These products are intended to be sterile. Ophthalmic drug products pose a potentially heightened risk of harm to users because drugs applied to the eyes bypass some of the body’s natural defenses.

FDA recommended the manufacturer of these products recall all lots on October 25, 2023, after agency investigators found insanitary conditions in the manufacturing facility and positive bacterial test results from environmental sampling of critical drug production areas in the facility. FDA also recommends consumers properly discard these products.

Conclusions

FDA is tasked with protecting the public health in the United States through various means, including review and approval of applications for new drug products, manufacturing facility inspections, responding to consumer complaints, and laboratory testing of products on the market, among others. Many of these reviews and inspections look for the implementation and application of GMPs.

In the case of non-application products, discussed at the PDA/FDA meeting by Director Godwin, certain higher-risk dosage forms need to be closely monitored from a microbiological standpoint, and testing can reveal whether problems exist in those areas.

While all firms producing drug products for the U.S. market are required to observe GMPs, those regulations are written broadly, and they are subject to interpretation by the agency investigators during manufacturing facility inspections. Surveying company inspections is a great way to find and understand what areas the agency is citing and the current hot topics.