Methods can be changed any time during and/or after product development. The change to faster, more sensitive, accurate, and/or reliable test methods is encouraged by the regulators. Besides providing sufficient qualification or validation results for the new method, method comparability results should also be provided. In some cases, product specifications may need to be re-evaluated and potentially adjusted to the established bias and/or increased sensitivity of the new method.
Regulatory expectations vary a little bit depending on product type and/or quality attribute tested. For example, for blood or blood plasma products, validation of potency and some safety test methods is expected much earlier (clinical Phase 1). For most other products, method validation is typically executed against the to-be-commercial specifications prior to process validation, which is typically initiated during the pivotal clinical phase. Method validation is usually completed one to two years prior to commercial license application(s), depending how much real-time stability data are desired following the process qualification runs (process validation stage 2).
Guo (FDU): The analytical methods need to be validated for any GMP activities. This is a GMP requirement as well as FDA expectation. The analytical methods should be properly validated even to support Phase I studies. Appropriate approaches should be considered to validate the analytical methods to support different clinical phases. The concept of ‘phase appropriate validation’ has been proposed and applied to method validation.
Regulatory Considerations
BioPharm: What regulatory parameters exist for analytical method development and validation for biopharmaceuticals?
Krause (MedImmune): A FDA draft guidance for development and validation was recently made available for public commenting (1). Biopharmaceuticals are in the scope of this draft guidance. A more comprehensive practical guidance, Technical Report 57, published by the Parenteral Drug Association (PDA) and specific for biopharmaceuticals, provides the best practical guidance currently available to industry and regulators (2). FDA used much of PDA TR 57’s content for their current draft guidance.
Guo (FDU): The International Conference on Harmonization (ICH) has a general guidance on method validation, ICH Q2(R1): Validation of Analytical Procedures: Text and Methodology (3). This is the guidance that the industry generally follows in performing analytical method validation. The ICH guidance, however, does not specifically address method validation for biopharmaceuticals. Interestingly, FDA issued a new draft guidance for industry on Analytical Procedures and Method Validation for Drugs and Biologics early this year (1). The new draft guidance supersedes the 2000 draft guidance for industry on Analytical Procedures and Methods Validation, and covers both small-molecule drugs and biologics. In comparison to the 2000 guidance, the new guidance specifically addresses analytical method development and suggests the parameters that should be evaluated during method development, including specificity, linearity, limits of detection (LOD) and quantitation limits (LOQ), range, accuracy, and precision. The robustness of methods is particularly discussed in the new draft guidance, and a systematic approach for method robustness study (e.g., design of experiments) should be adopted to ‘fully understand the effect of changes in method parameters on an analytical procedure’ (1). The new draft guidance refers to the ICH guidance Q2(R1) for more details on each method validation characteristics and also removes the recommended validation characteristics for various types of tests.
For the qualification of new reference standards, the new draft guidance recommends a two-tiered approach, which involves ‘a comparison of each new working reference standard with a primary reference standard so that it is linked to clinical trial material and the current manufacturing process’ (1). The new draft guidance does not address specific method validation recommendations for biological and immunochemical assays.
Quality by Design
BioPharm: How can method validation benefit from a QbD approach?
Krause (MedImmune): For a QbD approach for analytical methods, the analytical method lifecycle stages should consider the desired method performance at each product development stage. Starting with the appropriate, pre-established method performance expectations (Analytical Target Profile), the selection of the test methodology and instrumentation are the first step. Depending on the intended use of the method, typical performance criteria (accuracy, reliability, specificity, sensitivity, range, robustness/maintenance, as well as speed and throughput capacity, but possibly also costs and ease of operations) should be established early and re-evaluated as needed throughout product development.
The use of analytical platform technology (APT) methods can also greatly reduce the selection, development, and validation effort and lower the uncertainty/risk(s) for unsuitable method performance during product development. Since method performance criteria are well established, only product-specific suitability would need to be confirmed.
Guo (FDU): The QbD approach is more applied to method development than method validation since method validation is the process of demonstrating that a well-developed analytical method is suitable for its intended purpose. The QbD concept is often narrowly interpreted in literature for analytical method development, and the method robustness study is often used as an example of the application of the QbD approach. Well, the QbD approach is certainly applicable to the robustness studies and also consistent with the FDA expectation. The results of the robustness studies do not actually define the design space. A broader design space can be evaluated using the QbD approach during analytical method development. This would mean a significant more upfront effort in method development.
Krumenaker (West-Ward): QbD is not always employed in method development and validation because it is often considered to build time into the process. Often, labs are working under aggressive timelines to develop and validate methods. Using a pre-established set of parameters for method validation may be helpful in expediting the validation process, but it doesn’t necessarily provide relevant information about how the method will perform in ‘real world’ conditions. When QbD is utilized in the development stages, critical product attributes are identified. Why not utilize this information in regards to analytical methods? For small molecule products, light or humidity may affect the product, so there may be potential problems related to these conditions that could arise during testing. The same is true for biopharmaceuticals.