A Better Lifecycle for Analytical Methods?

Advancing analytical techniques is all well and good, but unless those advances in technology are accompanied by matching strides in technique management, the true potential of better methods may not be realized. Nowhere is this more important than in the production of pharmaceuticals, where analytical methods have to be at peak performance to ensure efficient manufacture and high quality of end products.

To this end, Hovione, a global contract development and manufacturing organization (CDMO), has proactively adopted method lifecycle management techniques (MLCM) for its chromatographic and detection systems, many of which it sources from instrument supplier Waters Corporation. MLCM techniques, say Hovione, offer benefits to company and customer alike. We sat down with Hovione’s Principal Analytical Chemist of Analytical Development, Antonio Ramos and Waters’ Principal Consulting Scientist Dr Paula Hong to discuss MLCM. We also find out how and why regulatory bodies like the International Council for Harmonization are putting MLCM at the forefront of future regulation. 

Ruairi Mackenzie (RM): What is method lifecycle management and why does it matter? 

Paula Hong (PH): Method lifecycle management (MLCM) is a continuous process that sets out to advance and document the capabilities of each analytical method used in the clinical development of a potential new drug. The modern concept of MLCM has been discussed extensively over recent years, as its adoption ensures the quality of pharmaceutical products across the globe. MLCM presents a framework for defining the principles and advancement of analytical methods that sets out to give a more structured alternative to analytical method development.

From the earliest discovery phases through to process development and commercialization, analytical control is essential in the success of drug development and manufacturing programs. Appropriate and effective analytical methods play a crucial role in decision-making, whilst also providing information about the impact of process changes on the quality of pharmaceutical products. The quality of analytical methods must embody the entire lifecycle process, including development, validation, transfer, and routine use. 

Antonio Ramos (AR): When implementing lifecycle management concepts into method development, both contract development and manufacturing organizations (CDMOs), and pharmaceutical manufacturers should have a good understanding of the three stages of MLCM. Before these three stages are implemented, the Analytical Target Profile (ATP) must be defined as the first step of MLCM. The ATP encompasses the prospective overview of the aims of the analytical method, and the predefined objective that stipulates the performance requirements [1]. The following three stages align with current process validation concepts, meaning CDMOs and manufacturers can find faster, more efficient, and less costly development and manufacturing processes.

The three stages of the analytical lifecycle are as follows:

Stage 1: Method design and development. ATP is used to drive activities. Risk assessment tools and statistical methods are used to facilitate understanding of the method (e.g. design of experiments, risk assessment matrix) and its performance characteristics (e.g. accuracy and precision, robustness). An ATP is used to drive method selection, design, and development activities. It’s a key parameter that facilitates greater continuous improvement of analytical methods and their choice.

Stage 2: Method performance qualification. This stage confirms that the analytical procedure delivers reproducible data which consistently meet the ATP. This includes the finalization of the Analytical Control Strategy (ACS), for example: a science-based definition of the allowable repeatability level of the reportable value. This stage also considers analytical transfer and implementation of compendial procedures.

Stage 3: Continued method performance verification. The ongoing assurance that the analytical procedure remains continuously in a state of control. This includes an ongoing program for routine monitoring of analytical performance data, as discussed in the FDA Method Validation Guideline from July 2015, and the systematic evaluation of changes. [2]

MCLM relies on an analytical quality-by-design (AQbD) approach, which enables more efficient development of a robust method that can lead to greater regulatory flexibility. 

RM: Lifecycle management has been at the forefront of new guidelines being proposed by the ICH. Why is lifecycle management regulation changing?

PH: As regulatory bodies such as the United States Pharmacopeia (USP) expand and update their industry regulations, their support and encouragement of lifecycle management has become apparent. The USP has published a series of ‘stimuli articles’ that inform a proposed USP General Information Chapter <1220> ‘The Analytical Procedure Lifecycle’ [1]. The articles explore the interpretation of MLCM in the ICH guidelines Q8, Q9, and Q10, and how the concept can be applied to analytical methods. These analytical methods then become part of a continuous verification cycle to demonstrate that they meet the acceptance criteria. In addition, ICH Q12 ‘Pharmaceutical Product Lifecycle Management’ is currently in draft and ICH Q14 for Analytical Procedure Development/Validation is underway [3]. These documents set out to implement additional definitions, which will unquestionably result in an upturn of CDMOs applying MLCM to their method development.

ICH Q12 and Q14, the latter of which will be dedicated to method development, are expected to be the game-changers that provide confidence to transform current practice. Importantly, the Food and Drug Administration (FDA), and other regulators around the world, are also calling for companies to shift the drug discovery process towards using data for generating further knowledge about potential new drugs.

Regulatory bodies are actively discussing MLCM concepts, thus creating a positive environment that will encourage CROs, CDMOs and pharmaceutical companies to adopt MLCM.  This will help their customers gain efficiencies and improve the quality of their drug products. Pharmaceutical companies are increasingly expected to apply structured and science-based approaches to analytical procedure development, such as AQbD and early risk assessment. The development of ICH Q12 was initiated to harmonize aspirations and challenges in the context of what we already have, what might be possible, and what might be induced to follow later. Advancements in Q12 set out to promote innovation and continual improvement and strengthen quality assurance and reliable supply of product. This will allow regulators to better understand, and have more confidence and trust in, a company’s pharmaceutical quality system for management of post-approval CMC (chemistry, manufacturing, and controls) changes.

