We previously described the ICH Q14 draft guidance, an entirely new policy document that is still in consultation in the U.S., although the consultation period in other nations has already closed. The Q2 series of guidances address the ongoing need to validate the methods used to ensure drug product purity and quality, a process that that may need to be repeated when the drug product is modified or when manufacturing is outsourced.
The preceding version of the Q2 guidance, now known as Q2(R1), was released in 2005, but the bulk of the content of Q2(R1) was already in place in 1996. That elapsed time shows up in this latest draft version, Q2(R2), which expands significantly on the description of validation methods, and which provides an entirely new section on the use of multivariate analytical procedures.
The scope of Q2(R2) includes new or revised analytical procedures used for stability testing and to justify product release, for both chemical and biological/biotechnical drug substances and products. It should be pointed out that the Q14 framework interacts with the Q2(R2) guidance, given that the design of the validation protocol per Q2(R2) is informed by the Q14 requirement that the manufacturer identify the objectives and performance characteristics of the analytical procedure (AP).
Q14 also requires that the manufacturer conduct a risk assessment for these APs prior to validation, another source of interaction between the two documents. Once the validation is complete, the elements of Q2(R2) feed back into Q14 via the role of the AP validation report in lifecycle management requirements under Q14.
Definitions Provide Links between Q2(R2) and Q14
The glossaries in Q2(R1) and Q2(R2) overlap somewhat, but the later version adds a number of definitions, including those for both AP control strategy and validation strategy. Among the other definitions that are new under Q2(R2) are:
- Analytical procedure attribute, defined as technology-specific properties that ensure the desired result is achieved;
- Intermediate precision, a description of the impact of variations in a given lab, such as the effects of varying environmental conditions; and
- Method-operable design region (MODR), which describes the AP procedure parameter ranges within which procedure performance criteria are satisfied without compromising the quality of the results.
It may be prudent to take special note of some of these definitions as they may incorporate some features of Q14, such as the mention of system suitability tests (SSTs). The Q2(R2) draft states that data drawn from an SST can be applied toward validation, but also toward any experiments conducted to account for changes to the parameters for proven acceptable ranges and MODRs.
The Q2(R2) draft states that any changes to an AP’s use may require only partial revalidation, but this section leaves the manufacturer with some leeway to make that determination, depending on whether the performance characteristics of the AP are significantly affected. There are several options available to the manufacturer, such as, co-validation, which would require only a subset of validation activities when transferring an analytical procedure to a different laboratory. Another option, cross-validation, can be used to demonstrate that two or more APs can be used for a given intended purpose, but the manufacturer must be able to provide data demonstrating that each AP meets the same performance criteria.
The section on multivariate analytical procedures does not specify the circumstances in which univariate procedures would be deemed insufficient to manage a continuous pharmaceutical manufacturing process. In any event, the manufacturer can use a single data set for both calibration and internal testing, although the test data subset in that scenario should be used in a rotational manner. However, the manufacturer will have to obtain an independent data set for validation, regardless of whether the calibration and testing processes relied on distinct versus overlapping data sets.
The manufacturer can make use of a reference analytical procedure to aid in the validation of a multivariate analytical procedure, but the draft recommends the use of the same samples for both when possible. This should be done within a time frame that avoids problems with the drug substance’s stability profile.
Q2(R2) Dramatically Expands Discussion of Validation
As might be expected, the section on validation takes up the majority of the Q2(R2) content and is much more detailed than in Q2(R1). This section starts with a discussion of the specificity/selectivity of the AP, and allows for the use of an orthogonal procedure to validate an AP. An experimental study may not be required for the AP if the technology used is accompanied by data that ensures that the technology’s technical parameters offer adequate assurance of the specificity of that technology. Other key elements of this portion of the draft include:
- The working range of the AP, which depends in part on whether a linear relationship between the analyte concentration and the procedure’s response is discernible;
- Accuracy and precision, which may be determined jointly when combined performance criteria are available; and
- Robustness, which should be demonstrated with deliberate variations in AP parameters.
The FDA’s docket for the Q2(R2) guidance is largely unpopulated as of the date of this blog, but some of the feedback from European Union (EU) stakeholders suggests that the final version will be modified somewhat. Among the criticisms arising from the EU is that this guidance lacks some critical specifics for radio-pharmaceuticals, and that there is insufficient clarity about the links between Q2(R2) and Q14. There is also some concern that much of the terminology seems directed toward chemical compound-based pharmaceuticals to the neglect of biopharmaceuticals. We will update our readers on the final versions of both these guidances when they become available.
