Extractables & Leachables Testing for Drug Packaging

With QbD lurking, testing methods must evolve

By Frances L. DeGrazio

With the FDA pushing for drug applications that include the incorporation of Quality by Design (QbD), bio/pharma companies are increasingly looking for ways to incorporate comprehensive, systematic approaches into their drug development processes. As QbD initiatives continue to gain momentum, pharmaceutical packaging will play an increasingly important role in the drug development process, because it is essential that packaging does not impact the effectiveness of the drug through contamination or interaction of substances that have migrating potential.

Photo courtesy of West Pharmaceutical Services

Consistent packaging can help drug manufacturers meet QbD requirements and industry standards for safety and quality in complex drugs. It can also help pharmaceutical manufacturers differentiate their drugs by equipping them with packaging components that are designed to prevent product loss, ensure shelf life and protect each drug from the individual challenges inherent in its makeup. Understanding the materials and variables that can affect drug properties requires extensive analytical study and assessment.

The FDA provides recommendations for the review and evaluation of drug packaging requirements in its Guidance for Industry, Container Closure Systems for Packaging Human Drugs and Biologics. Each NDA or ANDA must demonstrate that a proposed container closure system and its components have been designed to eliminate interaction with the drug dosage form.

Drug manufacturers are typically responsible for providing leachables data as part of their filings. The FDA recommends drug manufacturers perform extractables analysis as part of the qualification for new container and closure systems. Corresponding leachables analysis of drug products is part of the Suitability for Use criteria considered standard by the bio/pharma industry today and expected by global regulatory authorities. Performing and designing extractables and leachables studies has traditionally been an expensive and time-consuming process. However, implementing a streamlined and efficient extractables and leachables testing program early on in the drug development process can be a cost- and time-effective way for bio/pharma companies to evaluate the potential impact of drug packaging systems.

Components of a Successful Testing Program

Extractables are chemicals that can migrate from a drug product closure or container and have the potential for contaminating the dosage form. Under certain exaggerated solvent, temperature and time conditions, an extractable may be generated through an interaction with the closure system. Leachables, a subset of extractables, are chemical species that migrate from packaging under normal conditions of use or during stability studies. Leachables have the potential to interfere with drug product assays or medical diagnostic tests, change the pH level, increase a drug’s toxicity, or raise the impurity level of a drug to an unacceptable range.It is also critical from a due diligence standpoint to understand what external species may have migrated into the drug product itself.

Extractable screening during safety studies is an important part in choosing the appropriate container or closure for a dosage form and can minimize the time and expense needed for future suitability studies. Early assessment of extractables and leachables can eliminate potential late-stage packaging interactions and also help reduce exposure to regulatory and product-related risks.

Photo courtesy of West Pharmaceutical Services

Drug packaging suitability is based on four attributes: protection, safety, compatability and performance. Primary container and closure systems, as well as other packaging components, have the potential to interact with the dosage form. To be most effective, testing programs should evaluate the packaging and delivery devices and systems that will be used to ship, store and administer the drug for potential for drug interaction with the container or closure due to extraction, leaching or absorption. Factors that must be considered in evaluating container closure systems include: primary and secondary packaging components construction materials, labels, surface treatments, processing aids, dosage form active ingredient and excipients, sterilization, manufacturing and processing equipment such as filters, tubing and nozzles, and storage conditions.

Successful testing for container and closure systems should determine the following:

• whether the materials used in the construction of the container and closure components are safe for their intended use,
• whether the components cause changes in the quality of either the dosage form or the packaging components,
• whether the system provides adequate protection from factors that can degrade the quality of the dosage form over its shelf life, and
• whether the system functions in the manner for which it was designed.

How Testing Works

Extractables and leachables testing studies are recommended even if containers or closures meet compendial suitability tests. Testing should demonstrate that the extractable and leachable profile is acceptable for the specific dosage form and that levels observed will not be approached or exceeded during the drug’s shelf life. Test methods must be specific to the drug product and placebo in order to evaluate interferences, linearity and other critical factors. In addition, evaluators must test the final drug/packaging combination for leachables during stability studies.

