If a drug product is contaminated in any way by a chemical derived from its packaging, this can cause real problems for patients. These “leachables” have caused real-world problems ranging from mild and temporary gastrointestinal symptoms to full-blown immunogenic reactions.
At the less severe end of the symptom scale, in 2009 and 2010 various products reached patients that had a musty smell. This subsequently was identified as 2, 4, 6-tribromoanisole, and eventually traced back to a breakdown product of a fungicide, with which the wooden pallets used in storage and distribution were treated.
More dangerous effects occurred in patients taking Eprex (erythropoietin alpha) after a formulation change. The solubilizing agent, human serum albumin, was replaced with the chemically derived alternative, polyethylene glycol. This change increased the propensity for the new formulation to leach cross-linking agents from uncoated syringe elastomer into the product, which then reacted with the therapeutic protein to cause an antigenic effect.
While such problems are unusual, they do occur, and thus it is essential that all potential interactions between any individual component of a drug’s formulation and any part of its packaging are evaluated carefully. Only then can the manufacturer be assured that the packaging will have no deleterious impact on the product’s safety and effectiveness.
During the development and registration of every drug product, three crucial variables, drug, device and data, must be considered and understood. By considering each of these variables as the vertices of a “formulation triangle”, every study can be classified as lying within such a figure. For example, early phase studies of the action of an API in biological systems lie closest to the side connecting the Drug and Data vertices. Device compatibility studies, on the other hand, lie closest to the side connecting the Drug and Device vertices. Device performance testing can be considered to lie between the Device and Data vertices. The ultimate goal for both the developer and regulatory authority is to sample the entire space within the triangle. Only when information is available about all the possible interactions can a packaged drug product be declared safe and effective.
Extractables are those substances that can be extracted from the packaging material in some way, usually requiring the presence of strong solvents, elevated temperatures, or both. Leachables are, essentially, a subset of extractables, and require no unnatural extraction process to enter a drug product, as they are a natural interaction phenomenon between a formulation and its packaging. While both extractables and leachables might be additives that are deliberately incorporated into the packaging material, this is not necessarily the case as they might be low molecular weight fragments of the polymer, such as cyclic oligomers or even unreacted monomers.
The reactions used to make condensation polymers such as nylon are, essentially, reversible, and therefore a condensation polymer backbone can be a source of an extractable monomer created by the back reaction. Monomeric extractables are still reactive, and their free concentrations are usually low. Cyclic oligomers, such as the dimers and trimers of polybutylene terephthalate, are commonly observed extractables from this particular polyester. As long as formulation or any extraction solvent is not in contact with these materials, no observation of complete extraction will ever occur. This does not mean that such thermoplastics should be avoided as the mere presence of these chemicals may not cause deleterious effects on product quality. In fact it does illustrate that leachables will always be present in drug products and anything packaged in plastic.
The extraction process generally occurs at a solid–liquid interface, although it can occur at a solid–gas interface, particularly if a volatile organic compound is present in the packaging material. The rate of extraction depends on a number of physical and chemical factors, including the permeability of the solvent into the solid, the solubility of an extractable into that solvent, and the temperature and pressure of the system. In the laboratory, there are numerous ways in which to perform extractions. Typical techniques include Soxhlet extraction (diffusion-controlled); boiling point reflux (temperature controlled); equipment that allows elevated pressures above solvent boiling points such as accelerated solvent extraction (temperature controlled); and microwave extraction, to heat a polarisable or dipolar solvent above boiling points (temperature controlled).
The identity of extractables and leachables
Extractables and leachables fall into various chemical groups. Polymer additives are a major class of extractables, and differ both within types of polymers and even grades of the same polymer. They are added to polymers to impart desirable processing and end-use properties such as stability, and while they are not by default bad, there is the potential for them to be extracted or leach into a drug product. They cover a whole range of different functionalities, altering the mechanical, chemical or even electrical properties of the polymer.
Mechanical property modifying additives include nucleating agents that allow polymers to be processed at lower temperatures, cross-linkers that give a polymer mechanical strength and introduce a 3D structure, and fillers that impart both strength and heft. Fillers are typically inorganic substances such as clay, heavy metal oxides or carbon black. Plasticizers, which impart flexibility and give resistance to cracking, are a major class of additives, and may include both natural and synthetic oils, and phthalates. The use of phthalates is now under particular scrutiny.