Highlighted Posts - Greenleaf Health

Implications of Recent Third Circuit Court of Appeals Decision for FDA Drug Approval Framework

This article originally appeared in the Food and Drug Law Journal and is available here via Open Access.

Abstract

A recent Third Circuit Court of Appeals decision in United States v. Vepuri has the potential to undermine the legal framework for drug approvals in the United States. Specifically, this decision could shield copycat products from U.S. Food and Drug Administration (FDA) enforcement action and allow them to enter the market without FDA pre-approval. The loophole created by this decision is accompanied by concerns about product quality, patient safety, and other issues that would be flagged in a premarket review.

I. Introduction

The ongoing U.S. Fifth Circuit Court of Appeals litigation challenging the U.S. Food and Drug Administration’s (FDA’s) approval of mifepristone has generated a great deal of attention and concern about the implications for FDA drug approval decisions.¹ This Article discusses a recent decision by the U.S. Court of Appeals for the Third Circuit that has generated far less attention but also has the potential to undermine the legal framework for FDA drug approvals. The Third Circuit’s decision in United States v. Vepuri² potentially allows any firm manufacturing a copycat drug to market it without FDA approval and without fear of FDA enforcement action under 21 U.S.C. § 355(a), provided the copycat has the same chemical composition and labeling as a drug specifically approved by FDA pursuant to a new drug application (NDA) or an abbreviated new drug application (ANDA).

II. Background

In July, the Third Circuit Court of Appeals upheld an earlier decision of the district court to dismiss part of a criminal indictment against KVK-Tech, Inc. (“KVK-Tech”) and two KVK-Tech executives (Murty Vepuri and Ashvin Panchal) on the grounds that the conduct alleged in the indictment did not constitute an offense under 21 U.S.C. § 355(a).³ As further discussed below, § 355(a) prohibits a person from introducing a “new drug” into interstate commerce without an effective application in place.⁴

KVK-Tech manufactured hydroxyzine, a generic prescription drug indicated for the treatment of anxiety and tension.⁵KVK-Tech had three approved ANDAs to market different strengths of hydroxyzine.⁶ Contrary to the ANDAs, KVK-Tech had been introducing hydroxyzine into interstate commerce that KVK-Tech had manufactured using active pharmaceutical ingredient (API) sourced from a facility in Mexico that was not listed in the ANDAs or otherwise approved by FDA.⁷

KVK-Tech had stated in its ANDAs that the hydroxyzine active ingredient would be sourced from a UCB Pharma, S.A facility in Belgium.⁸ In 2008, two years after the initial approvals, Panchal appropriately filed an application supplement and obtained approval to source the active ingredient from a different company, a Cosma, S.p.A facility in Italy.⁹ Despite having two approved options for sourcing API, in October 2010, Vepuri authorized the purchase of three shipments of active ingredient from a Dr. Reddy’s Laboratories (DRL) facility in Mexico not listed in the approved ANDAs.¹⁰

FDA only discovered this unauthorized API substitution in June 2013, when it refused to permit a fourth shipment of DRL API to enter the United States on the grounds that KVK-Tech’s ANDA did not list the DRL facility as an approved API source.¹¹ By that time, however, KVK-Tech had already received the three prior shipments of API from DRL’s Mexico facility, which the government alleged was used to manufacture 368,000 bottles of hydroxyzine KVK-Tech distributed to customers.¹²

Following the border refusal, FDA inspected KVK-Tech, and Panchal made several false statements to FDA about where KVK-Tech was sourcing its API. For example, during a 2013 inspection, Panchal told FDA investigators that KVK-Tech had not received prior shipments of API from Mexico.¹³ When confronted with photographs to the contrary, Panchal indicated that he was not aware that UCB (the approved API manufacturer) shipped API from Mexico.¹⁴ In several communications with FDA during and after the 2013 inspection, Panchal and Vepuri falsely blamed the use of the unapproved DRL API on the incompetence of a former employee and made other false statements to FDA.¹⁵

As further discussed in the underlying district court decision, FDA had issued a warning letter to DRL’s Mexican facility for violations of Current Good Manufacturing Practices (CGMP) in June 2011.¹⁶ The warning letter was based on violations discovered during an FDA inspection of the DRL facility conducted in November 2010, and was unrelated to the API shipments to KVK-Tech.¹⁷ The CGMP violations were serious enough that, the following month, FDA also placed the facility on import alert, thereby authorizing the detention of all DRL API shipped to the United States.¹⁸ The three shipments of DRL API utilized by KVK-Tech in the hydroxyzine it distributed occurred in January, March, and May of 2011, shortly before the import alert was issued in July 2011.¹⁹ The import alert remained in effect until July 2012.²⁰

The defendants were indicted on several offenses. One of the offenses was a criminal conspiracy with several identified objects (or goals) of the conspiracy, including “with the intent to defraud and mislead, introducing or delivering for introduction, and causing the introduction or delivery for introduction, into interstate commerce of unapproved new drugs in violation of Title 21 United States Code, Sections 331(d) and 355(a)[.]”²¹ The district court struck down this portion of the indictment, and the Third Circuit upheld that decision.²²

III. Decision by the Third Circuit

The Third Circuit’s ruling hinges on a somewhat complicated interpretation of the term “new drug” as it is used in § 355(a), which provides: “No person shall introduce or deliver for introduction into interstate commerce any new drug, unless an approval of an application filed pursuant to subsection (b) [concerning NDAs] or (j) [concerning ANDAs] is effective with respect to such drug.”²³

To determine the meaning of “new drug” in § 355(a), the Third Circuit looks to the definition of the term at 21 U.S.C. § 321(p). The court parses the statutory language and finds, in relevant part, that § 321(p) defines “new drug” as “‘any drug . . . the composition of which is such that such drug is not’ . . . generally recognized among experts as safe and effective for the use ‘suggested in the labeling thereof.’”²⁴ The court concludes, therefore, “[t]he text of § 321(p) . . . defines a ‘new drug’ in terms of its composition and labeling.”²⁵ Additionally, a new drug under § 321(p) cannot be a grandfathered drug under the Food and Drugs Act of June 30, 1906, but this provision was not at issue in the case.²⁶

The Third Circuit notes that the Federal Food, Drug, and Cosmetic Act does not define the word “composition,” but explains in a footnote that “FDA has long interpreted the term to refer only to a drug’s chemical makeup—the ‘name and amount of each active and inactive ingredient.’ And, a drug’s ‘composition’ does not include the location or identity of the manufacturer of those ingredients.”²⁷

To support the position that the alleged conduct did constitute an offense under § 355(a), the government’s first theory was that because the API was sourced from a facility not listed in the ANDAs, the hydroxyzine KVK-Tech distributed was not the same “new drug” as the one with an effective approval.²⁸ Relying on the reasoning discussed above, however, the Third Circuit disagreed, holding that because the hydroxyzine manufactured with the API from Mexico “has the same [chemical] composition and labeling as the hydroxyzine for which an approval of an ANDA is effective, the government could not rely on the premise that the two drugs are different.”²⁹ Accordingly, the government’s argument that they were two different drugs did not state an offense of conspiracy to violate § 355(a).³⁰

