One criticism of these guidance documents is a continued level of ambiguity around certain topics. While it would be easier to receive clear and explicit guidance, guidance documents exist to drive critical thinking, not absent-minded action. After all, guidance that is too explicit will risk eventually being wrong. At the most basic level, these EMA regulations drive a practical agenda of quality risk management (QRM). When in doubt, follow basic QRM principles and provide evidence of clear scientific thinking around container closure integrity (CCI).
QRM applies to all aspects of the pharmaceutical manufacturing process. EMA’s ICH Q9 is the most relevant regulatory guidance document related to risk management, and QRM is inherent to all CCI regulatory guidance. A patient-centric view of QRM follows a distinct path to assess risks facing patient safety. Assessing QRM of pharmaceutical containers begins with a focus on patient care and identifies the critical quality attributes (CQAs) that the product must exhibit for patient safety. Does the drug need to be sterile? Is the active ingredient impacted by environmental contaminants such as oxygen or moisture? What CQA’s must the package exhibit to fulfill that quality requirement? Once a clear scientific understanding of the package requirements and associated risks has been established, an effective method for detecting the risk can be considered in alignment with the relevant regulatory requirements.
USP <1207> was published in 2016, adding significant depth and detail from the prior version. USP <1207> strongly encourages the use of deterministic CCI test solutions that provide the ability to control, calibrate, quantify, and repeatably determine the integrity of a container. It identifies probabilistic methods as being less reliable due to the presence of variable inputs and often subjective test results. USP <1207> prescribes specific methods and identifies critical quality risk management (QRM) approaches to improve container quality. Annex 1 aligns well with the guidance provided by USP <1207>.
Annex 1 calls for the use of validated physical test methods that are scientifically fit for purpose and with a scientifically valid sampling plan. USP <1207> calls for methods that test the container for leakage using appropriate physiochemical test methods that can be controlled, measured, and calibrated. Both documents encourage application of QRM for CCI. Both are calling for use of scientifically appropriate test methods to test for physical leakage.
Both Annex 1 and USP <1207> establish expectations for deployment of quantitative deterministic CCI methods. Annex 1 specifically calls for validated test methods related to container closure integrity. ISO/IEC 17025:2005 requires a validated test method to include the ability to show accuracy, repeatability, and reproducibility amongst other attributes. USP-NF/PF <1225> states that to be a validated cGMP test method it must meet standards for accuracy and reliability, have detection limits, and show linearity. Both USP and EMA document sets have expectations that validated methods are controlled, reproducible, and quantitative test solutions. USP <1207> articulates that requirement by defining deterministic methods as “ones that can be measured, calibrated, and controlled.” While Annex 1 does not explicitly state that a deterministic method is required, parallel standards strongly imply that deterministic methods are necessary for effective compliance with Annex 1.
Annex 1 establishes additional requirements specific to the sterile manufacturing environment. It focuses on the detection of physical leakage and states that visual inspection is not an integrity test method. Not all physical defects are visual in nature, and not all visual defects are physical in nature as it relates to container closure integrity. Annex 1 leans heavily on ICH Q9, and calls for QRM principles to address CCI.
The focus for inspection should be on selecting a test method that detects defects that present a risk to the patient, then maximizing assurance by deploying an effective sampling campaign to target that defect. Annex 1 establishes that detection performance of a test method should not be compromised simply to achieve 100% inspection. When deploying a test method, the priority is establishing a method that is able to detect defects that affect critical quality attributes (CQA), then the method can be leveraged to more automated approaches without compromising the ability to inspect CQA’s.
Annex 1 focuses on the fill-finish arena with a significant adjustment in how batches can be inspected. It establishes that automated test methods must have equal to or better detection performance as manual alternatives. This means that automating inspection should not compromise detection performance for the sake of 100% inspection. Ultimately, very few format classes will be subject to 100% inspection, and for those that are not, an effective sampling plan should be applied. A practical and effective product sampling plan is Squeglia’s Zero Tolerance sampling plan. For high-risk applications, acceptance levels of 1 defect per 10,000 can be applied. Batch sizes up to 1,250 units require 100% of the batch to be tested to achieve the appropriate confidence level. For larger batch sizes, testing quantities beyond the 1,250 sampling requirement does not establish a higher level of confidence. Annex 1 provides clear guidance that 100% inspection is only required for a specific subset of format types, and that scientific approaches to sampling plans are aligned with patient safety.
Conclusion
All regulatory guidance is pointing to a state of more quantitative deterministic testing that addresses QRM challenges. At a fundamental level, the technological improvements come from more direct quantitative controls of the specific quality attributes that matter. The more accurate and reliable the inspection technologies, the more effective supporting quality frameworks can be in managing quality. Ultimately, without a reliable physical measurement of CQA’s, the value of deploying any quality control system is debatable. Without a reliable and effective test method, there is no benefit to testing.
The shifts to improve patient safety are driven by both technological advances and a regulatory environment that continues to encourage the use of better inspection solutions. Approaching quality with a holistic, scientific understanding of the task at hand will engage these shifts more successfully. QRM is at the foundation of all processes within the manufacturing environment. The fact is all regulatory bodies are imparting a greater scientific understanding of container quality and therefore shifting to more advanced approaches to assure CCI.