Regulatory science opportunities for contamination controls and sterility assurance
Regulatory science applies scientific knowledge and methodologies to guide regulatory policies and practices. As opportunities to better understand contamination risks and implement risk mitigations arise, regulatory science can help guide contamination controls and sterility assurance for sterile products, supporting patient safety and product innovation. This article discusses how collaboration between manufacturers, regulatory agencies, researchers, and healthcare providers is critical to developing future requirements that will support innovation and international harmonization.Keywords – contamination controls, regulatory science, sterility
Introduction
Regulatory science is a multidisciplinary field that applies scientific knowledge and methodologies for the development, evaluation (including risk assessment), and implementation of regulatory policies and practices. The US Food and Drug Administration (FDA) has defined this field as “the science of developing new tools, standards, and approaches to assess the safety, efficacy, quality, and performance of all FDA-regulated products.”1 The goal of regulatory science is not only to establish regulatory requirements, but also to improve the development, review, and oversight of new drugs, biologics, and devices that require regulatory approval prior to dissemination.2Regulatory science provides a platform for collaboration by bringing together various stakeholders, including industry professionals, regulatory agencies, researchers, and healthcare providers, to share knowledge and expertise, conduct research and development, and promote the alignment of standards and guidelines across regions and markets. With advancing medical technologies and emerging and evolving regulations across the globe, such collaborative efforts can lead to flexible and robust regulatory approaches that embrace innovation.
Regulatory science has positively impacted innovation in the healthcare space, including supporting reliance principles, adaptive licensing, breakthrough therapy pathways, the use of real-world evidence and real-world data, and modified risk-based approaches.3,4 Advances in these frameworks reduce the regulatory burden on existing products, such as by extending product claims and accommodating changes in the manufacturing steps or labeling of products. By collaborating across these frameworks, stakeholders ensure that policies are not static but evolve in response to new scientific evidence, technological advancements, shifts in public health concerns, and supply chain challenges.
This article focuses on how regulatory science can be applied to contamination control and sterility assurance, which are essential to ensuring the safe provision and use of medical products, depending on their intended use. Efficacy and safety requirements are central to the development and provision of all medical products. Safety includes requirements for patient use, healthcare workers, and the environment (or sustainability). Contamination can be defined as the presence of material not intended to be part of a product or process.5 This includes chemical (including particulates) and microbiological (microorganisms and their associated toxins) contaminants. A major patient safety risk from unintended contaminants is infection, particularly in areas of the body that are usually considered sterile, such as deep organ spaces or the bloodstream. Additional risks can include toxicity, pyrogenicity, and other complications (e.g., granuloma formation from the presence of foreign debris). The impact of these complications is unfortunately often more pronounced in patients who are immunocompromised or more vulnerable due to underlying disease or conditions.
Various contamination control methods can be used to reduce such risks, such as cleaning (i.e., the removal of contaminants to defined levels), containment systems, cleanroom designs, and antimicrobial processes (disinfection and/or sterilization). Contamination control in a manufacturing environment should be strategic and depend on the product risks. This will require an integrated set of controls, planned actions, and conditions designed to limit product contamination to defined criteria.5 A component of contamination controls for higher-risk products (such as injectables and implantable medical devices) is sterility assurance. Sterility assurance is defined as a qualitative concept comprising all the activities that provide confidence that a product is sterile or free from microorganisms. As opportunities for understanding contamination risks and risk mitigations arise and product quality and patient outcomes are considered, regulatory science can help adapt guidelines and regulations accordingly to ensure there is no disruption to product innovation.
Sterile product risk management
Traditionally, sterile products are manufactured through two separate pathways that are often differentiated by their labeling and regulatory requirements. Note that medical devices intended to be sterile must be labeled as such, while pharmaceutical products are not required to do so.The first approach is by terminal sterilization, where the product is typically manufactured under controlled environment conditions and is sterilized within its packaging (sterile barrier) system. Such sterilization processes are conducted by exposure to methods based on ionizing radiation, heat, or antimicrobial gases.6 These processes are widely used in diverse types of food and medical products, such as medical devices and some pharmaceutical products, such as saline and water.
The second approach is aseptic processing, a manufacturing process used to reduce or prevent the risks of microbiological contamination in a product to achieve a defined microbiological quality appropriate for its intended use. Aseptic processes are widely used in the pharmaceutical environment, as many drug products may not be compatible with or are destroyed by the antimicrobial methods used for terminal sterilization. This can include the use of terminal sterilization of components used in the manufacturing process, strict aseptic conditions to maintain essentially sterile environments, and sterile filtration methods during final packaging to physically remove microbiological contamination. A combination of both approaches is often required or utilized to enable new types of sterile products.