Although FDA had issued a warning letter to DRL for producing adulterated API and placed the company on an import alert, the government did not argue that the composition of the KVK-Tech hydroxyzine was not the same “new drug” because of the use of the adulterated API. Presumably this was because the government did not think it needed to show adulteration to successfully seek unapproved drug charges under § 355(a). As a result of the government’s silence on the issue of adulteration, the court did not consider that the source of API could, in fact, have an effect on the “composition” of the drug, if, for example, the API were adulterated, as was the case with the DRL API substituted by KVK-Tech. Although we do not endorse the Third Circuit’s very narrow interpretation of the term “new drug,” we would argue that adulterated API almost certainly alters the composition of the drug and therefore creates a “new drug” even under the Third Circuit’s reasoning.³¹ The government, however, understandably omitted discussion of adulteration in the § 355(a) charges, because that section does not mention adulteration in the plain language of the provision.³²

The government’s second theory of liability was that “because . . . the ‘new drug’ was manufactured at a facility not included in the approved ANDA[,] . . . the approved ANDA stopped being ‘effective’ with respect to that drug.”³³ Relying on the Supreme Court’s decision in Weinberger v. Hynson, Westcott & Dunning, Inc.,³⁴ the Third Circuit rejected this second theory of liability as well, holding that “the approval of an NDA or ANDA ceases being effective only when it has been withdrawn or suspended.”³⁵

IV. Broader Implications of the Vepuri Decision

The Vepuri case has potentially wide-ranging implications for FDA’s regulation of drugs approved under either an NDA or an ANDA.

For example, the Third Circuit decision undermines the statutory framework requiring applicants to file supplements for approval of certain changes to approved applications. Under 21 U.S.C. § 356a, “a drug made with a major manufacturing change may be distributed only if, before the distribution of the drug as so made, the holder involved submits to the [FDA] a supplemental application for such change and the [FDA] approves the application.” Other non-major changes to an application require notification to FDA either in a supplemental application or in the annual report filed to the application.³⁶

To further expound on this point, a supplement for a major change, e.g., the change of an API supplier, provides the agency with information about the quality of the new API to ensure it has the same physicochemical properties as the approved ingredient. A new source for an active ingredient has the potential to significantly impact the impurity profile of a drug substance. The supplement should demonstrate the API supplier’s ability to produce the product as specified and should also provide stability data. A supplement also serves as a notification to FDA to conduct surveillance inspections of the facility to ensure compliance with applicable regulations, including but not limited to CGMP.

A sponsor could rely on the reasoning in the KVK-Tech case to make changes to a drug subject to an approved application without ever filing a supplement, claiming that those changes do not affect the composition or labeling of the drug. The sponsor could argue that those changes do not create a “new drug” and thus the approved application is still in effect, obviating any reason to file a supplement to the application. If this were the case, FDA would never be made aware of all manner of changes to an approved application, including major differences such as changes to API suppliers that could result in poor quality, contaminated, or adulterated drug product affecting patient safety.

Conveniently, the Third Circuit brushes over § 356a in a footnote, stating that “despite its apparent relevancy,” the court declined to further consider it because the government did not “rely on § 356a to establish that the defendants conspired to violate § 355(a).”³⁷ The district court, for its part, explicitly cited § 356a in support of that court’s “[ready acknowledgment] that the place of manufacture of a drug is critical” and its belief that “the [district court’s] ruling will not deprive the FDA of its ability to remedy this type of noncompliance.”³⁸ And yet those statements by the district court do not seem to hold true under the Third Circuit’s reasoning, which appears to render those statutory requirements voluntary, or at least challengeable by a sponsor as just described.

Also troubling, relying on the Third Circuit decision, companies could entirely forego submitting an application to FDA, claim that they are manufacturing drugs with chemical compositions and labeling identical to approved NDA and ANDA drug products, and argue that they were not introducing unapproved new drugs into interstate commerce in violation of 21 U.S.C. § 355(a). Ultimately, if this copycat tactic proved to be successful, it would serve as a serious disincentive for companies to file an ANDA. Why do so, if you could qualify under an existing NDA or ANDA by simply distributing a product with identical chemical compositions and labeling? Similarly, companies could also be dissuaded from conducting clinical research supporting an NDA if other companies could quickly begin distributing a drug product with an identical chemical composition and labeling under the umbrella of the very same approved NDA. In this latter case, private litigants could bring patent infringement suits to help ward off copycat products, but FDA would be powerless to do so.

V. Conclusion

After balancing the implications of letting the decision stand with the likelihood of success on appeal, the government did not file a petition for a writ of certiorari with the Supreme Court.³⁹ Overturning the decision would certainly have been beneficial, but losing the appeal would have created precedent for all federal courts, extending the reach, and the consequences, of a very unfortunate decision that is limited currently to the Third Circuit.

Rather than appeal, the agency may be planning to seek a legislative solution to this loophole for future applications. Our suggested fix is to amend the language of § 355(a) to read “No person shall introduce or deliver for introduction into interstate commerce any new drug unless an approval of an application filed pursuant to subsection (b) or (j) is effective with respect to such drug and such drug conforms to the approved application.” The Third Circuit gives a nod to this option in the decision itself, stating that “to the extent that our decision has identified a gap in the FDA’s ability to regulate the drugs that are introduced into interstate commerce, Congress has the tools necessary to fill it.”⁴⁰

Notes

1. See All. for Hippocratic Med. v. U.S. Food & Drug Administration, 78 F.4th 210 (5th Cir. 2023).

2. 74 F.4th 141 (3d. Cir. 2023).

3. Id. at 143–44.

4. 21 U.S.C. § 355(a)

5. 74 F.4th at 143.

6. Id. at 144.

7. Id.

8. Id.

9. Id.

10. Id.

11. Id.

12. Id.

13. Id.

14. Id.

15. Id.

16. United States v. Vepuri, No. CR 21-132, 2022 WL 541772, at *2 (E.D. Pa. Feb. 23, 2022).

17. FDA Warning Letter: Dr. Reddy’s Laboratories (June 3, 2011), https://wayback.archiveit.org/7993/20161022233302/http:/www.fda.gov/ICECI/EnforcementActions/WarningLetters/2011/ucm2 58679.htm (last visited Nov. 10, 2023).

18. 2022 WL 541772 at *2.

19. Id.

20. Id.

21. 74 F.4th at 145.

22. Id.

23. 21 U.S.C. § 355(a) (emphasis added).

24. 74 F.4th at 147 (emphasis original).

