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The lifecycle of analytical procedures, also known as analytical methods, for pharmaceutical development and manufacture depends on the reliability, robustness, and accuracy of analytical measurements. Regulators have focused on an enhanced approach to method development in recent years to ensure they meet quality and risk parameters while also facilitating critical decision-making. Analytical method lifecycle management (MLCM) is gaining popularity in the pharmaceutical industry and is enabling the development of more robust and dependable analytical procedures that consistently tackle variability issues.
Q: What is method life cycle management (MLCM) and how does it fit into pharmaceutical method development?
A: MLCM, also known as analytical procedure lifecycle management (APLM), combines activities of analytical method development, improvement, qualification, validation, transfer, and maintenance related to Good Manufacturing Practice (GMP) production. The pharmaceutical industry has begun to apply the MLCM concept to the lifecycle of an analytical method, from development through to retirement. This approach provides the industry with the opportunity to use the knowledge gained from the application of scientific and quality risk management to offer continuous improvement and assurance of data quality.
It is vital that analytical methods adapt along with the knowledge surrounding the product and process throughout years of operation. MLCM facilitates this evolution and provides a reliable procedure to monitor the product quality attributes.
Q: What tools are available to help pharmaceutical companies implement MLCM?
A: Quality-by-design (QbD) is a well-recognized approach for pharmaceutical manufacturing, defined by the revised ICH guideline Q8(R2) as “a systematic approach to development that begins with predefined objectives and emphasizes product and process understanding and process control, based on sound science and quality risk management.”1 QbD is now being extended to analytical methods—known as analytical quality-by-design (AQbD)—and includes an early risk assessment to clearly identify method parameters that influence method performance. It also includes risks associated with variability, sample preparation, instrument configuration, and environmental conditions.2 By its nature, MLCM requires a flexible but rigorous approach that will allow pharmaceutical companies to move beyond the checklist procedure of traditional method lifecycle management, and AQbD is gaining traction in the industry as a solution to this requirement.
Q: What are the regulatory requirements surrounding pharmaceutical method development?
A: Regulatory bodies have increased their focus on lifecycle management for analytical methods in recent years, and better control of their methods based on performance and understanding is fast becoming a compliance expectation. Both the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) and the United States Pharmacopeia (USP) Forum are developing new guidelines that include lifecycle management of analytical methods.
ICH Q8–Q11 guidelines were implemented between 2005 and 2012, and introduced a risk-based (systematic) and scientific approach to method development, encompassed by the QbD concept for processes, where there was previously no guidance. The implementation of ICH Q8 opened the door for lifecycle management in pharmaceutical method development, but it required further clarification for use. A new USP General Information Chapter <1220>—The Analytical Procedure Lifecycle3—has been proposed that examines how MLCM is described in ICH guidelines Q8–Q11 and how it can be applied to analytical methods.
The Expert Panel working on USP Chapter <1220> aims to address the fact that traditional validation experiments do not easily distinguish whether the method is suitable for the intended use. A stimuli article was released in 2013 proposing that “traditional approaches to validation, transfer, and verification should be integrated into the analytical procedure lifecycle process, rather than being viewed as separate entities.”4 In this stimuli article, the Expert Panel embraced the concept of QbD and translated these concepts into the analytical work. This was one of the first steps in developing the concept of AQbD.
A new ICH Q12 guideline5 has also been proposed, with the goal of closing the gaps that exist in the current ICH Q8–Q11 guidelines, namely post-approval flexibility. ICH Q12 will provide guidance to facilitate the management of post-approval changes in a more predictable and efficient manner across the product lifecycl, and promote continual innovation in the pharmaceutical industry.
Q: How can AQbD and MLCM help companies meet these guidelines?
A: Although USP Chapter <1220> is not yet a formal proposal, pharmaceutical companies are advised to consider adopting the suggested approaches to strengthen quality assurance and ensure a reliable product supply. One of the most important elements of an AQbD approach to MLCM is the development of an Analytical Target Profile (ATP), which is a unique element of the lifecycle approach. It stipulates the performance requirements for the analytical procedure and considers the level of risk of making an incorrect decision. The ATP is associated with the needs of the analytical data to be produced, rather than the analytical procedure itself. The appropriate method is chosen based on the ATP, which then goes on to be developed. The method includes all sources of variation that can be accepted in the analytical result.
Although some regulators are wary of using AQbD, ATP is widely accepted as a qualifier of the expected performance of a method because it is based on the statistical probability of acceptable wrong decision-making.
Q: Can you name some other benefits of the AQbD approach to method development?
A: With methods developed via AQbD, the impact of possible variables over the lifetime of a method has already been considered, minimizing the need for revalidation. The result is a systematic approach that defines a method’s goal, assesses risk, develops a design space, implements a control strategy, and continually works on improvements to increase method robustness and knowledge. The clarity of an AQbD product’s documentation greatly speeds up approvals, and can confer cost savings of up to 50% compared to standard QC methods.6
Traditional approaches to method development and lifecycle management do not factor in the effect of variation on method performance, but consist of distinct steps—method development, validation, transfer, and verification. MLCM with an AQbD approach improves method understanding and performance, leads to fewer out-of-specification (OOS) results, facilitates method transfer, and can relieve some regulatory pressure.
The novelty and opportunity in an AQbD approach for the pharmaceutical industry is that working within the design space of a specific method is seen as an adjustment, and not a post-approval change. This idea is a paradigm shift for pharmaceutical product development and manufacturing. Standard QC methods in the pharmaceutical industry have comparatively high costs and analysis run times, and AQbD provides high-quality data to facilitate timely data release and reduced regulatory risk.
