Implications and benefits

From an industry perspective, development of analytical methodology aligned with an ATP approach will require changes, including the way enhanced knowledge and understanding of the methods and their linkage to CQAs and CMAs are captured. The ATP approach described above will also require adjustment to the manner in which analytical methods and their assessment are presented in regulatory filings.

Traditional views on analytical-method validation and analytical method transfer may also need to be adjusted or supplemented with more focus on variation management and continuous verification throughout the method life cycle. A summary of the key changes required to support a QbD approach to analytical- method development, evaluation and improvement is provided in Table I.

All analytical methods used will be available for regulatory review during preapproval and routine inspections. Indeed, inspectable documentation could include the detailed analytical-methodology design, evaluation, and control strategy as an example method that can be used to meet the ATP and the approach the company takes to demonstrate the suitability of the method. Further, the example method could be used by the authority's testing laboratories to confirm that a drug product meets a particular CQA, as specified in the regulatory submission, or to ensure authentication of a suspected counterfeit drug product.

As the ATP approach evolves, additional focus will be required to define the evaluation/assessment (validation) of the analytical methods developed. Many of the methods developed may be aligned with ICH Q2(R1). Other methods, however, may require new approaches to ensure suitability. In addition, as multiple methods (alternative methods) may be in use and may be available for regulatory authorities, tools to compare the performance of these alternative methods with others and ensure equivalency will need to be established.

The investments required are significant on the part of industry and regulatory agencies. However, the potential returns from adopting an analytical QbD paradigm, as described, are even more significant.

The current situation

The barriers to successful implementation of an analytical QbD approach are no different than those facing other QbD initiatives. The authors have discussed the need to shift the paradigm of regulatory submissions away from traditional information-rich documents, to scientifically-sound, knowledge-rich documents that clearly and concisely define the product and process design space as well as the CQAs of the drug product. Common terminology and concepts will need to be agreed upon and adopted on a global basis, and training and education of resources in industry and within regulatory agencies may be needed to ensure success. In addition, although the examples discussed in this paper have focused on methods for new products and processes, the concepts and benefits are equally applicable to existing marketed products.

The foundation to overcome these barriers has been established. Regulatory agency and industry representatives around the globe are currently engaged in productive dialogue regarding QbD approaches for pharmaceutical processes and products. In fact, external authorities in the industry are already considering evidence of QbD approaches applied to analytical methodology. See, for example, the 2008 Stimuli article from the USP Ad Hoc Advisory Panel on Inorganic Impurities and Heavy Metals and USP Staff on the proposal of a new USP General Chapter for the control of inorganic impurities in drug and dietary supplement articles intended for use in humans (2). In this proposed General Chapter, a performance-based approach has been introduced for selection of appropriate analytical technology that would essentially provide flexibility in choice of technology so long as the technique can meet the requisite accuracy (trueness and uncertainty) and established sensitivity and specificity.

It would, therefore, be short-sighted to overlook the opportunity to further expand the application of these concepts to analytical measurements and methods. There is too much to be gained from the application of these concepts for all parties involved—the patient, the pharmaceutical manufacturer, and the regulatory agency.

Next steps

As noted, this position paper is intended to act as a stimulus for further discussion and engagement regarding the application of the QbD concept to analytical methods. Several steps are proposed to support further clarification and adoption of these concepts. These include:

• Further clarifying the approach to defining an ATP for a method based on an understanding of the process- control strategy requirements
• Clarifying how a QbD approach to method development and evaluation should be described in a regulatory submission
• Understanding the implication of a QbD approach on current method validation and transfer guidance (e.g., ICH Q2).

References

1. P. Borman et al., Pharm. Technol., 31 (12), 142–152 (2007).

2. USP Ad Hoc Advisory Panel on Inorganic Impurities and Heavy Metals, Stimuli paper (2008), http://www.usp.org/pdf/EN/USPNF/2008-04-0InorganicImpuritiesStim.pdf.