US FDA Update: Is it a Device? After the Fact Design History Files

Summary

Genus Medical Technologies upset the US FDA classification schema for imaging agents such as barium sulfate in the landmark litigation ruling¹ in the drug turned device manufacturer’s favor that only products meeting the definition of a drug must be regulated as such. This ruling has caused the Agency to reconsider its previous stance on classification of some combination products, including certain ophthalmic products such as those covered under 21 CFR 200.50 (c), i.e. ophthalmic drug products that include devices for administration or dispensing.

With this new perspective on combination products, FDA issued a guidance describing the Agency’s expectations for compliance with 21 CFR Part 4, Current Good Manufacturing Practice Requirements for Combination Products, for certain combination ophthalmic products that previously were not considered combination products.

Abbreviations: Current Good Manufacturing Practice (GMP), United States (US), United States Code (USC), Food and Drug Administration (FDA), District of Columbia (DC), Code of Federal Regulations (CFR), 21CFR820 or part 820 or the Quality System Regulation or QSR

Introduction

The long-standing definition of a device is established in Section 201(h) of the FD&C Act, 21 USC 321(h), as:

“an instrument, apparatus, implement, machine, contrivance, implant, in vitro reagent, or other similar or related article, including any component, part, or accessory, which is—

• recognized in the official National Formulary, or the United States Pharmacopeia, or any supplement to them,
• intended for use in the diagnosis of disease or other conditions, or in the cure, mitigation, treatment, or prevention of disease, in man or other animals, or
• intended to affect the structure or any function of the body of man or other animals, and which does not achieve its primary intended purposes through chemical action within or on the body of man or other animals and which is not dependent upon being metabolized for the achievement of its primary intended purposes”

This has been the definition since 1997 Amendments to the FD&C Act. Historically, accessories sold with ophthalmic drugs within the scope of 21 CFR part 200.50 (c) were exceptions to this definition. These components are not metabolized by the body yet were regulated as the drugs they accompany. Aligning its practices with the 2021 court decision, FDA has determined that the products in scope of part 200.50 (c) are now considered combination products. Given this revelation, the Agency issued a new guidance providing manufacturers 12 months to get up to speed with applicable requirements of part 820 (by way of part 4 for combination products), the Quality System Regulation for their device components; this is a tall order for those new to the QSR for devices. Note that this is contradictory to the EU EMA approach of stating that eye droppers contained in a combination product are not a medical device².

Figure 1. Connection between compliance to 21CFR part 4 and part 820 for device components

Why is this happening?

The District of Columbia (DC) Circuit Court of Appeals determined that imaging agents such as barium sulfate must be regulated as devices since it meets the definition of a device, not a drug. Despite being administered orally³, the radiographic contrast agent is not metabolized by the body and does not impact structure or function through chemical action of the tissues contacted as it passed through the body. These are key characteristics of devices as discussed in the FD&C Act.

With a renewed legal perspective on how to regulate contrast agents, FDA is reconsidering many other products that may have been mis-classified under current legal definition of devices and/or drugs including ophthalmic drug products that are packaged and sold with a device but are regulated as drugs.

What is the same?

Under 21 CFR 200.50 (c), eye cups, droppers and the like that were packaged and sold with ophthalmic drugs were historically, regulated as drugs. Subsequently, drug makers marketing and selling these products in the US were not subject to general controls for the devices utilized in their product.

However, these devices were subject to the GMPs of drug manufacturing including documented inspection, testing, approval, quarantine, and product disposition covered by part 211 of 21 CFR. The documentation of these processes align with parts of the QSR (21CFR820), and are not new requirements for these industry stakeholders⁴. These processes support GMP for medical devices but will not absolve manufacturers from the remaining parts of 21CFR820 for the applicable devices. The good news being that FDA does not intend to take action against firms marketing these products until March 2023⁵.

What is different?

