Applying a Lifecycle Approach to Your Analytical Procedures and Method Validation Programs

Regulatory expectations and requirements continue to evolve to ensure the quality and safety of drug products. Over the last five years, we have seen increased focus during regulatory inspections relating to:

• Custom instrument qualification based on specific user requirements.
• Software qualification, configuration and subsequent validation.
• Implementation of data governance policies and data integrity controls for all software platforms being used in a generic good practice (GxP) capacity.

Instrument qualification, software validation and data governance all contribute to protecting the quality and integrity of a laboratory’s electronic data, ultimately used to make quality-based decisions to determine whether a drug passes or fails the release specification. Many regulated laboratories have already implemented robust controls in all of these areas, minimizing their compliance risk.

Regulatory trends relating to analytical procedures

Every year the United States (US) Food and Drug Administration (FDA) publishes its inspection observation data. This valuable source of information provides a summary of the most common areas of non-compliance cited during regulatory inspections. The number of citations related to analytical procedures almost doubled from 40 in 2021 to 78 in 2022. This trend data signposts that analytical procedures are a focus area for the US FDA and other regulatory agencies.

Problematic methods

There are many analytical procedures used in regulated laboratories for GxP product testing that, while validated, are “problematic” during routine use.

Examples of problematic analytical procedures include:

• Variable chromatography – within the same analytical run, between different days or between different instruments.
• System suitability testing (SST) failures – it takes multiple attempts to pass SST requirements before samples can be tested.
• Duplication problems – requires additional time to raise deviation or out of specification (OOS) documentation, investigate and retest.

Regulatory guidance changes

Consequently, regulatory guidance and expectations regarding analytical procedure development and validation are in the process of changing to incorporate a lifecycle approach. The following documents were updated in 2022:

• ICH Q2 (R2) Draft – Validation of Analytical Procedures (24^th March 2022).
• ICH Q14 Draft – Analytical Procedure Development (24^th March 2022).
• USP <1220> Official - Analytical Procedure Life cycle (1^st May 2022).

These guidance documents are aligned in terms of their content and highlight the need to apply a lifecycle approach to analytical procedure development and validation, incorporating a risk-based approach and validation based on intended use. This new method essentially applies the principles of quality by design (QbD) to the analytical environment and has created the new term analytical quality by design (AQbD).

How to incorporate a lifecycle approach

The new guidance makes sense to me. The documents state that validation is required at earlier phases of analytical procedure development, and different approaches to validation can be used across the development life cycle as the analytical procedure evolves. This means that as an analytical procedure and its intended uses evolves, we will gain a better understanding of the drug product it is being used to test during the development life cycle.

Below is an example of how an analytical procedure can evolve across the drug development life cycle:

• Discovery and Phase I – The analytical procedure will be very simple at this point as we have limited knowledge of the drug product in terms of the manufacturing process, the impurity profile and don’t have characterized reference materials available. The analytical procedure may be limited to a basic chemical purity test in this early phase of development.
  
  
• Phase II – The analytical procedure may develop at this stage as we gain a better understanding of the drug product and impurity profile. For example, using a different column technology or gradient profile may provide better peak shape and separation of the known impurities. Characterized reference materials for the drug product and possibly known impurities should be available to provide more accurate quantitation. The analytical procedure has evolved from a very basic procedure to a more advanced and specific procedure.
  
  
• Phase III – The analytical procedure may change again during this final phase of development as we look to optimize the method in preparation for process validation and long-term commercial use. An example of procedure optimization would be changing the sample concentration to improve the detection (DL) and quantitation limits (QL). Characterized reference materials should now be available for the drug product and all known impurities to enable further changes in quantitation to provide more accurate data.

In the past, our GxP requirements would start to come into play during Phase III development as we start to think about process and analytical procedure validation in preparation for Phase III clinical trials and commercial supply.

Latest guidance, using risk-based thinking, QbD and AQbD, has resulted in GxP conditions being required in earlier phases of development in order to have confidence in the data and decisions that are being made.

Implementing a risk-based life cycle

The first draft of ICH Q2 (R2) – Validation of Analytical Procedures (March 2022) is a complete revision of the previous document (ICH Q2 R1) that became official in 1995. ICH validation guidance has not changed in the last 28 years, so it will not come as a surprise that the draft of ICH Q2 (R2) is radically different from the 1995 revision.

ICH Q2 (R2) states that a risk-based approach should be used, and validation should be performed based on intended use. Using a risk-based approach means that different validation strategies can be implemented at different phases of the development life cycle to demonstrate the analytical procedure is suitable for intended use at a specific point in time. This is a very different approach to the analytical procedure validation that we have used in the past.

A number of regulated laboratories are updating their standard operating procedures (SOP’s) for analytical procedure validation to incorporate a validation framework to cover all phases of the development life cycle.

Performing a reduced validation exercise at earlier phases in the development life cycle gives your laboratory confidence that your analytical procedure is providing meaningful data and helps defend the validity of data during regulatory inspection.

Here is an example of an analytical procedure validation framework (also see Table 1):

• Phase I – Limited reference materials available. Focus on validation parameters that only require the drug product.
• Phase II – Additional reference materials available allowing additional capability to assess validation parameters on both drug product and known impurities.
• Phase III –If the analytical procedure has significantly changed between Phase II and III then the safest option would be to perform a complete validation.

Table 1: An example of the different activities that take place within the various phases of the validation framework. 

Ever-evolving development life cycles

As your analytical procedures develop and evolve over the development life cycle, make sure that you perform elements of validation to provide evidence that your analytical procedure is suitable for its intended use. But it doesn’t stop there! As new technologies become available, you have the option to develop or optimize your analytical procedure further to improve the quality of the data and associated results.

Regulatory authorities and inspectors may consider an analytical procedure that has not changed in the past 5 – 10 years to be a red flag and may want to understand how robust the analytical procedure is on a daily basis. However, they will welcome continuous improvement provided that you have documented evidence of how the analytical procedure has evolved to improve the quality of data and results.

Regulatory guidance relating to analytical procedures is in the process of changing to a lifecycle approach to ensure that procedures are suitable for intended use across all phases of the development life cycle. I recommend assessing what validation activities can be performed across all phases of the development life cycle with the materials and knowledge available at that time. I would also recommend that regulated laboratories perform periodic risk assessments for all their analytical procedures used for product testing, to determine whether they are performing as expected and delivering the best quality results for your products. Doing this will give confidence that the method is suitable for its intended use, and also identify any problem methods that need redevelopment or optimization before the next regulatory inspection, helping to minimize future inspection risk.

About the author

Garry Wright is the European laboratory compliance specialist for Agilent Technologies and a member of the Agilent Compliance Council. Garry worked in the regulated pharmaceutical industry for 20 years prior to joining Agilent. His industrial experience focused on development and implementation of quality management systems, good manufacturing practice (GMP) training and compliance auditing. Garry’s role within Agilent is to provide compliance consulting services to Agilent and our customer network. Since joining Agilent, he has regularly presented on topics relating to regulatory compliance, data integrity and instrument qualification at compliance forums.