25. Id.

26. See 21 U.S.C. § 321(p)(1).

27. Vepuri, 74 F.4th at 150, n.8 (quoting U.S. FOOD & DRUG ADMIN., GUIDELINE FOR THE FORMAT AND CONTENT OF THE SUMMARY FOR NEW DRUG AND ANTIBIOTIC APPLICATIONS—GUIDANCE FOR INDUSTRY (Feb. 1987) and 21 U.S.C. § 355(b)(1)(A)) (citations omitted).

28. Id. at 149.

29. Id. at 150.

30. Id.

31. The warning letter to DRL cited the facility for not validating the analytical methods used to test its APIs and for the failure of its quality unit to ensure the APIs manufactured met intended specifications for quality and purity, among other violations. These violations not only rendered the API adulterated but raise such serious questions about the chemical composition of the API itself, that it could not reasonably be considered identical to the approved sources of API identified in the ANDAs. See FDA Warning Letter, supra note 17.

32. Separate provisions under 21 U.S.C. § 331 prohibit introducing into interstate commerce an adulterated drug (or causing a drug already in interstate commerce to become adulterated). 21 U.S.C. § 331(a) and (b).

33. 74 F.4th at 150.

34. 412 U.S. 609, 633 (1973).

35. 74 F.4th at 151.

36. 21 U.S.C. § 356a(d). See also 21 C.F.R. § 314.70.

37. 74 F.4th at 145, n.3.

38. 2022 WL 541772 at *7.

39. See Sup. Ct. R. 13 (a timely petition for certiorari must be filed within 90 days after entry of judgment).

40. 74 F.4th at 149, n.7.

Ashley, D., Auchincloss, K., and Oestreich, E. Implications of Recent Third Circuit Court of Appeals Decision for FDA Drug Approval Framework. Food and Drug Law Journal. 2023. Vol. 78, no. 3. p. 257-262. https://www.fdli.org/wp-content/uploads/2023/12/Ashley-Auchincloss-Oestreich-Implications-of-Recent-Third-Circuit-Court-of-Appeals-Decision-FDLJ-78-3.pdf.

WHO’s 6 Principles For An AI Regulatory Framework For Medical Product Development

This article was originally published as a guest column in Life Science Connect’s Outsourced Pharma.

In mid-October 2023, the WHO published a paper titled Regulatory Considerations on Artificial Intelligence for Health,¹ identifying the key principles that international regulatory frameworks for artificial intelligence (AI) should address and are, in fact, starting to coalesce around. The paper was developed in consultation with WHO’s Working Group on Regulatory Considerations (WG-RC) on AI for Health, whose members include regulatory authorities, policy makers, academics, and representatives from industry. The document is intended to serve as a resource for regulators, providing a list of 18 regulatory considerations to address in their emerging regulatory frameworks. It should be noted that the scope of the document extends beyond medical product development and is also intended to inform healthcare delivery.

The 18 regulatory considerations discussed in the paper fall under six broad categories: documentation and transparency, risk management, intended use and validation, data quality, privacy and data protection, and engagement and collaboration. Many of these themes, like transparency, risk management, and validation, have been discussed by the FDA and the European Medicines Agency (EMA), in public forums or in publications. Considering WHO’s global mandate, WHO’s paper also focuses on issues that are not necessarily prioritized by national authorities, such as international collaboration and the challenges in navigating national privacy laws and data protection regulations.

1. Documentation and Transparency

In line with several key regulators, WHO identifies transparency and documentation as the cornerstone for any effective AI regulatory framework. Referencing AI’s ability to self-improve, WHO emphasizes the importance of regulators “to be able to trace back the development process and to have appropriate documentation of essential steps and decision points.”² This echoes similar points made by both FDA and EMA in recent reflection papers. In the May 2023 discussion paper Using Artificial Intelligence and Machine Learning in the Development of Drug and Biological Products, FDA noted that documentation is needed across the entire medical product life cycle and stated that “accountability and transparency are essential for the development of trustworthy AI.”³

Importantly, WHO also identifies effective documentation as an essential tool to guard against bias and to establish trust. EMA in its Reflection Paper on the Use of Artificial Intelligence (AI) in the Medicinal Product Lifecycle⁴ encouraged sponsors to document areas of potential risk for bias or discriminatory outcomes prior to using a particular data set.

2. Risk Management

Considering AI’s self-learning capabilities, WHO recommends a total life cycle approach to risk management. Specifically, WHO states that a “life cycle approach can facilitate continuous AI learning and product improvement while providing effective safeguards.”⁵ To properly evaluate risk in pre-market development, WHO encourages developers to consider risk in terms of the intended use of the AI system and the clinical context. WHO identifies the International Medical Device Regulators Forum (IMDRF) Risk Framework for Software as a Medical Device (SaMD)⁶as a reasonable approach for regulators to adopt to support risk assessment.

In the post-market, WHO recommends manufacturers develop post-market surveillance plans that specify how manufacturers will monitor, identify, and respond to emerging risks. WHO recommends that an active reporting and investigative function be established. While referencing CONSORT-AI as an appropriate resource, WHO stops short of endorsing a specific reporting standard.

3. Validation

Again, acknowledging the likelihood of AI-related change, WHO emphasizes the importance of conducting analytical and clinical validation throughout the product life cycle. Analytical validation, also known as “technical validation,” is defined as the process of “validating the AI system using data but without performing interventional or clinical studies.”⁷ This process requires careful documentation of the development and data selection processes. Analytic validation also can include a benchmarking exercise where the model is compared to other tools and established performance standards. To facilitate this process, WHO notes that benchmarking software is being developed as part of the Open Code Initiative.⁸

Clinical validation is a process by which an AI product or tool is assessed in the context of its intended use. WHO again references the IMDRF on clinical evaluation of SaMD as an effective risk-based approach for determining the amount of real-world data manufacturers should collect to evaluate a tool’s intended use. The adoption of a specific approach to clinical validation by a regulator should also be dependent upon the resources and expertise available in that country.

4. Data Considerations

While recognizing data as the “most important ingredient for training AI/ML (machine learning) algorithms,” WHO highlights the challenge in identifying and defining good quality data. The difficulty in thinking about data lies in the numerous dimensions upon which it can be analyzed. WHO encourages regulators and developers to classify data based upon the 10 V’s: volume, veracity, validity, vocabulary, velocity, vagueness, variability, venue, variety, and value. Armed with this classification system, developers can then home in on key data challenges within their development programs. Some key data challenges highlighted by WHO include data management, data inconsistency, data usability, and data integrity.

WHO recognizes data as the most important ingredient for AI/ML algorithms, primarily because AI can readily amplify biases that exist in training data sets. Along these lines, WHO notes that improper data source selection can result in selection bias “when data used to provide the model are not fully representative of the actual data that the model may receive or the environment in which the model will function.”⁹ Thus, inappropriate data selection can easily distort a model’s output, which can undermine the generalizability of a model and raise ethical considerations.

