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
In the desired future state for a QbD-approach based submission, the focus of the analytical-measurement portion of the submission
will be to demonstrate a thorough understanding of the requirements for measuring the drug substance/product and process CQAs
used to define the design space of the process and describe how this understanding is translated into an ATP. The commitment
the company makes will be to ensure that any method used to measure CQAs and quality assurance meets the registered ATP, but
there shall be no commitment to follow the detailed analytical methodology provided as an example.
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
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.
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
- 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).
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),