Bringing a new biological drug to market requires a huge financial commitment and entails risks in every stage of the development process. The risk associated with selecting a vial/stopper/seal system for packaging the drug may not be in the forefront of early-stage thinking, but the risks are real nonetheless and can have profound impact on the drug product.
Selecting packaging for a parenteral drug is critical for a successful market launch. Packaging components must meet functional requirements to help ensure safety at the point of administration and must protect the purity of the packaged drug product for its shelf-life, usually a minimum of two years. Packaged drugs, especially highly sensitive biopharmaceuticals, can be harmed if the administration system and packaging components are not selected carefully to ensure compatibility with the drug.
With all that is invested in drug research and development, biopharmaceutical researchers must include packaging and administration system selection in their product development planning. Requirements for product purity, activity and shelf-life dictate a very high standard for injectible drug packaging, particularly for highly sensitive biopharmaceuticals.
The Food and Drug Administration’s (FDA) Guidance for Industry – Container Closure Systems for Packaging Human Drugs and Biologics (May 1999), states that pharmaceutical manufacturers should conduct extractables and leachables testing on their container closure systems and drug product. The guidance recommends that each New Drug Application (NDA) or Abbreviated New Drug Application (ANDA) contain enough information to demonstrate that a proposed package and its components are suitable for their intended use.
What’s more, FDA’s current thinking on Quality by Design (QbD) has implications for the biopharmaceutical industry. The Agency has stated that drug product quality should be designed into the process (using QbD, that is), not achieved by testing drug products into compliance. Controls should be in place as far upstream as possible. A QbD initiative for biopharmaceutical manufacturing is designed in terms of risk assessment, risk analysis and risk control.
Fluorocarbon film coatings provide protection from extractables from the component material while providing a high level of barrier protection for the drug product, therefore minimizing leachables.
Risk assessment should be integrated into product development and process development activities, which includes selection of the product’s packaging and administration system. To connect the drug administration system to the manufacturing process in a QbD environment, the biopharmaceutical company should conduct a risk assessment of the container closure system components during the early stages of product development.
An early-stage assessment can identify potential issues related to system component functionality, machinability and fitness for use with a specific biological product. It is especially important to evaluate potential extractables from elastomeric components such as vial stoppers and syringe plungers. A risk analysis can help identify a potential adverse effect to the product caused by system components, which helps the biopharmaceutical company to prevent or eliminate the potential risk. Risk control and mitigation are pertinent to the process scale-up phase of product development.
A QbD system strives to reduce risks to product quality by managing and controlling the source of materials and the effect of variability in materials used to manufacture products such as container closure system components. Biopharmaceutical manufacturers can advance their QbD process by working with component manufacturers that have appropriate in-process controls in place.
The potential impact of extractables
Minute particles of metals, plasticizers and other materials from packaging components may deactivate or denature biopharmaceuticals such as monoclonal antibodies. Whether in liquid or lyophilized form, biologically derived products possess properties that make them extremely sensitive to their packaging or delivery system. Proteins and peptides have a tendency to adsorb onto the surface of packaging containers and closures.
Lyophilized proteins are no less immune to the effect of packaging. Because lyophilized cakes are sensitive to moisture, an inadequate seal could cause water to enter the package and interfere with the activity of the drug product. Many biopharmaceuticals are sensitive to silicone oil, a material commonly used to lubricate elastomeric components so they will track properly on pharmaceutical filling lines. Component lubricity also facilitates the insertion of stoppers into vials and plungers into syringes.
Fluorocarbon films on stoppers and plungers provide needed lubricity and create a chemically inert barrier between the component and the packaged drug. Fluorocarbon films thus serve as both lubricant and a barrier to improve compatibility between the drug and the rubber closure. Extractables and leachables can be released into a drug product from a container closure system, other packaging materials or from the processing equipment.
These chemical entities may have a direct effect on the patient by being toxic, carcinogenic or immunogenic. They may also indirectly affect the quality of the drug product by introducing impurities that alter physicochemical properties of the active pharmaceutical ingredient. For these reasons, extractables and leachables pose significant safety risks for patients and could result in product recalls or misdirected clinical trials. It is essential to develop appropriate methods for the detection and continuous monitoring of these compounds and to establish appropriate acceptance limits.
