How to Avoid Leachables, Extractables, and Other Hazards in Parenteral Packaging

On August 12, 2003, Johnson & Johnson began recalling certain batches of its anemia drug, Eprex (epoetin alfa, sold as Procrit in the US), in most countries outside of the United States. The company had discovered low levels of extractables in its product. Further investigation revealed that chemical reactions with the stoppers of the drug’s packaging had tainted the medication.

This event highlighted the profound importance of proper pharmaceutical packaging. Without it, the best therapeutic in the world can be rendered ineffective, or-in the worst case-fatal.

As various speakers pointed out during a session on parenteral packaging at the AAPS National Biotechnology Conference that was held June 19–21 in Boston, the importance of packaging cannot be overlooked. Proper packaging maintains the integrity of a drug, contains and preserves product ingredients at their listed concentrations until the expiration date, maintains the original purity of the drug, and delivers and dispenses the drug. Key components of biologics packaging include containers, container liners, closures, closure liners, stopper overseals, container inner seals, administration ports, overwraps, administration accessories, and container labels.

“Although numerous options exist for packaging conventional drugs, choices for biologics are more limited because they have unique chemical, physical, and mechanical properties,” said Fran DeGrazio, vice president of marketing and strategic business development at West Pharmaceuticals, Lionville, PA (www.westpharma.com).

For example, protein molecules may be sensitive to heat, light, moisture, and chemical contaminants; small concentrations of metals, plasticizers, or other extractables can deactivate or denature therapeutic proteins/peptides; and low concentrations of these drug products render them especially sensitive to moisture and contaminants.

To accommodate these characteristics, about 75% of parenteral drugs are packaged with components made from butyls and halobutyls because of their superior chemical and physical properties, according to Brian Brucker, biotech technical account manager at West Pharmaceuticals.

Selecting correct stoppers is one of the most challenging aspects of parenteral packaging. They must be compatible with the drug, meet functional and physical requirements, and provide container closure and seal integrity. In considering the type of stopper to use, one must consider the type of sterilization (aseptic, terminal, or both) to be performed; the anticipated process cycle; and storage temperature. Typical concerns with stopper preparation include bioburden, endotoxins, particulate, silicone, and validation.

For any parenteral packaging component of biologics, major problems include extractables, leachables, leakage, and permeation.

DeGrazio explained that extractables include chemical species that migrate from packaging materials or other components under exaggerated solvent, temperature, and time conditions.

Leachables, in contrast, are chemical species that migrate under normal conditions. Extractables and leachables pose problems at every stage: they may interfere with drug product assays, or medical diagnostic tests; they may increase the impurity level of a drug product to an unacceptable level; and they may react with one or more drug product components, possibly-as in the case of Eprex-creating toxicity.

Package leakage-the mass flow of gas through a hole in the package wall-can result in loss of product, critical headspace, and microbial contamination. Permeation-leakage through the package wall itself-can cause a loss of headspace, solvent, or ingredients, and lead to moisture sorption or loss. Sometimes leakage is too small to see and can cause sterility failure, as well as loss of product, or loss of gases or vacuum.

To help biologics manufacturers manage their myriad parenteral packaging challenges, many suppliers are beginning to offer ready-to-sterilize and ready-to-use stoppers and seals.

Regulations governing primary packaging are contained in 21 Code of Federal Regulations 211, the FDA Guidance, Container Closure Systems for Packaging Human Drugs and Biologics-Chemistry, Manufacturing and Controls Documentations, and the United States Pharmacopeia.

-Marilyn Kochman