Extractables and Leachables (E&L) is a challenging topic to address during product development. A successful E&L program depends on whether the program design is based on the correct information on the container/closure system. The first critical step is the initial material characterization (determination of extractables) of the container/closure system to understand what can possibly migrate into the final drug product as a leachable. If the data from these studies is not applicable or insufficient for a sponsor’s product, it can lead to regulatory delays or recalls. Most of the container/closure systems used today are not proprietary but are purchased from component manufacturers.
As part of a service to their clients, many of these providers now offer extractable information on their products. However, the usefulness of this information can vary widely from manufacturer to manufacturer. The challenge for sponsors is to understand what information they need, what questions to ask their vendors, and how to evaluate the information for their specific application. This presentation will walk through a process for ensuring the right questions are asked and how that information should be evaluated.
Methods: A stepwise process will be presented that will enable companies to ensure they are asking the correct questions when interacting with their container/closure vendors. An example risk assessment and gap analysis process will be presented that covers how the data can be evaluated against a sponsor’s specific drug product.
Results: Representative case studies will be presented in applying the process to data provided by the component manufacturer.
Conclusions: By starting the extractables and leachables evaluation early, sponsors can avoid potential delays in their development time line, avoid recalls and, most importantly, avoid jeopardizing patient safety.
Compounds that can, under aggressive laboratory conditions, migrate out of materials
– Normally a subset of extractables
– Compounds that migrate into the drug product
Extractable ≠ Leachable
– Extractables don’t always leach
– Leachables don’t always extract
Regulatory Basis for Evaluation of Extractables/Leachables
The regulatory requirements for the evaluation of extractables and leachables are found within the Code of Federal Regulations (CFRs), as shown in the tables below. The regulations indicate that the requirements for all contact materials (i.e. final packaging system and manufacturing equipment) are the same.
Several guidances are available from the FDA which addresses extractables and leachables:
While the above information from the FDA addresses E&L studies, it doesn’t go into specifics in how the studies need to be performed. For guidance on performing E&L studies industry best practices documents can be used for designing studies. Some of the groups that have guidances available are:
Additionally, the USP has drafted new chapters, which are currently under review, for guidance on E&L studies:
Given the rise in E&L expectations, many component manufacturers have started providing extractable data on their materials. These data packages vary in the level of detail and in how the information was collected. This is not unexpected given the following:
As a result, the usefulness of these packages can vary significantly. It is important for a company to have a process in place to evaluate the information provided by the manufacturer (if any), and to determine whether the information is applicable to their product or whether additional studies will need to be performed. The following is a summary of a detailed process which can be used in walking through some of the main questions to be asked and in how to evaluate the information collected.
Step 1: Questions to ask the Vendor
The key to starting the evaluation is to ensure you have asked the correct information and have it available. This requires going to the manufacturer and obtaining as much information as possible on the contact materials, their materials of construction, etc. Below are some example questions which should be posed.
Is there a DMF?
Is there an extractables data package?
Has the component been used in a successful filing?
Are multiple resin sources available for polymeric components?
Different grades of resins?
Are all components made in the same facility/line?
What testing is performed on the components for release? i.e. How is variation controlled?
Will they implement a supply agreement?
Step 2: Perform Risk Assessment and Gap Analysis on the information provided.
Once the information from the above questions is received it is important to then evaluate the data in terms of the specific drug product and the specific application. Without a good evaluation process it can leave the company open to higher risk that there could be delays or surprises in the development.
Were chemical extractions performed or list of “possible” extractables given based on manufacturing process?
How were the chemical extractions performed?
Did the analytical methods go low enough?
Evaluation of Supply/Shipping chain
How Low To Go
One of the most challenging and common deficiencies is that the analytical methods didn’t go low enough for a specific drug products formulation/dosing regimen.
No direct regulatory guidance is available
Safety Concern Threshold (SCT)
Using the PQRI’s idea of the Safety Concern Threshold we can convert that to an equivalent analytical level for a specific product. The conversion takes into account the drug’s specific dosing regimen and the number of doses which are in each container/closure system. Example equations for converting the AET into a number of different units, depending on the usage, are shown below.
1Ng, Linda (CDER/FDA), “Current Regulatory Recommendations for Leachables in Ophthalmic Drug Products,” Thresholds and Best Practices for Parenteral and Ophthalmic Drug Products, 22-23 February 2011, Bethesda, MD.
One of the most critical issues in extractable evaluations is ensuring that the data you are making the decision meets the expectations based on the best practices recommendations. This requires evaluating the information for the specific drug product formulation and worst case scenario dosing regimen for a product. The following case study demonstrates that information provided by a manufacturer may be adequate for some cases but not acceptable for others.
The product is a parenteral with an aqueous formulation (same formulation for both scenarios) in a 20 mm glass vial with a 3.0 gram rubber stopper. The stopper manufacturer has provided an extractables package that used analytical methods with a quantitation limit (QL) of 5ppm. Asymptotic extractions were performed using water and IPA.
We will review the package against two different container closure scenarios:
For the evaluation of the data we are going to examine two specific items:
1. Extraction Solvent(s) vs. DP formulation
– The extraction solvents used (water and IPA) cover the polarity range of the DP formulation (aqueous) used above. In terms of extraction solvents used, the data provided by the manufacturer are applicable to the product.
2. QL of the extraction methods vs. AET needed
– Applying a 1.5 µg/day SCT, based on the PQRI current thinking for parenterals, we are able to compare the expected reporting level against the data provided by the manufacturer.
As can be seen in the table, for scenario 2, we are able to use the data provided by the manufacturer for evaluating the extractables profiles, however in the case of scenario 1, the analytical methods used didn’t go low enough.
Case Study #1 summary: The data provided by the manufacturer can be used for the evaluation in scenario 2. However, the data are not adequate for evaluating against the dosing regimen in scenario 1. As a result, it is likely that additional studies would be needed to achieve the lower QL required by the AET.
For this example we will evaluate another parenteral product with an oil based formulation (cottonseed oil) in the same container/closure system as in Case Study #1. The stopper manufacturer has provided an extractables package that used analytical methods with a quantitation limit of 5ppm. Asymptotic extractions were performed using water and IPA.
We will review the package against the following configuration:
For the evaluation of the data we are going to evaluate the same two items as we did in case study #1:
1. Extraction Solvent(s) vs. DP formulation
– The extraction solvents (water and IPA) are not representative, nor do they cover the polarity range of the formulation(cottonseed oil). As a result they would not be predictive of leachables in the product.
2. QL of the extraction methods vs. AET needed
– Applying a 1.5 ug/day SCT, based on the PQRI current thinking for parenterals, we are able to compare the expected reporting level against the data provided by the manufacturer.
As can be seen in the table, the QL (5ppm) and extractables data provided by the manufacturer does go low enough compared to the AET required for the drug product.
Case Study #2 summary: Based on the extraction solvent mis-match, the data provided by the manufacturer cannot be used in evaluation for the drug product. New studies would be required.
It is important to use the correct information and process to ensure that the development process is not delayed as a result of an E&L issue. By having the right information available, it is possible to avoid some of the most common pitfalls that can result in regulatory delays for products by having a well-defined process in place when choosing the container/closure system.
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