In the past, the FDA focused on Extractables & Leachables (E&L) testing in devices and drug products that had both a low administration risk and low packaging risk, such as topical solutions. Over time, the FDA has moved on to focus on higher risk products with high administration risk and high packaging risk, such as inhalers.
 
The FDA is now beginning to expand its area of focus for E&L testing outside products and devices with high administration and packing risk to include manufacturing components. For example, if a drug needs to travel through a tube during the manufacturing process, that tube needs E&L testing as well. This often falls outside the area of expertise for many companies, and those companies struggle to keep up with the increasing expectations from the FDA.
 
Contract Pharma spoke with Andrew C. Kolbert, Ph.D., President and Chief Technology Officer of Avomeen about this recent trend and what the industry is doing to keep pace with expectations.  –KB
 
Contract Pharma: What is the U.S. FDA’s role in overseeing Extractables and Leachables studies?

Andrew Kolbert: The FDA approves drug products, and extractables and leachables (E&L) testing is part of the expectation for a drug submission. However, the FDA guidance on E&L testing is generally not prescriptive and is open to interpretation as to its implementation. The United States Pharmacopeia (USP) came out with a guidance monograph, USP 1663 and 1664, and previously the Product Quality Research Institute’s (PQRI) has published comprehensive guidelines, which have for years been the defacto guidance for industry.

Because the FDA’s guidance on these matters is general, they don’t have to change any regulations to decide if and when prior approaches and standards are no longer acceptable. We usually learn about changing standards because clients start coming forward with a finding from the FDA for something the Agency used to not be concerned with.

Drug products are considered high risk if they have a high packaging risk and a high route of administration risk. The FDA did not previously focus on E&L for oral tablets and capsules because they require a low-risk form of administration and there is low risk of product-packaging contact. Instead, they were focusing on inhaled drugs because there was a high route of administration risk and risk of dosage and packaging interaction. Over time, industry has been performing E&L studies for high-risk products to products and processes that had lower risk. PQRI developed a matrix detailing these levels of risk 20 years ago to aid industry in self regulation.

CP: How has the FDA changed their approach to overseeing E&L testing in recent years?

AK: A few years ago, you would never have thought that the FDA would be worried about the tubing that a drug product travels through, or a stainless-steel holding tank, as material contact is so transient. This has changed as the FDA has evolved to make sure there is no risk to public health. They have worked their way down the matrix so that now they are concerned about manufacturing equipment, which isn’t on this matrix because it wasn’t on the FDA’s radar 20 years ago. This may include gaskets, tubes and hoses that the drug product touches before the packaging. Much of the concern now is with manufacturing equipment for injectables, but we are also seeing them concerned with manufacturing for oral drugs, which has a very low-risk profile.

It’s hard to say when this trend started. We just gradually start to see findings come from the FDA through our clients. Ten years ago, you would have never seen these findings.
For example, in 2011 Ortho-McNeil-Janssen Pharmaceuticals, Inc. recalled 40,000 pill bottles because of a manufacturing concern. There were two consumer reports that the product had an “uncharacteristic odor.” They found that some of the wooden pallets used by suppliers were contaminated with TBA (2,4,6 tribromoanisole), a byproduct of a chemical preservative sometimes applied to wood. The drug product in cartons around boxes contacted those pallets, and the analyte went through the cartons, the product boxes, and the bottles like they weren’t even there. The FDA was previously not focused on E&L in warehousing and manufacturing until recently, so cases like this may have happened occasionally even though manufacturing equipment and warehousing materials are at a low risk for E&L issues. Now they are choosing to focus on these to further improve the overall quality and safety of products.

CP: What complications arise from this increased focus on manufacturing?

AK: As mentioned above, there is a low but still potential risk of contaminating a drug product with harmful substances obtained through the manufacturing process. But now that the FDA has chosen to focus on this area, you are likely to get a finding from the FDA, and extending the amount of time to market, if you are not performing E&L studies on these manufacturing components.

Because the FDA is not making public statements every time its focus areas change, someone has to be the first one to receive this type of finding, and often it is the CRO that hears it from the first client. Then word gets around the industry by way of the CRO. When a company receives a finding from the FDA that they need to look at the E&L in manufacturing process, they may come to a CRO and ask for the work to be done in a compressed time frame. They may have to spend even more money to make sure it gets done quickly and correctly.

CP: How is the industry reacting to this recent trend?

AK: E&L work in general is much more frequently outsourced than other areas of drug development, as expertise in polymer science and additives is generally not core to their knowledge base.  Consequently, E&L is highly outsourced, and this area is growing in the pharmaceutical CRO space.

CP: What expertise is required from analytical CROs to keep up with these changing quality standards?

AK: While pharmaceutical scientists are experts in drug discovery, they are not experts in rubber, plastics, and polymer additives—the core requirements to interpret the results of E&L testing. Pharmaceutical CROs need to have polymer experts on staff in order to provide state-of-the art interpretation of testing as well as a safety assessment.

Many pharmaceutical companies also don’t have metals analysis laboratories, so are unable to perform E&L on stainless steel holding tanks or transfer lines. This work would generally need to be outsourced, not to mention USP 232/233 testing on raw materials much of which is being outsourced today as well.

CP: How are you addressing these changes in your lab?

AK: Many of our employees come from the plastics and polymers industry. We have employees who worked in other industries or people from General Electric with a resin background. We don’t hire exclusively from the traditional pharmaceutical background.

With this expertise, we have developed a database that includes 300 to 400 plastic additives. We bought every additive that goes into commercially available plastics and performed tests such as high-performance liquid chromatography and gas chromatography-mass spectrometry. This can help our experts quickly identify what they are finding through these E&L studies. This also means we have specialties other companies do not. For example, we can do metals testing in our elemental analysis unit. This type of expertise, not typically found in pharmaceutical companies, is needed to address the increased expectations from the FDA.
 

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Andrew Kolbert, Ph.D., MTM, is the President and Chief Technology Officer at Avomeen Analytical Services. He has 20 years of experience executing and managing analytical and product development programs, both internally and in external organizations.  His expertise is analytical chemistry in highly regulated areas including pharmaceutical development and testing, extractables and leachables studies, food contact migration studies, food additive and food contact notification testing and registration, and pesticide and insecticide testing under FIFRA. He has served as an expert witness to support litigation in the areas of pharmaceutical development and analytical testing. He has participated in FDA pre-notification conferences, FDA site audits, and trained FDA inspectors on analytical technology.