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.