WHO seeks to align biowaiver policy with ICH guidelines

The World Health Organization (WHO) wants to align its bioequivalence classifications with other global guidelines by reducing the number of in vivo studies required to prove bioequivalence with a reference product.

If adopted, the draft working document, Biopharmaceutics Classification System-Based Biowaivers, would align the agency’s policies with those adopted by the International Council for Harmonisation’s 2019 M9 Biopharmaceutical Classification System-Based Biowaivers guideline. Health Canada implemented the guideline in 2020, and the US Food and Drug Administration (FDA) adopted it in 2021.

In the WHO Biopharmaceutics Classification System (BCS) proposal, an active pharmaceutical ingredient (API) could be considered bioequivalent to the reference product if, in lab studies, it exhibits the same properties of aqueous solubility and intestinal permeability. If these can be proven in vitro, WHO could exempt the product sponsor from conducting in vivo bioequivalence studies, the agency wrote in its draft document.

WHO embarked on the project after experts attending a Joint Meeting on Regulatory Guidance for Multisource Products recommended that the agency’s Norms and Standards for Pharmaceuticals (NSP) Team update its existing BCS-based biowaiver requirements to harmonize with those created by the ICH. The draft document contains WHO’s current thinking on the topic.

If formally adopted, the guideline will replace the BCS-based biowaiver section of the WHO guideline Multisource (generic) pharmaceutical products: guidelines on registration requirements to establish interchangeability.

WHO categorizes APIs into one of four classes:

Class I: high solubility, high permeability
Class II: low solubility, high permeability
Class III: high solubility, low permeability
Class IV: low solubility, low permeability

BCS-based biowaivers are only available for Class I and Class III APIs.

The document contains specific details about how to assess solubility and permeability of APIs. In general, an API is considered highly soluble if the highest single therapeutic dose is completely soluble in 250 mL or less of aqueous media over the pH range of 1.2–6.8 at near body temperature. An API is considered highly permeable if the absolute bioavailability is at least 85%, or if 85% of the administered dose can be recovered in urine as parent drug.

These can be established by in vitro experiments or, in some cases, with human data from published literature. A caveat, the document says, is that even peer-reviewed articles might not include all of the testing details, which are needed to judge the quality of the data used for biowaiver application.

A Finished Pharmaceutical Product (FPP) might also be eligible for a biowaiver if all of its APIs satisfy the solubility and permeability requirements of being Class I or III agents; if the FPP is an immediate-release oral medication; and if it is the same dosage form and strength as the reference product. Buccal or sublingual products don’t qualify.

BCS-based biowaivers can only be applied to immediate-release, solid, oral forms or suspensions that deliver the API directly to systemic circulation. They must also be designed to be taken with water, the document notes. “If administration without water is also intended [e.g. orodispersible products], a bioequivalence study in which the product is dosed without water should be conducted.”

Excipients in a formula can affect a product’s potential qualification for a BCS-based biowaiver. They can impact solubility, gastrointestinal motility, transit time, intestinal permeability and – especially if they contain sugars – systemic absorption. To qualify for a BCS-biowaiver, the total amount of excipient has to be within a 10% range of the reference product’s excipient.

The potential risks of excipients should all be assessed mechanistically, keeping in mind the biowaiver class of the API. For example, Class I APIs with both high solubility and high permeability are less vulnerable to the effects of excipients. But Class III APIs, with their low permeability, may be absorbed only at specific sites and are more vulnerable to excipients that might affect absorption.

The FPP should also exhibit similar dissolution to the reference product. For a Class I API to qualify, at least 85% of both the test and the reference product should dissolve within 15 minutes for very rapid-acting compounds or within 30 minutes for a rapid-acting compound. For a Class III API to qualify, at least 85% of both the test and reference product should dissolve in 15 minutes or less.

WHO is seeking public comment on the draft working document until 31 August 2023.

WHO seeks to align biowaiver policy with ICH guidelines

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