In the last five years, the FDA has added scrutiny to extractables and leachables testing. The agency is consistently grilling companies on the quality of their tests, according to many packaging and processing personnel in the industry, and the result has been a strong focus on both closure/containment testing and analysis of upstream processing and storage plastics. Outsourcing providers have filled in this niche, helping Pharma and Biopharma companies navigate the tortuous path.

From our own Glossary of Terms, we offer the following definitions:

Extractable: A chemical species that can be released from a container or closure material of construction that has the potential for contaminating the dosage form of a drug. Under certain exaggerated solvent, temperature and time conditions, an extractable may be generated through an interaction with the closure system.

Leachable: A chemical species that has migrated from packaging or other components into the dosage form under normal conditions of use or during stability studies. Leachables are substances identified in a defined laboratory regimen by simulating use conditions. Leachables are a subset of Extractables.

Which is to say, extractables are the chemicals that, in worst-case scenarios, can come out of the plastics that will be in contact with the drug product; leachables are the chemicals that likely will come out (under regular circumstances) of those plastics and migrate into the drug product. So, after figuring out the worst that can happen, labs then need to figure out what’s probably going to leach in, and examine how it’s going to interact with the drug product.

No PNAs in the O-Ring!

The FDA’s interest in this arena is believed to be in response to a particular incident in the late-1990s in which a metered-dose inhaler (MDI) was found to contain harmful leachables. Evidently, the supplier of the rubber O-ring in the device wasn’t accustomed to the standards of the Pharma industry, and formulated the rubber using some polynuclear aromatics (PNAs), creating a health risk. Since then, the agency has asked for more analysis with submissions.

Following its initial interest in inhalables, the FDA began pushing for more information in injectables filings. Jon S. Kauffman, Ph.D., manager of method development and validation at Lancaster Laboratories, said, “We’re seeing increased interest in extractables and leachables testing in many dosage forms. There’s definitely an upswing in the amount of requests we’ve received.” He added that phthalates have been found in solid dosage drugs in blister packaging. “Those are potential endocrine-disruptors, so drug developers need to know about those as soon as possible,” he remarked, commenting, “This testing’s important throughout Pharma, but it’s absolutely critical for MDI products, because there are so many different components with which the drug comes into contact.” “MDIs are definitely more difficult to handle. It’s a challenge to isolate the product,” said Joseph P. St. Laurent, president and chief scientific officer of Chemic Laboratories. “But after you do that, it’s not as difficult to analyze. Now, nasal delivery systems—because they’re largely aqueous—have more matrix interference, from an extractables standpoint.”

In or Out?

The outsourcing model for extractables and leachables testing has followed the general trend in our industry: companies both small and large have chosen to work with contract service providers, for a variety of reasons. “In our experience, the client base for this testing ranges from very small to very large companies,” said Dr. Kauffman. “Projects in this field can go on for months; the smaller companies may not have resources in people or equipment and the large firms may find that this isn’t a core competence for them.”

“No doubt about it: extractables and leachables testing is a complicated affair,” a research scientist at a Top 10 Pharma company remarked. “You need to tie in toxicology, analytical, formulation, regulatory and more.”

The scientist continued, “We do both outsourced and in-house studies. We have certain criteria for what warrants sending this analysis out. Specialized knowledge is red flag. Some rubbers and some plastics—I work in injectables, so those are the primary substances my products come in contact with—are particularly complex, so it makes sense to outsource it to someone who has experience with it. These are one-time studies, so cost is important, but it’s not the first reason to go out of house with a study.”

West Pharmaceutical Services has added to its specialized knowledge base with its recent acquisition of Monarch Analytical Laboratories. Said Fran DeGrazio, West’s vice president of quality assurance and regulatory affairs, ” There’s a definite synergy in adding Monarch’s capabilities. Their focus was in glass and plastics, and they also have expertise in labels and adhesives, so they really complement our analytical offerings.” The move, she contended, added to West’s overall resource base, expanding from the company’s background in elastomers for closures.

This expertise is different than the standard stability testing that Pharma engages in. Leachables testing, even conducted within standard stability parameters, involves more than just performing a drug assay. The lab needs to have analytical methods in place that can find leachables. Pharma labs are used to looking at drug products for stability, but not necessarily for leachables.

Single Use, Two Extractions

Single-use disposable devices have also had an impact on extractables and leachables testing (and vice versa). Jerold Martin, senior vice president, global technical director, at Pall Corp., remarked, “Intermediate containers and filters require a much different type of testing than final dosage forms and containers.” Plastic filters, such as his company offers, have a relatively short contact time with drug product or intermediate, even though their surface area is high. Pall’s work on filters is primarily devoted to extractables, to iron out the worst-case chemicals.

Pall has taken to conducting a second extraction as part of its testing process. “This lets us figure out if the lower level of extractables are actually due to fewer extractables or two solubility limitations of the extract in the solvent that we’ve chosen. If you run that second extraction and find the same level of extractables as in the first run, then you may have a solubility issue with the solvent, and that could lead to false results,” Mr. Martin commented.

“For all of these materials, there are three stages. The first is what we consider the core validation data: basic USP and EP biocompatibility studies on the materials. Second, the manufacturers perform basic extractables testing in a reference fluid like Water For Injection. Third is basic chemical compatibility, with some standard buffers, where you check out things like resistance to pH. This way, you can qualify the physical characteristics of these materials, then look at extractables in these model fluids,” said Mr. Martin.

The upshot is that the way one would approach extractables in disposable systems isn’t all too different from how one would approach them in filters. “A lot of drug developers are comfortable with extractables from filters, because they’ve used them for a while, but they’re not as familiar with tubes and bags,” Mr. Martin commented.

Dr. St. Laurent at Chemic agreed, “We’re based near Boston, so we’ve worked with several Biopharma companies. Much of the equipment they utilize is disposable – biobags, filters, etc. – and we’ve witnessed a regulatory push in that direction, to better develop validated methods. We’ve got a pretty large extractables/leachables group, and we’re comfortable with both final dosage and upstream processing.”

Reaching Limits

Still, there are limits to the new testing technologies and methodologies. One sponsor-side researcher commented, “The science and the characterizations have advanced, but there are still some situations where modeling and accelerated methods don’t work.” He added, “Extractables and leachables don’t necessarily follow Arrhenius kinetics,” sending me scrambling for a dictionary.

Ms. DeGrazio at West concurred: “Sometimes there’s no substitute for long-term stability testing. We know that, in three months of the stability program, you might not see anything, but in one year, leachables might be present.”

She commented, “There are instances where there’s simply no correlation in forced/accelerated stability studies. They might show up leachables that don’t arise under regular circumstances, and other leachables may only show up under standard conditions, over time.”

Safety and Rigor

The providers I spoke to mentioned that there’s some level of educating they need to do with potential clients. “Most companies that come to us are aware that the FDA wants to see good science with extractables and leachables testing,” said one provider. “They know that the agency has more consistency about this.

“But some of them,” he added, “have the perspective that it’s a toxicity/safety concern. As in, ‘Well, if the extractables aren’t toxic, then do we really care if they’re in the product as a leachable?’ Sure, safety’s a primary issue for the FDA, but the application-holders are still responsible for knowing what’s in their products, and they need to be aware that these plastics have leached in, or they may face a lot of trouble down the line.”

“It has to do with the characterizing of packaging that”s being used,” said one Biopharma packaging manager. “The FDA’s mindset is, ‘The Pharma company needs to understand the package sufficiently.'”