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How to conduct a succesful compliant method transfer

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William E. Weiser - senior director, Global Quality Systems, Pharma Services at Thermo Fisher Scientific explores the  factors that make or break a successful compliant method transfer.

Method transfer is a vital process in pharmaceutical manufacturing, as scientists transfer methods between instruments that may be in different laboratories, sites or even organisations. However, successful liquid chromatography (LC) analytical method transfer can be a complex undertaking, particularly when transitioning from legacy to modern instrumentation. 

Deviations in instrument parameters can lead to difficulties in validating the method on the receiving instrument. Consequently, scientists in pharmaceutical manufacturing laboratories need to fine-tune multiple variables to obtain reproducibility and compliance, which often requires significant time and resource.

Inefficient method transfers can represent a significant drain on productivity, given that pharmaceutical manufacturers may perform hundreds of method transfers every year. From a regulatory perspective, this process is being increasingly monitored and is a crucial consideration for manufacturers to stay compliant. 

The Rigour: Start Strong with Detailed Documentation

There are a variety of scenarios in which method transfer is required in pharmaceutical manufacturing. An analytical development laboratory that has created a method may need to transfer it to a receiving QA/QC laboratory, in some cases, on a different site; alternatively, a pharmaceutical analytical services contract laboratory might receive methods developed by customers. 

In every circumstance, at the core of a robust method transfer is ensuring a seamless transition between the transferring and receiving laboratory. This is also important from a regulatory perspective; producing the method lineage from validation through release testing is a regulatory requirement across the world.

To maintain the appropriate documentation, it is valuable to understand the requirements of pre-approval inspections and general inspections, particularly as failure to pass these audits can delay drug development timelines in the first instance and even result in warnings for the laboratory, such as the FDA Form 483, blackmarking the facility.

Of equal importance, clear and thorough documentation with background information makes it much easier for the receiving laboratory to plan and execute a method transfer. If the transferring laboratory provides an abundance of detail, including highly defined system suitability criteria, the process can be completed much more easily. Where possible, strong communication between the laboratories is likely to result in a simpler, faster transfer, saving time and resource for the receiving laboratory, as well as reducing the likelihood that the transferring laboratory will need to provide support later in the process. 

The Basics: Have a Deep Understanding of Chromatographic Principles

Adjusting instrument parameters can be a highly complex process for scientists. However, trying to match settings is less about negotiating vendor-specific features and more about understanding the underlying mechanism affecting analytical separation.

For instance, disparities such as non-matching retention times may be caused by a range of factors, from different gradient delay volumes to column thermostatting principles. With a deep understanding of the basic working principles of chromatography, scientists can take a more informed approach towards troubleshooting and adjusting parameters. 

This also reflects regulators’ growing focus on the performance characteristics underpinning analytical methods. Regulatory agencies in the USA and EU now require analytical quality by design (AQED), to create well-understood, fit for purpose and robust methods. Key performance characteristics include:

A deeper understanding of chromatography will also enable scientists to prepare for further regulatory developments, helping to futureproof the laboratory as well as supporting method transfer today.

The Technology: Choose High-Performing Instruments

The instruments involved are another influential factor in a successful method transfer. For instance, legacy LC instruments might not offer the flexibility to adjust parameters effectively. Given the importance of reliability and repeatability, using outdated technology that cannot maintain consistency between consecutive runs risks pushing the method towards the edge of failure. 

High-quality, reliable instrumentation minimises technology-related artifacts. Using instruments that provide parameter flexibility to modify and match experimental conditions can streamline method transfer. 

With customisable features, scientists can match instrument settings more easily. For example, gradient delay volumes can be affected by the design and mixing behaviour of pumping systems. A tuneable system can physically match the gradient delay volume of the original system, improving consistency and transferability across instruments. Additionally, system dispersion effects will be impacted by the proximity of the column to the detector as well as the size (ID) and length of connective tubing. A custom injection program can be utilised to overcome these artifacts, matching the behaviour of the origin and new system. 

In addition to delivering greater flexibility, modern analytical instruments are integrated with real-time feedback capabilities that immediately communicate any failures or errors to either abort runs or troubleshoot. Systems can deliver warning notifications when results do not match method acceptance criteria. These tools also maintain comprehensive records that are useful when transferring methods and support full audit trails. 

Modern detectors, that provide an improved signal-to-noise ratio, will also support a wide range of quantitation with better sensitivity. Comprehensive detector capabilities ensure that the protocol works for a diverse range of samples in the receiving laboratory. Altogether, with high performing instruments, reproducibility is better optimised, enabling scientists to spend less time troubleshooting and more time focusing on more value-added activities.

The Outlook: Develop a Robust Plan and Stay UpdatedTaking a robust approach to the method transfer process can enable pharmaceutical manufacturers to minimise unexpected issues. That means performing method transfers in conditions that are as realistic as possible, instead of using artificial or synthetic samples as a ‘best case scenario’, which can pose significant challenges when the actual method is run with real samples. Equally, schedules should factor in workflow hiccups and unexpected problems, allowing sufficient time for troubleshooting when needed.

Looking ahead, it is important for scientists to remain updated on the latest principles of method transfer. Examining the guidelines provided by regulatory agencies will enable organisations to learn from best practices, while reading warning letters relating to unacceptable documentation and negative audits provides details on poor practices.

Conclusion

In summary, to complete a successful and compliant method transfer, laboratories benefit from a rigorous approach to documentation, a detailed understanding of chromatography and high-performing technology that has been designed with ease-of-use, reliability and robustness in mind. By pursuing best practice in method transfers today, laboratories can improve their performance and prepare for success as regulations evolve further. Ultimately, more streamlined method transfers can reduce the risk of delays to pharmaceutical manufacturing, ensuring that organisations can provide therapeutics for patients as planned.

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