Strategies to Address E/L Container Closure Challenges

In May, the PDA Letter had the opportunity to film CDER toxicology supervisor Dan Mellon for his thoughts on extractable/leachable challenges. Below is an expanded transcript.

PDA Letter: What are some of the common pitfalls that can impact approval of applications due to inadequate extractable/leachable (E/L) information?

Mellon: Extractable and leachable safety assessments can be some of the most challenging review issues in an Application, requiring a coordinated effort between the CMC and toxicology review staff.

From a toxicology perspective, based on our experiences reviewing these studies and working with our CMC colleagues, we have identified seven “pitfalls” that can negatively impact our ability to recommend approval of an application. By reviewing these common “pitfalls,” the Agency hopes to increase transparency regarding our expectations, improve the quality of the submissions, and hopefully prevent unnecessary delays in the review process.

These common “pitfalls” are:

1. Presence of compounds above the Qualification Threshold (QT) that have not been identified. As a toxicologist, I cannot conduct a risk assessment on a compound only defined by a relative retention time. If I don’t know the identity of the compound detected, I cannot conduct a toxicological risk assessment or conclude that there are adequate data to support the safety of the container closure system.
2. Inadequate sensitivity of the detection methods. If your assay cannot detect compounds at the requested Analytical Evaluation Threshold (AET), we cannot conclude that the study adequately identified all the compounds that could leach into the drug solution. We recognize that for large volume parenteral products, there may be significant technological limitations with respect to adequate analytical methods. If this is the case, you should discuss these challenges with the review division in order to determine the best path forward.
3. Use of an inappropriate qualification threshold. We commonly receive applications that conclude that there were no leachables detected above the ICH Q3A, Q3B or Cramer classification thresholds. These thresholds are not appropriate.
• The ICH Q3A and Q3B guidance documents specifically state that they are not applicable to extractables and leachables. These guidances are intended to apply to drug substance and drug product related impurities and degradants. Extractables and leachables are industrial chemicals with very different toxicological profiles unrelated to the drug substance. Therefore, use of these thresholds is not acceptable.
• The Cramer classification system employs qualitative structure activity relationships (or QSAR) that can inform risk assessment when there are no data and have been used to assess safety of compounds in foods. This method has been modified over the years and has been included in several commercially available computer programs. However, simply reporting on compounds present above those thresholds does not permit independent review of the data by the Agency and CDER has not independently validated this QSAR approach for extractables and leachables. Best practices dictate that the compounds be identified to permit independent risk:benefit evaluations and establishment of adequate safety factors and acceptable levels for route-specific risk assessments.
4. Inadequate stability data to examine trends in leachables over time. The risk assessment must take into account the highest level of a compound over the course of the shelf life. Compounds can be released at different rates over the shelf-life and compounds released early can degrade in the solution over time resulting in an increase in the levels of degradants over stability. Understanding these trends is essential to the risk assessment and data from one time point is not enough to establish a trend.
5. Inadequate toxicology justification to support a Permissible Daily Exposure (or PDE) as described in the ICH Q3C/Q3D guidances or referred to as an Acceptable Daily Intake (ADI) in the PQRI documents. Frequently, we receive risk assessments based on references that are not provided, not available to the public, or the source material is not even cited. We independently review these study reports to determine a PDE and without adequate references, we cannot independently determine acceptable levels.
6. Inadequate descriptions of how extractable data were used to design leachable assessments. Regulatory submissions frequently include multiple study reports with no clear discussion of how these data were used. What exact compounds from the extraction studies were targeted in the leachable studies and why? Lack of transparency in the process undertaken by the Applicant can result in lack of confidence that the assessment was done appropriately.
7. Inadequate extractable/leachable correlations. When there are higher levels of a compound in the leachable study or even new compounds detected in the leachable studies that were not present in the extraction studies, it diminishes confidence that the extraction studies were adequately designed to identify all the compounds that could be present in the final drug product. Without a clear logical explanation for discrepancies, a lack of an adequate extractable leachable correlation calls into question the validity of the assessment. This will result in more questions from the Agency.

PDA Letter: What advice do you have regarding safety assessments for extractables/leachables?

Mellon: My advice to organizations preparing submissions to regulatory authorities, such as the FDA, is to be extremely clear in how your assessments were designed.

Explain in detail how you designed the qualification program and how you leveraged the extraction study results to inform the design of your leachable study. Explain why you chose the solvents and extraction conditions utilized. Explain how you determined your analytical evaluation threshold and your Limit of Quantitation (LOQ). Make sure your analytical evaluation threshold is consistent with the review division’s safety concern threshold expectations. Provide a summary table of the compounds detected, their concentrations, the maximum daily dose that would result from use of the product, and the confidence in the identification of the compound. Evaluate at least three batches of the final to-be-marketed drug product over stability, and include multiple time points to identify trends over time. Submit study reports with an integrated discussion including hyperlinks to the individual study reports, which should clearly show how the data were generated and integrated to justify your approach. Refer to USP chapters <1663> on extraction studies and <1664> on leachable studies which provide excellent discussions of best practices for extractable and leachable studies consistent with the PQRI recommendations.

From a toxicology perspective, if you are relying upon a PDE/ADI assessment, explain why you chose the pivotal toxicology studies you did, including safety factors and provide copies of all references cited. Finally, don’t wait until late in development to begin planning these studies. The extractable leachable assessment should be built into the long-term stability studies, just like drug product degradants. Adequate planning and discussion with the Agency ahead of time is crucial to success.

PDA Letter: When would a post-marketing leachable assessment be needed?

Mellon: Even after approval of a product, it is not unusual for changes in the manufacturing process to trigger the need for new leachable studies. These data are almost always necessary prior to approval of a new chemistry supplement. A change in the components of the container closure system certainly require reassessment of the original extractable leachable conclusions and likely require new data. But other smaller changes in the manufacturing process may also require reassessment of the existing extractable leachable data and may well require new studies. Examples include: changes in excipients in the drug product formulation, changes in raw material suppliers, changes in sterilization methods, storage conditions, or shelf-life, and even changes to the upstream manufacturing process. Each of these can result in changes in the extractable leachable profile, potentially even introducing new chemicals and require reassessment of the existing toxicological risk assessments. Any changes should be accompanied by a thorough discussion of the existing data and, as needed, new stability studies or perhaps bridging studies to ensure that the container closure system is still adequately qualified for its intended use. It may be possible, depending on the nature of the change, to design a bridging study or use a simulation study to address minor changes, if there are adequate data to create a bridge. Planning ahead and obtaining Agency feedback on your plan will hopefully prevent unnecessary delays in implementation of manufacturing changes.