Article

E&L With Dr. Scull: Materials Risk Assessment for E&L Studies

09/28/23

By Engaged Expert Jim Scull

What is a Materials Risk Assessment (MRA)?

The MRA is a paper exercise in which the components of the project, be they part of a container closure system (CCS) or manufacturing train, are assessed in relation to their intended use and the specifics of the drug product formulation or manufacturing conditions.

The purpose of conducting an MRA is multifold;

To review all data provided by the vendor regarding the materials of construction (MOC) of the individual components, including any vendor-supplied extractables data
To provide an assessment of the gaps between the vendor data and the data required to meet regulatory agency expectations
To provide a study design that, when executed, will fill the identified data gaps, resulting in a complete E&L submission package

There are several advantages in conducting an MRA:

The MRA serves as a “submission-ready” document that provides a comprehensive review and assessment of the MOC and outlines target compounds that are likely to be found during the E&L study
The MRA not only provides a study design but also includes the rationale behind it
The conclusion of the MRA may determine that the vendor-supplied data for the MOC is sufficient for satisfying the extractables requirements, thus eliminating the need for further testing and allowing the project to progress directly to the leachables portion

How do we get started on our MRA?

Step 1: Ensure the person performing the assessment has in-depth knowledge of polymer chemistry, especially the typical additive packages used to prevent oxidation or enhance polymer performance. An example of such an additive includes slip agents applied to a polymer surface. A thorough understanding of such compound's reaction chemistries is necessary because the additive's degradation products often are seen in E&L studies. One of the main goals of a leachables study is to relate a specific leachable to its parent compound.

Step 2: Identify all of the system components that have direct contact with either the drug or the patient. Once these are identified, contact each component’s vendor to obtain all available extractables information. Information from other sources, such as vendor websites, technical application papers and research literature, also may be helpful. The assessor also may have a personal library of information gathered from prior assessments.

Step 3: In the case of a CCS project, the assessor receives the specifics of the formulation, dose regimen, route of administration, intended storage conditions and estimated product shelf-life. For a manufacturing train assessment, the flow path, contact time and temperature, and information on any component sterilization methods are necessary.

I have the information. What do I do with it?

Once the assessor has the above information, they conduct a thorough review relative to what E&L data is required to support submission to regulatory agencies. This step requires a good understanding of what agency reviewers expect for each particular application, either a CCS or a manufacturing train, for example.

In many cases, a gap between the known information and the information required for submission exists. Such gaps arise when the vendor information is too vague to be applicable or the extraction conditions employed in the vendors studies did not generate an extraction profile that would be indicative of the “real-life” usage of the components. An assessor truly makes an impact when the data gaps are identified and when a well-planned study designed to complete the E&L package fills those gaps.

The Results (an example)

Figure 1: The schematic of a piston pump used to contain and deliver a topical gel product. (Figure courtesy of Dr. Michael Ruberto)

Dosage Pump Schematic

Component	Schematic #	Leachables Risk
Container Round	Not Shown	Moderate Risk
Piston round	Not Shown	Low Risk
Cap	1	Low Risk
Actuator outer	2	Low Risk
Membrane	3	Low Risk
Actuator inner	4	Low Risk
Reduction plug	5	Low Risk
Bellows	6	Moderate Risk
Adapter Ring	7	Low Risk
Adapter	8	Low Risk
Label	Not Shown	Moderate Risk

In future blog posts, Jim will discuss how we get from the vendor data to the final risk designation and, ultimately, the E&L study design.

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About the Author

James R. Scull, Ph.D., Technical Director for Element Life Sciences, has more than 32 years of pharmaceutical development experience spanning all areas, from discovery support through manufacturing. His expertise includes applied analytical chemistry, toxicology, multi-dimensional separation science, extractable & leachable studies, CMC product development and oligonucleotide analysis.

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