Extractable and leachable contaminants from within a drug’s packaging can make their way into the drug product itself. While it is rare for products to become adulterated in this manner, it can and does happen, and thus it is essential that effective tests are carried out to detect and, if necessary, identify and quantify the levels of extractable and leachable substances that may be present in a drug dosage form.

While extractable and leachable contaminants are occasionally found in tablets and capsules, they are much more likely to be present in drugs that are formulated as liquids for parenteral administration or inhalation. Any part of the packaging system has the potential to cause this type of contamination, whether it is in direct contact with the product or not. Vials, ampoules, bottles and closure components all directly touch the product. Yet even the pack’s label, carton or shipping containers, which do not, can contaminate the drug.

An extractable is a compound that can be extracted from packaging material in some way. This usually involves elevated temperatures or aggressive solvents, and generally takes place at a solid-to-liquid interface. Examples of extractables include additives that modify a polymer’s properties, or by-products of the manufacturing process for that polymer, such as unreacted monomers or processing aids. A leachable, in contrast, is a compound that leaches into the drug product from its packaging, without any need for an extraction process.

Pharma companies are careful to control their supply chains; however there is always the potential for contamination. The demand for transparency that pharma places on its own suppliers rarely carry all the way down the supply chain. Thanks to a reliance on trade secrets further upstream, there is no guarantee that the masterbatcher, which supplies the container manufacturer, will disclose all the stabilizers, antioxidants, antistatic agents or processing aids it adds to the polymer. Similarly, the polymer manufacturer, which supplies the masterbatcher, might have added antioxidants or stabilizers, and residual monomer or catalyst may remain within the polymer. Even the chemical manufacturer that supplies the polymer maker might have introduced unexpected contamination.

Therefore, it is vital to detect the presence of any extractables and leachables before drug products reach patients. While the precise requirements differ among the various regulatory agencies around the world, there is a fundamental expectation that the pharma company will have taken all possible steps to ensure that the products it supplies remain free of contamination.

The regulatory requirements vary greatly depending on the dosage form. For example, FDA might approve an NDA for an oral tablet, with the only stipulation being that extractables from the polyolefin bottle it is to be packed in meet the USP container specifications. On the other hand, the NDA for a product supplied in a metered dose inhaler will likely state that all components of the delivery device, canister and actuator meet specific criteria and be analyzed separately, and that every batch of drug product must have leachables below a certain level by the end of its shelf-life.

At the very least, all components used in the manufacture of a finished dosage form must adhere to all the quality requirements laid down by the regulatory authorities in the country or region in which it is to be sold. A risk-based approach is taken in defining and interpreting how the components interact with the dosage form, and this requires a concerted and thoughtful approach from the company’s development team. At a minimum, this approach must be justified and documented as part of any product approval application.

Extractable and Leachable Detection
The two most challenging aspects of method development, as with all analytical chemistry endeavors, revolve around specificity and detection. For the necessary specificity to be achieved, any method must be able to distinguish extractables and leachables from drug substances and excipients, and also from other contaminants that may be present in the product from other sources, such as degradants or impurities remaining from the manufacturing process of the drug product itself.

Chromatography is often used to separate drug product constituents, with techniques that are capable of identifying specific compounds being used to provide both sensitivity and additional selectivity. However, the big challenge with leachables analysis is the sheer number of potential compounds that might be present. There are thousands of packaging additives that could be used, and so the first step is to understand which are most likely to be found. Leachables studies without a proper extractables characterization process usually result in failure, as neither specificity nor sensitivity can be established for the huge spectrum of potential contaminants.

While drug-like compounds have many similar physicochemical features, such as molecular weight, lipophilicity and the number of heteroatoms they contain, the molecular properties of polymer additives are much more variable. They allow them to disperse in polyolefins, which can be considered massively heavy hydrocarbons, but still have reactive features that enable them to interact with water or oxygen. This throws up real problems for carrying out analytical methods, because the properties of the formulation overlap with those of potential additives. As formulation technology pushes the boundaries of molecular space in terms of what molecules are considered drug like, this will only become more difficult.

