FDA’s new guidance on postapproval manufacturing changes for biosimilars focuses on current practice, new dosage forms

Biosimilarity and interchangeability: A quick recap

• The Biologics Price Competition and Innovation (BPCI) Act of 2009 intended to increase the number of biologic products on the market by creating two types of approvals for biosimilar products. Both types of approvals (biosimilars and interchangeables) utilize the same 351(k) pathway but have slightly different requirements. Biosimilars are biological products that are highly similar (but not identical) to a previously approved biologic, referred to as the reference product. Because of the complexities involved in the production of biological products from living organisms, minor differences between a reference product and its biosimilars are anticipated. Instead, approval hinges on the ability of sponsors to demonstrate there are no “clinically meaningful differences” between the proposed biosimilar and the reference product.
• Interchangeable products were established by the BPCI as a subset of biosimilars that are demonstrated to produce the same clinical result as the reference product in any given patient. In practice, the biggest difference between interchangeable products and biosimilars is that pharmacists can substitute interchangeable biosimilars without consulting the prescriber (though different state laws may apply). For sponsors, interchangeable products have historically required additional clinical studies (i.e., switching studies). These studies are intended to ensure that if products are used more than once by patients, “the risk in terms of safety or diminished efficacy of alternating or switching between use of the [proposed interchangeable products] and the reference product is not greater than the risk of using the reference product without such alternation or switch.” In switching studies, a two-arm trial design is commonly employed. During the lead-in period, all patients are assigned to the reference product followed by randomization to either the “switching arm” or “non-switching arm” of the study.
• Recently, the FDA has openly supported doing away with the interchangeable distinction. In its Fiscal Year 2025 budget proposal, the FDA requested that Congress “eliminate the statutory distinction between the approval standard for biosimilar and interchangeable biosimilar products” and “deem all approved biosimilars to be interchangeable with their respective reference products.” As the agency explained in the request, “The statutory distinction between biosimilars and interchangeable biosimilars has led to confusion and misunderstanding, including among patients and healthcare providers, about the safety and effectiveness of biosimilars and about whether interchangeable biosimilars are safer or more effective than other biosimilars.” [Read AgencyIQ’s analysis of this issue here]
• In the absence of Congressional action on this topic, the FDA has been working to tackle this issue itself. In a September 2023 guidance, the agency proposed eliminating the interchangeability statement from product labeling entirely, stating that all products, whether biosimilar or interchangeable, should be referred to as “biosimilar” on the product label. As AgencyIQ discussed in December 2023, the FDA moved to implement the aforementioned guidance – which was still in draft form and in its comment period – almost immediately. In June 2024, the FDA published a new draft guidance signaling its elimination of the costly and time-consuming switch study requirement for interchangeability, making it significantly easier for sponsors with biosimilar products to gain interchangeability status and reap the reimbursement benefits.

