Understanding Leaching from Stoppers into Lyophilized Drugs

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Pharmaceutical products come in contact with a wide range of polymeric, elastomeric, and/or metallic materials during their manufacture, storage, and/or administration. In some cases, unintended interactions with these materials may occur. In one such interaction, impurities can leach into the drug product, posing potential safety and efficacy issues. Global regulatory authorities require that extractable and leachable (E&L) studies be performed on contacting materials and drug products, respectively, in order to characterize this interaction and ensure patient safety and product quality (1–4).

For most pharmaceutical products, solvents mediate the interaction that results in leaching (e.g., a compressed liquid propellant in a metered dose inhaler; a liquid parenteral product stored in a polyvinyl chloride [PVC] bag; or a liquid ophthalmic product stored in a low-density polyethylene [LDPE] bottle), and the phenomenon is presumed to occur only with liquids. The Product Quality Research Institute (5,6), US Pharmacopeial Convention (7–9), and the International Organization for Standardization (10) have proposed directives for assessing these types of interactions. 

Primary packaging materials may leach into lyophilized formulations

However, a growing body of evidence suggests that primary packaging materials may leach into solid lyophilized drug formulations. Such solid formulations are typically used for drug products which are chemically or biologically unstable in solution, a situation encountered for many biopharmaceutical drug products. Consequently, as demand increases for biopharmaceuticals, so, too, does the number of lyophilized formulations on the market. 

Despite the increased prevalence of lyophilized drug formulations, it is not currently well known how they interact with primary packaging materials. Because lyophilized drug formulations are solids, it may be tempting to assume they cannot leach substances from their primary packaging systems. However, evidence suggests that the opposite is true. This article aims to provide insight into this interaction and discuss implications for the assessment of extractables and leachables in these products.

Leachables in lyophilized drug formulations

Can a solid leach substances from the materials that comprise its primary packaging and, if so, how do the qualitative and quantitative profile of leachables in solids compare to those for liquids? Table I presents leachable profiles published (11,12) for three lyophilized drug products, one drug product stored after reconstitution with water, and a 10/90 isopropanol/water solution.  

Table I. Leachable profiles of three lyophilized and one liquid drug formulation. All values are expressed as /vial. ND = Compound was present in the stopper but was not detected in the medium. - = Compound was not present in the stopper material.

Table I. Leachable profiles of three lyophilized and one liquid drug formulation. All values are expressed as /vial.
ND = Compound was present in the stopper but was not detected in the medium.
- = Compound was not present in the stopper material.

Even though the term “leach” is most often associated with liquids, this article uses it to refer to compounds that have migrated from a packaging material and into a solid matrix as leachables, with the understanding that the physiochemical mechanism driving leaching in liquids may not be the same as it is in solids. 

The leachable profiles presented in Table I illustrate two key points. First, all three lyophilized formulations were found to contain compounds that had leached from the stopper, so the lyophilized solid drug was affected by substances that had migrated from the packaging system. 

Second, it was shown that the third drug product, when reconstituted prior to storage, as well as a 10/90 isopropanol/water solution that had been stored in the same packaging system, contained no leachables or extractables. This difference suggests that an aqueous liquid formulation may have less or no propensity to leach substances from the same stopper when all other factors are equal.

It is likely the compounds listed in Table I were leachables in the lyophilized drug product but not the aqueous media because these substances are quite hydrophobic (octanol/water partition coefficients > 100,000). Thus, they would be expected to have no solubility in, or affinity for, a highly aqueous solution, whereas lyophilized drugs, containing no water, would interact differently with these substances. Other traits shared by these leachables are their relatively low molecular weight and moderate volatility, which would facilitate their diffusion from the stopper and into the lyophilized drug even though the solid would be considered a “static” medium.  

Analyzing qualitative leachable profiles

It is important to note the similarities in the qualitative leachable profiles reported for each drug product in Table I. This correlation is a function of the composition of the stoppers used to seal the vials, which are typically bromo-butyl or chloro-butyl rubber. 