Leachables are chemical entities that migrate under normal conditions from a container closure system and other packaging components under recommended conditions of product use and storage. Extractables, unlike leachables, are generated under extreme temperature and time conditions in the presence of an appropriate solvent (e.g., polar and non-polar organic solvents, purified water). Leachables are often a subset of extractables; however, they can also be derived by chemical modification (e.g. degradation) of extractables.
Evaluation of extractables is considered an essential step in the accurate prediction of leachables, and in the selection of an adequate container closure system for a drug product. The interaction of the drug product, the packaging components, manufacturing process, product quality attributes and storage conditions (e.g., temperature and duration) is critical in determining an extractables/ leachables profile.
During Phase I, a sponsor company should begin screening for vial closure designs and materials. By Phase II, sponsors should begin developing precise, validated methods for determining extractables and leachables.
Chemical leaching is often detected during product storage and rarely at the time of release. This emphasizes the need for comprehensive stability protocols that not only evaluate typical product quality attributes, but are also capable of detecting potential leachables. The potential impact of extractables on drug products is significant, especially with sensitive biopharmaceutical drug products that may contain extremely small amounts of active ingredient.
Perhaps more important than these materials’ toxicology is their potential to elicit serious immunologic responses, even at minute dosages.
Fluorocarbon film protects against extractables
Fluorocarbon films provide a barrier to protect the drug product against extractables from the elastomeric material, thereby minimizing leachables. When applied to stoppers or plungers, fluorocarbon films significantly reduce adsorption of the drug onto the stopper, which is critical for maintaining the product’s potency and shelf-life. In addition, fluorocarbon films provide lubricity to enhance performance on pharmaceutical filling lines without the need for free silicone oil, a potential source of particulate contamination.
The cost of selecting an inappropriate packaging and administration system can be high. Problems discovered during the drug development process can lead to delays. Problems discovered after the product is marketed can lead to an expensive recall and may affect the public’s confidence in the company. Because the stakes are so high, biopharmaceutical manufacturers should have a development plan for primary packaging.
This activity is frequently contracted out to firms that specialize in packaging components. Even if the effort is conducted in-house, team members should work closely with experts who have specialized knowledge of packaging and administration systems for biopharmaceuticals.
During Phase 1 drug product development, the team should begin screening closure designs and materials for their drug product. By Phase 2 – or earlier if possible – sponsors should develop precise, validated methods for determining extractables and leachables. When method development and validation is completed, testing is carried out using samples stored under in accordance with International Conference for Harmonization (ICH) guidelines.
Problems may also arise when a contract manufacturer recommends components solely because they have been validated with the contractor’s filling line. Components must be qualified with the drug product first, and then with the filling machinery. Requirements for lyophilized drugs Many biopharmaceuticals come to market in lyophilized form, which presents specialized process and packaging requirements.
The elastomers used to manufacture stoppers and syringe plungers adsorb and desorb water at varying rates. Under storage conditions, components that were not properly dehydrated can release water into the lyophilized product, affecting product stability over time. This can be especially problematic with lyophilized biopharmaceuticals, which tend to have very small cake weights when compared with traditional pharmaceuticals following lyophilization.
Because their weight is often in the range of milligrams or less, these cakes are significantly more sensitive to moisture, pH changes and extractables that migrate from the closure. A small difference in moisture in the lyophilization cake can make the difference between an active and denatured protein. Further, pH differences may be caused by contaminants and can seriously affect protein structure and activity. Fluorocarbon films, because of their barrier properties, can help reduce the potential of the stopper or syringe plunger as a source of leachables that could impact pH. Glass vials, however, can also leach ions that can impact pH.
Drug developers who underestimate the impact of the packaging and administration system on their biopharmaceutical products are assuming an unnecessary level of regulatory and product-related risk. The high value of biopharmaceuticals, coupled with injectible delivery in most cases, demands a high level of awareness of primary packaging, even in the early stages of drug development.
Developers should consider a fluorocarbon film for the stoppers and syringe plungers used to package and administer their drug. Given the long development times and consequences of selecting inappropriate packaging and administration systems, such measures are prudent and will lower costs in the long run.
About the Author
Fran DeGrazio has been with West since 1983. During her tenure, she has served in various functions within the analytical laboratory and R&D arenas. DeGrazio holds a B.S. degree in Chemistry from Cabrini College in Radnor, Pa.