Extractable and Leachable Regulations & Requirements
Extractables and leachable studies are required for pharmaceutical product submissions in order to ensure that plastic and rubber chemicals do not transfer into drug products at levels that cause public health concerns. These studies are customized and although there exist guidances from both the United States Pharmacopeia (USP) as well as the Product Quality Research Institute (PQRI), there is no prescriptive approach to these studies, allowing for some flexibility in their design. This also allows for some pitfalls in study design which can result in regulatory findings on review. Some of the more common ones we have seen include:
No Materials Selection Phase
Often E&L studies are done at a very late stage in drug development, when the packaging has been finalized or nearly so. At that point in development when extractables are observed above the safety concern threshold (SCT), there is often a panicked approach to justify raising the threshold limits based on toxicology arguments. This may or may not succeed, but in any case would have been unnecessary if the extractable screening had been done in early development prior to final material selection and supply chain arrangements, allowing a shift away from problematic materials which require significant toxicology arguments to get approved.
Combination of Components
In order to save cost as well as development time, some sponsors choose to perform the extractables screen on a combination of components. For example, bottles, liners, caps, and labels are mixed and a single study is performed rather than extractables studies on the components individually. There are two problems with this approach.
First, when an extractable is found it will be much harder to determine its source as well as its identity. Second, if the sponsor does not perform a controlled extraction study on the individual components, baseline data on those components will not exist. This is a problem as the agency expects the manufacturer to manage changes to their supply chain by performing controlled extraction studies on the individual components as new lots are procured.
Reverse Leachables Strategy
Another time and cost-saving measure is the “reversed leaching study” in which the sponsor chooses to avoid extractable screening and go directly to a simulated leaching analyses. Data will then be presented in filings to the agency that no additional peaks were observed relative to the bulk product. The problem with this approach is that without an extractables study, one does not know where potential leachants may appear in the chromatography and they very well may be masked by drug product signatures.
More correctly, a leachables method development should be performed based upon the extractable findings and that method would be validated prior to examining end-of-life or stability samples. Need help designing an E&L study? Talk to our regulatory experts.
Lack of Consideration of Processing Chain Materials
Recently, the agency has been giving a higher level of attention to manufacturing components that contact the drug product. Initially the focus had been on injectable drugs, but there have been findings in filings for even oral solutions. The current expectation is that all materials that contact the drug product during manufacturing, even though contact may be transient, must be evaluated for potential leachants. A decade ago, we would have advised that the FDA does not care about leachants from stainless steel, but that is no longer the case, so even stainless steel holding tanks must be evaluated for metals leaching.
Overly Aggressive SCT Calculations
When industry began addressing extractables from plastic packaging, a safety concern threshold was established, below which one did not have to be concerned with the impact to public safety from carcinogenic or non-carcinogenic effects of leachants.
From food packaging contact guidance, an SCT of 1.5 ug/day of an unknown analyte, assumed to be carcinogenic and assumed to be of average carcinogenicity, would raise the cancer rate in the population by one additional case in 100,000 individuals. Early SCTs, developed for inhaled drug products, were set to be 0.15 ug/day out of an abundance of caution, and provided for a risk based approach to thinking about leachants in drug products. SCTs have gone up over the years, particularly with low leaching risk/low risk of route of administration drug products and some sponsors have argued for SCTs as high as 20 ug/day. The FDA has stated at the Smithers Rapra Extractables and Leachables Conference in Bethesda, MD June 2019 that in no case will they accept SCTs higher than 5 ug/day, so exceeding that level will trigger a finding on review.
Our expert blogger is Dr. Andrew Kolbert, Avomeen’s President/Chief Technology Officer. Andrew has over 20 years of experience executing and managing analytical and product development programs in highly regulated areas, both internally and in external organizations.
Learn more about Andrew’s expertise and experience.