West Pharmaceutical Services, Inc.

Introduction

Development of combination products is increasing and with this growth in development, new and complex interactions among drug constituent parts, medical device constituent parts and related components have arisen. It is critical to understand the compatibility and performance of both the drug constituent part and the device constituent part, and of the drug-device combined use as a system.

There are several areas that should be considered for analytical testingduring combination product development that will be discussed in this article.

Compendial Testing of Components

Some of the most basic aspects of qualifying delivery systems for drug products and drug-led combination products are compendial compliance of the components of the systems. Typical testing includes analysis of the materials that will be utilized in the system, such as glass, plastic, and elastomers. There are several major compendial chapters that address testing of these materials for use with parenteral injectable products such as USP <381> Elastomeric Closures for Injections

Primary packaging and medical device suppliers may providecompendial compliance information on their materials, components or delivery systems.

Biocompatibility Testing of Components

Combination product biocompatibility is the analysis of a combined container closure system with a pharmaceutical drug product when in contact with, or in, the human body. The drug component of a combination product basically adds additional chemical variables to the medical device profile, and this requires risk assessment and planning.

A range of systematic biological tests needs to be completed, as outlined in ISO 10993 Biological Evaluation of Medical Devices, not only on the device constituent part of the combination product itself, but also on other constituent parts as relevant, such as the primary containment components. Testing may include in-process materials and processing aids that come in contact with the drug or device constituent parts, or combination product as a whole, during production, to control against negative safety or performance impacts.

Extractables and Leachables Analysis

Extractables, as defined in USP <1663>Assessment of Extractables Associated with Pharmaceutical Packaging/Delivery Systems, are organic and inorganic chemical entities that are released from a pharmaceutical packaging/delivery system and into an extraction solvent under laboratory conditions. Extractables themselves, or substances derived from extractables, have the potential to leach into the drug product under normal conditions and thus become leachables. Therefore, extractables analyses are focused on materials and systems.

Leachables, as defined in USP <1664>Assessment of Drug Product Leachables Associated with Pharmaceutical Packaging/Delivery systems, are organic and inorganic chemical entities that are present in a packaged drug product because they have migrated into the packaged drug product from a packaging/delivery system, packaging component, or packaging material of construction under normal conditions of storage and use, or during drug product stability studies. Leachable analyses are focused on what has migrated into the drug product.

USP Chapters <1663> and <1664> are informational chapters that provide guidance on a framework for extractables and leachables studies. As these guidelines are not prescriptive, it is important that pharmaceutical manufacturers have a strategy and an approach for extractables and leachables studies for their products early in drug product development.

Container Closure Integrity (CCI) Testing

Container Closure Integrity (CCI) is another key area that needs to be evaluated in the development phase of drug products. CCI is defined as the ability of a device components to prevent product loss, to block the ingress of microorganisms, and to limit entry of detrimental gases, or other substances over the shelf lifeof the drug product –thus ensuring that the drug product meets all necessary safety and quality standards. This terminology is synonymous with device integrity. CCI failures for devices include leakage, loss of product, increased concentrationof product, contamination, sterility failure, critical headspace loss, over-pressurization, or loss ofpressure.USP <1207>Package Integrity Evaluation –Sterile Products addresses CCI and provides guidance on how to evaluate integrity of devicesintended for sterile products.

“Combination products development has increased and is becoming even more complex due to advancements in drugs, technologies, and materials”

When considering techniques for CCI analysis, it is important to understand that there is no one test method that is appropriate for all product package systems. Method selection and validation should be based on what is best suited for the application, and the methods should target quantitative results (deterministic methods) versus qualitative results (probabilistic methods).Deterministic methods should be utilized when possible. Examples of deterministic methods include tracer gas, high voltage leak detection, vacuum decay and laser-based headspace analysis.

Particle Analysis

Another critical aspect of qualifying devicesand related components is particles and the particle burden. Particles may be visible or subvisible, and categorized as intrinsic, extrinsic, or inherent. Intrinsic particles may come from processing or devicematerials, including stainless steel components, gaskets, glass container, rubber components, fluid transport tubing and others. Extrinsicparticles are foreign to the manufacturing process, such as hair, non-process related fibers, and other foreign matter. Inherent particles are associated with specific drug product formulations such as suspensions, emulsions, aggregates, etc.Dependingupon the drug product, there are different USP requirements and guidances that can be used in developing a particle testing strategy.

Performance Testing

There are many aspects to consider when developing a sound approach to performance testing to qualify packaging and delivery systems, and combination products. These include assessing performance risks, establishing the testing strategy, and executing the testing plan. Identifying and assessing performance risks can help set the foundation for the product testing strategy.

After assessing and understanding the performance risks, the next step is to establish the testing strategy. This step is an output of risk assessments, but also receives input from guidances from ISO, USP, and others.

Summary

Combination products development has increased and is becoming even more complex due to advancements in drugs, technologies, and materials. Because the merging of device and drug is so complex, it is critical to have a multi-faceted testing strategy through every development phase of the combination product.