Primary barrier packaging is the single most important contributor to quality beyond the walls of the manufacturing environment. The improving quality landscape is driven by both advancing technologies and improving regulatory frameworks that provide practical and clear guidance. While regulations are developed by fragmented consortiums, each guidance document applies a similar patient-centric mindset to quality risk management (QRM) over the complete product life cycle. Changes to package and container quality have experienced the most significant regulatory focus in an effort to improve patient safety.
Interconnection of Guidance Documents
The Pharmaceutical Inspection Cooperation Scheme (PIC/S) gathered global regulatory bodies and industry networks' perspectives to produce the most recent EU GMP Annex 1: Manufacture of Sterile Medicinal Products. The European Medicines Agency’s (EMA) Annex 1 became the formal current good manufacturing practice (cGMP) guidance on August 25, 2023. There is often a concern that guidance documents from different regulatory regions have competing expectations that are difficult to balance. However, the various guidance documents are uniquely intertwined and provide common practice in supporting patient-centric package quality. Annex 1 makes strong reference to QRM principles that is outlined in the International Council for Harmonization (ICH) Guideline Q9 on Quality Risk Management document, which was published over a decade earlier, and it also offers some recognition to package quality concepts laid out by the United States Pharmacopeia (USP) Chapter <1207>: Container Closure Integrity Testing. Additionally, the new guidance provided in Annex 1 has significant implications for packaging and container closure integrity (CCI).
Nonetheless, one criticism of these guidance documents is the continued 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 QRM. When in doubt, following basic QRM principles provides evidence of clear scientific thinking around CCI.
QRM applies to all aspects of the pharmaceutical manufacturing process. ICH Q9 is the most relevant regulatory guidance document related to risk management, and QRM is inherent to all CCI regulatory guidances. A patient-centric view of QRM follows a distinct path to assessing risks facing patient safety. Assessing QRM of pharmaceutical containers begins with a focus on patient care and identifies the critical quality attributes (CQAs) 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 critical quality attributes 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 unreliable due to variable inputs and often subjective test results. USP <1207> prescribes specific methods and identifies critical QRM approaches to improve container quality. As mentioned, Annex 1 recognizes and 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.
Annex 1 and USP <1207> establish expectations for deploying 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 Chapter <1225>: Validation of Compendial Procedures mentions that to be a validated cGMP test method, it must meet standards for accuracy and reliability, have detection limits and show linearity. USP and EMA documents have expectations that validated methods are controlled, reproducible and should have 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 detecting physical leakage and mentions that visual inspection is not an integrity test method. Not all physical defects are visual, and not all visual defects are physical as they relate to CCI. 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 and then maximizing assurance by deploying an effective sampling campaign to target that defect. Annex 1 establishes that the 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 CQAs. Then, the method can be leveraged to more automated approaches without compromising the ability to inspect CQAs.
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 than 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 an effective sampling plan should be applied for those that are not. 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. Testing quantities beyond the 1,250 sampling requirement for larger batch sizes does not establish a higher confidence level. 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.
All regulatory guidances point to a state of more quantitative deterministic testing that addresses QRM challenges. At a fundamental level, 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 CQAs, the value of deploying any quality control system is debatable. Without a reliable and effective test method, testing has no benefit.
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 will engage these shifts more successfully. QRM is at the foundation of all processes within the manufacturing environment. All regulatory bodies are imparting a greater scientific understanding of container quality and, therefore, shifting to more advanced approaches to assure CCI.