The Role of Analytical Science in Implementing Quality by Design

The recognition that the current pharmaceutical industry's manufacturing performance was not as state of the art as other industries has been a key driver behind the increasing adoption of quality-by-design (QbD) concepts. The Gold Sheet from January 2009 compares the operations performance of the pharmaceutical industry with other industries such as automotive, aerospace, computer, and consumer packaged goods and across a long list of measures, the pharmaceutical industry compares poorly.

Industry efforts to address these performance issues have focused on Six Sigma/Operational Excellence concepts and, since the issue of new International Conference on Harmonization (ICH) guidelines (i.e., ICH Q8, 9, 10, and 11), on the concept of quality by design. These initiatives have significant implications for pharmaceutical analysts. The desire to improve first-pass yield with zero defects has seen laboratories come under great scrutiny to ensure that all the methods they run work right first time, every time. To reduce inventories and lead times to those typically achieved in other industries, manufacturing planners must know with absolute confidence how long manufacturing and testing will take; rerunning a problem method is no longer an acceptable option. Zero-defect goals have also seen a focus on understanding and improving process capability (i.e., reducing the overall process variation relative to specification), and therefore, there is a much greater focus on truly understanding the variation contribution of the analytical method to the overall process variation.

QbD concepts described in ICH Q8, 9, 10, and 11 provide approaches that can help achieve the desired improvement in process performance (1-4). ICH Q8(R2) and 11 recognize the importance of effective process development in understanding the relationship between process variables and process performance. ICH Q9 describes how risk-based approaches can be used to determine which variables are crucial to control. ICH Q10 highlights the importance of effective processes for maintaining the control strategy through the lifecycle of the product.

A major focus of discussion and implementation of QbD has been on the concepts included in the ICH Q8 definition (i.e., product and process understanding and process control). Understanding and control, however, cannot be achieved without a solid foundation of measurement or analytical science. During process development, analytical data are needed to provide the basis for process understanding. Control strategies based on this understanding are increasingly being developed based on recognition of the importance of identifying and controlling variation upstream rather than testing the end product. This control of variation has seen increasing use of process analytical testing (PAT) in preference to or in addition to end product testing, and with it, new technologies to be mastered by analytical scientists. QbD has also seen a focus on understanding and controlling attributes of excipients used in the manufacturing process, with increasing use of physical measurement technologies.

In addition to affecting what analytical scientists measure, the concepts of QbD, can also be used to enhance the robustness of the analytical methods themselves (5). One implication of such an approach is that it highlights the potential to re-examine the way that methods are developed and validated, in the same way that application of QbD to manufacturing processes has driven a revision in thinking of how process development and validation are performed (6, 7).

Taking advantage of the potential improvement opportunities through adoption of QbD concepts, however, does have some challenges. The ability to introduce improvements to analytical methods and to adopt new analytical technologies can be constrained, both through the need for industry to acquire new skill sets and through the challenges associated with making postapproval regulatory changes. These challenges are multiplied many times as a consequence of the global nature of the pharmaceutical business, with many stakeholders (e.g., regulators, pharmacopeias, consensus standards bodies) making harmonization of approaches particularly challenging.

What is measured

The introduction of QbD has challenged traditional thinking on pharmaceutical development and manufacturing. There has been a greater focus on developing science and risk-based control strategies based on product and process understanding over the more traditional approach of check-box compliance with reliance often on conventional end-product testing.

During process development, analysts are being challenged to provide more information on what process and material attributes are truly crucial to process performance. Greater emphasis on understanding the role the physical attributes of input materials play in the process has seen increasing adoption of advanced physical-properties measurement technologies. In-line measurement technologies coupled with multivariate statistical analysis techniques are being used to provide greater understanding of what is actually happening during each of the process steps.

Risk assessments of processes are increasingly being used to evaluate the need or value of a particular measurement within the control strategy to reduce the risk to product quality. A measurement, for example, may be applied to in-process quality control, or perhaps as an approach to improve detectability of a failure mode examined in a failure mode and effects analysis (FMEA).

The effectiveness of in-process control in assuring product quality has been recognized (8). A number of pharmaceutical companies have developed manufacturing processes where the controls are in process and a control strategy similar to Figure 1 is used.

Figure 1: Manufacturing process where the contols are in-process.

A PAT-enabled process allows increased sampling of the process material to be performed, thereby increasing the information about the process. The increased sampling can, however, increase the risk of failing a zero-tolerance specification found in a uniformity of dosage units test, for example. Pharmacopoeial authorities have recognized this disincentive to the adoption of large sample sizes and responded by proposing alternative approaches (9).

