More companies in the pharmaceutical industry today are adopting the principles of Quality by Design (QbD) for pharmaceutical development and manufacturing. Described in ICH Q8, Q9 and Q10 guidance documents, QbD enables enhanced process understanding, and a more systematic and scientific approach to development, so that better controls may be implemented. The end goal is more robust manufacturing processes than those that typically result from traditional approaches to drug development.

The QbD framework has many implications for manufacturers and regulators alike. This article describes how analytical methods can be viewed as "processes" and QbD concepts applied, to improve both method validation and transfer. Its goal is to stimulate thinking and discussion on how analytical method validation and transfer could evolve as industry increasingly adopts Quality by Design concepts.

But QbD cannot be considered without examining validation within a product lifecycle framework. The U.S. Food and Drug Administration (FDA) attempted to do just that in a recent draft guidance [1] designed to help achieve the goals of its “Pharmaceutical GMP's for the 21st Century – A Risk Based Approach” [2].

This guidance addresses some of the problems with traditional approaches to process validation, which were articulated by Moheb Nasr nearly five years ago [3]. Too narrow a focus on a "three-batch" approach to validation has encouraged a "don't rock the boat" mindset within the industry that can fail to foster continuous improvements in quality or efficiency.

The Need for Real World Verification

The same problems can be seen in analytical method validation and transfer, where the focus often shifts from ensuring the robustness of the method itself to ensuring the robustness of the documentation, and how well it will withstand regulatory scrutiny.

Methods for pharmaceutical products are normally validated by experts who have developed the method in accordance with ICHQ2 guidance (Validation of Analytical Procedures: Text and Methodology) or USP <1225> (Validation of Compendial Procedures). However, validation can be treated as a one-off event, with little consideration given to verifying how well the method will perform at everyday, "real world" operating conditions. All too often, regulators and industry use ICH Q2 or USP <1225> in a “check box” manner without considering the intent of these guidances, or the philosophy of method validation.

These issues continue after the method has been validated, when it is transferred to another laboratory. This transfer step requires that the knowledge of how to operate the method be transferred to those who will use it routinely, and that an exercise be performed, documenting that similar results have been obtained by both parties.

The transfer exercise is usually performed by the most competent analytical staff in the receiving laboratory, yet it may have little relationship with how the method will be used in routine, day to day operations.

It may come as little surprise, then, that most methods fail to perform as intended in the receiving laboratory, triggering efforts to identify variables that are causing the discrepancies, and repeated, costly testing and documentation.

The roots of method transfer failures can usually be traced to insufficient consideration of the routine operating environment during the method validation exercise, and lack of an effective process for capturing and transferring the tacit knowledge of the development analysts.

A QbD Framework for Analytical Method Life Cycle Management

If an analytical method is viewed, simply, as a process, whose output is data of acceptable quality, QbD concepts designed for manufacturing processes can be applied to analytical methods [4]. Thus, the concepts of lifecycle validation that are being developed for manufacturing processes might also be applied to analytical methods. 

QbD is defined as “a systematic approach to development that begins with predefined objectives and emphasizes product and process understanding based on sound science and quality risk management” [5] and FDA [2] has proposed a definition for process validation that is “the collection and evaluation of data, from the process design stage throughout production, which establishes scientific evidence that a process is capable of consistently delivering quality products.”

When considering a lifecycle approach to method validation, a similar definition could be adopted “The collection and evaluation of data and knowledge from the method design stage throughout its lifecycle of use which establishes scientific evidence that a method is capable of consistently delivering quality data.”
 
From these definitions, it can be seen that there a number of key factors that are important in a QbD\Lifecycle approach. These include:

• The importance of having predefined objectives
• The need to understand the method, or being able to explain the method performance as a function of the method input variables
• The need to ensure that controls on method inputs are designed such that the method will deliver quality data consistently in all the intended environments in which it is used
• The need to evaluate method performance from the method design stage throughout its lifecycle of use.

In alignment with the approach proposed in the draft FDA guidance for process validation, a three-stage approach could be taken with method validation. (See chart.)
Stage 1 – Method Design: Define method requirements and conditions and identify critical controls