Intervention Risk Evaluation and Management in Aseptic Manufacturing–Part II

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Pharmaceutical Technology, Quality and Regulatory Sourcebook, March 2024 eBook, Volume 2024 eBook, Issue 3
Pages: 14-24

IREM can be used for effectively assessing and mitigating risks and improving the overall sterility assurance level in all types of aseptic processing lines.

This article is a sequel of the article published in the Parenteral Drug Association’s Journal of Pharmaceutical Science and Technology (1) and provides industry with additional options and thoughts on meeting quality risk management (QRM) needs for the manufacture of sterile and microbiologically sensitive products. Part 1 of this article resulted in considerable industry response with respect to its utilization and increasing opportunities to address current technology needs and regulatory challenges. This response includes the use and refinement of the method for new applications. In this second article, the authors discuss and present more application scenarios where the Intervention Risk Evaluation Method (IREM) can be used for effectively assessing and mitigating risks of human interventions and improving the overall sterility assurance level of the final products, further refining and aligning the method with industry needs and regulatory expectations.

Although performing effective risk assessments has long been considered as beneficial for the design, performance, and evaluation of aseptic processes, as well as a strong regulatory expectation, it continues to be an area of concern and a challenge for pharmaceutical companies. With the advent of advanced therapy medicinal products (ATMPs), complex aseptic formulations, and modern manufacturing technologies, objective, data-driven risk assessment is becoming even more important to assess the risk of interventions in a more holistic way and with true representation of actual shopfloor conditions in any given line. This need reflects the current expectations of global regulators as defined in the contamination control strategy (CCS) and QRM sections of European Union and Pharmaceutical Inspection and Co-operation Scheme (PIC/S) Annex 1 guidance and regulations (2,3).

One key aspect that differentiates IREM from other risk assessment tools is that it empowers those performing aseptic processing activities to design their own risk assessment model and establish a mitigation strategy for themselves. IREM involves the people from the shopfloor or cleanroom who are responsible for performing the process control activities. This helps identify the core risk elements and risk mitigation steps. As such, it creates a better sense of awareness and ownership by those individuals for mitigating those risks.

This article focuses on manual or semiautomatic aseptic processes, which have come into significant use due to expansion of ATMP manufacturing and other complex biopharmaceutical manufacturing processes, and aseptic compounding that requires manual aseptic manipulations during these processes. The need for guidance to identify and mitigate aseptic processing risks for ATMPs and certain other manual operations has become a significant concern in the industry. The authors present a case study to illustrate the use of an IREM to evaluate the risks posed by interventions during aseptic compounding. The IREM team is encouraged to use a keyword approach to choose risk factors and ranking criteria that are meaningful and fit the circumstances at the site. In the following case study and in the previous article, five risk factors were identified as opposed to the three identified in early IREM publications (4).

The factors and associated criteria selected may not necessarily be optimal or applicable to other teams and other sites and are not meant to present prescriptive or exclusive risk factors and ranking criteria. However, they are still defendable, have a scientific basis, and are meaningful for the determination of relative risk ranking and mitigation for this site and circumstances. It is important that, for this site and circumstances, the risk factors and ranking criteria are applicable, have a defendable and scientific basis, and are meaningful to the assessment team. The flexibility of allowing the team to choose its own risk factors and criteria helps ensure that the company will use the IREM to its full potential, to establish and mitigate the line-specific risk factors, and not merely go through the formality of a risk assessment exercise.

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The figures and tables for this article may be accessed below:

Figure 1: Aseptic compounding process flow in a conventional laminar flow hood with rigid barriers used in this case. [Figure courtesy of the authors]


TABLE I. Definition of risk level for each risk factor.

TABLE II. Risk Class-A based on duration and complexity.

TABLE III. Risk Class-B based on proximity and human exposure.

TABLE IV. Combined Risk Class (A and B).

TABLE V. Final Risk level based on operator skill/experience.

TABLE VI. Risk levels and mitigation actions. CAPA is corrective and preventive actions.

TABLE VII. Risk ranking based on current intervention status.

TABLE VIII. Risk ranking based on mitigated intervention status (hypothetical).

About the authors

Subrata Chakraborty is founder and CEO at GxPFONT Consulting, INOVR. Hal Baseman is COO at ValSource.

Article details

Pharmaceutical Technology®
Quality and Regulatory Sourcebook eBook
March 2024
Pages: 14-24


When referring to this article, please cite it as Chakraborty, S. and Baseman, H. Intervention Risk Evaluation and Management in Aseptic Manufacturing–Part II. Pharmaceutical Technology Quality and Regulatory Sourcebook eBook. March 2024.