Postapproval manufacturing changes for biological products

• During clinical development or following a product’s approval, sponsors and/or manufacturers may identify the need for a change in the product, production process, quality controls, equipment, facilities, responsible personnel, or labeling. Broadly, these topics all fall under the umbrella of chemistry, manufacturing, and control (or CMC) changes. In these instances, the first step sponsors should take (per the FDA’s many guidances on manufacturing changes) is to perform a risk assessment to determine whether the modification has potential to impact the product’s quality. These assessments should be performed prior to any type of manufacturing change regardless of the stage of product development (i.e., including well before and after product approval). For additional information on this process, sponsors should refer to International Council for Harmonisation (ICH) guidelines Q8, Q9 and Q10 on the development of quality risk management processes, and the steps to conducting the risk assessment.
• For approved products, one of the next steps (following completion of the risk assessment) is to determine how the FDA should be notified of the proposed change and what information should be submitted in support of the change. For major changes—those with substantial potential to have an adverse effect on the product—a Prior Approval Supplement (PAS) should be submitted. In these instances, described in 21 CFR 314.70(b), the FDA must review and approve the change before the altered product can be distributed. Changes that have a moderate potential to have an adverse effect on the identity, strength, purity, or potency of a drug constitute moderate changes. These require notification through either a Changes Being Effected in 30 Days (CBE-30) or Changes Being Effected (CBE) supplement. The CBE and CBE-30 supplements operate more like a notification of a change to the agency, with the CBE-30 providing a 30-day window between the notification and the changes being implemented. The FDA can stop a manufacturer from continuing to distribute the product if it disapproves. Lastly, minor changes with a very small potential to impact product quality can be described in the sponsor’s next Annual Report to the FDA.
• Risk classification is highly dependent upon the product type and the manufacturing process. Generally, any changes that the FDA would categorize as warranting the completion of a bioavailability (BA) / bioequivalence (BE) study as well as those made to the “synthesis or manufacture of the drug substance,” or to the sterilization methods used during manufacturing would be considered major. Likewise, multiple smaller (or insignificant) changes could raise the overall level of risk to that of a major change. For instance, manufacturing a product at a different site which uses identical equipment to perform an identical process could be a minor change. However, a change in manufacturing site which then entails the use of different equipment could be considered a moderate change, and lastly, if the different equipment entails changes in the overall manufacturing process, it might rise to the level of a major change.
• If a change could impact product quality, a comparability study will likely be required. The ICH Q5E Guideline defines “comparable” as the conclusion that products have “highly similar quality attributes before and after manufacturing process changes and that no adverse impact on the safety or efficacy, including immunogenicity, of the drug product occurred.” To determine the effect of a manufacturing change, samples from both batches (i.e., pre- and post-manufacturing changes) should be analyzed using product quality attributes and process parameters along with predefined acceptance criteria to assess comparability.
• Any CMC changes (e.g., in equipment) for products that are more complex or aren’t as well-characterized, such as antibody drug conjugates or recombinant DNA products, will be considered higher risk than they would if the change was made to the production of standard, small molecule products. There is also a higher burden when it comes to switching the source or process used to manufacture active pharmaceutical ingredients or drugs that are required to be sterilized or labeled as sterile, including products sterilized via filtration or other means, those aseptically processed, and terminally sterilized drug products)
• One thing that sponsors can do to preemptively decrease the burden for reporting future manufacturing changes is to develop and submit a comparability protocol (CP) during clinical development or at the time of application submission. A CP is a well-defined, detailed, written plan for assessing the effect of specific CMC changes in the identity, strength, quality, purity, and potency of a specific drug product. These protocols are used to describe the change and present all the tests and studies to be performed along with the acceptance criteria to ensure the continued safety and efficacy of the product. In some cases, sponsors with approved products may also have the option to leverage a pre-specified CP in order to reduce the reporting requirements for manufacturing changes. The idea here is that sponsors with pre-specified CPs have already worked with the FDA to develop an agreed-upon plan for how product comparability should be demonstrated in case different types of CMC changes are made in the future. As a result of securing FDA’s blessing on the plan ahead of time, sponsors with these plans in place may be able to notify the agency of some manufacturing changes using a less burdensome approach (e.g., in the annual report instead of via a post-approval supplement).
• FDA’s guidance on biosimilar product development includes one Q&A on postapproval manufacturing changes. Last finalized in 2021, the guidance “ Questions and Answers on Biosimilar Development,” includes one question and answer on postapproval manufacturing changes – question Q.I.20. The content in that guidance is limited, but generally points sponsors to ICH guidelines on the subject, saying that they should “follow the principles outlined in the ICH guidance for industry Q5E Comparability of Biotechnological/Biological Products Subject to Changes in their Manufacturing Process.” The Q&A then summarizes some of the key aspects of that document, including comparability assessment contents and the use of reference materials. That final guidance, however, does note that “FDA intends to provide specific recommendations for postapproval manufacturing changes to interchangeable biological products in future guidance.”
• The user fee commitments called for guidance on this subject. As part of the current Biosimilar User Fee program (BsUFA III), the FDA committed to the publication of “a draft guidance on the nature and type of information, for different reporting categories, a sponsor should provide to support post-approval manufacturing changes to approved biosimilar and interchangeable biosimilar biological products” by September 30, 2024 – the end of federal fiscal year 2024.

The FDA has now issued a new draft guidance on the subject of postapproval changes for biosimilar and interchangeable biosimilars

