FDA Environmental Assessments and Categorical Exclusions Under 21 CFR Part 25 for Drug and Biologic Applications

FDA environmental assessments and categorical exclusions under 21 CFR Part 25: how they apply to drug and biologic applications

Key takeaways

• Every NDA, ANDA, BLA, supplement and IND must contain either a claim of categorical exclusion or an environmental assessment (EA). This requirement appears in Part 25 and in the application regulations themselves ^122361431109.
• Most drug and biologic actions are excluded under 21 CFR 25.31. The main routes are no increased use of the active moiety (25.31(a)), an expected introduction concentration (EIC) below 1 part per billion at entry into the aquatic environment (25.31(b)), naturally occurring substances (25.31(c)), and IND actions (25.31(e)) ^257258259260.
• A categorical exclusion does not apply when extraordinary circumstances exist under 25.21. FDA then requires at least an EA ²⁵⁶.
• For drugs, the clearest recent example is the Opill (norgestrel) OTC switch. FDA found the categorical-exclusion claim met the exclusion's definition but still required an EA because of potential harm to aquatic organisms below 1 ppb. It then issued a FONSI with precautionary mitigations ^237425238.
• For biologics, CBER has routinely required full EAs for live or genetically modified products, including oncolytic viruses, AAV gene therapies and live vaccines. Products composed of genetically modified human cells, and naturally occurring proteins and vaccines, have generally been excluded ^{283032257978321}.

The legal framework

Who must submit what

Under 21 CFR 25.15, every application or petition that asks FDA to act must include either an EA or a claim of categorical exclusion ¹²². A claim must cite the specific exclusion and state that, to the applicant's knowledge, no extraordinary circumstances exist. If those conditions are met, no EA is needed ²⁴⁴.

Section 25.20(l) lists the drug and biologic actions that normally require at least an EA: "Approval of NDA's, abbreviated applications, applications for marketing approval of a biologic product, supplements to such applications, and actions on IND's, unless categorically excluded in § 25.31 (a), (b), (c), (e), or (l)" ³⁵⁷.

The product-specific regulations restate the obligation:

Failure to submit an adequate EA for an action listed in § 25.20 is sufficient grounds for FDA to refuse to file or refuse to approve the application, unless FDA can determine that a categorical exclusion applies. Part 25 distinguishes an EA that is adequate for filing from one that is adequate for approval ¹²².

The human drug and biologic categorical exclusions (21 CFR 25.31)

Section 25.30 also lists general exclusions. Most cover agency activities, such as inspections, recall requests, guidance and procedural regulations, CGMP and GLP regulations, and certain labeling actions that do not change existing use levels ^399406408409.

The 1 ppb exclusion in 25.31(b) applies to NDAs, abbreviated applications and supplements. FDA's 1998 guidance states that it does not apply to BLAs ²⁹⁷. Biologics therefore rely mainly on 25.31(a), (c) and (e).

How to claim a categorical exclusion

FDA's final guidance Environmental Assessment of Human Drug and Biologics Applications (July 1998) is still the core CDER and CBER reference ²⁶⁸²⁹¹. A claim has three parts: a statement that the action qualifies, a citation to the specific exclusion, and a statement that the applicant knows of no extraordinary circumstances. Supporting data are ordinarily not needed, but CDER or CBER may request information to verify eligibility ²⁹².

Calculating the EIC for a 25.31(b) claim

The guidance gives the aquatic EIC as ³⁷⁵:

EIC-Aquatic (ppb) = A × B × C × D

• A = kg/year produced for direct use, expressed as active moiety
• B = 1/(liters per day entering publicly owned treatment works), using 1.214 × 10^11 L/day
• C = year/365 days
• D = 10^9 µg/kg

The calculation assumes that all drug product produced in a year is used and enters treatment works. It also assumes that use is spread across the United States in proportion to population and wastewater generation, and that no metabolism occurs ³⁷⁶. Calculations should use the active moiety, not the salt or complex. Metabolism data may be used to weight less active or inactive metabolites by their amount and relative activity. A metabolite of unknown activity is assumed to be as active as the parent. Alternative calculations, for example for geographically localized use, are allowed if justified ²⁹⁴.

How reviewers evaluate claims in practice

In CDER reviews, the product quality reviewer checks the claim against the cited paragraph:

• 25.31(a), no increase in use. For BENDEKA, the reviewer found the NDA would not increase use, noted the no-extraordinary-circumstances statement, and accepted the claim ¹⁷¹¹⁷². QBRELIS was accepted on the same rationale ¹⁷³¹⁷⁴.
• 25.31(b), EIC below 1 ppb. ALECENSA's exclusion was granted on an estimated aquatic entry concentration below 1 ppb. The reviewer also noted no extraordinary circumstances and no wild-sourced plant or animal material ¹⁷⁵¹⁷⁶. For VYZULTA, the applicant at first left out the no-extraordinary-circumstances statement. The claim was accepted only after it was added ¹⁷⁷¹⁷⁸.
• 25.31(c), naturally occurring substances. Therapeutic proteins such as HERCEPTIN and TEZSPIRE were accepted under 25.31(c) because approval was not expected to significantly change environmental concentrations ¹⁷⁹¹⁸⁰.