Considering further, the leachable profiles themselves consist of two compound classes: rubber oligomers, which represent low molecular weight termination byproducts of the polymerization reaction, and the antioxidant butylated hydroxytoluene (BHT). The low molecular weight oligomers have been previously characterized (13,14) and are always found in butyl rubbers. Conversely, BHT is an intentionally added substance and thus only would be present if it were included in the rubber’s formulation.

Qualitative vs. quantitative aspects of the leaching profile

The qualitative aspects of the leachable profile differ widely from its quantitative aspects. Possible explanations include:

• differences in the total pool of each compound in each stopper

• differences in the ability of each drug product to sorb leachables

• differences in the stoichiometry of the interaction (e.g., based on drug product mass or vial size). 

Additional work is required to better understand the quantitative aspects of this interaction.

Extractables from vial/stopper systems 

Extractables studies are performed on the components of a packaging system to achieve various goals. 

One goal, for example, could be estimating the qualitative/quantitative profile of leachables that may be encountered for a product. In this case, conditions and solvents would be selected to simulate actual contact conditions during product storage and use. An alternative goal would be to use more aggressive extraction solvents and test conditions to determine the material’s composition for quality assessment purposes. In this case, the packaging components for a lyophilized drug product would be handled just as those for any other packaging material (e.g., using organic solvent to extract the rubber material, as facilitated by solvent reflux).  

Despite the fact that lyophilized drugs are solids, it may be useful to use a solvent to perform a simulation-type extract study. Reasons for using this approach would include familiarity with various water/organic solvent mixtures for this purpose, and/or analytical compatibility with these media as opposed to the drug matrix, which could pose specificity concerns due to the presence of excipients or API.  

However, great care must be taken when using this approach because of the different interactions that may occur between solid and solvent-based formulation. For example, as discussed previously, use of a highly aqueous solvent would be inadequate to simulate the lyophilized drug, given the insolubility of the leachables. In fact, research has shown (11) that a solution of approximately 50/50 isopropanol/water would be required to mimic the extraction power of the third lyophilized drug product included in Table I. 

Table II presents extractables data obtained for a lyophilized drug product, polar solid medium (potassium chloride), and non-polar solid medium (activated charcoal) stored at the same mass in the same packaging configuration. Using this approach, it is clear that alternate solid media can be used to generate a range of extractable profiles. In this case, it seems logical that the non-polar solid extracts the highest mass due to the non-polar nature of the extractables. However, additional work will be required to quantify not only the extraction power of solid media, but the extraction properties of lyophilized drug products to determine whether a relationship can be established. 

Table II. Comparison of the leachable/extractable profiles of a lyophilized drug product to a polar and non-polar solid medium stored in identical packaging systems.

Table II. Comparison of the leachable/extractable profiles of a lyophilized drug product to a polar and non-polar solid medium stored in identical packaging systems.

What happens in storage

The previously discussed leachables data was relevant for lyophilized drug products after storage in their primary packaging systems. However, these drugs typically are not administered directly to the patient in lyophilized form, and thus these data do not necessarily quantify exposure. For example, the lyophilized drug often is reconstituted in an aqueous medium and then stored and/or administered via a syringe, bag, pump, and/or infusion set. As such, it is uncertain whether these compounds, which are hydrophobic as previously noted, remain in the drug solution through the process, or whether they are lost through some mechanism, such as precipitation or binding to the storage/administration systems. A recent study (12) assessed the concentration of these leachables throughout the storage and administration process. Variables assessed included contact with a polymeric drug delivery bag, administration set, polymeric composition of the bag (PVC versus non-PVC material), contact duration, and contact temperature.

Reduction in mass

Considering first the most consequential result of this study (i.e., the amount of each leachable administered to the patient), it was shown that the mass of a leachable generally was reduced or eliminated after some period of contact with the bag/administration set. However, it also was demonstrated that for certain leachables, namely the higher molecular weight, less volatile butyl rubber oligomers, storage at refrigerated temperatures, and/or short contact durations, most or all of the mass of the leachable in the lyophilized drug formulation would be exposed to the patient. An example of these trends can be found in Figure 1.