RM: Why is it important to comply with ICH guidelines, and what are the benefits of complying from both a patient and pharmaceutical developer perspective?

AR: With increasing interest and growth in MLCM and AQbD methodologies, we can expect that stable regulatory guidelines will be in place within the next two to three years. The implementation of this new ICH guideline will promote innovation and continual improvement, as well as strengthen quality assurance and the reliable supply of a product. In addition, further ICH guidelines and a new general chapter of the USP are under review to provide specific guidance about the analytical procedure lifecycle management approach. If the pharmaceutical industry continues to build more knowledge into analytical methods, it can use this information to improve their methods and make changes, potentially with regulatory flexibility. With that in mind, in around five to ten years, we will see a more standardized industry, driven by a more holistic approach to method management that aligns with regulatory guidelines.

Applying the concepts of MLCM to pharmaceutical processes creates a link between the product’s initial concept in the industrial case and the patient in the health care environment. Speaking from Hovione’s experience, we have proactively adopted MLCM to help our customers gain efficiencies and improve the quality of their drug products. It’s an added value for our customers when they understand that we are able to provide this new and improved way of method development. It’s good for them in terms of using our capabilities in this area. 

RM: How can instrument choice and lab setup make compliance with ICH guidelines easier?

PH: The abundance of scientific and quality control equipment to assist the lifecycle management process is integral as it can enable companies to increase screening efficiency, shorten the drug development process, and meet milestone objectives. However, rapid technological development results in quickly aging instrumentation which may cause workflows to become outdated. This poses a threat to data throughput and other measures of project productivity.

It is also important to standardize instrumentation across multiple sites and locations to support a proactive approach to MLCM. Acquiring the best analytical instrument is crucial to achieve the key performance parameters that are assessed, which include precision, accuracy, and reliability. Robust and reliable technology can reduce variability in an assay. For example, ultra-performance liquid chromatography (UPLC) and mass spectrometry detectors, as well as sophisticated chromatography data software, are imperative to the early adoption of MLCM methodology [4].

It is essential to implement software that can be used across multiple sites to enhance regulatory compliance, and to improve information management, storage, and data mining capabilities. The combination of advanced software, instrumentation, and AQbD is a powerful strategy for method development that leads to better, faster, greener analytical methods, as well as reducing costs and enabling resource optimization.

RM: How quickly do regulatory changes start to impact on pharma companies? What would you consider to be the key changes enforced since ICH's inception in 1990?

AR: As pharmaceutical companies and CROs are anticipating the inevitable changes in ICH regulations, we at Hovione became early adopters, making the commitment to use the MLCM concept prior to the regulatory changes to ensure we are ahead of the curve. We can expect other pharma companies and CROs to follow suit as they observe the benefits of implementing lifecycle management into their drug manufacturing process.

The main impact of the changes enforced since ICH’s inception has been a greater harmonization between the regulators and the pharma companies. It has facilitated an open dialog to ensure the safe and effective manufacture of pharmaceutical products, which has ultimately led to safer products for the end user. With over 60 guidelines published since 1990, it’s hard to pinpoint the key changes but for me, they’d be:

- ICH Q8 is intended to provide guidance on the contents of Pharmaceutical Development for drug products. The guideline does not apply to contents of submissions for drug products during the clinical research stages of drug development but the principles in this guideline are important to consider during these stages.

- ICH Q9 provides principles and examples of tools of quality risk management that can be applied to all aspects of pharmaceutical quality including development, manufacturing, distribution, and the inspection and submission/review processes throughout the lifecycle of drug substances and medicinal products, biological, and biotechnological products, including the use of raw materials, solvents, excipients, packaging, and labelling materials.

- ICH Q10 applies to pharmaceutical drug substances and drug products, including biotechnology and biological products, throughout the product lifecycle.

The elements of Q10 should be applied in a manner that is appropriate and proportionate to each of the product lifecycle stages, recognising the differences among, and the different goals of, each stage.

- ICH Q12 is the latest regulation that is going to transform the way that pharma companies work. As mentioned, at Hovione, we already have MLCM procedures in place, but it’s going to be reassuring to know that the industry will be working to the same high standards across the board.

References:

 [1] Proposed new USP General Chapter: The Analytical Procedure Lifecycle {1220}, USP Validation and Verification Expert Panel: Gregory P Martin, MS (Chair); Kimber L Barnett, PhD; Christopher Burgess, PhD; Paul D Curry, PhD; Joachim Ermer, PhD; Gyongyi S Gratzl, PhD; John P Hammond; Joerg Herrmann, PhD; Elisabeth Kovacs; David J LeBlond, PhD; Rosario LoBrutto, PhD; Anne K McCasland-Keller, PhD; Pauline L McGregor, PhD; Phil Nethercote, PhD; Allen C Templeton, PhD; David P Thomas, PhD; ML Jane Weitzel; Horacio Pappa, PhD, 17 October 2016

[2] Analytical Procedures and Methods Validation for Drugs and Biologics, Guidance for Industry, U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) Center for Biologics Evaluation and Research (CBER), July 2015, Pharmaceutical Quality/CMC

[3] 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, 28 July 2014

[4] Analytical Procedure (Method) Lifecycle Management Drives Method Development at Innovative CDMO. Waters Corporation, January 2019 (http://www.waters.com/webassets/cms/library/docs/720006514en.pdf) 

Paula Hong and Antonio Ramos were speaking to Ruairi J Mackenzie, Science Writer for Technology Networks