Validation failures, just like out-of-specification (OOS) results, occasionally occur when a firm performs risk-based validation. Practical guidance on how to handle these failures cannot be found in the existing literature because validation failures are not supposed to happen. In reality, however, they occur at somewhat predictable frequencies similar to the likelihood of obtaining OOS results whenever true risk-based validations are performed. This article follows-up from previous publications regarding this controversial topic.^1,2 It openly discusses the recovery process options for failed validations to stimulate the development of regulatory guidance. Although applicable to all validation projects, this issue is limited to analytical method validation (AMV) failures, and discussed with respect to the recently published guidance documents (CDER/FDA guidance, Investigating OOS Test Results for Pharmaceutical Production, and ICH Q10, Pharmaceutical Quality System).

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Challenging our systems by setting tighter acceptance criteria whenever needed is an important part of risk-based validation. In today's fast-paced and project-completion driven biopharmaceutical industry, failures are sometimes necessary to trigger much-needed process optimizations. Without intending to conceptually change the objectives of validation studies, this article provides practical guidance on how to handle occasional failures in a GMP environment. The setting of acceptable limits based on risks to patient and firm for all analytical method life cycle steps that include test method selection, development, optimization, validation, transfers, maintenance and retirement/replacement has been extensively discussed elsewhere.¹

Before we can clarify how to handle AMV failures, we should first define them in the context and intent of this article. A validation failure differs from a validation discrepancy as it results from failing to pass acceptance criteria (or preset test method performance specifications). This is more difficult to deal with than protocol discrepancies when we simply did not follow our approved protocol instructions.^1,2

Strictly speaking, failing to pass our protocol limits indicates that the to-be-validated test method is not suitable for its intended use. However, we cannot usually abandon the project and simply move on to another. Because the description of particular AMV failures may not be part of regulatory pre- or post-licensure submission, AMV failures can become a significant inspection risk to the firm. Similar to the handling of OOS results and unacceptable levels of discrepancies, the focus in regulatory inspections on how validation failures are managed may quickly shift towards the firm's quality systems if apparent deficiencies or violations exist.¹ Because of the similarity to the OOS investigation process, the principles applied here are similar to those discussed in the recently published CDER/FDA guidance for OOS results.³ The recently published ICH Q10 guidance addresses management's responsibilities in facilitating continuous improvements.⁴ Both documents support the need for 'open' recovery processes for failures, but they lack sufficient practical guidance.

The 'recovery mission'

AMV protocols for a critical test method can contain many acceptance criteria and often several ones for each validation characteristic. There is a predictable chance of not passing acceptance criteria especially when sample manipulations, such as spiking, are performed or if interfering matrix components exist. If everything passes acceptance criteria, we would likely consider the project completed and hold back on implementing immediate optimizations. To stay within the focus of this article, let us assume that we failed protocol acceptance criteria and that we must now deal with this situation.

Figure 1

Figure 1 illustrates the management of an AMV failure and its recovery process. The failure to pass our protocol acceptance criteria is highlighted in grey to visually represent the fact that we have entered the 'grey zone' where processes may no longer be governed by detailed procedures. It is now critical for future inspections, as well as project completion, to make good decisions. Once a validation failure is observed, it should be noted in a formal investigation report. To make decisions that keep in mind the interest of all stakeholders — especially the patient — we should now answer the questions in Table 1. The answers should lead us to the best possible course of action. However, the remedy may involve accepting some level of project completion risk (upper half of Figure 1) or inspection risk (lower part of Figure 1).