Designing a Testing Strategy
The strategy for testing packaging varies according to the dosage form, and not the packaging itself. For leachables, the design of a testing strategy will begin with gaining insight into both the drug product’s formulation and its intended use. The proposed dosing regimen, the number of doses per container and the duration of treatment, all must be known in order to develop a justifiable safety threshold that will be the lower limit on any analytical method’s limit of detection.

As most polymers are processed at high temperatures, in contrast to the majority of active pharmaceutical ingredients (APIs), packaging additives are not thermally labile. The use of Gas Chromatography (GC) to carry out the analysis is routine, as it is both robust and extremely selective. The combination with a broadly active yet sensitive Flame Ionization Detector (FID) is hard to beat for accurate stability studies for leachables. While the addition of Mass Spectrometric (MS) detection can increase selectivity, the robustness of the GC/FID system more than compensates for this. Should extraneous peaks in the GC/FID spectrum demand further investigation, it is relatively quick to implement a GC/MS process to enable identification.

The analysis of extractables is only performed to show how leachables that are found may impact the risk profile of the final product. Extractables studies on their own cannot provide sufficient information about quality to show that the proposed packaging is suitable for that product.

In addition to the information about dosing, a study should always include an appropriate list of potential contaminants or targets that might be present. Ideally, this should be found experimentally using an extractables study that is relevant to the specific formulation. However, this is not always necessary, as it may be available from previous studies, or even from the packaging suppliers.

Armed with this target list and safety threshold, the next step is to develop methods that can be used to detect and quantify relevant leachables in the drug product formulation. The method will then need to be validated to appropriate industry standard levels, such as ICH Q2.

The final step is to simulate what happens over time, by storing the drug product under environmental conditions that mimic expected use. This is exactly the same procedure as described in ICH Q1A(R2) through ICH Q1F stability guidelines. Product should be stored at various orientations under storage conditions that will be provided to users, i.e. CRT (20°C to 30°C) or refrigerated. At regular intervals, leachables stability analysis will be conducted to show how leachables profiles change over time. Generally, results at end of shelf-life are used to prepare the final risk analysis and acceptance for any detected leachables. In the absence of final marketed pack product at end of shelf-life, leachables results from product stored under accelerated conditions may be used at initial regulatory body application, but, as the FDA container closure guidance states, “The ultimate proof of the suitability of the container closure system and the packaging process is established by full shelf-life stability studies.”

Testing Challenges and Contaminant Dangers
Some potential contaminants, such as antioxidants, are commonly present in both packaging and the drug formulation itself. As they have two potential sources, a single method to quantify the total may be necessary as a quality check. However, levels of these ubiquitous additives are rarely sufficiently high to be a safety concern.

Others are particularly difficult to pinpoint. For example, surface modifiers such as antistatic additives are generally present at very low concentrations relative to the bulk component or the formulation. To make things even more challenging, these molecules are designed to be ambiphilic, with both non-polar polymer and highly polar charged features. Examples of these types of compounds include long chain fatty acids and amides. Both types of compounds are notoriously difficult analytes and the best analytical results are obtained by derivatization (esterification) with subsequent GC-FID or GC-MS detection. From a patient safety risk perspective, both classes of compounds are fairly benign and commonly found in foodstuffs. Their presence (or absence) can often highlight product performance or delivery as they are used to minimize interactions between formulation and packaging.

The limits for some extractable and leachable contaminants are notoriously difficult to meet. Historically, rubber was prepared by vulcanization, which involves heating a base polymer containing unsaturated hydrocarbons with mixtures of sulfur compounds plus unreactive carbon black as a filler. As well as elemental sulfur, which is not a huge safety concern, common raw materials in this process include 2-mercaptobenzothiazole and polynuclear aromatic hydrocarbons, both of which have very high toxic potentials. In addition, by-products of the vulcanization process include carcinogenic N-nitrosoamine species. Regulatory agencies expect that vulcanization will not be involved in the supply chain, with more modern processes that do not create these contaminant problems being used instead. They also expect that levels of any of these contaminants should be below detectable limits via mass spectrometry, for polynuclear aromatic hydrocarbons or chemiluminescence for N-nitrosoamines.