PAT-enabled processes may also present challenges to the traditional paradigm of batch release based on end-product testing and specifications. The PAT-enabled process may evaluate different attributes or end-points, use multivariate statistical analysis of process data, and also require an understanding of the distribution of data, all of which may affect the determination of appropriate acceptance criteria.

The implications of these changes include tools that support process understanding (e.g., granule porosity), new technologies and skill sets (e.g., near infrared, imaging, statistics), and new behaviors (e.g., risk assessment vs. check box compliance).

Application of QbD concepts to analytical methods

The concepts of QbD as articulated in ICH Q8, Q9, Q10, and Q11 are aimed at improving the robustness of pharmaceutical manufacturing processes and enabling continual improvement. They focus on taking a systematic structured approach to identifying process variables and how these variables relate to the desired process outputs and pharmaceutical products. Such enhanced understanding combined with application of formal risk-assessment processes are used to identify the critical attributes and parameters that should be controlled to assure product quality. Lifecycle knowledge and change-management processes then ensure that control strategies remain effective through the lifecycle. By considering an analytical method as simply a process, it is possible to apply these same concepts to provide enhanced confidence of the robustness of analytical methods. As mentioned above, this increased focus on robust methods is becoming an increasing area of concern for analytical scientists as non-robust methods undermine the ability to plan manufacturing and related quality assurance activities with confidence. Increased regulatory scrutiny on out-of-specification (OOS) investigations and effective root cause analysis of these is another key driver for ensuring method variables are well understood and controlled.

In 2010, the European Federation of Pharmaceutical Industries and Associations (EFPIA) and the Pharmaceutical Research and Manufacturers of America (PhRMA) jointly issued a white paper aimed at stimulating discussion between industry, regulators, and pharmacopeias on the potential benefits and implications of applying QbD concepts to analytical methods (5). A number of companies are now adopting this approach as they are seeing benefits in terms of increased method understanding, robustness, and ruggedness. During a Parenteral Drug Association (PDA) workshop, held Mar. 6–7, 2012 in Liverpool, UK, it was acknowledged that there are no regulatory barriers to adoption of a QbD approach for analytical method development and validation; however, it was also recognized that thinking may need to change about approaches to analytical method validation (10).

A lifecycle approach to method validation has been proposed (11) and indeed some of the concepts behind application of QbD to method development and validation have started to be promoted, particularly by the United States Pharmacopeia (USP) (12, 13) and through ASTM guidance on validation of PAT methods (14). Recently, USP has established an expert panel to explore whether the chapters on method validation, method verification, and transfer of analytical procedures may become amalgamated into a single chapter describing how methods are assured to be fit for purpose through their lifecycle. Sample replication levels, criteria for agreement between replicates, system performance requirements, repeat testing required for OOS and equivalence testing criteria should all ultimately be able to be linked back to an understanding of the methods performance and the targets for accuracy and precision that are required.

As noted above, a common understanding between pharmacopeias, regulatory agencies, consensus standards organizations, and industry on the description, application and interpretation of QbD concepts as applied to analytical methods is essential if they are to be more widely adopted. The PDA workshop recognized that alignment of understanding was key and that better clarity was desired on some of the terminology and concepts being used (e.g., method operable design region [MODR] vs. analytical design space [ADS], analytical target profile [ATP] vs. procedure performance acceptance criteria [PPACs]), and participants proposed the development of case studies to better illustrate the concepts. A key point that arose during the workshop that needs further discussion is whether a method is validated to meet a target performance (which is defined from the specification limits) or whether the specification limits are set based on the method capability.

Innovation and improvement

The ability to innovate and improve is crucial, not only to ensure the most up-to-date technologies are used to ensure patient safety, but also to improve efficiency and eliminate waste. There have been a number of recent examples of incidents where contamination of drugs has resulted in serious patient harm (e.g., heparin, melamine). These incidents have led to the development and introduction of modern analytical technologies (e.g., nuclear magnetic resonance [NMR]) to help mitigate risks of future occurrences. The pharmaceutical industry has not been quick to adopt new measurement technologies for a variety of reasons such as the significant costs, potential regulatory risk, and resources associated with changing the registered details globally. At the PDA workshop, an example was shown that illustrated the significant cost that a pharmaceutical manufacturer may be faced with attempting to introduce improvements to analytical methodology when products are registered in many global markets. Reducing the barriers to innovation and improvement through better regulation has been a focus of governments through programs such as the UKs Better Regulation of Medicines Initiative (BROMI) or the Executive Order 13563—Improving Regulation and Regulatory Review in the US.

