Developing multiple strengths of the same immediate-release oral product does not always mean conducting a separate in vivo bioequivalence (BE) study for every strength. That is the opportunity addressed by ICH M13B. The guideline provides a harmonised framework for obtaining a biowaiver for one or more additional strengths when BE has already been demonstrated for at least one strength and the additional strength meets the required scientific criteria.
The important point is that this is not an automatic exemption from BE testing. The additional strength must be supported by evidence showing an appropriate relationship to the strength for which BE has already been demonstrated. For sponsors developing generic products, managing post-approval changes, or introducing additional strengths during development, ICH M13B biowaiver principles can influence both study planning and the overall development strategy.
As of September 2026, ICH M13B has reached Step 5. In the European Union, it is scheduled to take effect on 17 March 2027, when it will supersede applicable parts of the existing EMA approach to additional-strength biowaivers.
Where M13B Fits in the ICH M13 Series
ICH M13 is being developed as a series addressing bioequivalence for orally administered immediate-release solid oral dosage forms.
- M13A establishes principles for BE study design and data analysis.
- M13B addresses biowaivers for additional strengths.
- M13C is intended to address highly variable drugs, narrow therapeutic index drugs, and complex BE study designs and data analysis.
M13B therefore builds on the BE framework established in M13A. The starting point is a strength for which BE has already been demonstrated. M13B then provides criteria for determining whether other strengths can be supported without additional in vivo BE studies.
What is ICH M13B?
ICH M13B is the second guideline in the M13 series and focuses on additional-strength biowaivers for immediate-release solid oral dosage forms intended to deliver drugs systemically. It applies during both development and post-approval phases. It can also be relevant when a new strength is introduced during development relative to the strength used in a pivotal clinical trial, which may serve as the biobatch strength. If one strength has established BE, another strength may not need a separate in vivo BE study when its formulation, manufacturing, pharmacokinetic relationship, and dissolution behaviour satisfy the M13B criteria.
The assessment therefore moves from simply asking whether another strength exists to asking whether the additional strength is sufficiently comparable to the biobatch strength.
What is an Additional-Strength Biowaiver?
An additional strength biowaiver allows a sponsor to seek a waiver of an in vivo BE study for one or more strengths that were not directly tested in vivo. The strength for which BE has already been demonstrated is referred to as the biobatch strength. The additional strength is assessed against that strength using the criteria established in M13B.
The assessment considers several connected elements:
- Pharmacokinetic dose proportionality
- Qualitative and quantitative formulation proportionality
- Manufacturing-process similarity
- Comparative dissolution
- Appropriate interpretation of the dissolution data
When a Sponsor Can Potentially Avoid Another BE Study
An additional strength may qualify for a biowaiver when the relevant M13B criteria are satisfied.
At a high level, the sponsor needs to establish that:
- A suitable biobatch strength exists
BE must already have been demonstrated for at least one strength, providing the reference point for the additional-strength assessment. - The pharmacokinetic relationship is appropriate
The dose-proportionality characteristics of the drug need to support the relationship between the additional strength and the biobatch strength. - The formulations are appropriately related
The additional strength should generally have the same qualitative core composition and an appropriately proportional quantitative composition. M13B provides defined exceptions and specific considerations for certain formulations. - Manufacturing is sufficiently comparable
The manufacturing process for the additional strength should be representative of the process used for the biobatch strength. - Dissolution profiles are similar
Comparative in vitro dissolution must demonstrate the required similarity between the additional strength and the biobatch strength under the conditions specified by M13B.
When these elements align, a sponsor may be able to support an additional-strength biowaiver rather than conduct another in vivo BE study. M13B provides a scientific framework for a waiver; it does not guarantee that every additional strength will qualify.
What is Dose Proportionality and Why Does It Matter?
Dose proportionality helps establish whether changes in dose produce a predictable change in systemic exposure.
For M13B, this matters because the strength selected as the biobatch provides the basis for evaluating the additional strength. If the drug does not show an appropriate pharmacokinetic relationship across strengths, the scientific basis for extrapolating BE from one strength to another becomes weaker. M13B therefore links the selection of the biobatch strength to the pharmacokinetic proportionality principles in M13A. This is one reason why the choice of strength for the original BE study should be considered strategically rather than treated as an isolated study-design decision.
Why Dissolution Matters
Comparative dissolution is one of the central pillars of an additional strength biowaiver. The purpose is to demonstrate that the additional strength and biobatch strength exhibit sufficiently similar in vitro dissolution behaviour under the conditions specified by the guideline.
M13B calls for dissolution testing using standardised multimedia covering approximately pH 1.2, 4.5, and 6.8, together with the applicable quality-control method. The guideline generally calls for at least 12 replicates for each strength being compared.
Where dissolution is not very rapid, profile similarity can be assessed using the similarity factor f₂ under the specified conditions. When variability is high, M13B provides a bootstrap approach involving the 90% confidence interval for f₂. Dissolution is therefore not simply supporting laboratory information. It is part of the scientific bridge connecting the additional strength to the strength for which BE has already been demonstrated.
