An extractables profile offers comprehensive knowledge of the materials involved in the
packaging components that are in direct contact with a drug product.

Biopharmaceutical manufacturers spend years developing and testing new drug and biologic products to ensure their efficacy, safety, and usability for patients. Such knowledge is extremely valuable, but those same principles often get overlooked in selection of packaging and delivery systems. Decisions on packaging and delivery often are made almost as an afterthought. However, issues related to components such as extractables and leachables can affect patient safety and product quality. In addition, a lack of extractables and leachables data in filings with the US Food and Drug Administration can delay therapeutic approval, wasting a company’s valuable time and money.

An extractables profile demonstrates comprehensive knowledge of the materials involved in packaging components that come into direct contact with a drug product. Extractables testing takes into account each component’s configuration, film, coating, and processing that can affect its extractables, offering a “snapshot” of data that can be used for the specific component being tested. However, a single snapshot is not enough to provide in-depth understanding of how packaging affects a drug or biologic over time. A component’s extractables profile can be affected by a number of changes: e.g., sterilization, washing, addition of coatings or films, stopper age and storage, and supply-chain driven changes in composition. Life-cycle management of a therapeutic may drive companies to change the drug’s presentation over time to suit patient needs. Such changes can require repeated extractables work, which again affects cost and time to market.

A comprehensive material profile — including data that evolve over time, across a manufacturer’s locations, and with different component configurations — can deepen a manufacturer’s understanding of the components that touch its drug or biologic (and ultimately, the patients who receive that medicine). A holistic approach to extraction studies can help pharmaceutical manufacturers not only save money, but also mitigate risk and enhance compatibility of packaging and delivery systems for a drug product by aiding in component selection. By identifying potential extractables early in process development and maintaining an ongoing knowledge of materials used in primary packaging, biopharmaceutical manufacturers can improve understanding of compatibility while reducing risk and expediting total development and launch timelines.

Early Testing Helps Reduce Risk
Many biomanufacturers select packaging components for their life-saving products with little thought of how such materials can affect their contents. Packaging needs to provide container–closure integrity and ensure that a drug or biologic can be delivered safely and effectively to patients. Extractables from components that come into direct contact with a product become critically important because they could migrate into the product.

Packaging components often are selected based on convenience. Biomanufacturers increasingly use contract manufacturing organizations (CMOs) to fill and package their products. These companies rely frequently on a CMO to assist with packaging selection. And although many CMOs have great expertise in fill and finish, they typically do not manufacture elastomers or primary packaging materials, so most such companies lack a complete understanding of the material profiles of primary containers. Often a CMO will recommend vials, stoppers, and seals based on experience or for machining purposes. People making those recommendations may not consider the attributes of a particular therapeutic in relation to the materials used for its primary containment. But not doing so can lead to costly mistakes.

Example: A CMO recommends a stopper that it routinely uses with great success to a biomanufacturer, who accepts the recommendation without gaining full understanding of the chemical attributes of that elastomeric component. After several months, the product sponsor experiences stability problems with this drug. Seeing protein aggregation in stored products, the sponsor must investigate the cause of the instability. It immediately focuses on elements that could be leaching into the product, particularly focusing on the vial and stopper that directly contact the protein formulation. Upon investigation, the company determines that zinc has leached into the product. At this point, the biomanufacturer reaches out to the elastomer manufacturer, who confirms that zinc is indeed part of the stopper formulation. But the protein is incompatible with zinc, which is leaching from the stopper into the formulation.

After a biomanufacturer determines that it must change the stopper, a best practice is to ask the elastomer manufacturer for a recommendation. With knowledge of the materials used to make elastomeric formulations and extractable data — in addition to key information from the biomanufacturer — the elastomer company can recommend a more appropriate formulation that includes a protective film. The new stopper would thus allow the biomanufacturer’s CMO to package this biologic safely and effectively.

In such an example, the biopharmaceutical company may have to delay the start of a clinical trial for over six months just to change the investigative product’s primary packaging. With a better up-front understanding of the primary container’s material profile, such a situation could be prevented.

The Science of Elastomers
Elastomers are polymers that can stretch to twice their length and return to their original shape when the stretching force is removed. Many ingredients are used to make these polymers, so unfortunately, many substances can leach from them as well. Rubber is made from many ingredients, making it a source of concern for extractables and leachables. Some materials of construction include the base polymer, curing agents, an accelerator, an activator, antidegradants, plasticizers, fillers, and pigments. All of those ingredients are critical in rubber manufacturing, but they also can contribute to leachables.

Elastomeric closures are formed using heat and pressure. A curing agent forms cross-links between polymer chains, which reconfigure to distribute an applied stress. It is that network of cross-links that largely determines the physical properties of tensile strength, elongation, and compression set. Accelerators are important because they control the time it takes for rubber to cure, and activators improve the efficiency of cross-links. Plasticizers are used as processing aids, and antidegradants help stabilize stoppers from UV, oxygen, and ozone degradation. Pigments might be used for color, and fillers are added to alter an elastomer’s physical properties by extending its functionality. A filler could be clay, talc, polyethylene, or other ingredients. When in contact with a drug product, any of those substances could cause a reaction. Every rubber formulation is unique and can have varying amounts of ingredients as well as different extractables profiles. In the past, many elastomers contained natural rubber for its excellent functional properties; however, patient concerns regarding natural variations and uncertainties have led new formulations to be made using synthetic isoprene or halobutyl polymer.

