Prepare an in-vivo bioavailability or bioequivalence waiver request

What evidence belongs in an in-vivo BA or BE waiver request?

Name the exact evidence to be waived and the applicable regulatory or scientific basis. Map each criterion to the proposed product, formulation, comparator, batches and supporting reports. Distinguish solution-based, additional-strength and BCS arguments. A BCS request needs an in-scope product, substance classification and class-appropriate excipient and dissolution evidence; high solubility or a passing QC test alone is insufficient.

Before you begin

In-vivo BA/BE evidence waiver requests under applicable FDA provisions; not a blanket waiver of clinical or nonclinical studies.

What you will prepare: A criterion-to-evidence justification with an explicit submission-placement decision.

Name the evidence being waived and the supporting route

Identify the application, product, strength, dosage form, route, comparator and exact in-vivo evidence for which relief is sought. Distinguish a product for which BA/BE is self-evident under specified regulatory conditions, an additional-strength justification and a BCS-based biowaiver. These are different scientific arguments.

For a BCS request, use M9 only after establishing that its scope fits the product. Document substance solubility and permeability evidence, product dissolution and the applicable excipient conditions. “Highly soluble” alone does not establish the full BCS waiver case, and the same excipient approach cannot be assumed for every BCS class.

Build the evidence matrix before the letter

For each applicable criterion, identify the supporting study, batch, formulation, method, result and limitation. Connect the tested batches to the proposed commercial composition and the referenced product. For an additional-strength argument, identify the strength studied in vivo and the actual proportionality, manufacturing and dissolution evidence supporting extrapolation. Have the biopharmaceutics owner confirm the appropriate product-specific approach.

For a solution-based request, examine the exact product category and ingredient/concentration conditions in 320.22 rather than assuming all solutions qualify. A formulation difference affecting absorption or local availability needs substantive assessment. Organize the request as scope, governing basis, criterion table, limitations, scientific references and requested decision; place full reports in their scientific modules.

Resolve 1.12.13 and 1.12.15 with the publishing owner

The FDA catalog contains both 1.12.13: Request for waiver for in vivo studies, and 1.12.15: Request for waiver of in vivo bioavailability studies. The inspected mapping appendix explicitly maps 320.22(a) to 1.12.15. It does not establish a universal rule that one heading is for ANDAs and the other for NDAs.

Record the actual waiver purpose and supported eCTD implementation, then resolve any ambiguous local placement with the regulatory-publishing owner or FDA technical clarification. Do not duplicate the same request in both locations merely to avoid the decision. A heading label cannot expand the scope of a scientific waiver.

Worked review: a formulation change breaks an old rationale

Fictional editorial exercise: a BCS waiver draft cites dissolution work on a formulation whose absorption-relevant excipient changed before filing. The letter still calls the tested and proposed products identical.

Reconcile the formulation versions and assess the impact on the specific waiver criteria. If new data are needed, mark the request incomplete. Change the dosage form to one outside the applicable M9 scope: select a different justified approach rather than preserving the BCS label.

Test the proposed waiver route before writing the conclusion

Start with eligibility, then assess the evidence. Do not select a favorable dissolution result first and search for a waiver label to attach to it.

Read the regulatory conditions literally. Section 320.22(d)(2) describes another product for which the same manufacturer has obtained approval, and paragraph (d)(2)(iv) states that paragraph (d) does not apply to delayed-release or extended-release products. Do not automatically use that provision for every strength in an initial application or every modified-release product. Establish the appropriate scientific and regulatory basis for the actual case. Under (f), FDA can require in-vivo evidence for good cause when a difference may affect BA or BE.

M9 covers immediate-release solid oral dosage forms or suspensions intended for systemic delivery, and excludes narrow-therapeutic-index products from its BCS approach. It addresses highly soluble Class I and Class III substances. A high-solubility argument normally uses the highest single therapeutic dose, rather than simply the highest tablet strength: M9 specifies the volume, pH and temperature conditions and separately describes a qualified circumstance involving the highest reference strength and supporting dose-proportional PK evidence. Document which argument is actually being made.

The table is a screening aid, not the complete study method. M9 specifies comparative conditions including at least 12 units of each product per profile and the defined media; it addresses variability, profile comparison and excipient exceptions in detail. A single QC dissolution value does not establish that the comparative study met those conditions. Keep individual results, methods, protocols and reports available, including results that do not support the preferred conclusion.

Fictional boundary exercise: a Class III test product reaches 86% mean dissolution at 30 minutes but only 81% at 15 minutes in one required medium. The author labels it “rapid” and concludes that the BCS waiver is supported. That result does not meet M9's very-rapid expectation for Class III in that medium. Reassess the evidence and proposed approach; do not average across media or switch the substance's BCS class to preserve the conclusion. A value exactly at 85% at 15 minutes meets that numerical threshold, but still does not establish the rest of the waiver case.

For multiple strengths, M9 expects comparison of test and reference dissolution at each strength. Distinguish that BCS package from a separate additional-strength rationale. Reconcile every report with the proposed formulation, and assess excipient changes before reusing earlier data.

Close the request with a criterion-by-criterion conclusion and explicit limitations, linked to the full scientific reports. Reconcile the reference product with the ANDA basis and RLD comparison. Resolve placement using the mapping discussed above; neither a Module 1 heading nor a well-written letter establishes the scientific waiver.

Frequently asked questions

Sources and revisions

Requirements, source recommendations and editorial preparation advice have different roles. Review the scope and revision of the source you use.

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