There are examples from the pharmaceutical industry where flexibility to use any appropriate method is allowed (e.g., FDA's melamine guidance) (15) which states "alternative method or methods can also be qualified for use in screening components for the presence of melamine" and defines the performance required as, "The test method used should be suitable for detecting melamine contamination in at-risk components down to at least 2.5 parts per million (ppm)," or FDA'S Heparin Guidance (16) that again allows alternative methods to be used. Recent proposed changes to the FDA guidance on sterility testing are "intended to provide manufacturers of biological products greater flexibility and to encourage use of the most appropriate and state-of-the-art test methods for assuring the safety of biological products" (17).

The concepts of comparability protocols/postapproval change management protocols introduced in October 2012 in the US and in Europe may provide a mechanism of facilitating easier postapproval changes. Again, as previously stated, from an industry perspective it is crucial that there be alignment in thinking in this area.

Global alignment of stakeholders

As highlighted already, it is key for an industry that manufactures and markets globally to have a regulatory framework that also operates globally (aligned and harmonized). In the field of analytical science, the regulatory framework is defined by a number of stakeholders—the regulatory authorities, the pharmacopeias, and other standard setting bodies such as ISO and ASTM, which may be recognized by the regulatory authorities. With the changes associated with the introduction of QbD, it is important that the thinking and concepts are aligned across these different bodies. The development and publication of ICH Q8, 9, 10, and 11 have played a significant role in motivating alignment among the ICH regions; however, not all the thinking in this area is integrated. It is, however, recognized that the European Pharmacopoeia has already been offering flexibility including the use of alternative approaches for a number of years, which is expressed in particular in the Ph.Eur. (General Notices section 1.1). Moreover, the European Pharmacopoeia has been playing a leading role in developing thinking on the implications of large sample sizes (9). The USP has been promoting the concept of performance-based monographs and has issued examples of these in a new USP Medicines Compendium as well as a general chapter on how to define performance requirements for methods. USP has also recently established an expert panel that is looking to revise its guidance on method validation and verification. ASTM has been developing guidance on how PAT methods should be validated, while the EMA has issued new draft guidance on use of NIR (18). FDA is promoting thinking on the use of confidence intervals for batch release decisions with reference to ASTM guidance on this topic (19).

Ensuring global alignment is an extremely difficult goal; however, from an industry perspective it is the key barrier to innovation and effective implementation of QbD. To advance these concepts, more must be done in this area. It is encouraging to see that pharmacopoeia authorities have agreed to discuss global good pharmacopoeial practices under the auspices of the World Health Organization (WHO).

Target state

The ultimate goal of QbD has been summarized in a statement from Janet Woodcock, director of the Center for Drug Evaluation and Research (CDER) at FDA, who suggested during a ISPE and AAPS-sponsored CMC workshop on Oct. 5, 2005, that a mutual goal of industry, society, and regulators is "a maximally efficient, agile, flexible pharmaceutical manufacturing sector that reliably produces high-quality drug products without extensive regulatory oversight." To achieve this goal, it is crucial that we move from a checkbox, compliance-focused culture to one that is founded on a science- and risk-based approach to assure quality and compliance.

Acknowledgement

The authors would like to acknowledge the support of the Parental Drug Association and the assistance of Georg Roessling, senior vice-president PDA Europe; Susanne Keitel, director of European Directorate for the Quality of Medicines; and Jean Louis Robert, chair of the EMA Quality Working Party in helping organize and facilitate the workshop.

References

1. ICH, Q8 Pharmaceutical Development (R2) (August 2009).

2. ICH, Q9 Quality Risk Management (November 2005).

3. ICH, Q10 Pharmaceutical Quality System (June 2008).

4. ICH, Q11 Development and Manufacture of Drug Substances (May 2012).

5. M. Schweitzer et al., Pharm. Technol. 34 (2), 52–59 (2010).

6. FDA, Guidance for Industry, Process Validation: General Principles and Practices, Revision 1 (January 2011).

7. EMA, Note for Guidance on Process Validation (EMA/CHMP/CVMP/QWP/70278/2012-Rev1).

8. FDA, Guidance for Industry, PAT–A Framework for Innovative Pharmaceutical Development, Manufacturing and Quality Assurance (September 2004).

