Beyond Isolated Risk Scores: Integrating Contamination Controls with PDA/ANSI 03‑2025
Brent Lieffers, Senior Director, Innovation Advocacy, Cytiva
Brent Lieffers explains how the new PDA/ANSI 03‑2025 standard reframes aseptic quality risk management. Moving beyond isolated FMEAs, it evaluates the totality of contamination controls as layered “Swiss cheese” defenses, emphasizes prevention and detection of control failures, and provides a lifecycle dashboard to prioritize improvements and support Annex 1 expectations.
1. The newly released PDA/ANSI standard introduces a lifecycle-based approach to contamination control. What industry gaps or challenges was this standard primarily designed to address?
The typical FMEA-based risk assessments that most of us are familiar are designed to evaluate risks in isolation, whereas this standard strives to assess contamination risk under an integrated system of controls. This is directly in line with the statement in Annex 1 Section 2.3 on Contamination Control Strategy (CCS), namely that the “collective effectiveness should be considered together”.
2. How does a holistic contamination control strategy differ from traditional risk assessment methods commonly used in aseptic manufacturing today?
When considering a holistic CCS, I like to refer to the Swiss Cheese model developed by James Reason back in the 1990’s. In the model, defenses (in our world, against contamination) are like slices of cheese, where the holes in each slice represent vulnerabilities. Multiple layers of protection then work together to provide a much higher degree of certainty to prevent contamination that any one layer could by itself.
3. In your view, why is it becoming increasingly important for manufacturers to move beyond isolated risk assessments toward integrated contamination control systems?
The overall systems used to make an injectable drug are very complex. This is exactly why it is now an expectation for manufacturers to have a CCS in order to ensure they are systemically looking across their entire process, understanding all routes and controls of potential contamination, and then addressing appropriately. This is what Quality Risk Management (QRM) is all about, with the highest priority on design (eliminate, prevent, reduce/mitigate hazards).
4. Could you explain how the PDA/ANSI standard aligns with evolving global regulatory expectations around aseptic processing and contamination control?
There are multiple key aspects listed within the standard, all in support of meeting the CCS development and maintenance requirements of EMA/PIC/s Annex 1. Of note, it “focuses on assessment of the strength and effectiveness of the totality of controls rather than on individual controls”. The standard also “focuses on contamination prevention and detection of control failures before contamination could occur”. This is a key differentiator in that we are not focused on solely detecting contamination. That is too late and the damage is done. Rather, we are looking to detect the failure of controls, thereby providing the opportunity to prevent contamination from occurring.
I think it is worth mentioning that the standard also aligns well with emphasis found in ICH Q9 on minimizing subjectivity and bias in assessing risk.
5. What are some of the biggest weaknesses you observe in conventional risk management tools when applied to complex aseptic operations?
While I think there are quite a few, so I’m going to pick on just two.
First, I’ve seen the subjectivity inherent in an FMEA used to nudge the numbers just enough to get a desired result. This is not quality risk management, it is gaming the Risk Priority Number to get a desired outcome, and can lead to underprioritizing genuinely critical risks.
The other weakness is what we have been discussing, where the tool assesses individual controls rather than the cumulative suite of controls.
Actually, I’ll quickly slip one more weakness in. Most risk assessment tools like an FMEA end up being a one-and-done exercise and are not integrated into the over site quality system as a living continuous improvement activity.
6. During your presentation, you will discuss situations where the PDA/ANSI methodology offers advantages over commonly employed assessment tools. Could you share an example of where this approach significantly improves decision-making?
Well, there is actually an example provided in the standard itself regarding stopper bowls, but I’ll pick on another topic that has been getting significant attention recently: open door changeover activities in an aseptic filling isolator. First, I want to be clear that I am not talking about any type of aseptic activity after the isolator has been brought into Grade A operational condition. That simply should not occur in a well-designed isolator filling workcell or system. Using the PDA-ANSI standard, we evaluated the risk of contamination when doing changeover on a Cytiva SA25 workcell. We turned each contamination control into a “cheese slice”, failure modes into “holes”, and converted prevention/detection rankings into layer and stack protection scores, making risk-based decisions visible, comparable, and prioritizable. In this situation, we found that the many layered controls (airflow bias, gowning, glove sanitization, task separation, real-time particle monitoring, etc.) rolled up on the contamination control risk dashboard solidly in the Green/Low Improvement Priority category. Such a result improves decision-making as it helps prioritize where improvement projects and resources should be directed.
7. How can manufacturers ensure that contamination control strategies remain effective throughout the entire product lifecycle rather than only during validation stages?
While Annex 1 addresses lifecycle management and even specifically calls out “ongoing and periodic review”, that can unfortunately sometimes just result in a cursory mention in an annual management review meeting or putting a procedural requirement in place to review the CCS every two years. We are used to change control processes, and the various document reviews they require. In a sense, any time we effect a change, we could potentially be changing process risk, either in a positive or negative manner, so evaluating that each time needs to be ingrained into the culture such that it becomes second nature. That also means that the CCS may need to be updated more frequently than just during the mandated review cycle, and that is a good thing. It demonstrates that you are committed to ensuring product and patient safety by evaluating changes, both before and after implementation, by holistically assessing the risks while pursuing improvements.