Prescreening procedures should begin with a basic evaluation of container and closure options. The process can involve multiple temperatures and conditions for acceleration. Extractables can be identified through analytical testing, such as liquid chromatography/mass spectrophotometry (LC/MS), gas chromatography/mass spectrophotometry (GC/ MS), inductively coupled plasma (ICP) and infrared (IR). Suppliers of these systems may be able to provide information on testing procedures. The testing laboratory can then develop methods and complete validation of them.

To begin, the laboratory will first identify a potential extractables list, which will include chemicals that can leach into the product from the container or closure formulation. If the laboratory has prior experience with certain potential extract-ables, previously used methods are chosen for the study. Otherwise, the laboratory will engage in methods development and conduct an assessment to determine the potential for analytical interference, the limits of quantification (LOQ), and typical percentage of recovery of spiked extractables in non-degraded and degraded product and placebo.

If there is significant interference during method feasibility testing — such as HPLC column deterioration evidenced by peak fronting, peak splitting, retention time shortening and poor recovery after multiple injections for extractables — the laboratory concludes that these extractables cannot be detected by that particular method. If issues with column performance are noted, dilution of drug product with an organic solvent and cleanup injections between sample injections may be investigated, and analysis of these extractables by other methods with a new sample preparation technique may be attempted.

Photo courtesy of West Pharmaceutical Services

Methods development is typically required to test for leachables. Sometimes methods development studies are expanded to improve sample preparation before analysis with a particular instrument. A cleanup step between sample injections might be made with certain solvents to maintain column performance. Once appropriate methods are developed and verified through multiple sample preparation repetitions and varying factors, formal procedural methods are written in detail for method validation.

Methods validations for detection of leachables in placebo and dosage form are based on International Conference for Harmonization Guidelines. A validation plan for each identified test method is developed and approved by the client which including detailed standards and sample preparation techniques, system suitability, validation criteria and pass/fail specifications.

Once the appropriate test methods are validated, samples are analyzed for leachables. Then testing of development and stability lots is performed under accelerated, long-term conditions. If leachables are found, toxicological evaluation should be conducted and routine testing or testing of the annual stability lot may be necessary.

The leachables testing may be incorporated into the master stability study protocol. This phase of testing allows for monitoring of leachables during long-term storage and will assess any negative or positive impacts that may occur with the primary packaging components. It will also allow an understanding of maximum quantities over shelf life.

Recent Developments in Testing

Because extractables and leachables testing can require extensive chemical analysis and toxicological evaluation, it can be an expensive and time-consuming process for bio/pharma companies that do not have the expertise on staff. One option to reduce strain on internal resources is for drug manufacturers to outsource the process.

Our firm offers an extractables evaluation service that helps drug manufacturers determine which analytes to focus on when developing methods for leachables testing. West’s E2L™ service ranks how likely extractables are to migrate into a drug product as low, medium or high risk.

Outsourcing services such as this can reduce, by months, the time needed for leachables testing and significantly speed up the drug development process to bring drugs to market more quickly.

Increased emphasis on the QbD approach to drug development is forcing pharmaceutical companies to reevaluate the costs and safety measures associated with achieving high quality. Although not yet widely adopted, QbD is arguably an essential strategy, especially given the increasingly complex and expensive drug products — such as biologics — soon to flood the market. Ensuring a drug is packaged with a safe and effective container/closure system is a key component of a QbD initiative as it is essential that packaging does not impact the effectiveness of the drug product.

To comply with industry standards and ensure the development of quality drug products, drug manufacturers are tasked with identifying extractables and leachables for possible chemical and toxicological impact early in the drug development process. Testing must be built into the qualification and stability studies of the container and closure system early in the product development cycle in order to assure suitability for use with the dosage form.

New programs such as E2L can help drug manufacturers take on the complex and daunting task of extractables and extractables analysis for qualifying a drug product’s container/closure system by providing appropriate testing processes using validated methods. By working closely with their component suppliers from the earliest stages of drug development, pharmaceutical and biopharmaceutical companies can establish the safety and compatibility of the dosage form with a packaging system early on in order to help mitigate future risks and aid in a successful product launch.

Frances L. DeGrazio is vice president, marketing & strategic business development, at West Pharmaceutical Services, Inc.