Dr. Rushing has led CMC development programs for a wide array of pharmaceutical products, including parenteral and inhalation drugs, drug/device combinations, and other therapies with complex delivery systems. Dr. Rushing is a subject matter expert in HPLC and GC method development and validation, extractables and leachables program design, and analytical regulatory submission requirements, and he has drafted multiple IND and NDA submissions. Dr. Rushing is a coauthor of the Parenteral Drug Association (PDA) Technical Report No. 65 Technology Transfer.
Q: Which industries do you most commonly deal with when it comes to analytical method transfer?
A: EAG provides analytical services to just about every industry you can think of, so it’s a wide range—pharmaceutical, biotechnology, agrochemical, industrial chemicals, medical devices, packaging, consumer products, electronics—you name it. Some require testing against industry-standard or fairly straightforward methodologies, such as ISO methods or compendia methods. However, in my particular role at the Columbia, Missouri, facility, I focus on pharmaceutical and biopharmaceutical development. In this field, methods are mostly proprietary and unique to the product. Transferring a method can be a complex process, and if not done correctly, can lead to costly delays.
Q: Which analytical technologies do you deal with most often?
A: When we’re dealing with the pharmaceutical side, it’s a wide range. Of course, it’s very heavy in chromatography, so HPLC, GC, UPLC, and capillary electrophoresis, but then we also get into other techniques during the method transfers, either from titration methodologies, water content methodologies, or ELISA techniques on the biotech side— there’s a variety of additional analytical technology that we bring in.
Q: What are some of the key trends or changes in methods transfer today?
A: Overall, from a regulatory standpoint, there’s ever-increasing scrutiny to ensure methods are being appropriately and scientifically transferred in. For example, we have observed the FDA in the pharmaceutical and biotech areas have a greater focus on the scientific design and acceptance criteria to ensure that the transfer is meaningful and that the method can be executed appropriately.
Q: How are those changes affecting labs?
A: It is really pushing the labs to give a more significant amount of thought and effort to planning the method transfer exercises. Historically, it was common to treat transfers as a simple check-box exercise. It was just assumed that if the method was validated, it would transfer with ease. This led to multiple issues in terms of transfers failing, or running into issues after the method was transferred inappropriately, jeopardizing the validity of the data. With these new expectations, and with the complexity of some of today’s analytical techniques, there’s a big driver to spend more time up front in looking at how the methods actually perform, what the areas of concern of the method are, and what design should be used to transfer the method to ensure validity of the data.
Q: What are the most common challenges labs run into with method transfer?
A: One is a lack of communication. That doesn’t mean the two sides aren’t communicating, [but] that the key information sometimes is not being communicated effectively. Either there is key information that is not housed in the analytical method—sometimes there are references to other external documents, in-house SOPs, or other techniques that one facility will use that the other facility does not—or there is, for example, a misinterpretation on how to perform part of that analytical method. I see it commonly in terms of how people interpret certain instructions, for example, if the instructions say to make a 5 ppm solution. Well, there are two different definitions of ppm—the volumetric and the gravimetric. Which definition is being used by the transferring facility? The biggest issue is ensuring that both sides, the sending unit and the receiving unit, are communicating effectively and all the key information required for a successful transfer is executed. The majority of the issues we find are preventable. They’re actually not method performance issues—the methods work fine—it’s that some piece of key information, something that is vital to the performance of the method, isn’t getting transferred appropriately.
Q: How can labs avoid such challenges?
A: The first step is coming up with the understanding of why you are transferring this method. The second part is gathering all the required information that the receiving unit is going to need to execute [the method], and that typically starts a review of the analytical method. Is it written in a way that anyone who is external to your company can read and understand, since it’s typically between companies or between laboratories that you’re doing [method] transfer? Is there any instruction that’s unclear, or does it rely on a different procedure that is used in-house that defines how that procedure is performed? We recommend putting together a transfer package. This will include the original validation report, method development reports, a detailed list of known issues (no method is perfect—all methods have some performance issues), and real-world examples of the data, for example, actual chromatograms, if it’s a chromatographic method. This will ensure that all the information is effectively transmitted to the receiving unit.
The other big thing in how to prevent those issues is on the training side. A lot of transfers are done by what I refer to as “paper training.” You simply hand over the method and the receiving unit reads through it, trains themselves, and executes it. That’s a fairly ineffective way to perform method training. It can be done on simple methods, but with more complex methods, it really requires a hands-on training session where someone who is experienced in how the method is performed on a day-to-day basis physically trains an analyst wherever you’re transferring that method to. The experienced person walks the receiving analyst through the method and they generate data; that way you can ensure that the techniques being used by that current facility are being appropriately transferred.
Q: What can happen if method transfer isn’t done properly?
A: There are a number of issues. The first is just from a regulatory standpoint. Many industries require that the transfer occur under applicable regulatory guidelines—it is executed under a protocol so if you end up with a failure, you then need to run through the regulatory investigation process. Why did you have a failure? Does the failure impact any data that’s been generated at the other facility? Is this a method-related issue or is it a training issue? It becomes a quality assurance or regulatory-driven investigation, which of course can lead to delays and timeline issues in terms of how quickly you can complete that transfer. The other issue is from a timeline execution standpoint in that method transfers are typically done as a precursor to some key milestone coming up—release of new products, initiation of stability studies, release testing of actual drug product, or manufacturing starts. Any delays that are encountered in transferring that method can have an impact on those next steps of the development process, which can then delay the overall development process and the potential drug development timelines.
Q: What are some of the resources you’ve found to be most helpful for method transfer?
A: There are several documents that are available; the WHO guideline on technology transfer and USP <1224>, which is very informative in terms of the types of method transfers that can be performed. The PDA (Parenteral Drug Association) has issued white papers (TR 56 and 65), which are a very detailed process of how to perform technology transfers. While there are a lot of different guidelines out there covering a wide array of industries, they all explain the same basic process. One of the key resources will be to establish a standard operating procedure that you can refer to as “This is how we perform transfers,” not just “Here’s how we do it this time and we do it a different way that time.” By establishing the standard procedure, you can ensure that all the right questions are being asked and answered.
Q: How do you expect method transfer to change further into the future?
A: I think there’s going to continue to be increased regulatory scrutiny of method transfers. Method transfer now is already complicated enough, because of the number of different places that require method transfers. In this virtual age, companies are embracing outsourcing [of] their work to contract research organizations or they have multiple different laboratories or they are a virtual pharmaceutical company that has no laboratories, so you end up with an analytical method being transferred up to six times or more over the lifetime of that method. This adds complexity into the process for the future, because this trend is just continuing to increase as more companies embrace the outsourcing or modular-type system. It’s fragmented, in that [these companies] have manufacturing done here, stability done there, release testing done here for the drug product, another drug product done in this manufacturing site, API over here—so you end up testing in a lot of different places. I think there will continue to be an increase in oversight of the method-transfer process, especially for the regulated industries, to ensure that the method transfers are being performed appropriately.