5. Privacy and Data Protection

WHO identifies the patchwork of different data protection regulations and privacy laws as a significant barrier to the further development of AI-enabled medical products. Indeed, WHO notes that “some 145 countries and regions have data protection regulations and privacy laws that regulate the collection, use, disclosure and security of personal information.”¹⁰ Many of these countries have their own definitions and interpretations of “privacy,” “confidentiality,” “identifiable,” “anonymous,” and “consent,” among other concepts. The jurisdictional scope of each country or region’s regulations may overlap and may restrict cross-border transfers of data.

To reduce barriers to cooperation among regulators and sponsors, WHO recommends agencies consider regulatory sandboxes — a tool that was socialized during COVID-19. These sandboxes can help regulators acquire “a better understanding of the AI systems during the development phase and before they are placed on the market.”¹¹ Sandboxes provide a limited form of regulatory waiver that allow developers the opportunity to test new technologies without regulatory repercussions as well as provide regulators the opportunity to consider and test new regulatory approaches.

6. Engagement and Collaboration

WHO concludes the paper stating that greater collaboration among all stakeholders can improve the quality and safety of AI in general. Using case studies from an array of health authorities around the globe, WHO encourages regulators to position themselves as facilitators of innovation and partners in development. A broad engagement strategy, one that collaborates with patient advocacy groups, academia, healthcare professionals, industry, and other domestic government partners is encouraged.

Conclusion

WHO’s timely document highlights the key principles that international regulators are beginning to build their regulatory frameworks upon. Common to all regulators is the importance of and emphasis on transparency, documentation, and effective risk management. The alignment of these principles is critical when it comes to international collaboration among stakeholders, as it can help improve the quality and safety of AI in healthcare. Data quality as well as divergent privacy laws and data protection regulations across jurisdictions will continue to pose a challenge to regulators and developers alike.

References

World Health Organization (WHO), “Regulatory Considerations on Artificial Intelligence for Health,” October 2023, https://iris.who.int/handle/10665/373421.
Ibid., page 8.
Food and Drug Administration (FDA), “Using Artificial Intelligence and Machine Learning in the Development of Drug and Biological Products,” May 2023, https://www.fda.gov/media/167973/download?attachment.
European Medicines Agency (EMA), “Reflection Paper on the Use of Artificial Intelligence (AI) in the Medicinal Product Lifecycle,” July 2023, https://www.ema.europa.eu/en/news/reflection-paper-use-artificial-intelligence-lifecycle-medicines.
WHO, “Regulatory Considerations on Artificial Intelligence for Health,” page 29.
International Medical Device Regulators Forum (IMDRF), “Software as a Medical Device: Possible Framework for Risk Categorization and Corresponding Considerations,” September 2014, https://www.imdrf.org/sites/default/files/docs/imdrf/final/technical/imdrf-tech-140918-samd-framework-risk-categorization-141013.pdf.
WHO, “Regulatory Considerations on Artificial Intelligence for Health,” page 22.
United Nations, ITU, “Open Code Initiative,” https://www.itu.int/en/ITU-T/focusgroups/ai4h/Pages/opencode.aspx.
WHO, “Regulatory Considerations on Artificial Intelligence for Health,” page 28.
Ibid., page 33.
Ibid., page 37.

Implementing MoCRA: FDA Releases New Draft Guidances on Insanitary Conditions for Tattoo Ink and Cosmetic Product Registration and Listing

This article was originally published in the Food and Drug Law Institute’s Update magazine, Winter 2023, and is shared with permission.

Since enactment of the Federal Food, Drug, and Cosmetic Act (FDCA) in 1938, the evolution and technological innovation of cosmetic products in the U.S. market have presented the Food and Drug Administration (FDA) with unique regulatory challenges. These challenges, along with commercial globalization and limited resources and enforcement authorities, created a need for a broader and more modern cosmetics regulatory framework.

To meet this need, in December 2022, Congress enacted and President Biden signed into law the Modernization of Cosmetics Regulation Act of 2022 (MoCRA) as part of the Consolidated Appropriations Act, 2023.^[1]This marked the first major update to FDA’s cosmetics oversight since 1938. MoCRA reforms reflected the challenges of regulating a modern cosmetics industry with increasingly diverse products, including a shift towards greater safety and quality for cosmetics, bringing cosmetics regulation more in line with FDA regulation of other types of regulated products. For example, MoCRA provides FDA with new authorities related to adverse event reporting, good manufacturing practices (GMPs), facility registration and product listing, labeling, recordkeeping, and mandatory recall authority. To implement these requirements, new FDA guidance and regulations for the cosmetics industry are forthcoming.

In that vein, FDA recently released two draft guidances to implement MoCRA, both of which are discussed in this Article.^[2]

I. Key Takeaways from FDA’s New Tattoo Ink Draft Guidance

In June 2023, FDA announced the availability of Draft Guidance for Industry: Insanitary Conditions in the Preparation, Packing, and Holding of Tattoo Inks and the Risk of Microbial Contamination (“Tattoo Ink Draft Guidance”).^[3] When finalized, the guidance will represent FDA’s current thinking on “insanitary conditions of tattoo ink preparation, packaging, or holding that may render the inks injurious to health because of microbial contamination.”^[4]

FDA regulates tattoo inks as cosmetics under the FDCA. The FDCA defines “cosmetic” by reference to a product’s intended use(s). The term “cosmetic” means “articles intended to be rubbed, poured, sprinkled, or sprayed on, introduced into, or otherwise applied to the human body or any part thereof for cleansing, beautifying, promoting attractiveness, or altering the appearance . . . .”^[5] Tattoo inks are cosmetics because they are articles intended to be introduced into or otherwise applied to the human body for beautifying, promoting attractiveness, or altering the appearance.^[6]

The FDCA prohibits the introduction of an adulterated cosmetic into interstate commerce.^[7]Under the FDCA, a cosmetic is deemed to be adulterated if it “has been prepared, packed, or held under insanitary conditions whereby it may have become contaminated with filth, or whereby it may have been rendered injurious to health.”^[8]FDA issued the Tattoo Ink Draft Guidance to assist tattoo ink manufacturers and distributors in identifying situations in which a tattoo ink may become contaminated and potentially injurious to health, thus resulting in the adulteration of the tattoo ink.

While the draft guidance is intended for tattoo ink manufacturers and distributors, the cosmetic industry at large can benefit from reviewing the draft guidance. Key takeaways in the draft guidance for the larger cosmetic industry are discussed in more detail below.

FDA Is Preparing to Implement New Regulatory Requirements Applicable to Cosmetics Established by MoCRA

Issuing the Tattoo Ink Draft Guidance is among the first actions that FDA has taken to implement its new regulatory authorities under MoCRA. Indeed, FDA stated in the Tattoo Ink Draft Guidance that it “intend[s] to conduct rulemaking to establish good manufacturing practice regulations as part of the implementation of [MoCRA], which requires FDA to establish good manufacturing practice regulations that, to the extent practicable and appropriate, are consistent with national and international standards.”^[9] FDA also held a public meeting in June 2023 to receive input from stakeholders on topics related to cosmetic GMPs.^[10]In addition, FDA recently issued Draft Guidance for Industry: Registration and Listing of Cosmetic Product Facilities and Products (“Cosmetic Registration & Listing Draft Guidance”), which “provides recommendations and instructions to assist persons submitting cosmetic product facility registrations and product listings to FDA.”^[11]

As FDA’s recent guidance documents and its commitment to conduct rulemaking indicate, the agency has begun transitioning the cosmetic industry from a period of voluntary compliance, with regulatory controls designed to ensure the safety and quality of cosmetic products, to an era of mandatory compliance under the framework established by MoCRA.

