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.