An Overview of Risk Assessment Strategies for Extractables and Leachables - The author describes several approaches for risk assessment of extractables and leachables. - BioPharm International


An Overview of Risk Assessment Strategies for Extractables and Leachables
The author describes several approaches for risk assessment of extractables and leachables.

BioPharm International
Volume 25, Issue 1, pp. 39-45


In a quality-by-design (QbD) approach to manufacturing, the goal is to design in the quality of the final product by understanding all critical parameters and implementing robust manufacturing processes to control those parameters, as opposed to attempting to test in the quality from an unstable, poorly understood manufacturing process. The importance of QbD in extractables and leachables risk assessments, particularly in the OINDP application, was recently discussed (23).

Figure 1: Strategies for mimimizing the risks of leachables. (ALL FIGURES ARE COURTESY OF THE AUTHOR)
In the risk assessment of leachables, the critical QbD goal is to understand and control the safety of the tool in the application. The author's preferred process for achieving this safety is shown in Figure 1. The base of the pyramid is the responsibility of the tool manufacturer and is where most of the safety is built in, as indicated by its size. Knowledge of the technical literature could, for example, be used to understand and predict the impact of gamma sterilization on physical properties and the amount and type of gamma-induced leachables.

The green levels in the figure represent steps only the user of the tool can perform because they are highly application specific. The brown level represents steps that both the manufacturer and user of the tool can perform. The manufacturer of the tool tends to perform generic analytical testing, whereas the end user is more likely to perform analytical testing closely aligned with the application of the tool. The size of each level reflects the degree to which it helps lower the risk of leachables that affect safety. The key point in the graphic is to not be overly reliant on analytical chemistry and subsequent toxicological assessment of the analytical data, but to understand, robustly design in, and control the safety of leachables, rather than to test in the quality in the final application.


When Fawley published his milestone paper on the threshold approach to toxicology, the phrase "common sense" was prominent in the title (24). While it took many years to gain legal acceptance, the threshold strategy is now well entrenched and is being expanded on a global basis to a multilevel threshold strategy using the TTC approach. The FDA CFSAN still has only the single-level TOR, which individual scientists at FDA have described as too inflexible (25).

The pharmaceutical arena has seen some well-publicized examples of leachables that potentially might affect patient health; virtually all were from container closures. Examples in the past few decades have included polycyclic aromatic hydrocarbons from carbon black fillers in elastomers, N-nitrosoamines or mercaptothiazole in rubbers, and diethylhexylphthalates from plasticized polyvinyl chloride blood and intravenous bags and tubing (26, 27). Even permeation of leachables from labels and their adhesives through a low-density polyethylene film into a drug-containing vial has been observed (28).

In the biopharmaceutical industry, the published leachable examples are fewer due to the relatively short time that biologics have been manufactured. The issues in biopharmaceuticals seem more centered on API interactions with leachables and less about potential direct toxicological issues, undoubtedly due to the greater inherent instability of biologicals relative to traditional small-molecule pharmaceuticals (29). Nevertheless, a rubber leachable after a formulation change apparently caused an increased risk of red-cell aplasia in European patients receiving EPO therapy (30).

Case histories of leachable problems present several clear trends in risks due to leachables. Because of their complex formulations and manufacturing processes, cured elastomers often have a much greater chance of having leachables with direct health risks than thermoplastics, and drug-leachable instability interactions are much more prevalent problems than direct leachable toxicity concerns. The higher risk of cured elastomer issues should be addressed by minimizing contact area and time, or selecting noncured (i.e., TPE) elastomers or over-molded elastomers (31). Drug-stability studies should be performed early in the material evaluation process, and analytical-leachables studies done to characterize the performance of acceptable materials or establish root cause for materials that reduce drug stability.


The goal of any risk assessment should be to promote a rational resource allocation to address potential problems, with the highest risk areas receiving the highest scrutiny. To assess the toxicological risk of leachables from product-contact surfaces, one must understand material science, solubility parameters, the effects of sterilization procedures such as gamma irradiation, application-specific parameters (i.e., contact time, temperature, surface area and volume, solution properties, and proximity to the final formulation), and relevant toxicology to assess the value of extractables and leachables testing.

This scientific assessment must be combined with information from the material supplier. Supplier information should substantiate that the raw materials have appropriate 21 CFR clearance for the application, the proper controls are in place for cGMP manufacturing, and whether available generic extractables or leachables data can help in the risk assessment. Often the risk assessment using the combination of the manufacturer's generic leachables data with the end-use application-specific parameters and a TTC approach will conclude that further leachables studies are not necessary to establish the safety of the leachables in terms of direct toxicity.

Table III: Toxicological risk assessment of leachables for three devices/applications. OINDP is orally inhaled and nasal drug product.
Table III shows the analysis of the toxicology risk using a series of potentially important variables when using three devices in three applications, roughly based on the protocol suggested by the Biopharmaceutical Process Extractables Core Team (17). Other possible risks from leachables, such as product formulation instability or assay interferences, would be assessed separately.

The first section of the table contains estimations of six variables that could affect the concentration of observed leachables. The second section contains estimations of two variables related to the potential toxicological risk of the leachables. Rather than assign numerical values to each risk level, such as the 1–10 scale previously suggested, the overall risk is estimated with high, medium, or low categories. Rather than sum up the numerical risk levels to achieve an overall risk assessment, the relative risk of toxicology of the leachables and the relative risk of the amount of leachables are evaluated separately. The two risks are viewed as multiplicative, in line with the normal definition of risk as equal to the degree of the hazard times the level of the exposure. This separate evaluation allows for the possibility that if the toxicology is estimated to be low risk, then the concentrations of the leachable are not as important, much as in the TTC approach.

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