Fundamentally, it is essential for patient safety that drug products do not interact with their packaging, and there have been several examples in recent years when products have been withdrawn after such contamination was found. It is equally essential to prove that this is the case, and that any leachables or extractables that do find their way into the product remain below safe levels, even after storage right through to the expiry date. Only by designing an effective and predictable product testing strategy that reliably meets the demands of the regulators can a company be sure that its products are free from contamination by extractable and leachable substances. 

Selected References

• US FDA “Draft Metered Dose Inhaler (MDI) and Dry Powder Inhaler (DPI) Drug Products. Chemistry Manufacturing and Controls Documentation”, November 1998
• US FDA “Guidance for Industry: Container Closure Systems for Packaging Human Drugs, Biologics, Chemistry, Manufacturing and Controls Documentation”, May 1999
• International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, ICH Harmonised Tripartite Guideline “Specifications: Test Procedures and Acceptance Criterria for New Drug Substances and New Drug Products: Chemical Substances”, October 1999.
• US FDA “Guidance for Industry: Nasal Spray and Inhalation Solution, Suspension, and Spray Drug Products: Chemistry, Manufacturing and Controls Documentation,” July 2002
• Feinberg, T.N. “Hyphenated Characterization Techniques” In Handbook of Isolation and Characterization of Impurities in Pharmaceuticals-Volume 5 (S. Ahuja and K.M. Alsante, Eds), 2003
• International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, ICH Harmonised Tripartite Guideline “Stability Testing of New Drug Substances and Products Q1A(R2)”, February 2003.
• International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, ICH Harmonised Tripartite Guideline “Validation of Analytical Procedures: Text and Methodology Q2(R1)”, November 2005
• International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, ICH Harmonised Tripartite Guideline “Impurities in New Drug Products Q3B(R2)”, June 2006
• Norwood, D.L., et al. “Safety Thresholds and Best Practices for Extractables and Leachabels in Orally Inhaled and Nasal Drug Products,” PQRI submission to US FDA, September 2006
• Norwood, D.L.; Paskiet, D.; Ruberto, M.; Feinberg, T.; Schroeder, A.; Poochikian, G.;Wang, Q.; Deng, T.J.; DeGrazio, F.; Munos, M.K.; Nagao, L.M. ”Best Practices for Extractables and Leachables in Orally Inhaled and Nasal Drug Products: An Overview of the PQRI Recommendations” Pharmaceutical Research,  2008
• Norwood, D.N.; Mullis, J.O.; Feinberg, T.N.; Davis, L.K. “N-Nitrosamines as “Special Case” Leachables in a Metered Dose Inhaler Drug Product” Parenteral Drug Association Journal of Pharmaceutical Science and Technology, 2009
• International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, ICH Harmonised Tripartite Guideline “Pharmaceutical Development Q8(R2)”, August 2009
• International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, ICH Harmonised Tripartite Guideline “Impurities: Guideline for Residual Solvents Q3C(R5)”, February 2011
• Markovic, I. “Regulatory Perspective on Safety Qualification of Extractables and Leachables,” FDA PQRI PODP Workshop.  February 2011
• Leachables and Extractables Handbook: Safety Evaluation, Qualification, and Best Practices Applied to Inhalation Drug Products (D.J. Ball, D.L. Norwood, C.L.M. Stults, and L.M. Nagao, Eds), January 2012

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Thomas Feinberg, Ph.D., is director, Development & Clinical Services, at Catalent Pharma Solutions. He can be reached at tom.feinberg@catalent.com.