ICH M10 Bioanalytical Method Validation Guideline – What the New Draft Means for Bioanalysis

The International Council of Harmonisation (ICH) has released a draft new guidance for bioanalytical method validation, and it has created quite a buzz, exemplified in a webinar hosted by Bioanalysis Zone.

A panel of experts came together to discuss the guidance set by the regulators, what it means for scientists and how it will change lab practices, interpreting the finer points set out, and how it differs from equivalent guidelines, such as the FDA’s guidance released late last year.

Of the 5 industry experts taking part in the webinar, four were representing contract research organizations (CROs) and one was from pharma giant Janssen, all high-level scientists within their organizations and eager to comment on the new guidance. Here’s what they had to say.

On interpreting the guidance

The webinar kicked off with an overview of the guidance’s legibility. Is it easy to understand? Does it make sense? Are there any points that are challenging to understand or interpret?

Turns out, the ICH M10 guidelines fare better than its predecessors: all the experts agreed that the document has less controversy than previous versions. But, like any guidance being examined and torn apart by specialists in the field, it isn’t perfect.

Dilution linearity

Among the points brought up, dilution linearity was probably of the most concern. The guidance recommends scientists at the bench do three independent runs and then the sample analysis. On top of adding to the overall project operating costs, this change absorbs more of a scientist’s day. What is the regulator’s rational behind this recommendation?

The panelists voice where they stand, which is particularly apparent when the subject of dilution factors comes up. 1 in 10 or 1 in 20 dilution is uncommon for many labs, but this is not the case for Bioanalysis QPS, where dilution factors  is already standard practice. This dissimilarity between standards in operating companies, whether CRO or sponsor, highlights that even though these 5 panelists all represent companies conducting bioanalysis, there can still be a large gap in what labs need and the regulations they implement.

Mid-QCs and LBAs

Typically, scientists look at low QC levels and high QC levels, but not the mid-QCs. But the ICH recommends looking at mid-QC levels for chromatographic assays between 30%-50%, while looking at the geometric mean for ligand binding assays. Does it make sense to apply both arithmetic and geometric means for small molecule and LBA? The experts admit geometric means makes sense if you have a multi-parameter curve.

While scientists asked for more prescriptive guidelines, they are not sure about seeing mid-QCs between 30% and 50% for LBA assays, not without good scientific rationale.

If this is put into practice, where does one draw the line? The panelists stress that these assays should be similar, and so regulators should offer some clarity. Regulatory bodies have said scientists should add as many QCs as required especially when it comes to bioequivalence, without the need for validation. It’s down to good scientific judgement, looking at the data and seeing what makes sense for your samples, what works.

Differentiation between a batch and a run

Every company has their own definitions of a batch, run, and acceptance criteria, depending on their procedures and workflows. It depends on the assay, and how many runs you need to get that quantifiable data point. So, when the ICH guidance uses these terms interchangeably in several places throughout the document, this creates confusion. Each company should define what a run versus a batch means for each assay (or platform type) followed by clearly stating the acceptance criteria that will be applied. Then the opportunity for misinterpretation is eliminated.

Assessing multiple samples

Some companies, including Bioanalysis QPS, have already implemented this suggestion, before it appeared in the new ICH M10 draft. More samples in separate tubes gives a higher chance of accurate results, and so a better chance of seeing technical variations and observing differences, say, if each tube is stored differently.

Logistically, creating so many samples is labor-intensive, but practical.

On their overall impressions of the guidance

When it comes to the general impressions on the quality of the guidance and implementing it in daily lab life, the team of experts were mostly positive: the guidance is more prescriptive, detailed and specific, not leaving much room for misinterpretation in its 60-pages of content.

It’s well-written and structured; the scope is defined early on. The scope excludes biomarkers, a point that was a ‘slippery slope’ with the FDA guidance.

On recommendations of standardized reports

Reporting is a much-talked about issue in the R&D space, and the ICH might not be up to speed on the challenges involved.

The guidance recommends standardizing the reporting format. In theory, this has its advantages, as any person looking at the report will immediately understand what they’re reading. But the experts all agree that this is not something ever likely to happen.

From a CRO perspective, this is unfeasible, as each sponsor wants the report in their own format so that it is easier consumed at that organization. And if hundreds of sponsors were to sit down to decide what should be in a standardized format, they’d be debating it for months. Considering each organization requires something else, reaching a decision would be extremely difficult. And across industries, it’s definitely not an option.

What, then, is the solution?

According to the panelists, software is the best solution. Sponsors and CROs alike should tell scientific software providers what they need – a platform that will take experimental tables, data, and results and collate it into a standardized report, with just the click of a button. While it would take time and effort to create a template, it would increase efficiency, reduce costs, and trim timelines.

However, one of the experts pinpointed a flaw in this solution: CROs usually ask sponsors what they want to include in the report, but a standardized report format could limit this list.

And from a CRO’s standpoint, the report is the only product they give the sponsor. A standardized report format means there would be no way to stand out from their competition, potentially hurting business and brand image.

Reporting is vital to the industry, and solutions are a hot topic. Harmonizing the summary is a growing trend – making it easy to read and adding links to jump to relevant sections of the report. Then CROs can add distinguishing features and stamp on their brand throughout the rest of the document.

On implementing the guidelines

The FDA’s guidance has been out for some time (since late 2018), and yet companies are still working on updating their SOPs. How long will it be before the ICH M10 guidelines are implemented? Both sponsors and CROs will look at the guidance and see how their SOPs align now and what they must do to incorporate the guidelines and reach the level of the FDA and/or ICH.

A single guidance would be great, but each country has their own laws and regulations, making it difficult and time-consuming for a company operating on a global level. While the EMA built upon the FDA guidance, the ICH bears differences in how it is executed, so they can’t be rolled together to make a single set of SOPs.

However, as one of the experts pointed out, this is a draft document, and things can change before the official version is released in late 2020. As long as labs follow guidelines that are scientifically sound, when the work comes under regulatory scrutiny, scientists can justify their decisions.

Looking for such a solution? Our Bioanalysis Solution ticks all the boxes, helping collate experimental information and make reporting easy – find out more about it here.

You can read the full ICH M10 Guidance here.