Why testing and inspection is necessary within laboratories

Amy B. Miller, director, lab services, PMO and supply chain and Daniel L. Bantz, technology manager, performance and packaging, labs, both from West Pharmaceutical Services, explains the importance of testing and inspecting within laboratories.

The development of new drugs, especially combination therapies, is a complex venture associated with in-depth analysis and difficult decisions prior to commercialization. Many factors need to be considered when packaging drugs for ease of use by patients, so that they meet the highest quality standards, and are safe for use.

As combination products become more prevalent, as well as the need for scientific data to support regulatory requirements for pharmaceutical manufacturers, the challenge of using traditional glass or engineered polymers (plastics for combination products) remains similar. Regardless of the material, it is critical to understand the compatibility and performance of the primary packaging system with both the drug product and the delivery systems for successful development and commercialization of the drug product. At West, we implement efforts to attempt to help customers keep costs lean, product development efficient, risks low, and regulatory approval seamless.

We believe that the drug chooses the primary packaging, and in many cases a polymer-based system is the right choice. For example, a drug product may be sensitive to silicone oil, requiring use of a polymer syringe instead of a glass syringe, or a drug product may require storage at cryogenic temperatures and require the use of a polymer vial instead of a glass vial. At the outset of drug product development, it is critical to consider the suitability of the planned packaging/delivery system so the right choice can be made. In order to ensure this, a well-planned testing strategy is needed, comprising evaluation of extractables/leachables, particles, container closure integrity, and system performance. 

Extractables/leachables

Through gross compatibility studies utilizing exaggerated conditions, it can be determined early on if any extractables from polymer containers sand elastomer stoppers/plungers can leach into the drug products effecting safety and efficacy. Once that is determined, utilizing the data collected from the compatibility study, a formal development program for extractables and leachables can be implemented based on United States Pharmacopeia (USP) Chapters <1663> Assessment of Extractables Associated with Pharmaceutical Packaging/Delivery Systems, <1664> Assessment of Drug Product Leachables Associated with Pharmaceutical Packaging/Delivery Systems, and ICH Q3D Guideline for Elemental Impurities.

Particles

Understanding particle load from polymer container and elastomer stopper/plunger is needed as particles affect efficacy and patient safety. Utilizing USP (USP <787> Subvisible Particulate Matter in Therapeutic Protein Injection; USP <788> Particulate Matter in Injections; and USP <789> Particulate Matter in Ophthalmics) visible and subvisible particle loads can be determined. Typical methods are membrane microscopy, Light Microscopy Image Analysis (LM/IA), and Light Obscuration (LO). When possible, particles should be identified through techniques such as optical microscopy and Scanning Electron Microscopy with Energy Dispersive x-ray Spectroscopy (SEM/EDS). This is especially important for controlling particles by identifying their source.

Container Closure Integrity (CCI)

A pharmaceutical manufacturer must determine the Maximum Allowable Leakage Limit (MALL) for the drug product in order to evaluate CCI of the packaging/delivery system. USP <1207> Package Integrity Evaluation – Sterile Products defines MALL as the greatest leak rate (or leak size) tolerable for a given packaging/delivery system that poses no risk to drug product safety and quality over shelf life. USP <1207> provides guidance on how to evaluate CCI such as deterministic methods, which are strongly endorsed compared to probabilistic methods. Deterministic methods are tracer gas leak detection (frequently with helium), high voltage leak detection, vacuum decay, and frequently modulated spectroscopy headspace analysis (frequently with oxygen). These methods must be developed and validated for the specific system. It must be demonstrated that the packaging/delivery system meets the MALL for the drug product. MALL varies with each drug product and system.

System performance

To understand performance and functionality (essential in design verification testing), testing should be based on established guidelines and standards, such as ISO standards. An excellent example is ISO 11040 Prefilled Syringes — Part 8: Requirements and Test Methods for Finished Prefilled Syringes. It includes tests such as Deliverable/Residual Volume, Tip Cap Pull-Off Forces and Torques, Liquid Leakage Beyond the Plunger, and other methods useful in evaluating performance. ISO 11040 also includes pharmaceutical requirement tests such as drug-container interaction, biological requirements and particles. In many cases, especially when novel devices such as new combination products are being evaluated it is necessary to create custom testing strategies and methods. These should be in alignment with established guidelines and standards such as ISO 11040-8, and those that are FDA recognized consensus standards. It is emphasized that the test methods employed, custom or not, require validation in order to be used for stability and release testing. This is especially true for combination products. In fact, utilizing a testing approach as here described is not just a best practice, but an expected practice. 

When developing a testing strategy, other factors may need to be considered such as those particular to the specific drug product. It may be necessary to employ a contract laboratory, and it is necessary to ensure the laboratory is GMP and FDA compliant and ISO certified. Depending on the drug product, the laboratory may need a DEA license. The laboratory should also have proper facilities/equipment and, more importantly, scientific staff capable of both developing and executing a testing program that successfully navigates regulatory requirements.

Creating a comprehensive testing strategy, from initial compatibility through stability and release is essential, regardless of the drug product, types of materials, systems and devices chosen. The right contract testing partner is necessary to accomplish this and ensure the availability of scientific data that helps ensure optimized results to patients, as well as fast regulatory approval and delivery to market occurs.