ICH M9: Biopharmaceutics Classification System-based Biowaivers

On October 19, 2016, the International Council for Harmonisation (ICH) has announced a new guideline, M9: Biopharmaceutics Classification System (BCS)-based Biowaivers, providing recommendations to support the biopharmaceutics classification of medicinal products.

The guideline is part of efforts to harmonize regional differences in guidance documents and follow the international expansion of the council last summer. The proposed guideline is intended to help minimize the number and type of bioequivalence studies that have to be carried out, depending on the region/regional guidance.
Currently, pharmaceutical companies have to follow different approaches, particularly as the US, EU, Japan, Canada and World Health Organization all offer separate but at times overlapping guidance on bioequivalence and biowaivers.
"Biopharmaceutics Classification System (BCS)-based biowaivers may be applicable to BCS Class I and III drugs, however BCS-based biowaivers for these two classes are not recognized worldwide," ICH says. "In addition, even the classification itself may differ. This means that pharmaceutical companies have to follow different approaches in the different regions."

For example, the EU Guideline on the Investigation of Bioequivalence states:

"Applying for a BCS-based biowaiver is restricted to highly soluble drug substances with known human absorption and considered not to have a narrow therapeutic index. The concept is applicable to immediate release, solid pharmaceutical products for oral administration and systemic action having the same pharmaceutical form. However, it is not applicable for sublingual, buccal, and modified release formulations. For orodispersible formulations the BCS-based biowaiver approach may only be applicable when absorption in the oral cavity can be excluded."

According to the Biopharmaceutical Classification System (BCS) drug substances are usually classified to four classes upon their solubility and permeability:

  • Class I - high permeability, high solubility
  • Class II - high permeability, low solubility
  • Class III - low permeability, high solubility
  • Class IV - low permeability, low solubility

ICH says the main issues to be resolved can be divided into supportive data for the classification of the medicinal products into one of the four classes of BCS, and supportive data for the waiver itself.

The recommendations in the ICH guideline will address:

  • Supportive data for classification, including solubility, permeability and literature data;
  • Supportive data for a waiver, which could involve establishing cut-off values of dissolution criteria depending on whether the drug is considered a BCS Class I or a BCS Class III drug and establishing what are critical excipients which may influence the rate and/or extent of absorption of a drug.

Additionally, the conditions for dissolution testing should be established. Furthermore, clarification is required in relation to the question if a BCS based biowaiver is only applicable for pharmaceutical equivalents and wether the BCS based biowaiver should be matched 1 to 1 (i.e., if comparability should be shown between each strength).

ICH says it expects to reach Step 2 of its process of adopting the guideline in the first half of 2018, while adoption of the Step 4 document is likely to occur in the second quarter of 2019.

For more information please see the M9 Concept Paper and Business Plan on the ICH Website.

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