Contributing writer Tanuja Koppal, PhD, talks to Andrew Macintyre, PhD, senior director, alliance management at Precision for Medicine, about common compliance issues that come up for pharma and biotech laboratories. With many decades of preclinical and clinical development experience, working in several global contract research organizations (CROs), as well as pharmaceutical companies and having submitted numerous documents for regulatory submissions such as IND, BLA, CTA, and 510(k) applications in a variety of therapeutic areas, Macintyre discusses ways to routinely monitor and ensure compliance for assay development, and shares ideas on what can be done if compliance is not met.
Q: What are some of the common compliance issues that come up in pharma/biotech?
A: I think of compliance in terms of how you build and manage an assay. There is a danger of talking about it just from a compliance perspective as there are elements of understanding the constructs of an assay and how it is run daily. I think of it as buckets of compliance—what type of assay is it, is it a kit from a reliable vendor, how are you going to use that kit? Are you going to use an external standard as a reference? Are you going to use three levels of quality control (QC) as in a pharmacokinetic (PK) assay and how are you going to monitor that? It’s different when using the assay for a phase 1 study for six months, as opposed to using it for a phase 2 study, which can last two years.
Standard operating protocols are very important—how is the method run, is there a sample analysis plan? How are the assays monitored in a batch run, and how are they monitored longitudinally over a period of days, weeks, and months?
Everyone talks about making sure the assays are fit-for-purpose, but that’s a very general term and people rarely know what it means. We all know how to validate PK and anti-drug antibody assays, but the challenge lies in validating biomarker assays for regulatory submissions. There is never a detailed plan on how these assays are run and how the biomarkers are validated. Its relatively easy for phase 1 studies when there are less than 100 samples, but when it comes to phase 2 or 3 studies, it can become very challenging to manage these assays. For Biologics License Applications filings, it is critical to understand how these assays work. QC is about understanding the science and making sure assays are running correctly and validated properly. Quality assurance, on the other hand, is making sure that all documentation is in place and what is reported is how it was run and what was generated. The compliance and quality are holistic.
Q: What can lab managers do to ensure compliance is met?
A: You should think of the assay as an organic living entity that you have to keep an eye on so you can answer any questions that come up about its performance over time. If you are running the assay in different labs globally, it’s important to make sure that they are running identically and under the same controls. It’s important to maintain the same degree of robustness, especially when using CROs. Regulators want to see how robust the assay is over time, and each agency has their own ways of managing that. In the US, it’s more of a guided discussion, whereas in Europe they may want you to think of it proactively. Regulators want simplicity and clarity of answers. Informal conversations with the FDA are good but also use your lab team and scientists as trusted partners. Some of them are experts and have probably seen these questions arise before. They can sometimes provide a high level of detail which can explain the performance criteria and what is seen.
“In terms of the data, a simple question is: how do you manage repeats?”
If you are working with a CRO there needs to be a two-way, continuous discussion on how the assay is built, how it is monitored, how it’s going to be used, and where it’s going to be submitted. For a two- or three-year-old assay, it’s important to keep monitoring it to see if it is still relevant and what needs to be changed. It’s cheaper to do this prior to the regulatory scrutiny, rather than re-analyzing and re-doing the assay later. The project manager is often the point of contact and repository of all the knowledge. They should make sure that all the notes, memos, meetings are filed properly to keep the granularity of all the information in place. This is important especially when there is a transition and people need to know what changes were made and why.
Q: Any advice in terms of designing, developing, monitoring, and interpreting protocols and study data for compliance purposes?
A: It is very important that samples are prepared correctly and there is an understanding of how the assay is run. There are pre-analytical variables, as well as sample preparation details that need to be well-documented. For instance, people just say plasma and don’t clarify whether it was EDTA plasma or citrated plasma or heparinized plasma. Similarly, information about the matrix used for running the assay is sometimes not specified. When the protocol says spin the sample for an hour in a refrigerated centrifuge, it’s helpful to specify if the centrifuge needs to be pre-chilled, how the tubes should look after spinning, and how the sample should be extracted from the tube after spinning. Explaining the details of the lab protocols is a critical component of sample prep. Having a sample analysis plan helps determine how the assay should be managed over weeks. Sometimes, upgrading or downgrading assays can be very challenging. Most assays in preclinical are done in good laboratory practice (GLP) fashion, but it’s difficult to make a non-GLP assay into a GLP-compliant assay once the study is done.
Data reporting and analysis is also a big part of compliance. In terms of the data, a simple question is: how do you manage repeats? Often samples are run above the lower limit of quantification or upper limit of quantification. What about the dilutions, how do you report that? Sometimes you get a run-in error where you have run the same sample twice. How do you deal with those results? Do you use the first one, the second one, or take an average of the two? QC is not just about checking the numbers to make sure everything is reported correctly. It’s about looking at the patterns in the data so any discrepancies can be flagged. Make sure to document the patterns you are expecting to see, so there are no problems when you are doing data analysis further down the line.
Andrew Macintyre, PhD, brings more than 20 years of expertise in immunological research and industry experience. He has worked in a wide variety of international environments developing, validating, and executing assays for pharmacokinetic, immunogenicity, and biomarker assessments. He currently serves as senior director, alliance management for Precision for Medicine where he leads strategic planning initiatives for the evaluation and validation of new assays and platforms, provides oversight of laboratory testing operations, and guided laboratory compliance efforts to meet quality goals and regulatory standards for research and development activities.