Analytical methods are at the core of demonstrating the quality of pharmaceutical products. When these methods fail to perform as expected, the quality of these products is called into question. Certainly, we expect to identify quality issues if they exist, but we want to avoid raising the alarm if the issue is only because the method is not performing as expected. Virtually every laboratory has experienced issues resulting from methods that were not sufficiently rugged or well designed, and we propose that these issues may be avoided by implementing a systematic process for method lifecycle that addresses many issues that can be anticipated. This approach is illustrated in Figure 1.
Building on the traditional processes of method development, method validation and method transfer, the lifecycle approach incorporates some additional elements including identification of an analytical target profile, use of quality-by-design elements to enhance method understanding, use of an expanded qualification process and introduction of a change control approach to continued method usage. This lifecycle approach can be broken down into three stages: method design, method qualification and continued method verification.
The first stage, method design, includes three components: the analytical target profile, method development and method understanding. The purpose of the analytical target profile (ATP) is to address the actual requirements of the method. These requirements and criteria are not necessarily the same as instrument capability; they should correlate to critical analytical performance characteristics and include meaningful acceptance criteria. They may include some or all of the characteristics described in ICH Q22 or USP General Chapter 3, as well as others that are important for the method or for the laboratory. The ATP attempts to address such questions as: What is the purpose of the method (e.g., to measure a major component, or stability-indicating)? What are the specificity requirements? What are the accuracy and precision requirements? What are the resource constraints (instrumentation, run time, reagents)? Are there other constraints such as extraction challenges or solution stability? An example of an ATP for a chromatographic stability-indicating method is shown in Figure 2. The second component is method development, for which most labs already have some excellent processes in place. We encourage their continued use, augmented with the guidance from the ATP. Once reasonable conditions for the method have been ascertained, and conformance to the ATP requirements has been established, it is time to enhance method understanding by incorporating some quality-by-design concepts. This includes exploring the method operating conditions and performing a risk assessment for the various method parameters. For chromatographic methods, this should address sample preparation as well as chromatographic conditions.
Practical Approach to Stage
Let’s discuss how this might be implemented. We’ll use a content uniformity chromatographic method for a solid oral dosage form (tablet) with two potencies as an example. In establishing the requirements, we consider the characteristics listed in USP General Chapter : accuracy and precision, linearity and range, specificity and limit of detection, and limit of quantitation. There may be other criteria that are important to the laboratory, for instance, the analysis must be able to be performed on equipment that is already in the laboratory, with a minimum time period for solution stability and a maximum run time. Previous experience with similar methods and familiarity with the laboratory data acceptance criteria are very helpful in establishing the acceptance criteria. Accuracy and precision are important characteristics for this method, and we want to set an acceptance criterion that limits the probability that we will generate an out-of-specification result if the tablet is within specification, or generate an acceptable result if the tablet is actually out of specification.
Based on previous experience, if we keep accuracy to a mean of +/- 2.0% and method precision to not more than 2.0 percent, we will accomplish this requirement. This also implies that injection must be tighter than method precision, for which a relative standard deviation (RSD) of not more than 1.0 percent should be acceptable. The range required for this method will be selected such that it will cover both potencies, without need for unnecessary second dilutions. Linearity requirements will be fairly standard, so the acceptance criterion for the correlation coefficient of the least squares regression analysis will be set to not less than 0.99, with an added requirement that the y-intercept of the regression line be not more than 4 percent (to avoid unacceptable bias).
Specificity requirements may be minimal, especially if drug substance impurities and drug product degradation products are controlled in separate methods. In this case, let’s assume there is a significant peak at the void volume, so a requirement will be established that the peak at the void volume and the peak of interest must be well resolved, that is, resolution factor (Rs) is not less than 2.0.
Since this method is not intended to address minor peaks, limit of detection and limit of quantitation are not critical quality attributes, and no requirements are set for this method. For the other requirements identified by this laboratory, the acceptance criteria might include HPLC with UV detector for the equipment; solution stability of at least 48 hours to allow the ability to rerun chromatography if necessary; and run time of not more than six minutes, which would allow sameday analysis and interpretation of results, when needed.
The second stage involves demonstration of the method qualification. First, we need to ensure that the facility, the instruments and the analysts are appropriately qualified. This is analogous to installation qualification for instruments. Next, we need to demonstrate that the method meets the requirements identified in the analytical target profile. This is similar to traditional method validation. Finally, at this point we apply the method to actual manufacturing samples in the facility where they will be produced using the analytical equipment and personnel that will be used to generate data. Once again, the qualification experiments may be dependent on the stage of development. Also, it is anticipated that existing knowledge and data will be utilized whenever feasible. These qualification experiments provide the framework for future method changes or transfers.
By including a step that ensures that the facility, instruments and analysts are qualified, we ensure that the laboratory is prepared to move forward with the method validation (and, yes, there have been instances where this basic step was skipped and methods have subsequently failed the validation experiments), and we establish the expectations for future laboratories that may need to run this method.
Before proceeding to the traditional experiments that evaluate the characteristics listed in USP , it is valuable to verify that the other requirements (instrumentation, solution stability, run time) established by the laboratory have been met. Since the performance of the method is already well understood (based on the activities in Stage 1), demonstration that the method meets the validation requirements should be straightforward, and for most methods a well-designed experiment can accomplish this in two or three days, based on the solution stability requirements.
Looking next at the real-life situation (actual manufacturing samples, facility, equipment and analysts) is a very valuable addition, challenging the method under realistic conditions of use before releasing it for routine purposes.
The third stage addresses continued method verification. This would include continued use in the original laboratory for an extended period of time, but may also involve method revisions, transfer to a different laboratory or method verification, in the case of a compendia procedure. As we approach any of these changes, is it appropriate to consider the method lifecycle approach and revisit the earlier stages? Are the requirements identified in the analytical target profile still applicable? Have laboratory investigations, out-of-specification results or changes in expectations indicated the need to revisit the requirements? Most quality control or stability laboratories use some form of control charting to watch for trends. Do the control charts identify a cause for concern? For any changes to the method, or Ready Qualify Launch Information Volume Product Data Lifecycle Design Discover Ideation Initiative Management Design BoM contains Material, Formula, Testing & Regulatory Design BOM Manufacturing BOM Materials Formula Testing Regulatory Global Specification Management (Product Data Record) changes to the laboratory in which the method will be executed, a change control approach is recommended. This includes identifying the nature of the change, the rationale for the change and then assessment of the potential impact of the change. Part of this process will examine the need for revalidation or partial revalidation. The data generated during the initial stages of the method lifecycle can be useful in evaluating whether the quality of the data that will be generated by the method following the changes will meet or exceed the quality prior to the changes.
Using the lifecycle approach described here has the potential to improve the quality of data generated in pharmaceutical laboratories, and to reduce the frequency of laboratory investigations or out-of-specification results. This approach builds on the method validation experiences of the last half-century but adds several steps with very high return on investment, based on some real-life experiences. Experienced laboratory managers will recognize that the additional steps make sense and do not add significantly to the resources required to bring a method to the point where it can be implemented. The benefits of this approach will be realized throughout the life of the method. USP has recently convened an Expert Panel to review and update its general chapters on validation, verification and transfer of procedures, and perhaps some of these concepts will be incorporated into the revised chapters.