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Regulatory Focus™ > News Articles > 2020 > 2 > ICH M9 to Take Effect in EU by End of July

ICH M9 to Take Effect in EU by End of July

Posted 11 February 2020 | By Zachary Brennan 

ICH M9 to Take Effect in EU by End of July

About two years after first opening a consultation on the guideline, the European Medicines Agency (EMA) said Tuesday that on 30 July, the International Council for Harmonisation’s (ICH) M9 guideline on biopharmaceutics classification system-based biowaivers will take effect.

The M9 guideline has been in the works at ICH since at least 2016, and may help to avoid unnecessary in vivo bioequivalence studies.


Two drugs containing the same drug substance(s) are considered bioequivalent if their bioavailabilities (rate and extent of drug absorption) after administration in the same dose lie within acceptable predefined limits, according to the guideline.

The BCS (Biopharmaceutics Classification System)-based biowaiver approach may be used to substantiate in vivo bioequivalence, according to the EMA guideline.

“Examples include comparison between products used during clinical development through commercialization, postapproval changes, and applications for generic drug products in accordance with regional regulations. The BCS-based biowaiver is only applicable to immediate release, solid orally administered dosage forms or suspensions designed to deliver drug to the systemic circulation. Drug products having a narrow therapeutic index are excluded from consideration for a BCS-based biowaiver in this guidance,” the guideline says.

BCS-based biowaivers are applicable to drug products where the drug substance(s) exhibit high aqueous solubility and, either high intestinal permeability (BCS Class I) or low permeability (BCS Class III).
Biopharmaceutics Classification System (BCS)
 Class I: high solubility, high permeability Class II: low solubility, high permeability
Class III: high solubility, low permeability Class IV: low solubility, low permeability
The 18-page guideline explains when a drug substance is considered as highly soluble or highly permeable, how solubility and permeability can be assessed and evaluated.

What drugs can be considered eligible for a BCS-based biowaiver are also discussed.

“To be eligible for a BCS-based biowaiver, the sponsor should justify why the proposed excipient differences will not affect the absorption profile of the drug substance under consideration, i.e., rate and extent of absorption, using a mechanistic and risk-based approach,” the guideline says.

And when companies employ the BCS-based biowaiver approach, the guideline adds that comparative in vitro dissolution tests should be conducted “using one batch representative of the proposed commercial manufacturing process for the test product relative to the reference product.” In the final section, the guideline offers tips on documentation, just before two annexes.

In the first annex, M9 discusses permeability assays employing cultured Caco-2 epithelial cell monolayers derived from a human colon adenocarcinoma cell line, which “are widely used to estimate intestinal drug absorption in humans.”

The second annex includes decision trees on assessing excipient differences.

In addition to EMA’s work on M9, the US Food and Drug Administration (FDA) opened its consultation on the guideline in October 2018 and has yet to finalize the guidance.

ICH M9 on biopharmaceutics classification system based biowaivers


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