The evolution of the SMEPAC guide

A new edition of the guideline for evaluating containment performance

The ISPE SMEPAC guideline, the benchmark for containment testing since 2005, is being updated with the release of its third edition. Twelve years after the last edition and more than a year of work by a team of leading international experts in engineering, safety, and industrial hygiene, the document will soon be available as an ISPE publication later this year (2024).
The pharmaceutical industry faces complex challenges daily to ensure the health of its workers and respect for the environment, while meeting very high regulatory and normative standards. In this context, the recently published ISPE Good Practice Guide SMEPAC serves as an update to a best practice that has been the benchmark for evaluating airborne particle emissions from containment systems for nearly two decades. Below, we briefly look at some of the new and updated elements that were the subject of in-depth investigation and discussion by the drafting committee during the preparation of the document. Compared to previous editions, this updated version introduces, for example, application to complex systems, a significant deepening of support for assessment strategies, greater attention to the choice of surrogates, and an expansion of the guidelines in the analysis and interpretation of data. An appendix with test protocols applied to the latest technologies in the field of containment completes the detailed theoretical analysis in the first part. These updates reflect the experience gained by the industry in recent years, with the aim of providing practical tools to address changes in the regulatory and technological aspects of pharmaceutical production. The approach remains as pragmatic and flexible as possible, not prescriptive, offering tools that can be adapted to the specific case under analysis and the organizations in which it will be applied.

The officialization

The first novelty of the document lies in the title of the guide itself, for which the acronym SMEPAC (Standardized Methodology for the Evaluation of Pharmaceutical Airborne Particle Emissions from Containment Systems), which has always been used by industry operators as a nickname to refer to this best practice, is now officially adopted. This choice, in addition to giving definitive recognition to the name itself, immediately emphasizes an expansion of the scope of the Good Practice Guide (GPG), which now aims to encompass not only individual components, but also complex containment systems and integrated processes. The focus on the increasing complexity of containment systems used in the modern pharmaceutical industry is in fact explicitly stated: the guide is not limited, as before, to evaluating the containment capacity of individual pieces of equipment, such as transfer valves or glove boxes, but extends the scope of application to entire systems, including those being introduced with Continuous Manufacturing. This expansion responds to the need to adapt to the technological trends of the pharmaceutical industry, where automation and integration of multiple operating phases are now consolidated realities.

Containment Performance Assessment as a complete investigation tool

In this edition, moreover, the containment test, more fully defined as Containment Performance Assessment (CPA), is described for what it is in its broadest and most useful sense: a true quantitative assessment tool that, relying on a solid standardization of methods and defined conditions, is capable of generating reproducible and comparable results over time. And so the CPA does not have as its sole purpose the simple measurement of particle emissions from a system, but is identified as a complete investigation tool. Its main function is to ensure that systems meet specific containment standards both at the beginning and throughout their life cycle. This can be achieved through the definition, analysis of the critical points of the system in question and the process in which it is inserted, a complete design of the strategy and methods of testing, a conscious analysis of the factors that can influence the results and an interpretation of the data functional to the objective of the investigation.
One of the central aspects of the CPA is its flexibility in adapting to different operating scenarios. For example, it can be used to evaluate the performance of new systems in the design phase, to confirm manufacturer declarations regarding containment specifications, or to monitor equipment that is already installed and operating. In any case, the CPA offers a level of detail that allows not only to identify any gaps in containment, but also to develop strategies to improve performance or correct any problems.

Test materials

Moving on to the test materials, the section of the guide dedicated to them has been revised and expanded, with even greater attention to the selection criteria. The document goes into more detail in the evaluation and selection of surrogates, the substances that, thanks to their traceability, allow the degree of containment to be assessed, considering the impact that chemical-physical properties such as solubility, dustiness and stability can have in fully simulating the conditions of aerosol propagation both in the solid and now also liquid state. This attention is based on the lessons learned by the industry in recent years, where it has been shown that an inadequate choice of materials can compromise the reliability of a test.

Testing strategy

Continuing with the list, among the most relevant in-depth analyses of this edition is the inclusion of a new chapter dedicated to the testing strategy, in which each of the critical elements distributed in the remaining chapters of the guide is summarized in a systematic list of steps, a sort of checklist that in a practical way helps the evaluator to face during the assessment both simple systems but also complex installations and multi-step processes. Simple devices, for example, require a more direct approach focused on the critical points of emission, while complex systems, such as integrated production lines, require an overview that considers the emissions of each component and the possible disturbances that the interference between them can generate, a vision that can be obtained by deploying the multidisciplinary skills of the various figures involved, for example site engineers, operators, technology suppliers, occupational hygienists and process safety. The chapter is completed by an example of a sampling strategy reported in the appendix of the document.

Data interpretation

A final renewed aspect concerns the interpretation of the data. The third edition offers more detailed tools to analyze and manage the test results, described in a completely revised and expanded section, with a more practical approach. The intent of the section is to select and evaluate the best statistical tools for data analysis at the service of the assessment, trying to mediate the intrinsic variability of the sampling and analysis processes, particularly important in a context in which containment systems could be compared with each other or monitored over time. In the chapter, the contribution and methods of estimating data below the limit of quantification according to the most up-to-date calculation methods are also analyzed, indications are given on how to evaluate data from surface sampling, suggestions are given on how to manage non-compliant tests and how to give an indication of the frequency of repetition of assessments during the entire life cycle of containment systems. This is because the stated intent of this latest version is to give robustness to the assessment, from monitoring to the representativeness of the simulation, ensuring a documentary record that stands the test of time and allowing a comparison between the different technological and procedural solutions in terms of containment performance obtained.

Conclusion

The production of HPAPI (Highly Potent Active Pharmaceutical Ingredients) constitutes a rapidly expanding segment of the global pharmaceutical industry, both in the field of small molecules and advanced therapies. As observed in a recent article in this journal [Ascca News 3/2024 – p. 32] these substances by their very nature require containment technologies and a strategic approach to containment control that meets the needs expressed by regulatory trends in product quality and obligations in the field of safety and environment projected towards constant improvement and control throughout the life cycle of products and processes. An updated and expanded best practice in its vision, oriented towards a multidisciplinary approach and capable of increasing the availability of representative and comparable data over time, will be a very useful tool at the service of experts in the sector for the coming years.