The manufacture of biopharmaceuticals presents some unique challenges when ensuring product quality and patient safety. Analytical testing can provide the data needed to produce a safe and effective drug product. The development and validation of analytical methods is crucial in drug development. While the biopharmaceutical industry has had success in reducing risk by incorporating analytical platform technologies for monoclonal antibody products, new molecules and drug conjugates pose additional challenges, according to Stephan Krause, principal scientist, analytical biochemistry, at MedImmune.
The extended drug development timeline of biopharmaceuticals also poses a challenge. According to Yong Guo, professor of pharmaceutical sciences at the School of Pharmacy, Fairleigh Dickinson University (FDU), analytical development and cross-functional development teams should work together to anticipate changes when creating the development timeline. Alice Krumenaker, manager, QC Stability Administration, at West-Ward Pharmaceuticals, suggests that an analytical method may need to be modified and/or updated during the drug-development process to minimize inaccurate data, and the modified method may need to be revalidated.
Technologies, such as FDA’s quality-by-design (QbD) initiative, may have a positive impact on analytical method development and validation according to Paul Smith, EMEAI laboratory compliance productivity specialist at Agilent Technologies, because methodologies are identified early in the development process.
BioPharm International spoke with Krumenaker, Krause, Guo, and Smith about the challenges involved in analytical method development and validation in biopharmaceutical manufacturing.
Biopharmaceutical Challenges
BioPharm: What are the challenges involved in analytical method development and validation for biopharmaceutical manufacturing?
Krause (MedImmune): The use of analytical platform technologies for common product types, such as monoclonal antibodies, has lowered the uncertainty/risk for the manufacturer; therefore, less development, qualification, and/or validation work is required. More challenges typically exist for new types of molecules and/or conjugate products. For example, patient-specific cancer vaccines require conceptually a different approach in that some (routine) test methods should test for non-patient-specific manufacturing (batch-to-batch) consistency versus those that are patient-specific critical quality attributes. A direct potency test method may not exist, and instead, several surrogate test methods may need to be used for potency. Obviously, whenever new test methods are to be used throughout product development, more focus should be on the development, optimization, and validation of these new methods.
Guo (FDU): As in any drug-development program, there are, of course, many challenges involved in analytical method development and validation for biopharmaceuticals. I would like to mention one particular challenge to analytical development. Often times, the development timelines are compressed for various reasons; however, insufficient consideration is given to analytical method development and validation. People expect the analytical methods to be ready all the time regardless of timeline or resource changes. To handle this challenge, the analytical development team needs to be closely working with the cross-functional development team to anticipate the changes and actively participate in any relevant discussion regarding the timeline. It is also important for analytical development to educate and work with the project managers to be more visible during the development process.
Biopharmaceutical Development Timeline
BioPharm: How is analytical method development incorporated into the long development timeline of biopharmaceuticals? Can methods be changed mid-stream? At what point should analytical methods be validated?
Krumenaker (West-Ward): Method development and validation are typically done in the product development stage. While the method may go through various iterations during product development, as the final formulation emerges, the method will be optimized and ready for validation. The analytical method will become part of the submission package and, once a submission is approved, there is usually great resistance to submit changes to FDA. So at this point, it is important to have confidence in the method and its ability to be transferred from R&D to quality control or, in some cases, to a contract organization that will be doing the testing. A successful validation will provide this level of confidence.
As far as making changes to the method goes, if the changes are necessary, they must be made. Sometimes, changes to a process, necessary reagents no longer being manufactured, improvements in technology or other circumstances out of the lab’s control may result in a method no longer being suitable as written and/or as validated. Depending on the extent of the changes, some form of revalidation is likely to be needed. This may range from a simple verification, demonstrating that the method still performs as intended, to a full-blown validation for significant changes. In addition, this may impact the regulatory submission; however, the bottom line is if the original method isn’t accomplishing what it needs to accomplish, it needs to be modified and updated to minimize the possibility of inaccurate results. In that event, all appropriate amendments must be made to the original submission.
Krause (MedImmune): The timing and effort spent on method development correlates with the degree of novelty of the product type and manufacturing process. The sooner methods are optimized, the lower the risk will be to overall product development.