M13A vs. M13B: The Difference
In practical terms, M13A establishes the BE foundation, while M13B determines when that foundation can support additional strengths without another in vivo study.
Which Products Fall Within the Scope of M13B?
M13B applies to orally administered immediate-release solid oral dosage forms designed to deliver drugs to the systemic circulation, including:
- Tablets
- Capsules
- Granules or powders for oral suspension
The guideline covers both development and post-approval situations. It also addresses specific considerations for fixed-dose combination products and certain formulation situations, including high-potency drug products and justified deviations from direct compositional proportionality.
M13B is not a universal biowaiver framework for every dosage form or every BE situation. Its scope should therefore be confirmed before applying the criteria to a specific product.
The Formulation Relationship Matters
The additional strength generally needs to maintain the same qualitative core composition as the biobatch strength, with quantitative proportionality between strengths.
M13B allows certain justified deviations from direct proportionality. It also provides specific provisions where the drug substance represents no more than 5% of the product core weight across strengths. For high-potency products meeting this criterion, an additional-strength biowaiver may be possible when the relevant excipient relationships are maintained in accordance with the guideline.
Colour and flavour excipients that are not expected to affect bioavailability may generally vary between strengths. Changes in non-functional coating or capsule-shell composition require appropriate consideration where they could affect bioavailability.
Manufacturing Consistency is Part of the Evidence
M13B does not assess formulation composition in isolation. The manufacturing process for the additional strength should be representative of the process used for the biobatch strength. Equipment should be of the same type and operating principle, with process-parameter differences limited to those that may be necessary because of equipment or scale changes. This means a sponsor should be able to explain not only that two strengths have comparable compositions, but also why differences in their manufacture are not expected to undermine the basis for the biowaiver.
Bracketing can Provide an Alternative Path
Not every product will meet the standard criteria for a straightforward additional-strength biowaiver. M13B also describes a bracketing approach for certain situations where the standard criteria are not fully met. Depending on the product and the specific circumstances, testing selected strengths may provide a basis for supporting intermediate strengths.
This is particularly relevant when a sponsor is dealing with several strengths and wants to avoid unnecessary testing while still maintaining an appropriate scientific basis for BE assessment. Bracketing should not be treated as a shortcut. The applicability of the approach needs to be assessed against the specific M13B conditions and the product’s formulation and performance characteristics.
What Data Should a Sponsor Prepare?
A strong M13B strategy should be supported by a clear, traceable evidence package.
Key information can include:
- Biobatch information
Documentation identifying the strength and batch used to establish BE, including the relevant study or pivotal clinical-trial context. - PK and dose-proportionality assessment
Evidence supporting the relationship between strengths and the selection of the biobatch. - Formulation composition
Qualitative and quantitative composition of the biobatch and additional strength, including any deviations from direct proportionality and their scientific justification. - Manufacturing information
Evidence showing that the manufacturing process is representative and appropriately comparable. - Dissolution methodology and results
Protocols, media, apparatus, sampling conditions, batch information, individual and mean dissolution data, and the applicable similarity assessment. - Scientific justification
A clear explanation of how the complete dataset satisfies the M13B criteria and supports the proposed waiver.
The guideline also highlights the importance of retaining enough of the original biobatch for anticipated dissolution testing. Where the original biobatch is unavailable, representative batches may be considered in defined circumstances with appropriate scientific justification.
Regulatory Considerations for Global Development
ICH M13B is intended to support greater harmonisation, but implementation still occurs through regional regulatory frameworks. ICH guidelines are implemented by individual ICH regulatory members according to their applicable national or regional requirements. Therefore, a sponsor developing the same product for multiple markets should not assume that publication of M13B automatically means identical implementation everywhere.
In the EU, M13B becomes effective on 17 March 2027 and will supersede applicable parts of the existing EMA approach to additional-strength biowaivers.
For global development, teams should therefore assess:
- The implementation status in each target market
- Current regional or product-specific requirements
- The timing of submission relative to implementation
- Whether existing BE data were generated under an applicable framework
- Any regional requirements that remain outside the scope of M13B
How M13B Could Affect Generic Drug Development Strategy
M13B can change the way sponsors think about the development of multiple strengths. Instead of planning separate BE studies for every strength by default, sponsors can assess early whether one strategically selected strength can serve as the biobatch and whether other strengths can be supported through the M13B framework.
This can influence:
- BE study planning
- Strength selection
- Formulation development
- Comparative dissolution planning
- Batch retention strategy
- Manufacturing development
- Post-approval strength additions
- Submission sequencing
The potential benefit is not simply fewer clinical studies. A well-designed strategy can reduce unnecessary testing while creating a more coherent evidence package for regulatory review.
