Extractables and Leachables: Best Practices to Ensure Patient Safety

When developing a drug product, it is vital to ensure the product that reaches patients has not been contaminated or adulterated in any way by its packaging. Although the risk is low for solids, such as tablets and capsules, with liquid injectable and inhalable drugs, there is a real possibility that chemicals from the packaging might leach into the drug itself. Regulatory bodies, such as FDA, have strict rules regulating adulterants; therefore, conducting studies to identify and quantify any such contaminants is an important step in the drug-development process.

At first consideration, this issue might seem of purely academic interest, and unlikely to cause real problems in patients. In practice, there are numerous examples where patients have been adversely affected by adulteration caused by contaminants leached from packaging materials. One good example of how patients were harmed by a lack of study was the increase in cases of pure red-cell aplasia (PRCA) for some patients taking Johnson & Johnson's Eprex (erythropoietin alfa) in the late 1990s. A change in the formulation was made wherein the original biologically derived, solubilizing agent human serum albumin was replaced with the chemically derived and (it was presumed) less problematic solubilizer polysorbate 80 (1). Along with the formulation change, the manufacturer changed the rubber composition of the syringe from a coated plunger to that of an uncoated plunger. There was an interaction between the rubber and the polysorbate 80 in the new formulation that was missed when the changes were evaluated. Chemical components of the alkylphenol disulfide vulcanization agent within the rubber were extracted by the polysorbate 80, and these reactive compounds bound to the active protein. This "modified protein" induced an immunomodulatory effect in patients, and the result was that patients started producing antibodies against the very protein that was supposed to be helping them (2, 3).

WHAT ARE EXTRACTABLES AND LEACHABLES?

Although it may seem to be a circular definition, extractables are compounds that can be extracted out of packaging components, typically using elevated temperatures and harsh solvents; in other words, they are related to the composition of the packaging material. These chemicals might be additives that are introduced into a polymer to modify its properties, but also may be by-products of the polymer manufacturing process, such as unreacted monomers, residual catalysts, processing aids, or degradants. Typically, extractables are extracted at a solid–liquid interface, and occasionally a solid–gas interface if the extraction is carried out by a volatile organic compound. The interaction depends on the permeability of the liquid solvent into the solid, the solubility of the extractables in the solvent, and the temperature and pressure of the system.

Leachables are compounds that leach into the drug-product formulation from the packaging materials or container-closure system. A subset of extractables, leachables are chemicals associated with primary and secondary packaging that have the potential to be found in the packaged-drug product without resort to any "harsh" extraction conditions.

Primary packaging components are those that are either in direct contact with the drug product or have the potential to be in direct contact. They include the container itself, whether vial, bottle, or ampule. These components further include container liners; closures such as screw caps, stoppers and metering valves; closure liners; stopper overseals; container inner seals; administration ports; and overwraps. Secondary packaging components are integral to the final marketed package but are not in direct contact with the product. Although this indirect contact decreases many possible paths for product contamination, they still pose a risk. Container labels, administration accessories, cartons, and shipping containers are included in this category.

Leachables derived from secondary packaging components are typically more volatile than those arising from primary packaging. Examples of these chemicals include label components, such as benzophenone, tribromoanisole, and trichloroanisole from wooden pallets. The latter recently resulted in large product recalls, including Tylenol, Lipitor, Topamax, and Risperdal (4).

There are many points in the manufacture of a drug's packaging where an extractable or leachable chemical might be introduced. The pharmaceutical company that packages the product will likely demand full disclosure from the molding shop or converter, for example, where their plastic containers are made and lubricants or colorants might be introduced. This practice does not, however, extend further up the supply chain. The converter sources from a masterbatcher, which may add stabilizers, antioxidants, processing aids, and antistatic agents. The masterbatcher buys materials from the polymer manufacturer, whose products may contain residual catalysts, processing aids, antioxidants, and stabilizers. Additionally, the polymer manufacturer buys monomers from a chemical manufacturer, which might be a source of residual storage stabilizers and bulk chemicals.

All the way through the supply chain, the processes are protected by trade secrets, with companies reluctant to share full details of what might have been introduced during their step of the manufacturing process. As the pharma sector only represents a fraction of the overall plastics market, they have limited influence on what the upstream companies within the packaging supply chain might add that may have the potential to cause problems further down the line in the pharma industry.

THE US REGULATORY SITUATION

In the US, both adulterated and misbranded products are banned from interstate commerce, under the provisions of the Federal Food, Drug and Cosmetic Act (5). Anything that is not intentionally added could, potentially, cause the product to be considered adulterated, even if it remains safe. Any extractable or leachable that finds its way into the drug product is automatically deemed an adulterant. The Act, in its clause on adulteration, also specifies that "if the container is composed, in whole or in part, of any poisonous or deleterious substance which may render the contents injurious to health," the product is equally deemed to be adulterated (5).