Both terminal and aseptic approaches deploy various methods of contamination control in accordance with their respective quality and regulatory compliance requirements. For medical devices, examples of regulations and standards include the FDA’s quality system regulation (21 CFR 820), the EU Medical Devices Regulation (Regulation 2017/745), and International Organization for Standardization (ISO) standards on quality management systems, heat sterilization of health care products, and aseptic processing of health care products (ISO 13485, ISO 17665, and ISO 13408-1, respectively). For sterile medicinal products, examples of regulations and standards include the FDA’s current good manufacturing practice (GMP) in manufacturing drugs and for finished pharmaceuticals (21 CFR 210 and 211), the EU’s collection of GMP guidelines for pharmaceuticals and active substances (EudraLex Volume 4 – GMP guidelines), and the United States Pharmacopeia’s sterile compounding and sterility testing standards (USP <797>, and USP <71>). Recent regulatory requirements under the EudraLex GMP Annex 1 guidelines for sterile medicinal products highlight the importance of quality risk management and an overarching contamination control strategy for manufacturing facilities.7 Some examples of international guidance and standards that apply to sterility assurance and sterilization are given in the accompanying Table.
General regulatory landscape and challenges
The regulatory requirements and expectations of a product will vary depending on the product type (e.g., medical device or parenteral drug) and the various country/economic area regulatory requirements. In general, obtaining approval (or clearance) and managing post-approval change requirements for quality-controlled microbiological products can be restrictive, often requiring detailed regulatory review prior to commercialization.8 For example, in medical device sterilization, post-approval changes can include those that may be considered technically major or minor. Minor changes can include adding new sterilization vessels that are essentially equivalent to existing, approved equipment, transferring sterilization to a different location without changing the process conditions, or making minimal changes to the sterilization process that do not impact the safety or efficacy of the process or the product.Major changes could include switching from one type of sterilization process to another (e.g., from radiation to an antimicrobial gas or heat process) or significant changes that may be considered as altering the safety or effectiveness of the process (e.g., altering exposure conditions, temperature, pressure, or radiation dose). Although existing guidance documents can generally help interpret the impact of such changes, most changes in a sterilization process or aseptic method, including changes in packaging or transportation, are considered substantial and require regulatory approval.5 This requirement applies even though manufacturers are already obligated to continuously review and approve changes to product design or production, complete associated validations, and document such changes in their quality management system.
The requirements for approval of the variety of changes that may occur over the lifecycle of a product can also vary from region to region. For instance, changes to contamination control processes are often subject to regulatory approval in pharmaceutical manufacturing. International guidance, such as that of the International Council for Harmonisation (ICH), recommends a risk-based approach based on knowledge management to justify these changes.9 But there is little guidance on what changes would be considered significant in contamination control strategies. For example, in the US, approved biologics license applications may require reporting any change in the manufacturing process, quality controls, equipment, or facilities that impact contamination controls, irrespective of the risk or benefit. The opportunity to classify these changes as substantial, moderate, or minimal and reduce the need for regulatory clearance is an area that could benefit from further definition and harmonization internationally.
Opportunities for contamination controls and sterility assurance
There are opportunities in the field of regulatory science to develop new guidance that can provide frameworks to reduce the regulatory burden of changes in contamination control and sterility assurance while ensuring that product quality and safety standards are maintained.One possibility is that changes could be proposed, reviewed, and approved during initial product submissions, such as quality requirements for changes in sterile filtration methods used for sterilization-sensitive drug products, or changes in the location or type of sterilization modalities used. Up-front discussions and associated approvals could establish risk-based requirements to allow these changes without further regulatory approval. This may also include agreement on a critical risk framework defining when post-approval changes for microbiologically controlled products are required.
The recently published FDA draft guidance on predetermined change control plans (PCCPs) illustrates this possibility.10 A PCCP documents proposed modifications to a device/process and outlines how they would be planned, validated, and implemented, and how the impact would be assessed as part of a pre-planned protocol. Changes in sterilization, packaging, transport, or expiration dates using well-established methods were described as potentially appropriate for inclusion. However, the inclusion of other changes in the PCCP, such as the utilization of a new manufacturing or sterilization site, may require further discussion as in some cases these changes may be considered major in a risk assessment. The FDA has also been exploring sterility change master file pilot programs for changes in sterilization processes or facilities – for example, when reducing the gas concentrations used to sterilize medical devices.11 These regulatory approaches present a significant advancement in regulatory science in the US and could be leveraged as part of harmonization practices internationally.
