Implementing ICH M10: Finally, a Harmonized Bioanalytical Method Validation Guidance

Adopted on May 24, 2022, the International Council for Harmonisation (ICH) has released a new guideline to standardize bioanalytical method validation (BMV) practices.

Until recently, different global regulatory agencies had varying requirements for validating bioanalytical methods and performing sample analysis.

Now, the International Council for Harmonisation (ICH) has released a new guideline that aims to standardize bioanalytical method validation (BMV) practices. [1] The final step 5 ICH M10 guideline, adopted on May 24, 2022, has been ratified by various regulatory agencies including the U.S. Food and Drug Administration (FDA). For the EU’s European Medicines Agency (EMA), the ICH M10 will be coming into effect on January 21, 2023. 

As already stated in global white papers [2,3] published after the public consultation period, ICH M10 does not seem to require significant changes compared to previous guidance/guidances. [4,5] Indeed, a white paper summarizing the 2019 Workshop on Recent Issues in Bioanalysis (WRIB) stated that the new guidance “has already been positively received by the global bioanalytical community and only a few major topics were identified which required further discussion.” [2]  

Some recommendations may result in minor changes for certain types of validation tests and sample analysis procedures. Hence, it is important to work closely with a contract research organization (CRO) that is at the forefront of understanding and implementing these changes so you can continue to meet industry and regulatory standards without experiencing major disruptions in your projects.  

For example: [1] 

• In the 2018 FDA guidance [4], the lower limit of quantification (LLOQ), low-, mid-, and high-range quality control (QC) samples are recommended for accuracy and precision runs. ICH M10 specifies that for chromatography method validation, low-range QCs should fall within three times the LLOQ, mid-range QCs should be about 30 – 50% of the calibration curve range, and high-range QCs should be at least 75% of the upper limit of quantification (ULOQ). Ligand binding assays, on the other hand, require using the geometric mean of the calibration curve range for the mid-range QC sample. 
• ICH M10 stipulates that QC samples must always bracket study samples, whereas the previous FDA guidance did not contain this requirement. 
• Chromatography dilution QC samples need to be included during sample analysis. They must have a concentration that surpasses that of the diluted study samples. Alternatively, they need to have a higher concentration than the ULOQ. ICH M10 also states that if dilution QC samples for ligand binding assays have a concentration that exceeds the ULOQ, the concentration of the QC samples should be adjusted to represent the actual sample concentration range.  
• The former FDA guidance required incurred sample reanalysis (ISR) for bioequivalence or pivotal pharmacokinetic or pharmacodynamic studies. ICH M10 also requires ISR for bioavailability studies, first clinical trials, pivotal early patient trials, and first trials in patients with impaired renal or hepatic function. 

ICH M10 also includes slightly altered requirements for documentation and reporting. In some cases, additional data will need to be provided to regulatory agencies. For example, when performing comparative bioavailability and bioequivalence studies, the bioanalytical report needs to provide internal standard response plots from all runs. This also applies to failed runs. [1] 

Some additional updates in M10 relative to the 2018 FDA guidance:

• The 2018 guidance specifies fresh QCs for P&A while M10 doesn’t but rather specifies fresh calibrators
• M10 has a section on analytes that are also endogenous but biomarkers are out of scope while the 2018 guidance has a small section on biomarkers
• M10 has overall acceptance criteria across runs for sample analysis data, consistent with the EMA guidance but not previously an FDA requirement
• The 2018 guidance was not specific about evaluating hemolysis or lipidemia.  M10 has 1 lot of each in addition to the 6 selectivity lots.
• M10 has more detail on cross-validations
• M10 discusses dilution QCs in sample analysis including multiple dilutions in a run should have QCs at the highest and lowest dilutions

Other minor changes reflect current industry standards. For example, ICH M10 clarifies that the guideline was developed to support performing animal studies that follow the 3Rs — Reduce, Refine, and Replace. [1] 

Frontage has expertise in carrying out studies according to the most recent bioanalytical method validation guidance/guidances across global markets. Contact us to learn more about our state-of-the-art bioanalytical solutions and discover how we can help you become compliant with ICH M10. 

References

1. Bioanalytical Method Validation and Study Sample Analysis: M10. International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use. Adopted May 24, 2022. Accessed October 14, 2022. https://database.ich.org/sites/default/files/M10_Guideline_Step4_2022_0524.pdf  
2. 019 White Paper On Recent Issues in Bioanalysis: FDA BMV Guidance, ICH M10 BMV Guideline and Regulatory Inputs:  https://www.future-science.com/doi/pdf/10.4155/bio-2019-0270
3. GCC Consolidated Feedback to ICH on the 2019 ICH M10 Bioanalytical Method Validation Draft Guideline: https://www.future-science.com/doi/pdf/10.4155/bio-2019-0207 
4. Bioanalytical Method Validation: Guidance for Industry. U.S. Food and Drug Administration. Published May 2018. Accessed October 14, 2022. https://www.fda.gov/files/drugs/published/Bioanalytical-Method-Validation-Guidance-for-Industry.pdf 
5. Guideline on Bioanalytical Method Validation. European Medicines Agency. Published July 21, 2011. Accessed October 14, 2022. https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-bioanalytical-method-validation_en.pdf