Figure 1. Comparison of leachable mass (relative to that in the original vial) in drug solution following contact with an intravenous bag at ambient and 5 C for up to seven days (168 Hours) [figure courtesy of the author].

Figure 1. Comparison of leachable mass (relative to that in the original vial) in drug solution following contact with an intravenous bag at ambient and 5 °C for up to seven days (168 Hours). [Figure is courtesy of the author.]

This research uncovered other notable aspects (e.g., the correlation between leachable mass loss from the drug solution and temperature, and the lack of any difference in loss of the leachables from solution that had been stored in bags composed of PVC and non-PVC materials).

The data discussed in this article, as well as the author’s experience assessing leachables in liquid and lyophilized drug formulations, suggest that lyophilized products have an increased propensity to leach. Research showed that several semi-volatile organic compounds from the butyl rubber stoppers that comprise their primary packaging system leached into lyophilized product, while they did not leach into an aqueous liquid formulation stored in the same packaging configuration.  

Despite these findings, anecdotal evidence and personal experience suggest that most industry professionals would expect lyophilized products to show less, or no, risk of leaching. For example, the modified FDA Centers for Drug Evaluation and Research and Biologics Evaluation and Research (FDA/CDER/CBER) risk-based matrix for leachables (included in the United States Pharmacopeia (USP)<1664> and presented in Table III) lists sterile powders for injection as being a low risk for leaching, whereas injectable solutions are considered medium risk, something that does not adequately reflect the interaction occurring for these products.

Table III. Modified FDA Centers for Drug Evaluation and Research and Biologics Evaluation and Research (FDA/CDER/CBER) risk-based approach to consideration of leachables.

References

1. U.S. Code of Federal Register (CFR). Title 21, Chapter I, Section 211.94 (a) (Government Printing Office, Washington, DC).
2. FDA, Guidance for Industry: Container Closure Systems for Packaging Human Drugs and Biologics (Rockville, MD, May 1999).
3. FDA, Guidance for Industry: Metered Dose Inhaler and Dry Powder Inhaler Products-Quality Considerations (Rockville, MD, April 2018).
4. EMA, Guideline on Plastic Immediate Packaging Materials, European Medicines Agency (London, Dec. 2005).
5. Product Quality Research Institute, “Safety Thresholds and Best Practices for Extractables and Leachables in Orally Inhaled and Nasal Drug Products,” Sept. 8, 2006.
6. D. Paskiet, D. Jenke, D. Ball, et al., PDA J. Pharm. Sci. Tech. 67, 430–447 (2013).
7. USP, <661>, USP,(US Pharmacopeial Convention, Rockville, MD, Currently Official).
8. USP,  <1663>, USP, (US Pharmacopeial Convention, Rockville, MD, Currently Official).
9. USP, <1664> USP,(US Pharmacopeial Convention, Rockville, MD, Currently Official).
10. ISO, Standard 10993: Biological Evaluation of Medical Devices.
11. S.A. Zdravkovic, PDA J. Pharm. Sci. Tech. 71, 488–501 (2017).
12. S.A. Zdravkovic, J. Pharm. Sci. online,DOI: 10.1016/j.xphs.2018.06.028, July 10, 2018.
13. I. Kuntz, K.W. Powers, C.S. Hsu, et al., Makromol. Chem. 13/14, 337–362 (1988).
14. P. Christiaens, L. Habel, Proceedings from the Smithers-Rapra E/L USA Conference, Providence, RI, 2013).

About the Author

Steven A. Zdravkovic is a senior research scientist at PPD Laboratories, Middleton, WI. 

Article Details

BioPharm International
Vol. 32, No. 2
February 2019
Pages: 21–24, 41

Citation 

When referring to this article, please cite it as S. A. Zdravkovic, “Understanding Leaching from Stoppers into Lyophilized Drugs,"BioPharm International32 (2) 2019.