FDA Is Still Attempting to Clearly Distinguish Between the Definitions of “Cosmetic,” “Drug,” and “Device”

Historically, FDA has struggled to draw a clear line between cosmetic and drug/device claims. This effort remains evident in the Tattoo Ink Draft Guidance.

The FDCA defines “cosmetic,” “drug,” and “device” by reference to the product’s intended use(s).^[12]

As previously stated, “[t]he term ‘cosmetic’ means (1) articles intended to be rubbed, poured, sprinkled, or sprayed on, introduced into, or otherwise applied to the human body or any part thereof for cleansing, beautifying, promoting attractiveness, or altering the appearance . . . .”^[13]
“The term ‘drug’ means . . . articles intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease in man . . . ; and . . . articles (other than food) intended to affect the structure or any function of the body of man . . . .”^[14]
“The term ‘device’ . . . means an instrument, . . . implement, . . . or other similar or related article . . . intended for use in the diagnosis of disease or other conditions, or in the cure, mitigation, treatment, or prevention of disease, in man . . . , or . . . intended to affect the structure or any function of the body of man . . . .”^[15]

Because the regulatory requirements for cosmetics vary considerably from those for drugs and devices, accurately distinguishing between claims that reflect the intended use of a “cosmetic” versus a “drug” or “device” is critical.^[16] For example, cosmetics and cosmetic ingredients—with the exception of color additives—do not require FDA review or approval prior to marketing. In contrast, cosmetics marketed with drug or device claims are considered to be drugs or devices and may require approval or clearance prior to commercialization. However, the line between a “beautifying” (cosmetic) claim and a “therapeutic” or “structure/function” (drug or device) claim can often be ambiguous, given that many beautifying products affect the body to some extent.

To clarify this distinction, FDA has previously suggested that “products that are represented to have only ‘physical’ effects on the skin are cosmetics, while those for which a ‘physiological’ effect is asserted are drugs.”^[17] FDA has interpreted “physical” effects as “mechanical” changes that “cover” the skin (e.g., makeup) or affect “the outermost layers of the skin” (e.g., by softening or moisturizing).^[18] FDA has interpreted “physiological” effects as those which cause biochemical or deep-tissue changes, or which “influence the functioning of cells.”^[19]

In the Tattoo Ink Draft Guidance, however, FDA did not follow this approach. The Tattoo Ink Draft Guidance treats tattoo inks as a cosmetic, despite FDA historically treating such products as drugs and devices due to their deep insertion in the skin below the epidermis (affecting more than the outermost layers). Moreover, the Tattoo Ink Draft Guidance also contradicted FDA’s relatively recent application of this approach as set forth in Guidance for Industry and FDA Staff: Regulatory Considerations for Microneedling Products (“Microneedling Guidance”).^[20]Table 1 below compares the differing approaches in the Tattoo Ink Draft Guidance and Microneedling Guidance.

Table 1.

Tattoo Ink Draft Guidance

Microneedling Guidance

· “Tattoo inks bypass the body’s primary physical barrier against pathogens, because they are inserted below the epidermis.”^[21]
· “Tattooing involves puncturing the epidermis about 100 times per second with needles and depositing ink 1.5 to 2 millimeters below the surface of the skin, deep into the dermis . . . .”^[22]

“FDA considers claims or statements that indicate penetration or some effect beyond the stratum corneum into living layers of skin by such products to be evidence of a firm’s intent to affect the structure or function of the body. The stratum corneum is a dead layer of skin that is naturally shed through the desquamation process. Therefore, claims or statements regarding the removal of the stratum corneum are not considered an intent to affect the structure or function of the body. In contrast, explicitly or implicitly claiming or stating that a microneedling product penetrates living layers of skin (e.g., epidermis and dermis) would be considered an intent to affect the structure or function of the body.”^[23]

Thus, the approach in the Tattoo Ink Draft Guidance is inconsistent with FDA’s approach in the Microneedling Guidance because the tattoo inks are injected well below the stratum corneum. According to the Microneedling Guidance, penetration beyond the stratum corneum would cause a product to be a drug or device.

II. Key Takeaways from Registration & Listing Draft Guidance

As discussed above, under MoCRA, certain owners and operators of facilities engaged in the manufacturing or processing of a cosmetic product for distribution in the United States must now register their facilities (FDCA § 607(a)) and list their products (FDCA § 607(c)) (“Section 607 Requirements”). To help facilitate implementation of these requirements, FDA recently issued Draft Guidance for Industry: Registration and Listing of Cosmetic Product Facilities and Products (“Cosmetic Registration & Listing Draft Guidance”).^[24]

The Cosmetic Registration & Listing Draft Guidance outlines elements of the Section 607 Requirements, including descriptions of who must register and list their products, what information must be submitted as part of registration and listing, and when registration and listing submissions must be made. The Cosmetic Registration & Listing Draft Guidance also provides information about how submissions can be made, whether combination drug/cosmetic products are subject to Section 607 Requirements, and the extent to which registration and listing information may be publicly disclosed. The comment period for initial feedback on the Registration & Listing Draft Guidance closed on September 7, 2023, but cosmetics industry stakeholders should remain engaged and look for future opportunities to provide input.^[25]

Registration & Listing Elements Look Familiar; They Are Not Dissimilar from the Now-Discontinued Voluntary Cosmetic Registration Program (VCRP)

As part of its development of the new registration and listing system, FDA ended the former Voluntary Cosmetics Registration Program (VCRP) earlier this year.^[26] The Cosmetic Registration & Listing Draft Guidance notes that information in the VCRP will not be transferred into the new system, and previous submissions will not satisfy the new Section 607 Requirements.^[27]

The VCRP was a voluntary program implemented via regulations found at 21 C.F.R. Parts 710 and 720. The new Cosmetic Registration & Listing Draft Guidance provides more detail than parts 710 and 720, but those who are familiar with the VCRP will notice similarities to the new, mandatory program and should not have trouble meeting the required registration and listing requirements.

Who Must Register and List

The Registration & Listing Draft Guidance adopts statutory definitions of terms relevant to Section 607 Requirements^[28](i.e., “cosmetic product,”^[29] definitions for “facility,”^[30]“responsible person,”^[31]and “small businesses”^[32]), but also sets forth new definitions^[33] for several terms/phrases not defined by the statute (i.e., “contract manufacturer,” “manufacturing or processing of a cosmetic product,” and “DUNS number”).