CBER applies the same discipline. It checks that the applicant cites a specific paragraph, supports the criteria and addresses extraordinary circumstances, and it asks for corrections when a claim is incomplete ⁵⁰⁷⁶:

The common deficiencies are procedural: citing the wrong paragraph, or leaving out the no-extraordinary-circumstances statement.

Extraordinary circumstances: when an exclusion fails

Under 21 CFR 25.21, FDA requires at least an EA for an ordinarily excluded action if extraordinary circumstances indicate the action may significantly affect the human environment. The regulation gives two examples ²⁵⁶:

• 25.21(a): data showing potential for serious harm to the environment at the expected level of exposure
• 25.21(b): adverse effects on endangered, threatened or otherwise federally protected species or critical habitat

The 1998 guidance adds that environmental harm includes effects beyond toxicity to organisms. It also covers potentially harmful emissions not adequately addressed by other requirements, and actions that threaten a violation of environmental protection requirements ²⁹⁵²⁹⁶.

Endocrine-active drugs

FDA's March 2016 guidance Environmental Assessment: Questions and Answers Regarding Drugs With Estrogenic, Androgenic, or Thyroid Activity addresses the main known gap in the 1 ppb threshold ³⁴⁵. Research shows these drugs may cause developmental or reproductive effects in aquatic organisms below 1 ppb. A low EIC therefore does not rule out extraordinary circumstances. FDA reviews these claims case by case, may request more information, and requires an EA if it finds extraordinary circumstances. Sponsors should consult FDA early in development ³⁴⁸.

When FDA has required a full environmental assessment

Opill (norgestrel) OTC switch: the leading drug example

For NDA 017031 Supplement 041 (decision date July 13, 2023 ¹⁸⁸), FDA found that the applicant's categorical-exclusion claim met the exclusion's definition. However, the data available at the time showed potential for serious environmental harm at the expected exposure level. This is an extraordinary circumstance under 25.21(a), so an EA was required ²³⁷. The concern was that biologically active levonorgestrel could cause developmental or reproductive effects in aquatic organisms even below 1 ppb ⁴²⁵.

The EA found that the aquatic environment was the main receiving compartment and that fish life-cycle testing gave the most sensitive endpoint. Modeled risk quotients were at or below 1 for median concentrations under both flow scenarios and for the 90th percentile under mean flow. They exceeded 1 at the 90th percentile under low flow and at higher percentiles ⁴²⁶. Terrestrial risk was not a concern, and risk to predators was negligible ⁴²⁷.

FDA's FONSI adopted "selected precautionary mitigations." It concluded that some adverse impacts were possible but that approval was not expected to have a significant environmental impact, so no environmental impact statement would be prepared ²³⁸²³⁹. Opill is a useful precedent: it is a recent CDER case in which a 25.31(b)-type claim was overridden by 25.21(a) and resolved through an EA with mitigation.

Other NDAs with full EAs and FONSIs

Drugs@FDA review packages include EAs and FONSIs for a range of small molecules. In most cases the published excerpts do not state the specific trigger.

The Biktarvy record shows that FDA evaluates each active moiety in a fixed-dose combination separately. One component can require an EA while the others are excluded ²²⁹.

Gene therapies, vectored vaccines and live biologics

FDA's March 2015 guidance Determining the Need for and Content of Environmental Assessments for Gene Therapies, Vectored Vaccines, and Related Recombinant Viral or Microbial Products sets out the framework for these products (GTVVs) ³¹⁸³¹⁹:

• INDs are ordinarily excluded under 25.31(e). The sponsor must still claim the exclusion and state that it knows of no extraordinary circumstances ³⁸⁴³⁸⁵.
• BLAs may qualify under 25.31(c) if the product occurs naturally in the environment and approval does not significantly change its environmental concentration or distribution, or under 25.31(a) if use of the active moiety does not increase ³⁸⁶³⁸⁷.
• Products FDA generally considers naturally occurring include GTVVs with functional protein-coding sequences from species within a single genus (including qualifying same-genus reassortants), GTVVs that differ from wild type only by attenuating point mutations or deletions, killed or inactivated GTVVs shown to be unable to replicate, and genetically modified human cells ^389390321.
• Products FDA does not consider naturally occurring include GTVVs engineered to express a functional protein-coding sequence from a different genus. Applications for these should include an EA. FDA's examples are a plasmid vaccine expressing a viral envelope protein and a viral vector expressing a human enzyme ³⁹¹³⁹².
• EA content for these products should address susceptible organisms, potential disease or injury, and genetic instability (for example, replication-competent adenovirus formed by recombination) ³²³. Where biologically active product could be released, it should also address the likelihood of infection, persistence or colonization, considering tropism, host range and selection pressures ³²⁴.

