Laurie Goldman, Particle Sciences
Q: Can you explain your experience with analytical method validation and your current responsibilities?
A: I began conducting analytical method validation in the electronics chemical industry under an ISO quality system, and so many of those validation fundamentals readily transferred to validation under International Conference on Harmonization [ICH] guidance ICH Q2. Having worked in leadership roles in the pharma space for more than 15 years, I now oversee Particle Sciences’s team of almost 30 analytical chemists, who are conducting more than 25 validations of analytical methods per year. Most of our analytical methods are developed to support our clients in Phase I/II clinical trials, but we have also recently begun developing and covalidating robust methods in support of Phase III/commercial manufacturing.
Q: How have method development and validation evolved in recent years as regulations change and instrumentation/technology improves?
A: From FDA guidance, USP chapters, and ICH guidelines to an increase in industry publications, it is now possible in many cases to find a basis for making justifiable decisions surrounding what to include in a validation or in the use of a particular approach. Industrywide, I believe analytical chemists, management, and clients/sponsors have recognized the connection between putting the time into cultivating sound and robust methods during the early development stages of a project and the ease of validating at the time a project moves to clinical/commercial production. Improvements to the sensitivity of analytical instrumentation have allowed us to overcome some challenges related to achieving low-level reporting limits. The increased availability of orthogonal analytical methods has allowed us to identify interferences and eliminate them in some cases. As instrumentation software continues to advance, the ease of constructing validation data packages and data validation packages is increasing. That juxtaposition of words is not a mistake. In the age of data integrity concerns, the audit trail from validation data is something that is scrutinized within our department as well as by our quality assurance department.
Q: What questions should researchers ask before undertaking the design and planning of analytical method validation?
A: I think the most important question to answer is “What purpose is the method intended to serve?” We strive to develop and validate “fit for purpose” analytical methods. This provides the best value for our clients and reduces risk to the project. We take into consideration the development phase of the project, the knowledge base that exists around the analyte, the regulatory requirements for a particular dosage form/route of administration, the analytical methodology/detection, and the history of the product and method. We want to know in advance of the validation that we can meet the intended requirements of the method, from system suitability limits to the criteria listed in the validation protocol. We conduct a wide range of scouting experiments to make sure that our methods perform with a known degree of certainty that ensures we can measure pertinent product parameters within acceptable tolerances. We view the validation documentation and experimental execution as the formal record for verifying the performance of the method, but we also have a very good idea of that performance going into the validation.
Q: How can poor method design affect the validation process?
A: An analytical method/measurement is a process like any other—“garbage in, garbage out.” Methods that suffer from poor peak shape, shifts in retention time, analyte carryover, or any other lack of reproducibility provide problematic results. These methods might produce data that is explainable and usable after compensations are made, but a series of corrections to data within the execution of a validation study can cast doubt on the reliability of the underlying data, method, analytical chemist, or lab. In rare instances,
this type of issue may show up only when there is a change made to the instrument or analytical chemist. In these instances, the documentation of the steps or the settings in the method may be inadequately described. A poorly designed method will ultimately cost project teams a great deal of time in reanalysis, reperforming of the validation, or reviewing of any invalid data. Any of these items can also cause a delay in timelines. In addition, as instrumentation use is often scheduled out a few weeks in advance for multiple projects, any reanalysis can affect not just the project that required the rerun but may also affect any projects that follow in the queue.
Q: What steps can labs take to avoid delays?
A: The key is to document, review, and repeat. Particle Sciences’s analytical services department has the advantage of working closely with our formulations teams, and we are involved in developing and establishing analytical methods during the early development stages of a project. We gain insight from the formulators working on the projects, and we have the opportunity to use, evaluate, and fine-tune many of our methods using multiple research, scale-up, or engineering batches. We routinely run scouting experiments and will make use of lab-scale simulated batches that are just outside specification where necessary. We regularly review forced degradation data to ensure we maintain specificity and have identified primary/specified impurities. We also evaluate a compilation of historical system suitability results or performance checks against a history of the method. From this evaluation, we can select a set of meaningful system suitability criteria that ensure the correct functioning of the measurement system for every run.
Q: What resources do you recommend for those who have questions about method validation guidelines?
A: Compendial chapters, ICH guidelines, and FDA guidance are valuable sources of validation requirements and information with regard to approaches. In addition, there are numerous organizations that run conferences and symposia where there is ample opportunity for overviews, training, and getting ideas from colleagues. Finally, USP workshops and meetings are typically attended by experts from the FDA. These workshops provide insight into current trends and answer questions on a particular topic as well as provide a forum for discussion directly with regulators.
Q: What are some of the biggest challenges labs face when it comes to method validation? What can be done to better handle these challenges?
A: Sample preparation is a challenging and integral part of any analytical method that is being validated. Everything from the sampling technique to the stability of a sample preparation can affect the reproducibility of a measurement. These items need to be as robust as the instrumental analysis, and really need to be explored and probed in early method development stages. Complex dosage forms typically mean more challenges for sample preparation, including the use of aggressive extraction techniques that may affect analyte stability and concerns over extraction efficiency that may affect accuracy. Particle Sciences has an advantage in that our formulators can provide samples of an alternate loading, matrix, or physical property compared with the target product profile. We can then use these alternate samples to fully investigate the capabilities of the analytical method during development and validation.
Q: What changes or trends do you expect to see in the future for analytical method validation?
A: Everything in pharmaceuticals and analytical methodology is getting more complicated. We are seeing a steady shift to biopharmaceuticals from small-molecule analytes, and there is a large increase in complex dosage forms and the use of biodegradable polymers or devices. And while instrumentation and its software become easier to use, the networking and administration of them becomes more intricate. Due to the challenges associated with developing reproducible methods for these types of formulations, I anticipate that more techniques will become standardized. And as sample preparation for complex dosage forms becomes more standardized, the results generated for these complex dosage forms should become more reproducible. Several of the sample preparation approaches we developed for drug-eluting devices and biodegradable particles are starting to gain traction in the industry.
Laurie Goldman joined Particle Sciences, a Lubrizol LifeSciences company in Bethlehem, Pennsylvania, in 1997 as analytic and quality manager. Building on a solid quality control and quality assurance framework from previous experience in the electronic chemicals, mining, and inks/coatings industries, she established and grew the state-of-the-art analytical laboratories at Particle Sciences. As director of analytical services, she oversees a department of 28 chemists and technicians. She holds a BS in chemistry from Muhlenberg College, has co-authored numerous publications, and has been certified in statistical process control, quality engineering, and quality auditing.