• First up, why this guidance now? According to the agency, the guidance – which is in Q&A style – “provides answers to commonly asked questions from applicants and other interested parties… regarding postapproval manufacturing changes.” In effect, the agency appears to have been fielding questions about the topic, and is looking to give answers in one place. The guidance “is intended to inform prospective and current applicants of the nature and type of information that applicants should provide in support of manufacturing changes to licensed biosimilars and licensed interchangeable biosimilars in different reporting categories.”
• The new draft guidance is fairly short, clocking in at 13 pages total, about seven of which are the Q&A – with four individual questions. The policy recommendations are broken into two parts: recommendations for reporting categories and recommendations for product quality data. The bulk of the guidance is in the latter category; only Q1 addresses “Recommendations for Reporting Categories,” while the rest of the Q&A (i.e., Q2-Q4) is focused on recommendations for product quality data. The guidance goes beyond the scope of the information offered in Q.I.20, including information on introducing a biosimilar/interchangeable biosimilar to a manufacturing site or area where other products are being manufactured (Q3) and what to do when seeking supplement approval for a new dosage form or strength (Q4).
• Q1: What information does FDA recommend, by reporting category, to support manufacturing changes for these products? Again, the three reporting categories for post-approval changes are a PAS, CBE-30/CBE-0, or Annual Report. The new draft guidance goes over the basics of when each report type is appropriate, and asks applicants to “clearly identify the reporting category under which the change is being reported.” For a PAS/CBE-30/CBE-0 (i.e., a supplement submission for a manufacturing change), then “the applicant should specify the supplement as a CMC supplement,” and cover letters should include a comprehensive list of the changes. Manufacturing changes that impact labeling should have those labeling changes in the CMC supplement.
• The rest of the guidance, Qs 2-4, is on recommendations for product quality data. As in the FDA’s 2021 guidance on biosimilar development more broadly (see above, Q.I.20), the agency continues to recommend applicants follow the principles in ICH’s Q5E Comparability of Biotechnological/Biological Products Subject to Changes in their Manufacturing Process guidance for industry. The new draft guidance goes a little bit deeper on the subject, referring to Q5E’s call for applicants to conduct a comparability exercise (see more on the subject from that guidance here) and references ICH’s definition of quality attributes (data and information necessary to establish comparability that is commensurate with the type of manufacturing change). At a high level, the new draft guidance summarizes many of the key points from Q5E on the goals of comparability exercises (including side-by-side analytical comparisons of “a sufficient number of lots” and stability data), the need for comparative stability studies and how they are “especially important when the proposed manufacturing changes can alter protein structure or purity and impurity profiles.” The new draft guidance also points applicants to 2019 draft guidance on the Development of Therapeutic Protein Biosimilars (comparative analytical assessments) and the ICH Q6B guidance on test procedures and acceptance criteria.
• The draft guidance explains that “Data and information submitted in support of manufacturing changes should demonstrate that quality attributes remain comparable among prechange and postchange products and should demonstrate that consistency in the quality, safety, and efficacy is predictable.” This may mean the product will need to be evaluated at “multiple stages of manufacture,” as it should be “evaluated at the process step most appropriate to detect a change in the quality attributes.” Comparisons of analytical data “from the postchange material to the historical analytical data (i.e., prechange material) may be sufficient to support a manufacturing change if the quality attributes of the prechange and the postchange material are comparable,” it notes, and goes on to describe the comparative analytical assessment (CAA, as described in the 2019 draft guidance cited above) expectations. If applicants are using a subset of “all available historical data” they should provide a justification, and if there has been a change in analytical assay, then “adequate assay bridging data on assay performance should be provided.”
• Back to the questions: Q2, reference materials. This guidance uses the following definition for in-house reference material: “appropriately characterized material prepared in-house by the manufacturer from a representative lot(s) for the purpose of biological assay and physiochemical testing of subsequent lots” (see ICH Q6B). As recommended in the 2021 guidance, the new draft guidance again recommends the use of “a well-qualified, in-house reference material in the comparability exercise” (note: The 2021 guidance uses “standard” instead of “material”). The new draft guidance, however, goes on to further describe the importance of this in-house reference material, which is “an important calibration point for the evaluation(s) conducted in a comparability exercise.” If the applicant asserts, and the FDA agrees with, an “informed pr diction” that there is no adverse impact expected postchange, FDA may not require additional information beyond the in-house reference material comparability exercise – “However, demonstration of comparability to support manufacturing change(s) should provide adequate assurance that a postchange product remains biosimilar to or interchangeable with a reference product.” If there are differences in quality attributes between prechange and postchange material, “comparison to the data from the reference product submitted to support licensure should be considered to help assess the potential impact and acceptability of these differences.”
• Q3: How should proposals to introduce a biosimilar/interchangeable “into a multiproduct manufacturing area or a multiproduct contract manufacturing facility be reported?” Notably, this question is not addressed at all in the 2021 guidance on biosimilar product development. However, the agency does open its answer to this question by pointing to other guidance documents that can provide more information: Changes to an Approved Application for Specified Biotechnology and Specified Synthetic Biological Products (July 1997), CMC Postapproval Manufacturing Changes for Specified Biological Products To Be Documented in Annual Reports (December 2021), and Chemistry, Manufacturing, and Controls Changes to an Approved Application: Certain Biological Products (June 2021).
• Q3 continued: The agency goes into the types of risks that might be associated with introducing a licensed biosimilar or interchangeable biosimilar into a multiproduct manufacturing area or multiproduct contract manufacturing facility, including “cross-contamination or product mix-ups” in sites or areas where the reference product or another biosimilar/interchangeable is manufactured. While the agency generally recommends that identity testing can detect and control risks, “a respective single identity test for each product might not always be able to distinguish between the different products” when they are all the same reference biological product and its biosimilars/interchangeables. When this is the case, “in addition to identity tests for each product, current good manufacturing practice requirements, including applicable manufacturing and procedural controls (e.g., separate manufacturing areas, control of personnel, process, and material flow, and control of materials, as applicable) to prevent cross-contamination or mix-ups, must be followed.”
• Q4: What is the “nature and type of CMC information” recommended to support supplement approval for a new dosage form or strength? When submitting a supplement for a new dosage form or strength for a biosimilar or interchangeable biosimilar product, “applicants must include information demonstrating, among other things, that the dosage form and the strength of the proposed biosimilar or the proposed interchangeable biosimilar product “are the same as those of the reference product.” This is considered a major change – and thus, typically requires a PAS.
• Supplements of this type “generally should include the following CMC-related information: (1) adequate comparability data between a licensed biosimilar or interchangeable biosimilar (i.e., prechange product) and the proposed biosimilar or interchangeable biosimilar with the new dosage form or strength (i.e., postchange product), (2) comparative analytical assessment (CAA) data, and (3) manufacturing data (e.g., process validation) to support the proposed postchange product,” according to the new draft guidance. However, the “extent” of the data (comparability, CAA) will depend on the risk assessment of differences – and, in “some cases,” additional data like pharmacokinetic studies might be needed. While the agency notes that previously-submitted CAA studies might provide a model for the design of these studies for a new dosage form or strength, “applicants should assess whether additional CAA studies with the new dosage form or the new strength are appropriate.”
• The draft guidance goes on to give two examples: In one, an applicant’s supplement proposes a new strength with the same administration, dosage form, excipients, and for the same patient population and indication as a biosimilar or interchangeable biosimilar already licensed. In this case, the previously submitted CAA and a “risk-based comparability exercise… may be reasonable.” In the second, the supplement seeking a new dosage form/new strength is also intended for a different patient population/indication than an already-licensed biosimilar or interchangeable biosimilar. In this case, the applicant can use the previously-submitted CAA but “should also include a risk-based targeted CAA between the proposed product with the new dosage form and strength and its reference product and include a risk-based comparability exercise.” In general, the agency recommends that sponsors come to the agency to discuss their approaches here.