Medical Device Constituent Parts

Myriad accoutrements may be packaged and sold with ophthalmic drugs in the US. In the specific circumstances of part 200.50(c), this can include droppers, eye cups or other devices to dispense ophthalmic drug products⁶. Given the previous posture of regulating these as drug products, these devices were only subject to the requirements for pharmaceutical GMP mentioned above. Now, the device constituent may be subject to full QSR depending on the classification of the device when reviewed as a standalone product.

Design History and Controls Documentation After The Fact

Drug manufacturers will need to review their manufacturing documentation and specifications to support compilation of their DHF after the fact. FDA explicitly states that firms may leverage existing testing data to develop the DHF in the guidance⁵. This is providing firms the ability to avoid reinventing the wheel, establishing new user needs and specifications and even control process, policies, and procedures. These requirements may require a shift in thinking about this data and how to capture and store this information but will be advantageous for firms to take this approach to creating after the fact DHFs and design control processes, procedures, and policies. New devices or future changes to existing devices should be developed and executed under design controls as part of 21 CFR 4 compliance.

Post-Market Safety Reporting Requirements

Post-market safety reporting requirements are expected to be met by manufacturers or applicants with these combination products as described in part 4 (b). Firms should establish processes and procedures to meet these requirements over the next year.

Marketed Over-The-Counter (OTC) Drug Products

Over-the-counter (OTC) drug products approved via 505G of the FD&C Act, via OTC Monograph administration process, FDA expects that these applicants and manufacturers leverage currently available data and information in compilation of the QSR requirements commensurate to device classification over the next 12 months. However, FDA does not intend to take action for noncompliance to part 820 for OTC combination products that have a low-risk class I constituent parts until further assessment against the QSR requirements is complete. The Agency is also providing some additional grace over the next year to OTC combo manufacturers for their device constituent parts for compliance to 21CFR part 4, post-market safety reporting requirements.

Products with Pending Applications

For ophthalmic drug manufacturers with pending applications that fall under part 200.50(c), FDA requests that these firms submit an updated FDA Form 356h, NDA or ANDA application form identifying additional manufacturing and disposition facilities. FDA will consider this update during the product review and may choose to assess compliance with applicable sections of QSR during pre- or post-approval inspection or require objective evidence to demonstrate compliance during the application review⁵. However, this pre-approval inspection is not anticipated for the products within scope of the March 2022 guidance.

What happens next?

The Agency will need to further assess actions necessary to comply with CFR 820 and provide further guidance to industry despite pointing to part 820 by way of part 4 for GMPs. The guidance remains silent on other sections of 21CFR that are pertinent to devices within scope such as part 807, establishment registration and device listing for manufacturers along with if and when the Agency expects manufacturers or applicants to be compliant with these sections of the CFR. Also, prescription ophthalmic devices with drugs are not addressed in the guidance. It will be interesting to see how the Agency approaches regulating these additional classes of devices as 200.50 is not restricted to OTC device/drug combo products.

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References:
1. Genus Medical Technologies LLC v. U.S. Food and Drug Administration. The Federal Register :: Genus Medical Technologies LLC Versus Food and Drug Administration; Request for Information and Comments. Published 09 August 2021. Accessed 09 Jun 2022.
2. Guideline on medicinal products used with a medical device (europa.eu). European Medicines Agency. QWP-BWP Guideline on medicinal products used with a medical device (europa.eu) Published 22 July 2021. Accessed 09 Jun 2022.
3. SilQ Package Insert. Genus Medical Website. Microsoft Word - SilQ Package Insert 5.8.17.docx (genusmedical.com) Published 08 May 2017. Accessed 09 June 2022.

4. 21 CFR part 211Subpart E. The Code of Federal Regulations Title 21. CFR - Code of Federal Regulations Title 21 (fda.gov). Last updated 29 March 2022. Accessed 09 June 2022.
5. Certain Ophthalmic Products: Policy Regarding Compliance With 21 CFR Part 4 Guidance for Industry. Guidance for Industry (fda.gov). Published 22 March 2022.
6. 21 CFR part 200.50 subpart C. The Code of Federal Regulations Title 21. CFR - Code of Federal Regulations Title 21 (fda.gov). Last updated 29 March 2022. Accessed 09 June 2022.