CBER review records show this framework applied to licensed products:

The pattern is consistent. Engineered viral and bacterial vectors, whether replication-competent or not, have gone through full EAs. Shedding, biodistribution and disposal data have been central to each review. Genetically modified autologous cell products such as KYMRIAH, and naturally occurring proteins and vaccines such as GARDASIL 9, have been excluded under 25.31(c) ⁷⁹⁷⁸.

What a full EA involves

Content requirements (21 CFR 25.40)

An EA is a concise public document that gives FDA the evidence and analysis to decide whether to prepare an environmental impact statement (EIS) or a FONSI. It must briefly discuss the need for the proposal, the alternatives, the environmental impacts of the action and alternatives, and the agencies and persons consulted. It should focus on environmental issues from the use and disposal of the FDA-regulated article ³⁹⁴. If potentially adverse impacts are found, the EA must discuss any reasonable course of action that carries less environmental risk ³⁹⁴.

A scientifically justified tiered testing approach is acceptable, and testing may stop when results suggest no significant impact. Applicants may propose study protocols for FDA review and may incorporate information by reference ³⁹⁵³⁹⁶. FDA must ensure that any necessary mitigating measures are carried out as a condition of approval ³⁹⁷.

Tiered fate and effects testing (1998 guidance)

When an EA is required, it normally focuses on the environmental fate and effects of the active moiety and any structurally related substances ²⁹⁹. The guidance recommends microbial inhibition testing to assess possible disruption of wastewater treatment ³⁰¹. Toxicity endpoints are compared with the maximum expected environmental concentration (MEEC), which is the greater of the EIC and the expected environmental concentration ³⁰²³⁰³.

• Tier 1: acute toxicity in at least one suitable organism. A toxicity-to-MEEC ratio of at least 1,000 generally ends testing unless sublethal effects occur at the MEEC ³⁰⁴.
• Tier 2: acute base-set testing, with a threshold ratio of 100 ³⁰⁵.
• Tier 3: chronic testing, with a threshold ratio of 10. Chronic testing is also triggered when effects are observed at the MEEC ³⁰⁴³⁰⁵.

FONSI, EIS and public disclosure

A FONSI briefly explains why an action that is not otherwise excluded will not significantly affect the human environment and why no EIS will be prepared. It includes the EA or a summary of it, and is signed by the responsible FDA officials ³⁶⁵³⁶⁶. If FDA cannot reach a FONSI, an EIS must address environmental impacts, unavoidable adverse effects, alternatives, short-term versus long-term productivity, and irreversible commitments of resources, using CEQ procedures ²⁴⁵²⁴⁶. All of the drug and biologic EAs described above ended in a FONSI, except ERVEBO, for which the published review does not document a FONSI.

EAs and FONSIs are public documents ³⁵⁴. Because many drug and biologic applications, and in some cases their existence, are protected from disclosure, FDA does not release environmental documents before approval unless the application's existence has already been made public ³⁵³. Applicants must put protected data in a separate confidential section and summarize it in the public EA as far as possible ³⁵⁶.

Practical implications for sponsors

• Get the claim language right. Cite the specific 25.31 paragraph and include the no-extraordinary-circumstances statement. Missing statements and wrong paragraph citations are the most common reasons CDER and CBER reviewers send claims back ^1775082.
• Do not rely on the 1 ppb threshold for hormonally active drugs. The 2016 endocrine guidance and the Opill precedent show that FDA may require an EA, aquatic risk modeling and mitigation even when the EIC is below 1 ppb ^348237238.
• Assess each active moiety separately in combination products. One component may need an EA while the others are excluded, as with Biktarvy ²²⁹.
• Plan EA-quality data early for vector-based biologics. Shedding, biodistribution, environmental stability and disposal data drive the CBER EA. CBER has asked for revised EAs when release was not quantified, as with IMLYGIC ²⁸. Products expressing sequences from a different genus should expect to file an EA rather than a 25.31(c) claim ³⁹¹.
• Remember that BLAs cannot use the 1 ppb exclusion. Biologic sponsors must justify exclusions under 25.31(a), (c) or (e) ²⁹⁷³⁸⁶.