A collection of regulations (see Table I) also apply to drug packaging as well as cGMP regulations; these include regulations on food additives and indirect food additives that might inadvertently find their way into a product, such as adhesives and adjuvants. It is not only the packaging itself that has to be considered. The equipment used in the packaging process has the potential to introduce adulteration as well. Subpart D of 21 CFR 211 specifies that manufacturers need to ensure that the surfaces of the equipment do not alter the strength, quality, or purity of the drug product (6). Non-compliance with these regulations at a minimum will result in delays to any application and possible, as discussed previously, full product recalls.

Table I: US regulations affecting drug-product packaging.

ENSURING COMPLIANCE

Numerous guidance and best practice documents are available to assist companies in ensuring they comply fully with all regulations and requirements. The International Conference on Harmonization (ICH) produces many of these, covering topics, such as impurities, stability testing, specific processes, and devices. But not a single ICH guidance document addresses what should be done with regard to characterization and control of extractables and/or leachables. As stated in ICH Q3B (R2) Section 1.3: "[i]mpurities arising from excipients present in the new drug product or extracted or leached from the container closure system are not covered by this guideline" (7). The standard threshold of 0.1% for reporting of "unknowns" during release and stability testing does not apply to leachables.

The Product Quality Research Institute (PQRI) also provides advice and guidance. PQRI is a not-for-profit consortium of organizations that work together to generate and share timely, relevant, and impactful information that advances drug-product quality and development. In 2001, PQRI started work on developing scientifically justifiable thresholds for the reporting and safety qualification of leachables in orally inhaled and nasal-drug products, and best practices for characterization of extractables from crucial components used in corresponding container–closure systems. Believing that the best practices would be sufficiently instructive, the safety qualification of extractables would be scientifically justified as they relate to leachables, except for special-case compounds such as polynuclear aromatic hydrocarbons (PAHs) and N-nitrosamines.

The outcomes of the studies conducted were published in 2006 as Safety Thresholds and Best Practices for Extractables and Leachables in Orally Inhaled and Nasal Drug Products (OINDPs) (8, 9). Prior to this publication, the question of safety being the driver for design of extractables and leachables studies was not agreed upon by industry, academia, or regulators. The key finding in the document was the Safety Concern Threshold (SCT), which sets the analytical level below which no additional safety margin would be necessary. This level, at 0.15 micrograms per day, is very low and is based on the most toxicologically sensitive endpoint for chronic exposure (i.e., genotoxicity). With the SCT, analytical scientists could design both extractables and leachables studies in a logical and safety-based manner. Additionally for regulators, the risk profile of unknown leachables was now controlled and based on sound science.

Having developed these threshold concepts for OINDPs, PQRI desired to extrapolate these principles into the evaluation and safety qualification of leachables in container–closure systems for parenteral and ophthalmic drug products (PODPs). Starting in 2007, a new Working Group, functioning under the auspices of PQRI and its member organizations, designed work plans to address these dosage forms. The key difference between the challenge of OINDPs and PODPs has been summarized by many scientists as "The Dilemma."

Generally, "The Dilemma" refers to the extreme difference in dose volume between OINDP dosage forms and PODP dosage forms. A typical pressurized metered-dose inhaler (pMDI) dosing regimen, for example, may stipulate that patients receive 75 microliters of product twice a day while a typical large-volume parenteral product may entail up to 1 liter of product once per day. For either case, the target SCT will be 0.15 micrograms, meaning that the resulting level to be checked for the pMDI is 1 ppm while that for the parenteral is more than 6000-fold lower. These levels are a challenge to current analytical technology, as other factors such as the formulation, nature of these dosage forms, and possible duration of treatment need to be considered.

Regardless of the outcome of the current PQRI project, the logic behind devising a threshold and then designing the studies is established. No longer should analytical scientists be blindly setting levels of either sensitivity or selectivity with no regard to patient exposure. Similarly, no longer will toxicologists or regulators have no agreed-upon tolerable risk level for leachables.

Thomas Feinberg, PhD, is a director in the Development & Analytical Solutions business of Catalent Pharma Solutions, tom.feinberg@catalent.com.

REFERENCES

1. K. Boven, S. Stryker, et al., Kidney International, 67, pp 2346-2353 (2005).

2. N. Casadevall, J. Natal, B Viron, et al., New England Journal of Medicine 346, pp. 469-475 (2002).

3. I. Markovic, "Regulatory Perspective on Safety Qualification of Extractables and Leachables," presented at FDA PQRI PODP Workshop, February 2011.

4. A. Sawant "Preliminary Results of a PDA Task Force Examining the Cause, Prevention and Management of TBA and TCA Taints" presented at 2011 PDA/FDA Pharmaceutical Supply Chain Conference, June 2011.

5. Federal Food, Drug and Cosmetic Act.

6. 21 CFR 211, Subpart D.

7. ICH, Q3B(R2), Impurities in New Drug Products, Section 1.3 (ICH, June 2, 2006).

8. D. Norwood, D. Ball, J. Blanchard, et al. "Safety Thresholds and Best Practices for Extractables and Leachables in Orally Inhaled and Nasal Drug Products," PQRI submission to US FDA, September 2006.

9. D. Norwood, D. Paskiet, M. Ruberto, et al., Pharmaceutical Research, 25, pp. 727-739 (2008).