9. EU, Chapter 2.9.47, European Pharmacopeia (Apr. 2012).

10. PDA, Worskshop on Analytical Science and QBD, Mar. 6–7, 2012.

11. P. Nethercote et al., PharmaManufacturing 2010, www.pharmamanufacturing.com/articles/2010/060.html, accessed Feb. 4, 2012.

12. USP, Medicines Compendia, General Chapter <10> (July 2011).

13. USP, General Chapter <1033> Biological Assay Validation (2010).

14. E55.02 WK16888 A Risk Based Guidance for the Validation of PAT Methods – Draft

15. FDA, Guidance for Industry, Pharmaceutical Components at Risk for Melamine Contamination (Rockville, MD, August 2009).

16. FDA, Guidance for Industry, Heparin for Drug and Medical Device Use: Monitoring Crude, Heparin for Quality, Draft Guidance (Rockville, MD, February 2012).

17. 77 Federal Register 26162, pp. 26162 -26175.

18. Guideline on the use of Near Infrared Spectroscopy (NIRS) by the pharmaceutical industry and the data requirements for new submissions and variations EMEA/CHMP/CVMP/QWP/17760/2009 Rev 2.

19. ASTM E2709–Standard Practice for demonstrating ability to comply with an acceptance procedure.

PDA workshop on analytical science and QbD

The Parenteral Drug Association (PDA) organized a workshop, held on Mar. 6–7, 2012, aimed at identifying the role analytical science plays in supporting the implementation of quality-by-design (QbD) concepts and some of the challenges and opportunities QbD creates. The workshop provided a forum for regulated industry and key stakeholders from regulatory authorities (FDA, European Medicines Agency, and the UK's Medicines and Healthcare products Regulatory Agency) and pharmacopeias (European Pharmacopoeia, British Pharmacopoeia) to explore the implications of QbD on analytical science and to assess the future direction and implementation challenges. Diverse representation including analytical scientists and regulatory affairs staff involved in development and manufacturing engaged in an open exchange of ideas during the three topic breakout sessions and the plenary panel discussions conducted over two days. Challenges and issues were identified for topics covering:

1. How the critical product and process attributes that are measured change with a QbD approach
2. The implications of QbD on specification limits and sampling
3. How QbD concepts can be applied to analytical methods development and how this affects method validation approaches
4. How implementation of improved and innovative methodologies can be facilitated
5. The challenges of global alignment of standards.

The workshop participants suggested a number of potential actions that might help address these challenges including:

1. Agreeing on unique, unambiguous, and well-defined terminology
2. Reviewing existing International Conference on Harmonization (ICH) guidelines, and developing a white paper on proposed revisions and potential new guidelines, if any, that would support and enhance the role of analytical methods in QbD
3. Exploring, during the forthcoming revision to the EU variations guidance, how the Post-Approval Change Management Concept might be used to facilitate continuous improvement and innovation of analytical methodology
4. Establishing mechanisms to ensure global alignment of new pharmacopoeial\regulatory texts and guidance in this area (e.g., large sample size guidance and method validation)
5. Developing case studies and aligned terminology to ensure consistent understanding of how QbD can be applied to analytical methods and further explore how analytical target profile (ATP) can be presented in regulatory submissions
6. Holding further workshops in the US and in Asia focusing on case studies in order to support global alignment of concepts.

At the PDA workshop, Bernadette Doyle, vice-president, technical, GMS within GSK, presented an industry view on the ideal future state as:

1. Every test performed adds real value in assuring patient safety, product quality, and process robustness
2. Analytical processes (e.g., method development, validation, transfer, change management, issue resolution) are fit for purpose and underpinned by a science- and risk-based approach
3. Analytical methods are robust, continuously improved across the product lifecycle, and reflect best-in-class technology
4. Knowledge is maintained and refreshed to support future learning and analyst competency
5. Continuous improvement of analytical methods is not constrained by regulatory barriers
6. There are clear and appropriately harmonized standards (or mutual acceptance) of analytical measurement activities across all markets.

Phil Nethercote* is head of analytical and API analytical lead, GMS, at GSK. Graham Cook is senior director process knowledge/quality by design at Pfizer. Moheb Nasr is vice-president, CMC regulatory strategy at GSK. Siegfried Schmitt is senior consultant at PAREXEL. Lucinda Buhse is director of the division of pharmaceutical analysis at FDA.

*To whom all correspondence should be addressed.