How Regulatory Teams Should Assess an M13B Biowaiver Strategy
An effective assessment should begin before the additional strength is fully developed. The strongest strategy is therefore not simply “apply M13B.” It is to determine early whether the product‘s scientific, formulation, manufacturing, and regulatory evidence collectively support a waiver
Regulatory teams should consider:
- Start with the biobatch
Confirm that the strength selected as the reference point provides an appropriate foundation. - Assess the formulation relationship
Compare composition across strengths and identify any deviations requiring justification. - Check manufacturing comparability
Confirm that differences in scale, equipment, or process parameters remain consistent with the guideline. - Plan dissolution early
Ensure the biobatch will be available and that dissolution studies can be conducted under the required conditions. - Evaluate the complete evidence package
Do not assess dissolution, composition, or PK proportionality independently. The waiver depends on the relationship among these elements. - Check regional implementation
Confirm how and when M13B applies in each target market. - Identify exceptions early
Consider high-potency products, fixed-dose combinations, bracketing, instability, or formulation deviations before the eCTD submission strategy is finalised.
Common Gaps that can Weaken an Additional-Strength Biowaiver
Some gaps are often easier to address during development than during submission review.
Several issues can create avoidable regulatory uncertainty:
- Selecting the biobatch without considering the proportionality of exposure across strengths
- Treating formulation proportionality as a purely numerical exercise
- Planning comparative dissolution after the original biobatch has become unavailable
- Underestimating the importance of manufacturing comparability
- Assuming similar dissolution alone is sufficient
- Failing to document justified deviations from proportionality
- Treating regional implementation as automatically harmonised
- Using a biowaiver rationale that does not clearly connect all supporting evidence
What M13B Means for Post-Approval Lifecycle Management
The value of M13B extends beyond initial generic drug development. Sponsors may introduce additional strengths after approval for commercial, clinical, or market-access reasons. In such situations, the ability to evaluate an additional-strength biowaiver can become a lifecycle-management consideration.
However, post-approval applications may present practical challenges, particularly when the original biobatch is no longer available or its dissolution data were not generated under the current M13B approach.
The M13B Q&A provides clarification for such situations. In exceptional circumstances, representative batches may be considered when the original biobatch is unavailable, provided they appropriately represent the formulation and manufacturing process and the scientific justification is adequate. This makes early batch retention and evidence planning relevant well beyond the initial submission.
The Strategic Value of M13B
M13B is more than a mechanism for avoiding an additional clinical study. Its broader value lies in encouraging sponsors to connect:
BE study selection → formulation design → manufacturing → dissolution → regulatory strategy
When these elements are planned together, a sponsor can make a more informed decision about whether an additional strength truly requires another in vivo BE study. The objective is not simply to minimise studies at any cost; it is to generate the right evidence for the regulatory question being asked.
How DDReg Supports M13B Biowaiver Strategies
DDReg can support sponsors in assessing the regulatory and scientific basis for additional-strength biowaiver strategies, building on its experience in BA/BE biowaiver justification and regulatory submission support.
Support can include reviewing applicable regulatory requirements, assessing the available BE and formulation evidence, evaluating the proposed biowaiver rationale, identifying potential evidence gaps, supporting dissolution and documentation strategies, and helping align the approach with target-market expectations.
For global development programs, this assessment can also help determine where M13B can support a common strategy and where regional implementation or additional requirements need to be considered.
Conclusion
The introduction of ICH M13B provides a more structured basis for evaluating whether additional strengths can be supported without conducting another in vivo BE study.
The opportunity depends on more than having multiple strengths of the same product. Sponsors need to establish the appropriate biobatch, demonstrate the required pharmacokinetic and formulation relationships, maintain suitable manufacturing comparability, and provide comparative dissolution evidence that meets the guideline’s criteria.
With M13B taking effect in the EU on 17 March 2027, sponsors developing immediate-release oral products should begin assessing how the new framework may affect current and future development programs.
Frequently Asked Questions
ICH M13B is an ICH guideline for obtaining biowaivers for one or more additional strengths of orally administered immediate-release solid oral dosage forms. It provides criteria for determining whether an additional strength can be supported without conducting another in vivo bioequivalence study when BE has already been demonstrated for at least one strength.
An additional strength may qualify when the applicable M13B criteria are met. These include an appropriate pharmacokinetic dose-proportionality relationship, suitable formulation proportionality, comparable manufacturing processes, and acceptable comparative dissolution. The waiver is not automatic and must be supported by the overall evidence package.
A sponsor should prepare evidence covering the bio batch strength, dose proportionality, formulation composition, manufacturing process, and comparative dissolution. The package should also clearly explain any justified deviations and demonstrate how the available evidence satisfies the applicable M13B criteria.
No. An M13B additional-strength biowaiver should not simply rely on a previous BCS-based biowaiver. The M13B criteria must be assessed independently for the additional strength. The ICH M13B Q&A specifically clarifies that a “waiver on a waiver” approach is not supported.