Written By BRIAN MULHALL / Chief Executive Officer
On August 1, 2016, the USP <1207> General Chapter, Package Integrity Evaluation – Sterile Products, became effective. The chapter has three sub parts:
- USP 1207.1 Package Integrity in the Product Life Cycle – Test Method Selection & Validation
- USP 1207.2 Package Integrity Test Technologies
- USP 1207.3 Package Seal Quality Test Technologies
These chapters were, and are, designed to improve the overall quality of the container and package systems used for pharmaceutical and medical products. With almost five years of active implementation, they have proven to be a much-needed tool that impacts the quality and safety of drug products. However, as a service provider that works daily with clients on method development, validation and implementation of the strategies and procedures outlined in USP <1207>, there still remains a number of misconceptions on how best to use and engage these specific requirements. Unlike USP General Test and Assay Chapters that outline specific and easy to follow test methods, the USP <1207> General Information Chapter presents a number of complex issues that must be considered to ensure an effective and worthwhile CCI strategy is developed and implemented.
Misconception One: USP <1207> Provides Step-by-step Instructions to Performing CCIT
USP <1207> is a USP General Information Chapter and, as such, provides guidance and considerations surrounding a topic. This is opposed to a detailed and specific method for performing an analysis, as would be found in a USP General Tests and Assays Chapter. A quick comparison to USP <661> Plastic Packaging Systems and their Material of Construction provides a good example. USP <661> defines a series of tests and assigned specifications for specific plastic materials such as HDPE, LDPE, and Polypropylene. Relatively simple and straightforward. If you are using HDPE, then you perform the prescribed tests and the results must fall within the defined acceptable range. USP <1207> does not operate with the same level of simplicity. There are many factors that influence the specific parameters, steps, or methods used to evaluate CCI of a product-package system, making it infeasible to account for all variables in a list of steps and specifications. In addition, while the USP <1207> chapters outlines a variety of acceptable test technologies, methods employing these technologies need to be DEVELOPED and VALIDATED to the specific product, package, and study goals being evaluated. Unlike USP <661>, which can be considered as “plug and play”, USP <1207> is not.
Misconception Two: USP <1207.2> Technologies (Methods) are Interchangeable
In more cases than not, clients assume that the USP <1207> methods are equivalent options and that any of the methods (Vacuum Decay, High Voltage, Helium, Laser Headspace, etc.) are interchangeable and can be applied to their product and package system. The typical request of “I have 50 samples that I need you to perform High Voltage Leak Testing (insert any other CCI test method) on” is a common request. Unfortunately, the correct response to such a request is not simple and straightforward. The selection of the optimal test method for a specific product and package system is dependent on a number of key factors. What is the composition of the product? What type of package system is being used? What are the storage conditions? What stage of the product life cycle are we dealing with? What is the reason and overall objective of the CCI testing? Understanding these critical issues will help to define the optimal method for that specific system.
Thus, USP <1207> methods are NOT INTERCHANGEABLE and selection of the method that meets your product, system and objective is critical. Once the optimal method is selected, two critical next steps are required: METHOD DEVELOPMENT and METHOD VALIDATION. A method must be developed that is specific to product-package system and intended use, and that method must then be validated to ensure it meets all typical USP requirements of a “validated method”, harmonized with ICH Q2 (R1). Once this is completed, product testing can commence.
Misconception Three: USP <1207> CCI Testing Moves Quickly from Concept to Implementation
In today’ culture of “instant access” or “instant gratification”, it is generally assumed that USP <1027> testing can be quickly implemented and completed. As a service provider, it would be ideal from our perspective too if this were the case. Samples would be submitted, testing would be completed quickly and reports would be issued. In many cases, this is easily accomplished with a number of USP requirements – our USP <661> test request being a good example – simple and straightforward with a relatively short timeline. USP <1207> testing does not have this luxury.
As referenced in misconception two, there are a number of factors that must be considered and there are a number of steps to ensuring a feasible and ultimately valid test method is used. Once this is all organized and a successful test plan is clearly defined, other issues impact the time schedule. Three crucial ones impact the time schedule of each USP <1207> testing program: Change Parts, Positive Controls and Reference Standards. The specialized instruments used are similar to the test methods in that they are not plug and play. Depending on the type of sample being testing, change parts will be required that enable the instrument to hold or handle that specific sample. These parts must be designed and developed to the exact specifications of the sample package. At a minimum, this eats up a few weeks of the “time schedule”. Positive control sample are typically needed and required as a critical component for the method development process. As part of almost every CCI program, some of the positive controls are constructed from the empty container, often in the form of a certified laser-drilled hole. Like change parts, this is not a routine and simple process and typically takes a few weeks to sort and accomplish. Finally, in some cases (example: laser-based headspace), reference standards must be created from the sample package system containing exact concentrations of target gases. Collectively, these critical steps impact the implementation timeline of a successful CCI program.
Summary: The implementation of the USP <1207> Container Closure Integrity Testing requirements has become a widely accepted expectation and requirement from the regulatory agencies. Over the past five years, we have seen a constant increase in the demand for CCI testing and it is not expected to abate any time soon. Understanding the “basic complexities” of these unique methods will help to better align goals and expectations going forward. It is safe to assume that regulators will be asking for the “integrity data” for your package system. Implementation of a CCI strategy early in the product life cycle (example: before FDA submission) would be ideal. Understanding that the development of a USP <1207> program is not a simple “plug and play” program will help to better align expectation and timelines. While your routine USP qualification testing requirements for the plastic container or glass bottles are easily defined and work within a short time window, the same cannot be said for container closure integrity testing. There are a number of critical factors and requirements before a CCI method can be satisfactorily defined as routine. Consideration of these factors will enable you to develop the test method that is most optimal for your product and package systems and one that will help you to easily meet the regulatory requirements now expected.