Generally, every person that owns or operates a facility engaged in the manufacturing or processing of a cosmetic product must register with FDA, pursuant to Section 607(a)(1). The Cosmetic Registration & Listing Draft Guidance defines cosmetic manufacturing or processing as “engaging in one or more steps in the making of any cosmetic product by chemical, physical, biological, or other procedures, including manipulation, sampling, testing, or control procedures applied to the product.”^[34]An entity that “solely performs” (re)labeling, (re)packaging, holding, and/or distributing of cosmetics,^[35] is excluded from the statutory definition of facility, and from the registration requirements restated in the draft guidance. “Packaging” and “repackaging” do not, however, include filling a product container, and thus, product filling would necessitate facility registration.^[36] Additionally, beauty shops, salons, and retailers are excluded from the statutory definition of facility, and do not need to register with FDA unless they also manufacture or process a cosmetic product.^[37]

With respect to a contract manufacturer’s obligation to register their facility, the Cosmetic Registration & Listing Draft Guidance notes (consistent with the statute) that only a single registration is required per facility, even for those that manufacture cosmetic products for more than one responsible person and/or those that manufacture cosmetic products of their own.^[38] Alternatively, a responsible person whose products are manufactured or processed at a contract manufacturing facility may also submit the facility registration on behalf of that facility, alleviating the contract manufacturer’s need to register their own facility. In other words, either the contract manufacturer or the responsible person (i.e., the entity whose name appears on the product label) must register a single manufacturing facility, but not both.^[39]

For product listing, the responsible person must submit the required information, pursuant to Section 607(c)(1). As defined in Section 604(4), the responsible person is the manufacturer, packer, or distributor whose name is on the label of the product.^[40]Additionally, certain small businesses, as defined in Section 612(b), are not required to register facilities and list cosmetic products.^[41]However, four exceptions to this exemption may apply, depending on the nature of the cosmetic product.^[42]

What Information Must Be Submitted

The first step in a facility’s registration submission process involves obtaining a facility registration number (i.e., the FDA Establishment Identifier (FEI)).^[43]Facility owners or operators can request a new FEI number, or determine whether a facility has an existing FEI number through the “FEI Search Portal”^[44]available on FDA’s website. Once they obtain an FEI number, facility owners must provide FDA with the following data as part of a registration submission, pursuant to Section 607(b)(2) and as outlined in the Cosmetic Registration & Listing Draft Guidance:^[45]

Name of the owner and/or operator of the facility;
Facility’s name, physical address, email, telephone number (for foreign facilities, the contact information for the U.S. agent);
FEI number;
All brand names of cosmetic products manufactured or processed at the facility;
Applicable cosmetic category;^[46] and
Type of submission being made (i.e., initial registration, content update (annual), or abbreviated renewal).

The Cosmetic Registration & Listing Draft Guidance also restates language from the statute as to the data that must be included in a product listing submission, including:^[47]

All relevant FEI numbers (i.e., facilities where the responsible person’s cosmetic products are manufactured or processed);
Name and contact information of the responsible person;
Name of the cosmetic product as it appears on the label;
Applicable cosmetic category;
List of ingredients in the cosmetic product (including fragrances, flavors, or colors);
Product listing number (if any) assigned by FDA; and
Type of submission being made (i.e., initial, content update, or abbreviated renewal).

Although Section 607 requires that the “applicable cosmetic category” be included in both registration and listing submissions, the statute does not describe more precisely what those categories are. In the Cosmetic Registration & Listing Draft Guidance, FDA has developed an initial list of various cosmetic product categories, included in Appendix A.^[48] The appendix includes many recognizable categories of cosmetic products, such as lotions, sprays, oils, and serums, but also contains other less standard products, such as “nail extenders.”^[49]

Significantly, the system for categorizing types of cosmetic products laid out in Appendix A is similar to the system that FDA’s Center for Devices and Radiological Health (CDRH) now uses for organizing various device types—medical device classification product codes.^[50]FDA likely will use these cosmetic categories for some of the same purposes for which it uses device product codes. CDRH has explained that it uses product codes “to obtain quality and reliable data, and perform analyses that are often reported to Congress, the Government Accountability Office (GAO), the general public, the media, and industry.”^[51] Device product codes also have several other important uses, including tracking medical device adverse event reports, imports and exports, and recalls.^[52] Therefore, aside from purposes related to registration and listing, FDA could use cosmetic product categories for many of the same reasons, including tracking adverse event reporting, imports/exports, and recalls. Given the many possible uses for these cosmetic product categories, industry feedback on them will be essential to ensuring that the organizational system for cosmetics is appropriate and effective. FDA seems to recognize the importance of this feedback and specifically requested comments on these product categories.^[53]

Through the Cosmetic Registration & Listing Draft Guidance, FDA also requests various optional data be submitted as part of registration and listing submissions, beyond what is required under Section 607 Requirements.^[54]These items include the parent company name, the facility Data Universal Numbering System (DUNS) Number, Unique Ingredient Identifiers (UNIIs), and any additional contact information relevant to the specific submission, among others.^[55]

When Must Registration and Listing Submissions Occur

The statutory deadline for fulfilling Section 607 Requirements is December 29, 2023; this applies to owners and operators of facilities engaged in the manufacturing or processing of cosmetic products prior to December 29, 2022,^[56]and to responsible persons engaged in the marketing of cosmetic products prior to December 29, 2022.^[57] However, in November 2023, FDA announced in Guidance for Industry: Compliance Policy for Cosmetic Product Facility Registration and Cosmetic Product Listing (“Cosmetic Registration & Listing Compliance Policy”) that it would delay enforcement of Section 607 Requirements for six months, or until July 1, 2024.^[58]This delayed enforcement also applies to owners and operators of facilities engaged in manufacturing or processing of cosmetic products after December 29, 2022, as well as for responsible persons engaged in the marketing of cosmetic products after December 29, 2022; they too now have until July 1, 2024 to meet registration and listing requirements.^[59]

The Cosmetic Registration & Listing Draft Guidance also describes timing requirements, consistent with those in Section 607, for submitting amended facility registration information (i.e., within 60 days of a change), as well as updated listing information (i.e., annually).^[60]Distinct from the statute, the draft guidance recommends that submissions involving updated information include changes resulting in a registration cancellation or a discontinued product.^[61]For purposes of renewals, the draft guidance again adheres to the statutory language and calls for facilities to renew their registration with FDA on a biennial basis (i.e., every two years), even if registration information remains unchanged since their most recent past submission (FDA intends to provide an abbreviated renewal registration submission option for unchanged renewals).^[62]

The Draft Guidance Continues to Emphasize That the Cosmetic Registration & Listing Requirements Do Not Apply to Cosmetic Products That Are Also Drugs

The Cosmetic Registration & Listing Draft Guidance notes that Section 607 Requirements do not apply to cosmetic products that are also drugs, nor do they apply to the facilities that manufacture such products (unless the facility also manufactures or processes a product that is solely a cosmetic).^[63] This is partly consistent with Section 613 of the FDCA, which states that “a cosmetic product or facility that is also subject to the requirements of subchapter V shall be exempt from” Section 607 Requirements.^[64]

Interestingly, subchapter V in the statute sets forth regulatory requirements applicable to both drugs and devices, indicating that “a cosmetic product or facility that is also subject to the requirements” applicable to drugs or devices “shall be exempt from” Section 607. However, the Cosmetic Registration & Listing Draft Guidance only mentions drugs, stating that certain requirements do not apply to cosmetic products that are also drugs.^[65]That being said, this may be an area where clarity is needed as to FDA’s expectations with respect to registration and listing exemptions for cosmetics that are also devices.

