Hal Baseman

The microbiologist is testing the microbial contamination in the sample under vertical laminar air flow cabinet, concept of microbial laboratory in pharmaceutical industry, selective focus photograph. | Image Credit: © Sukjai Photo-stock.adobe.com

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.

Intervention Risk Evaluation and Management in Aseptic Manufacturing–Part II

Quality and Regulatory Sourcebook eBook March 2024

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.


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]

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 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).

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

®
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

Articles

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

The objective of our industry is to manufacture and distribute high quality, healthcare products and therapies that benefit the public. One of the basic challenges to meeting this objective involves producing drug, biologic, and medical-device products that not only are safe, effective, and compliant with global regulatory requirements but also readily available for use by the patient. Achieving this objective means that these products must remain available and affordable, as well as a reasonable business proposition for manufacturers. To that end, today’s drug manufacturing industry must address issues related to drug shortages, quality metrics, drug-product costs, innovative therapies, counterfeit products, and supply chain integrity. 

Industry associations, in particular the Parenteral Drug Association (PDA), have a strong role in helping the industry meet challenges. For nearly 70 years, PDA has been the leader in providing thoughts on the current needs, best practices, topics, and positions that are important to the manufacturing of quality drug products. PDA does this by providing venues for exchange of information and connecting people, science, and regulation through the publishing of oft-cited technical reports and papers, international conferences and meetings, and hands-on Training and Research Institute education courses.

Through these and other efforts, much knowledge has been gained throughout the years. This knowledge results in better process understanding, helping us design processes, establish control systems, and make informed decisions. This understanding is especially relevant in recent years, where the industry has seen changes, faced issues, and noted an evolution of product manufacturing technologies and methods. As we consider the state of our industry, the following guiding and linked principles emerge:

The use of science- and risk-based approaches to make decisions related to the evaluation, design, qualification, operation, and monitoring of sterile product manufacturing processes is beneficial, if not essential, for the development and implementation of process control strategies.

The use of technology should be considered and encouraged to reduce risks to product quality identified in manufacturing processes and operations. The best use of new technology will come from a partnership of manufacturers, regulators, and suppliers.

Traditional testing and monitoring methods may not always be the most effective way to mitigate risks from newer technologies and product manufacturing processes. Where this is true, critical thinking and innovative methods must be considered. 

New products, therapies, and packaging configuration will continue to present challenges to existing and traditional methods for development, manufacture, validation, and testing of sterile products.   

Where scientific expectations are similar and agreed upon, requirements and guidance should be consistent in technical language and definition, thus reducing the risk of misunderstanding of global regulatory expectations. 

The industry is beginning to recognize that the most effective way to address drug product manufacturing issues is to focus directly on improving the manufacturing process. Efforts on quality systems, risk-based decision-making, process development, validation, contamination control, and supply chain integrity are essential elements of information and knowledge exchange. Using all tools at our disposal to better understand and control the variables inherent in our manufacturing process will provide opportunity to improve those processes. PDA will continue to support the industry as a leader in efforts to provide that knowledge and understanding, as it has done for the past 68 years. 


Hal Baseman is chief operating officer for ValSource and chairman, Parenteral Drug Association Board of Directors. hbaseman@valsource.com.

Industry associations play a strong role in helping the pharmaceutical industry meet challenges.