Defined as chemical species that migrate from packaging or other components under appropriate solvent, temperature, and time conditions, extractables are often found under exaggerated conditions and typically include an array of molecular species that can come from particular components. By contrast, leachables are chemical species that migrate from packaging or other components into drug products under normal conditions. Elastomers and other polymers are often the focus of extractables and leachables concerns because they have complex chemical profiles. Regulatory agencies have increased their focused on extractables and leachables since the FDA published a guidance in 1999 (1). It states,

“Every proposed packaging system should be shown to be suitable for its intended use: it should adequately protect the dosage form; it should be compatible with the dosage form; and it should be composed of materials that are considered safe for use with the dosage form and the route of administration. If the packaging system has a performance feature in addition to containing the product, the assembled container closure system should be shown to function properly.”

Selecting elastomeric formulations is more complicated for biologics than for synthetic, small-molecule drugs. Proteins tend to be sensitive to many substances, which forces biomanufacturers to have a better understanding of how packaging components will interact with their therapeutic products. Biologic formulations themselves are more complicated than those for classical drugs. Often, a solubilizing agent such as polysorbate is added to help large molecules dissolve in aqueous solvents. Adding such an ingredient can facilitate the migration of extractables from rubber into therapeutic formulations. Barrier films can be used to stop these drugs from interacting with their stoppers, but such films do not stop all extractables from crossing over. So extractable and leachables studies remain necessary.

Testing for Extractables

Primary packaging should provide container–closure integrity, but it also needs to ensure that a drug product can be delivered safely and effectively to patients.It is critical to understand how primary packaging can affect a drug product. Leachables can migrate out of primary container–closure systems into drug products. Leaching can give rise to impurities, particles, aggregation, and other incompatibility issues that affect the quality of a biotherapeutic. Leachables also can cause immune response in patients, as was the case with Eprex epoetin alfa from Janssen-Cilag Pty Limited in Australia (2). Such effects can interfere with drug product assays and diagnostic tests.Extractables often are studied to qualify the materials used in primary containers and ensure that they will be appropriate for a particular drug or biologic. Results from such studies are also used to determine targets in the development of analytical methods for leachables testing. It is critical for biopharmaceutical companies to understand the material profiles of components they use, and typically the best way to accomplish that is through extractables testing.

Extractables studies provide an initial, qualitative, and semiquantitative determination of the types of chemical species that can be extracted from a material under extreme conditions. Such conditions are designed to be more rigorous than anything the material would experience under actual use. Components such as stoppers typically are extracted by refluxing them in solvents. Multiple extractions using different solvents of varying polarities are used to produce a comprehensive profile. That allows for detection and identification of the greatest number of extractable species regardless of the chemical nature of the actual drug product matrix. To ensure that as many extractables are captured as possible, a series of analytical techniques such as liquid chromatography/mass spectrometry (LC-MS), gas chromatography/mass spectrometry (GC-MS), inductively coupled plasma (ICP), and ion chromatography (IC) should be used. The results will be a materials profile that gives a biomanufacturer a better understanding of components that directly contact its product.

Extractables testing can be viewed as a snapshot in time. Testing typically is completed on one lot of product, which represents a sample of the polymer material. Biomanufacturers often seek a more complete understanding of such materials. A comprehensive data package includes numerous extractables studies completed over several years of analyzing the many variables associated with multiple configurations that can affect an extractable profile. That gives sponsor companies an in-depth look at packaging issues that could affect their therapeutic products over the course of their shelf lives. Such variables include the effect of elastomeric curing, potential differences among multiple manufacturing sites, design of the components, and their manufacturing and postmanufacturing processes. All those factors should be considered to gain a complete materials understanding.

A comprehensive study such as West Pharmaceutical’s Verisure analysis can provide a sponsor company with a deeper understanding of how packaging materials change over time and across multiple manufacturing facilities with different processing and sterilization. To develop an in-depth understanding of the many factors that can interact with a drug product, biomanufacturers should work closely with their packaging partners, not only to select a product that will be compatible with their drugs, but also to ensure that several “snapshots” will be taken to determine how a biotherapeutic and its packaging interact throughout the product’s life cycle. Product sponsors should work closely with packaging manufacturers early in drug development to determine when and how often an extractables profile should be conducted. Working together, both companies can help to ensure the compatibility of these products with their chosen container– closure systems throughout the therapeutics’ life cycle.

References

1 CBER/CDER. Guidance for Industry: Container Closure Systems for Packaging Human Drugs and Biologics — Chemistry, Manufacturing, and Controls Documentation. US Department of Health and Human Services, Food and Drug Administration: Rockville, MD, May 1999; www.fda.gov/downloads/ Drugs/Guidances/ucm070551.pdf.

2 McCormick D. Small Changes, Big Effects in Biological Manufacturing. Pharm. Technol. November 2004: 16.

Whitney Winters is senior manager of emerging biotech and analytical services at West Pharmaceutical Services, 530 Herman O. West Drive, Exton, PA 19341; 1-610-594- 2900; whitney.winters@westpharma.com; www.westpharma.com. VeriSure is a registered trademark of West Pharmaceutical Services, Inc., in the United States and other jurisdictions.