Q: How would AQbD be successfully implemented?
A: The lifecycle proposed in USP Chapter <1220> begins with the definition of the ATP and follows three stages, which together adopt the policy of AQbD:
Stage 1: Method design, development, and understanding
Stage 2: Procedure performance qualification—analytical results are shown to be acceptable according to the ATP
Stage 3: Continual procedure performance verification—how does the method continue to perform in the design space previously defined in the ATP?
Historically, stage 2 has encompassed the “validation” stage, so there was initially some pushback against <1220> regarding the change in terminology. This stage is designed to demonstrate the precision and accuracy of the method within the established range, with one total measurement.
Q: Do you think there are any barriers to the wider implementation of AQbD-based MLCM and, if so, what are they and how can they be overcome?
A: A recent survey answered by 100 method developers from innovator and generic pharmaceutical companies cited limited time, regulatory guidelines reluctance to change, disruption to current workflows, and lack of training and education as key barriers to developing and optimizing analytical methods.7 Despite many respondents indicating an openness to adopting an MLCM approach, many did not feel as though they had the resources or tools to address this change. Better technology, education, and more cross-team communication were identified as requirements to consider MLCM.
Partnership between pharmaceutical companies, pharmaceutical service providers, and instrument vendors is crucial to advance lifecycle management in method development. Accurate, reliable instrumentation enables the flexibility that the industry requires to develop innovative drugs.
Q: Regulators are interested in data integrity and method robustness. How can pharmaceutical companies work with instrument vendors to ensure long-term method continuity?
A: MLCM and AQbD are set to change the way the pharmaceutical industry brings products to market, as global regulatory bodies continue to develop new guidelines that specifically address lifecycle management of analytical methods. Method development strategies are influenced significantly by the choice of analysis made during the method design process. High-performance liquid chromatography (HPLC) and ultrahigh-performance liquid chromatography (UHPLC)-based methods are commonly used in pharmaceutical applications and are considered the typical equipment for method development.
The robustness, dependability, and reproducibility of modern UHPLC systems, such as the Waters ACQUITY UPLC, enable pharmaceutical laboratories to access more information faster and earlier in the method development process. When used under the current guidelines, MLCM and AQbD with sophisticated analytical equipment help develop methods that are user-oriented, designed for routine use, easily transferrable, and time- and cost-efficient. Compliance is important for software as well as hardware, and many pharmaceutical laboratories rely on software solutions like Waters Empower Chromatography Data Software to handle the data and ensure its integrity, which is critical to MLCM. Data trending contributes to reducing risk, lowering costs, and improving regulatory compliance, and serves as the basis for continuous improvement during the product lifecycle. Such software solutions also allow analytical laboratories to understand how sources of variability impact method performance.
For more information on the Waters ACQUITY UPLC, visit http://www.waters.com/waters/en_US/UPLC-UHPLC-systems-and-detectors-for-sub-2-micron-separations/nav.htm?cid=10125009&locale=en_US.
For more information on Waters Empower Chromatography Data Software, visit http://www.waters.com/waters/en_US/Empower-3-Chromatography-Data-Software/nav.htm?cid=513188&locale=en_US.
A case study discussing the partnership between Chromicent and Waters is available to download at: www.waters.com/chromicent
References
- International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, ICH Q8 (R2): Pharmaceutical development, 2009.
- Parr, M.K. and Schmidt, A.H. Life cycle management of analytical methods. J. Pharm. Biomed. Anal. 2018, 147, 506–17.
- Proposed new USP General Chapter: The Analytical Procedure Lifecycle {1220}, USP Validation and Verification Expert Panel: Gregory P. Martin, MS (chair); Kimber L. Barnett, Ph.D.; Christopher Burgess, Ph.D.; Paul D. Curry, Ph.D.; Joachim Ermer, Ph.D.; Gyongyi S. Gratzl, Ph.D.; John P. Hammond; Joerg Herrmann, Ph.D.; Elisabeth Kovacs; David J. LeBlond, Ph.D.; Rosario LoBrutto, Ph.D.; Anne K. McCasland-Keller, Ph.D.; Pauline L. McGregor, Ph.D.; Phil Nethercote, Ph.D.; Allen C. Templeton, Ph.D.; David P. Thomas, Ph.D.; M.L. Jane Weitzel; Horacio Pappa, Ph.D.; Oct 17, 2016.
- Stimuli to the Revision Process. Lifecycle Management of Analytical Procedures: Method Development, Procedure Performance Qualification, and Procedure Performance Verification [PF 39(5)]; https://www.uspnf.com/sites/default/files/usp_pdf/EN/USPNF/revisions/lifecycle_pdf.pdf.
- International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use. Final Business Plan; Q12 Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle Management, July 28, 2014.
- The Method Detectives: Building a New Business Model with Analytical Procedure (Method) Lifecycle Management. Waters, Chromicent GmbH; www.waters.com/chromicent
- http://blog.waters.com/method-lifecycle-management-survey-reveals-barriers-and-enthusiasm-for-change
Dr. Alexander H. Schmidt and Mijo Stanic are Chromicent founders and joint CEOs, and Dr. Paula Hong, Ph.D., is principal consulting scientist, Waters Corporation, 34 Maple St., Milford, MA 01757, U.S.A.; tel.: 508-484-3555; e-mail: [email protected]; www.waters.com