Analysis and What’s Next

• The issuance of the guidance does fulfill the BsUFA III commitment, referenced above, to issue a draft guidance on this subject by the end of federal fiscal year 2024. Per the BsUFA commitment letter, the agency should “work towards the goal of publishing final guidance within 18 months” after the comment period, which would anticipate a final guidance around March 2026 – unless, of course, the agency chooses to issue a revised draft guidance, depending on feedback on this round. Comments are due September 23, 2024.
• If and when this new draft guidance is finalized, Q.I.20 from the final guidance cited above will be removed: “FDA intends to withdraw Q&A I.20 from that guidance when this guidance becomes final.” In effect, this new draft guidance will carve out the information offered in Q.I.20 (above) into its own guidance.
• The new draft guidance includes information on both biosimilar products and interchangeable biosimilar products, noting in a statement on the new draft guidance that “The agency has since [the 2021 guidance] determined the principles that apply to postapproval manufacturing changes to licensed biosimilar products are also relevant to licensed interchangeable biosimilar products and today’s guidance provides recommendations for both.” This is an expansion of scope, compared to the 2021 Q&A, which stated at the time that the documents would be separate.
• The guidance also offers additional information beyond what was available in that 2021 guidance, but many of the key themes are carried through; this includes the FDA’s continuing recommendation that applicants refer back to the ICH Q5E document on comparability of biotechnological/biological products subject to changes in their manufacturing process, and reliance on ICH definitions of key terms like quality attributes and the conduct of comparability exercises. Still, the new draft guidance does offer additional information that was not included in that 2021 Q&A guidance, such as expectations for considering risk in multiproduct manufacturing areas/multiproduct contract manufacturing facilities. Whether the agency’s guidance goes deep enough into those topics to satisfy industry’s questions, however, remains to be seen.

To contact the author of this item, please email Rachel Coe ( rcoe@agencyiq.com) / Laura DiAngelo ( ldiangelo@agencyiq.com).
To contact the editor of this item, please email Kari Oakes ( koakes@agencyiq.com).

Key Documents and Dates

• Postapproval Manufacturing Changes to Biosimilar and Interchangeable Biosimilar Products Questions and Answers
• Docket FDA-2024-D-2581
• Comments due September 23, 2024