8. What role does Quality Risk Management (QRM) play in strengthening operational resilience and product assurance in sterile manufacturing facilities?
QRM provides a structured decision-making framework that allows an manufacturer to anticipate failures before they occur rather than reactively responding after the fact. End of batch sterility testing in inherently limited by sample size and can only retrospectively provide limited assurance, but a proactive QRM program can effectively serve as the primary assurance system. The PDA/ANSI standard methodology is designed to drive organizations toward leading-indicator detection and stronger prevention controls, which is the foundation of a truly resilient sterile manufacturing operation.
9. With increasing manufacturing complexity, how should organizations balance scientific rigor, operational efficiency, and regulatory compliance within their contamination control programs?
I think it is worth pointing out that rigorous scientific risk assessment and operational efficiency are not inherently in conflict, as a well-designed contamination control system prevents the far more costly disruptions of deviations, investigations, and rejected batches. Regulatory compliance can be a foundational floor rather than a restrictive ceiling, and if QRM is a general operational practice rather than just a compliance exercise, then the outcome will be better overall performance. Embedded QRM/CCS as part of routine operation is far preferable to treating as a separate compliance burden.
10. From your experience, what are the most common misconceptions companies have about contamination control in aseptic environments?
I think a common misconception is that an aseptic process simulation (or media fill) is an adequate demonstration of sterility assurance. This can be particularly problematic when used to justify risky interventions. An APS is a snapshot in time, so just because you executed a certain intervention and didn’t see contamination, it cannot provide continuous assurance of the contamination control’s ongoing effectiveness over the next six months until you perform another APS.
Another misconception is that more environmental monitoring can compensate for weaknesses in controls, especially when typical lagging EM data can only confirm that contamination has already occurred.
11. How can cross-functional collaboration between quality, engineering, manufacturing, and regulatory teams improve the effectiveness of holistic risk management programs?
By simply putting together the right team, as called out in the standard under the section Selection of Risk Assessment Team, all those cross-functional groups must collaborate. It is mandatory to have all the requisite SMEs participate, bringing together both the explicit knowledge and tacit knowledge or the process cannot function. This cannot be done in a conference room by a couple people and a consultant, but will typically require the quality unit, product development, quality control/microbiology, engineering, regulatory affairs, manufacturing, validation, supply chain, etc., all working together.
12. What implementation challenges should organizations anticipate when adopting the PDA/ANSI standard, particularly for legacy sterile manufacturing facilities?
I think the short and brutal answer is, don’t expect a risk assessment to justify outdated processes or equipment. An objective risk assessment like the PDA/ANSI standard, will help differentiate between controls that are green (low priority), yellow (medium priority), and red (high priority). High improvement priority controls are NOT effective and need immediate improvement or replacement. That’s not to say that all legacy facilities will light up red, but there needs to be a commitment up front that contamination controls that are lacking will be addressed promptly.
13. As technologies such as automation, robotics, and advanced environmental monitoring continue to evolve, how do you see the future of aseptic risk management changing over the next five years?
The first priority of QRM is appropriate design, followed by implementation of well-designed procedures, and finally (yes, Annex 1 says “finally”) monitoring to demonstrate the expected performance. This lines up nicely with the Risk Control Hierarchy, which, from most to least effective, says Eliminate, Prevent, Reduce, and Detect. I foresee a future where we continue to definitively eliminate hazards by design, shrinking what remains to prevent and reduce. This should then directly impact what is left to detect via monitoring. Monitoring a lagging indicator is not a control, and does not give assurance of sterility. I would like to see the embrace of robust quality risk management bring about a paradigm shift where we see highly automated, humanless and intervention-free aseptic processing managed with leading indicators where potential contamination control failures are detected before contamination can occur.
14. What key takeaway would you like attendees of the summit to gain from your session regarding the future of contamination control and quality risk management in aseptic manufacturing?
Having a Contamination Control Strategy is not an option. You have to create and maintain a CCS, so be bold. Embrace Quality Risk Management, learn to effectively use risk assessment tools like the PDA/ANSI standard, pursue innovation and continuous improvement based on data and scientific rationale, and go bravely into a better future!
Author Bio
Brent Lieffers is Sr. Director of Innovation Advocacy at Cytiva, joining the company in 2022 after serving as General Manager for its Aseptic Filling business. He brings over 30 years of pharmaceutical experience, spanning API manufacture through fill/finish, across clinical to large-scale commercial operations. A strong advocate for outcome-based compliance, Brent champions QRM/QbD, robust risk assessment, real-world data, and scientific rationale to advance technology and improve patient safety, with focus on prevention, lifecycle risk management, and holistic contamination control systems.