In addition, the same electronic submission process used to register an establishment and list a drug will be available for cosmetic facility registration and product listing. The consistency between these processes is intended to streamline the submission of registration and listing information for cosmetics facilities and products for entities that also submit drug establishment and listing information.^[66]

FDA is developing an electronic portal for submitting cosmetic facility registration and product listing information, called Cosmetics Direct.^[67] Additionally, pursuant to the Structured Product Labeling (SPL) Implementation Guide with Validation Procedures, cosmetics facility registrations and product listings are now included within the SPL framework, and Cosmetics Direct will be an FDA-provided SPL authoring tool.^[68]The Cosmetic Registration & Listing Draft Guidance notes that a paper form (i.e., Forms FDA 5066 and 5067)^[69] will also be accepted as an alternative submission method; however, FDA is “strongly” encouraging electronic submissions for more efficient data management.^[70]Both submission tools (i.e., use of the electronic portal and the paper form) will be accessible on FDA’s webpage once developed.^[71]

Limited Disclosure of Cosmetic Registration & Listing Information

The Cosmetic Registration & Listing Draft Guidance notes that FDA will only publicly disclose cosmetic product facility registration and listing information to the extent permitted by law.^[72] Pursuant to Section 607(d), product listing numbers will not be made available for public disclosure.^[73] Additionally, pursuant to Section 607(e), brand names from facility registration submissions or facility registration numbers from product listing submissions will not be made available in response to requests made under the Freedom of Information Act, 5 U.S.C. § 552.^[74]

Conclusion

Both the Tattoo Ink Draft Guidance and the Cosmetic Registration & Listing Draft Guidance are important for members of the cosmetics industry. The draft guidances indicate that FDA is on its way to implementing MoCRA. Therefore, cosmetics industry stakeholders should take full advantage of the comment process for the draft guidances, as well as future public meetings and commenting opportunities, to ensure their valuable input is considered during FDA’s implementation efforts.

In addition, although the modern regulatory framework for cosmetic products is in its infancy, the Cosmetic Registration & Listing Draft Guidance demonstrates how the new cosmetic regulatory framework draws from existing regulatory concepts and requirements (like facility registration and product listing) that exist for drugs and devices. Thus, in addition to paying attention to what already exists for cosmetics (e.g., the VCRP), the cosmetics industry could also benefit from close review of regulatory frameworks for drugs and devices for more clues as to how FDA may implement MoCRA.

Finally, the Tattoo Ink Draft Guidance shows how MoCRA has not fixed all problems with respect to regulation of cosmetic products. The jurisdictional ambiguity related to distinguishing a drug or device from a cosmetic has been a long-standing issue for FDA, and the Tattoo Ink Draft Guidance further demonstrates that clearly distinguishing between cosmetics and drugs/devices remains challenging.

[1] See Consolidated Appropriations Act, 2023, Pub. L. No. 117-328, §§ 3501–3508 (2022).

[2] This Article was finalized in November 2023 and does not include FDA policy updates or announcements that have occurred since then.

[3] Draft Guidance for Industry: Insanitary Conditions in the Preparation, Packing, and Holding of Tattoo Inks and the Risk of Microbial Contamination (June 2023), https://www.fda.gov/media/169265/download [hereinafter Tattoo Ink Draft Guidance]; 88 Fed. Reg. 38,516–18 (June 13, 2023).

[4] 88 Fed. Reg. at 38,516.

[5] FDCA § 201(i), 21 U.S.C. § 321(i) (emphasis added).

[6] See Tattoo Ink Draft Guidance, supra note 3, at 3.

[7] FDCA § 301(a), 21 U.S.C. § 331(a).

[8] FDCA § 601(c), 21 U.S.C. § 361(c).

[9] Tattoo Ink Draft Guidance, supra note 3, at 7.

[10] Public Meeting: Good Manufacturing Practices for Cosmetic Products, June 1, 2023, https://www.fda.gov/cosmetics/cosmetics-news-events/public-meeting-good-manufacturing-practices-cosmetic-products-06012023; see also Docket No. FDA-2023-N-1466.

[11] Draft Guidance for Industry: Registration and Listing of Cosmetic Product Facilities and Products at 3 (Aug. 2023), https://www.fda.gov/media/170732/download.

[12] “Intended use” may be inferred from a manufacturer’s promotional claims. Specifically, “FDA may consider, among other things, any written or oral claims or statements in any label, labeling, advertising, and/or promotion of a . . . product by or on behalf of a firm in determining whether a . . . product is intended to cure, mitigate, treat or prevent disease or affect the structure or function of the body.” Guidance for Industry and FDA Staff: Regulatory Considerations for Microneedling Products at 7 (Nov. 10, 2020), https://www.fda.gov/media/107708/download [hereinafter Microneedling Guidance].

[13] FDCA § 201(i), 21 U.S.C. § 321(i) (emphasis added).

[14] FDCA § 201(g)(1), 21 U.S.C. § 321(g)(1) (emphasis added).

[15] FDCA § 201(h)(1), 21 U.S.C. § 321(h)(1) (emphasis added).

[16] See also Compliance Program Guidance Manual § 7329.001, “Cosmetics Program; Import and Domestic,” https://www.fda.gov/media/78441/download.

[17] E.g., FDA, Cosmetic Labeling Guide (Oct. 1991) (“one may say that a cosmetic is a product intended to exert a physical, and not a physiological, effect on the human body”).

[18] Letter from Cosmetics Manufacturers to John M. Taylor, Associate Commissioner for Regulatory Affairs at 3–4 (Sept. 11, 1987) (describing FDA’s interpretation of the distinction).

[19] Id.

[20] Microneedling Guidance, supra note 12, at 7–8.

[21] Tattoo Ink Draft Guidance, supra note 3, at 5.

[22] Id. at 4.

[23] Microneedling Guidance, supra note 12, at 7.

[24] Draft Guidance for Industry: Registration and Listing of Cosmetic Product Facilities and Products (Aug. 2023), https://www.fda.gov/media/170732/download [hereinafter Cosmetic Registration & Listing Draft Guidance].