The use of risk management plans, as well as early engagement with regulators, should be standard practice in product development. Risk management plans help confirm that a manufacturer has considered all potential risks associated with a change. For example, a risk assessment approach that is used to justify the adoption of x-ray as an alternative method for device sterilization based on the previous approval of gamma sterilization processes.12 Radiation sterilization of medical devices is achieved using three traditional means of delivering dose (measured in kGy) under ISO 11137-1:13 gamma, x-ray, and e-beam.6
In the past, the most widely used method of sterilization was gamma irradiation with controlled exposure to a Cobalt-60 source, but in recent years, the use and capacity of x-ray irradiation have increased significantly. Radiation sterilization methods are well defined and recognized by the FDA as traditional sterilization methodologies. Therefore, adopting x-ray-based methods as an alternative method, using the same radiation dose range as a previously validated gamma sterilization process for medical devices and supplies, appears practical. Notably, the applicable International Organization for Standardization (ISO) standards for radiation sterilization13 and more recent publications14 provide guidance on transferring products between different radiation sterilization sources. This is important as it may be incorrect to assume that the change from exposure to an existing gamma radiation source for sterilization to an x-ray radiation source is different when this is often not the case.12,14
While the method used to generate the radiation dose may change, in most cases the actual sterilization process that the product can be exposed to does not significantly change. Overall, important variables in the change to a sterilization process to consider will include requirements for antimicrobial efficacy as well as product safety. A risk assessment can highlight that any residual risk associated with a change from using an existing, validated gamma sterilization process to a new x-ray process can be negligible. For example, if the radiation dose with the new x-ray process falls within the range previously validated for an existing gamma sterilization process, then the risks may be considered low when justified based on the associated process and product. In this specific example, temperature fluctuations during sterilization can be shown to be lower with an x-ray process than with gamma radiation, and the potential exposure to various types of oxidizing agents (generated in the atmosphere due to the presence of air, water, and energy) may also be lower.
Therefore, an existing validated gamma sterilization process may be considered more of a worst-case scenario from a risk point of view than a new x-ray process and allow for the adoption of that process as equivalent. Nevertheless, a detailed risk assessment would be required to address product-specific or process-specific challenges, including transportation and sterilization location logistics. By combining knowledge, scientific data, risk assessments, and regulatory science, manufacturers can achieve greater flexibility in the overall supply chain of the product without causing an unnecessary regulatory burden.
Other examples of when risk-based approaches in microbiological quality and sterility assurance can be employed may include:
- Minor design changes that can support sustainability goals (e.g., reducing or using alternative materials in packaging design)
- Ethylene oxide (EO) sterilization process condition or location changes (e.g., reducing EO gas concentrations or extending aeration times)
- Sterilization modality changes (e.g., from EO to alternative radiation or gas-based processes such as those based on vaporized hydrogen peroxide)
- Deviations from microbiological quality specifications (e.g., minor design or process changes, adoption of rapid microbiological methods, or analytical technology to replace traditional microbiology culturing methods)
- Alternative use of parametric release or rapid quality indicators (e.g., biological or chemical indicators) for product release post-sterilization
- Changes or updates to reusable device processing instructions that help to address or clarify customer needs without the need for post-approval regulatory clearance internationally
- Applying risk-based concepts such as microbiological quality levels that may determine the overall patient risk and identify the necessary critical control points in a manufacturing process that cumulatively meet product safety requirements
Rather than focusing on final product endpoint testing, risk-based approaches encourage a more end-to-end mindset.15 The use of alternative statistical methods, such as the Bayesian statistics framework, to assess product risks may be considered in these cases. Bayesian statistics uses probability to represent a degree of confidence, combining prior beliefs with data to form a final expectation or conclusion (e.g., sterile or non-sterile). This method differs from existing frequentist methods, which often depend on testing large numbers of final product samples to confirm product quality requirements (e.g., sterility testing). Alternative statistical methods may become even more important to enable new patient-specific technologies such as 3-D printed implants and advanced therapy medicinal products.
These examples of risk assessment and alternative statistical methods can also inform the evolution of standards (e.g., radiation- or heat-based sterilization processes or aseptic manufacturing) and pharmacopeia requirements, making them more regulatory-ready, streamlining approval or clearance processes, and accommodating post-approval design changes throughout the product lifecycles.
