Over the past two decades there has been significant development in the analytical techniques used in the testing of biological products. The revisions to the ICH Q2(R2) and ICH Q14, therefore, bring timely guidance to these matured techniques i, ii.
Although the requirements for analytical development following a standard approach are well described, the guidance is also flexible and allows deviation from the standard methodology as long as it is justified.
In this blog, I will share some key highlights from the new guidance, drawing on my industry experience.
Addressing uncertainty
The guidance does help to clarify analytical methods that can best support the development of biological medicines, in particular at key phases where uncertainty or deviation from the standard approach can potentially lead to delays or significant cost and effort to a drug developer.
One of the key phases in the analytical development lifecycle is in toxicology studies for investigational new drug (IND) applications. Material and data generated here will be used to evaluate your process performance at the next key milestone and so, while you need suitable analytics to satisfy the regulators, future comparability and process development will be significantly hampered if these methods are fundamentally not suitable for later phase validation. Simple and forward-thinking choices include selection of analytical techniques and instrumentation that are mature and commonly used for GMP release, and avoiding the use of cutting-edge technologies that may change through the development lifecycle of the product or have potential limits with availability.
The second major phase is Phase III and biologics license application (BLA), where the assays that often cause the most difficulty and risk are potency assays and product impurity assays where the impurities are not fully characterized. ICH Q2 now discusses the analytical development lifecycle with a focus on the validation protocol and report and the relation this has with the guidance provided in ICHQ14 where assay development and lifecycle methodologies are discussed.
The guidance does provide clarity in areas of ambiguity from regulatory authorities. For example, with cell and gene therapies, recent Q&A sessions with the US Food and Drug Administration have suggested robustness testing should be performed during validation iii. However, the ICH guidance notes that robustness testing in a validation protocol can be risky unless you are certain that it will meet the pre-defined criteria. If you already know for certain that the method will meet robustness criteria, that probably means that you have already tested this attribute. Therefore, the more conservative approach is to keep this information as a part of analytical development ready to be provided rather than to include the robustness testing in the validation protocol.
A clear benefit of the new ICH Q2 guidance is provided in the illustrative examples of analytical techniques in Annex 2. Examples include techniques where the description in the previous guidance required interpretation and some subjective decision-making in defining assay performance characteristics.
The main difference between the new guidance and the previous ICH Q2 guidance is the level of detail provided, the inclusion of specific examples for techniques such as mass spectrometry and qPCR, and the discussion of platform analytical procedures that are already a significant benefit for monoclonal antibody, RNA and LNP technologies.
Given that examples are provided, and the expected components of the analytical validation are more clearly laid out, deviation from these would not be advised without clear scientific and risk-based justification.
ICH Q14 updates
ICH Q14 is a more recent inclusion in the ICH guidance and provides clear methodological tools for assay development that can help to structure your analytical development process using a science and risk-based approach familiar to process developers.
This provides clear definition of aims, scope and utilization risk assessment to focus development and document performance, supporting development of your clinical, manufacturing and analytical processes and assays in a phase appropriate manner. The methodology allows clear description and evaluation of the development process, which can help regulators understand all aspects of the development process and quality of your processes. This can save additional work, characterization or potential development holds, which can add to be the time and cost involved in the development process.
ICH Q14 describes a minimal versus an enhanced approach to analytical development. With the minimal approach, where product characteristics are identified, an analytical technology is selected and evaluated with a focus on specificity, accuracy, precision and later robustness.
The enhanced approach structures and documents these same tasks in a manner that aids the development lifecycle. This makes proper use of formal risk assessments, definition of the analytical target range, uni- or multivariate experiments and the formal definition of the analytical strategy including proven acceptable ranges.
The enhanced approach provides a better documented and more organized understanding of analytical parameters and performance aiding the qualification and validation. It also reduces risk of further analytical development throughout the product development lifecycle and provides structure to support analytical comparability.
The extended approach has significant benefit when used from early phases in several cases. For example, product and analytical techniques may not be fully understood in early phases but information from these early phase analytics may be pivotal in support of future analytical changes and in support of scale-up and later process development. As a medicine is developed, the in-process testing and release specifications inevitably develop alongside process understanding, and so a more complete understanding of analytical characteristics can help provide certainty around the impacts of process changes on product safety and efficacy.
While the draft of Q14 has been available since 2022, the update contains some minor differences. For example, the definition of the minimum elements of analytical development has had a minor adjustment to remove ambiguity.
There is specific mention of stability of sample preparation and reagents in this version of the guidance. The addition of an example assay transfer with no assay change has also now been included in ICHQ14.
A framework for analytical procedures
Both guidelines now include validation principles for advanced analytical procedures such as mass spectrometry and spectroscopic techniques like near-infrared and Raman. The new guidelines provide a framework for the development of analytical procedures, emphasizing a science- and risk-based approach.
The life cycle management concept has been introduced to ensure continuous improvement and adaptability to technological change in line with the methodologies used in process development. These guidelines are designed to support the availability, safety, and efficacy of every dose of medication.
About the author:
Christopher Rogers is a senior manager, regulatory affairs, within the CMC biologics regulatory team at PharmaLex.
Notes
i ICH Q2(R2) Guideline on validation of analytical procedures. chrome-extension://efaidnbmnnnibpcajpcglclefindmkaj/https://www.ema.europa.eu/en/documents/scientific-guideline/ich-q2r2-guideline-validation-analytical-procedures-step-5-revision-1_en.pdf
ii ICH Q14 Analytical procedure development – Scientific guideline. chrome-extension://efaidnbmnnnibpcajpcglclefindmkaj/https://www.ema.europa.eu/en/documents/scientific-guideline/ich-q14-guideline-analytical-procedure-development-step-5_en.pdf
iii OTP Events, Meetings, and Workshops, FDA. https://www.fda.gov/news-events/otp-events-meetings-and-workshops