[25] 88 Fed. Reg. 53,490–92 (Aug. 8, 2023), https://www.federalregister.gov/documents/2023/08/08/2023-16771/registration-and-listing-of-cosmetic-product-facilities-and-products-draft-guidance-for-industry. Although the comment period has closed, an interested party can submit comments at any time. See 21 C.F.R. § 10.115(g)(5). To ensure that FDA considers comments on a draft guidance before it begins work on the final version, it is best practice to submit comments before the comment period closes.

[26] Constituent Update: FDA Has Stopped Accepting Submissions to the Voluntary Cosmetic Registration Program (Mar. 27, 2023), https://www.fda.gov/food/cfsan-constituent-updates/fda-has-stopped-accepting-submissions-voluntary-cosmetic-registration-program-vcrp.

[27] See Cosmetic Registration & Listing Draft Guidance, supra note 24, at 4.

[28] See id. at 4–6.

[29] FDCA § 604(2), 21 U.S.C. § 364(2); Cosmetic Registration & Listing Draft Guidance, supra note 24, at 5.

[30] FDCA § 604(3), 21 U.S.C. § 364(3); Cosmetic Registration & Listing Draft Guidance, supra note 24, at 5.

[31] FDCA § 604(4), 21 U.S.C. § 364(4); Cosmetic Registration & Listing Draft Guidance, supra note 24, at 6.

[32] FDCA § 612(b), 21 U.S.C. § 364h(b); Cosmetic Registration & Listing Draft Guidance, supra note 24, at 6.

[33] Cosmetic Registration & Listing Draft Guidance, supra note 24, at 4–6.

[34] Id. at 6.

[35] FDCA § 604(3)(B)(viii), 21 U.S.C. § 364(3)(B)(viii); Cosmetic Registration & Listing Draft Guidance, supra note 24, at 5.

[36] FDCA § 604(3)(C), 21 U.S.C. § 364(3)(C); Cosmetic Registration & Listing Draft Guidance, supra note 24, at 6.

[37] FDCA § 604(3)(B), 21 U.S.C. § 364(3)(B); Cosmetic Registration & Listing Draft Guidance, supra note 24, at 6.

[38] FDCA § 607(a)(3), 21 U.S.C. § 364c(a)(3); Cosmetic Registration & Product Listing Draft Guidance, supra note 24, at 7.

[39] Id.

[40] See also Cosmetic Registration & Listing Draft Guidance, supra note 24, at 6.

[41] Id.

[42] FDCA § 612(b), 21 U.S.C. § 364h(b); see also Cosmetic Registration & Listing Draft Guidance, supra note 24, at 6.

[43] See Cosmetic Registration & Listing Draft Guidance, supra note 24, at 8, fn 3.

[44] FEI Search Portal, https://www.accessdata.fda.gov/scripts/feiportal/index.cfm?action=portal.login.

[45] Cosmetic Registration & Listing Draft Guidance, supra note 24, at 8.

[46] See id. at 12–15.

[47] FDCA § 607(c)(4)(A), 21 U.S.C. § 364c(c)(4)(A); Cosmetic Registration & Listing Draft Guidance, supra note 24, at 8–9.

[48] Id.

[49] Id.

[50] See Guidance for Industry and FDA Staff: Medical Device Classification Codes (Apr. 11, 2013), https://www.fda.gov/media/82781/download [hereinafter Medical Device Classification Codes Guidance]; see also FDA Product Code Classification Database, https://www.fda.gov/medical-devices/classify-your-medical-device/product-code-classification-database.

[51] Medical Device Classification Codes Guidance, supra note 50.

[52] Id.

[53] See Cosmetic Registration & Listing Draft Guidance, supra note 24, at 12, fn 6.

[54] See id. at 8–9.

[55] The Data Universal Numbering System (DUNS) number is a unique, site-specific identification number assigned to a facility’s physical location. The UNIIs are generated based on scientific identity characteristics in accordance with ISO 11238 and can be searched through FDA’s UNIIs search service, Global Substance Registration System (GSRS). See FDA’s GSRS, https://precision.fda.gov/uniisearch.

[56] Cosmetic Registration & Listing Draft Guidance, supra note 24, at 10; see also FDCA § 607(a)(1)(A), 21 U.S.C. § 364c(a)(1)(A).

[57] Cosmetic Registration & Listing Draft Guidance, supra note 24, at 11; see also FDCA § 607(c)(2)(B), 21 U.S.C. § 364c(c)(2)(B).

[58] Guidance for Industry: Compliance Policy for Cosmetic Product Facility Registration and Cosmetic Product Listing (Nov. 2023), https://www.fda.gov/media/173606/download; 88 Fed. Reg. 77,323–24 (Nov. 9, 2023).

[59] Cosmetic Registration & Listing Compliance Policy, supra note 24, at 4.

[60] See Cosmetic Registration & Listing Draft Guidance, supra note 24, at 10–11; see also FDCA § 607(a)(4) & (c)(5), 21 U.S.C. § 364c(a)(4) & (c)(5).

[61] Cosmetic Registration & Listing Draft Guidance, supra note 24, at 10–11.

[62] Cosmetic Registration & Listing Draft Guidance, supra note 24, at 10; see also FDCA § 607(a)(2), 21 U.S.C. § 364c(a)(2).

[63] See Cosmetic Registration & Listing Draft Guidance, supra note 24, at 11; see also FDCA § 613, 21 U.S.C. § 364i.

[64] FDCA § 613, 21 U.S.C. § 364; see also 21 U.S.C. §§ 351–360fff-8.

[65] Cosmetic Registration & Listing Draft Guidance, supra note 24, at 11.

[66] Id.

[67] In September 2023, FDA requested comments on its newly developed draft electronic submission portal (Cosmetics Direct) along with paper forms (Forms FDA 5066 and 5067). See 88 Fed. Reg. 63,960–63 (Sept. 18, 2023), https://www.federalregister.gov/documents/2023/09/18/2023-20139/agency-information-collection-activities-submission-for-office-of-management-and-budget-review; see also Draft Cosmetics Direct: Electronic Submissions Portal Screenshots for Commenting (Sept. 2023), https://www.fda.gov/media/171557/download?attachment.

[68] See Structured Product Labeling (SPL) Implementation Guide with Validation Procedures (Oct. 2023), https://www.fda.gov/media/84201/download?attachment; see also Cosmetics Constituent Update: FDA Issues Update on Cosmetic Product Facility Registration and Cosmetic Product Listing (Nov. 2023), https://www.fda.gov/cosmetics/cosmetics-news-events/fda-issues-update-cosmetic-product-facility-registration-and-cosmetic-product-listing?utm_medium=email&utm_source=govdelivery.

[69] See 88 Fed. Reg. 63,961.

[70] Cosmetic Registration & Listing Draft Guidance, supra note 24, at 4.

[71] Id. at 10.

[72] See id. at 9.

[73] Id.; see also FDCA § 607(d), 21 U.S.C. § 364c(d).

[74] Cosmetic Registration & Listing Draft Guidance, supra note 24, at 9; see also FDCA § 607(e), 21 U.S.C. § 364c(e).

3 records