Challenges in innovating regulatory science
Regulatory science has enabled greater flexibility across many product areas by developing new guidelines that provide a framework for evaluating risks – for example, in continuous manufacturing processes, where the benefits of the process are balanced with the need to meet product quality and safety standards. The FDA, EMA, and ICH have issued or adopted guidance to assist manufacturers in transitioning to continuous manufacturing without compromising sterility assurance or product integrity.16,17The inability to adapt regulatory requirements to evolving manufacturing technologies, emerging contamination threats, and supply chain issues may lead to risks to public health if the current pace of regulation does not keep pace with innovation. For example, delays in bringing new products to market limit access to potentially life-saving technologies. Adaptation is particularly needed because of the presence of opportunities in sterility assurance, supply chain disruptions, increased production costs, regulatory inconsistency across markets, and regulatory delays in emergencies.
Opportunities in sterility assurance. Without the regulatory flexibility needed to adapt aseptic processing or sterilization processes, there may be over-reliance on outdated, onerous, or less efficient sterilization methods or controls. If newer, more effective technologies, such as rapid microbiological methods, process monitoring technologies, or continuous sterilization techniques, cannot be adopted, new technologies and therapies may be delayed or deemed too burdensome or costly to be commercially viable. If regulatory frameworks remain rigid, manufacturers may not be able to implement more precise or efficient sterility assurance methods to enhance product solutions and patient impacts.
Disruptions in supply chain. In cases where sterility assurance processes cannot be updated or adapted due to strict regulatory requirements, manufacturers may face delays or bottlenecks in production. These delays can lead to production slowdowns or even temporary cessation of manufacturing, which in turn leads to delays in product availability or even shortages of critical medical products.
Increased production costs. Hesitations to adopt more efficient sterility assurance methods or microbiological quality approaches due to regulatory inflexibility may require manufacturers to continue using more expensive or resource-intensive processes. Reliance on these processes can lead to increased production and drug or medical device costs, which in turn can increase costs to the patients and the healthcare system.
Regulatory inconsistency across markets. Microbiological quality assurance requirements may vary significantly between regions (e.g., between the FDA, EMA, and other regulatory bodies). A lack of flexibility or harmonization of regulations could result in manufacturers being unable to implement a standardized process that complies with all regional requirements, leading to delayed or disrupted product availability in certain markets. This could impact global access to essential medicines and medical devices, especially in regions that rely on imports for critical healthcare products.
Regulatory delays in emergencies. During public health emergencies, such as outbreaks of infectious diseases, manufacturers may need to rapidly adjust their processes to accommodate new vaccines, medical devices, or other products and respond to increased demand. Without regulatory flexibility, these adjustments could be delayed, preventing timely response to public health crises, and impeding rapid production of critical medical supplies.
Conclusion
As medical technologies advance, modifications to existing processes will be required. Regulatory science approaches can be flexible and robust to keep pace with innovations in the healthcare space. To support these changes, collaboration between manufacturers, regulatory agencies, researchers, and healthcare providers across different regions and markets will be critical in the development of harmonized standards and guidelines Experience in areas such as contamination control and sterility assurance show how regulatory science can offer science-based risk assessments and pre-determined change controls to reduce the regulatory burden while ensuring that product quality and safety standards are maintained.Abbreviations
EMA, European Medicines Agency; EO, ethylene oxide; FDA, Food and Drug Administration; GMP, good manufacturing practice; ICH, International Council for Harmonisation; ISO, International Organization for Standardization; PCCP, predetermined change control plans.
Citation McDonnel G, Dauria R. Regulatory science opportunities for contamination controls and sterility assurance. Regulatory Focus. Published 18 September 2025. https://www.raps.org/News-and-Articles/News-Articles/2025/9/Regulatory-science-opportunities-for-contamination
About the authors
Gerald McDonnell, PhD, BSc, is the vice president of microbiological quality and sterility assurance at Johnson & Johnson. He has more than 30 years of experience in innovation, R&D, quality, and compliance of healthcare products, focusing on microbiological quality. Dr. McDonnell has a Bachelor of Science in medical laboratory sciences from the University of Ulster and a doctorate in microbial genetics from the University of Dublin, Trinity College. He can be reached at [email protected]
Raina Dauria, MS, RAC, is vice president of global regulatory affairs policy and talent at Johnson & Johnson MedTech. During her 25+ year career, Raina has worked on regulatory strategy, submissions, and approvals for devices, biological, and combination products. She has overseen regulatory affairs, clinical research, field scientific affairs, and quality assurance functions. Dauria holds a Bachelor of Science in biology from Fairfield University and a Master of Science in drug regulatory affairs and health policy from the Massachusetts College of Pharmacy and Health Sciences. She has been RAC certified since 1998. She can be reached at [email protected]
References
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