Contamination control is critical for safeguarding product quality, ensuring compliance
The need for pharmaceutical manufacturers to adopt comprehensive contamination control strategies has never been greater to ensure product quality and patient safety, as well as regulatory compliance. The stakes are high for pharma products to remain contaminant-free, requiring a robust strategy that includes environmental monitoring, testing, cleaning, and sterilization — among other safeguards.
Contamination in pharmaceutical manufacturing can be microbiological, chemical, physical, or particulate, according to Paolo Perracino, manager of contract manufacturer Axplora’s Farmabios site in Gropello Carolli, Italy.
When it comes to microbial contamination, Alberto Alemán, director of aftermarket solutions for aseptic equipment company Steriline, points out that it can compromise the sterility of a drug and directly endanger patients.
“Particulates, even something as small as fibers from clothing or packaging, can cause issues when injected into the bloodstream,” Alemán said. “Then there’s cross-contamination, if traces of one product end up in another, you risk dosage errors or unexpected reactions.”
Perracino notes that each threat presents serious risks to patient safety, product efficacy, and regulatory compliance, such as Annex 1 of the European Union’s Good Manufacturing Practice guidelines (EU GMP Annex 1). He contends that sterile and high-potency manufacturing require particularly stringent controls, as even minimal contamination can lead to recalls, non-compliance, or patient harm.
“The margin for error is zero,” Perracino said. “Cross-contamination, in particular, is a major concern in facilities handling hormones, cytotoxics, or steroids. Even trace levels can lead to adverse patient reactions. That’s why we’ve built layers of control into both our infrastructure and our daily routines.”
Axplora recently announced a €35 million expansion of its Farmabios site, more than doubling its footprint and bringing total recent investment to over €80 million. The capital expenditure is in response to rising demand for complex, high-potency active pharmaceutical ingredients (HPAPIs).
The Farmabios site’s RS40 building, a dedicated high-containment facility for potent compounds, includes segregated processing suites built to Occupational Exposure Band (OEB) Level 5 containment standards and supports Occupational Exposure Limits (OEL) as low as 10 nanograms per cubic meter. Each unit is designed with stand-alone workshops and fully isolated process rooms to mitigate cross-contamination risks, with the micronization areas equipped with isolators specifically designed for HPAPI handling.
“Our high-containment areas, like the new RS40 building, are designed for safe handling of highly potent compounds with strict zoning, closed systems, and automated controls,” Perracino said. “We rely on highly automated control systems to reduce manual handling, and we maintain rigorous monitoring of all environmental parameters. It’s a strategy that combines engineering, digital control, and human discipline.”
Fundamentals of CCS
An effective contamination control strategy (CCS) provides a structured plan designed to identify, control, and mitigate risks of contamination throughout the product lifecycle, according to Perracino, who sees CCS as the “backbone of any reliable pharmaceutical manufacturing operation” with personnel training, environmental monitoring, and equipment segregation as key pillars of the strategy.
CCS is not just one process or one standard operating procedure, Alemán said. “It’s the sum of all the controls, procedures, technologies, and habits that together protect the product from contamination.”
Steriline designs isolators and filling lines to reduce risk and human intervention, according to Alemán.
“From an engineering standpoint, we design our equipment, especially isolators and filling lines, with contamination control in mind from day one,” he said. “That means minimizing manual interventions, reducing dead zones, integrating automated sterilization cycles, and simplifying cleaning and disinfection.”
At the same time, human error remains one of the top contamination risks, Perracino noted.
“A strong CCS covers everything from the physical layout of the site to the daily habits of our teams,” Perracino said. “That includes air handling, gowning, cleaning procedures, and validated flows for materials and personnel.”
“Humans are the biggest source of contamination, so gowning, behavior, and training are critical,” Alemán acknowledged.
When it comes to training, Axplora has created a culture where contamination control is second nature, Perracino commented, where “everyone at the site needs to understand not just how to follow procedures, but why those procedures exist.”
Perracino argues that the revised EU GMP Annex 1 has made CCS a regulatory requirement for sterile manufacturing environments, with the growing complexity of APIs and high-potency products making robust CCS implementation essential — bringing together facility design, technical systems, and human behavior into a single, risk-based approach.
Alemán points out that the updated EU GMP Annex 1 emphasizes not just controlling contamination, but proactively understanding where it could come from, how it moves, and how to block it.
“It’s like designing a house to stay cool in summer: you don’t just install a fan, you design insulation, ventilation, materials, orientation — the whole ecosystem needs to work together,” according to Alemán.
With the latest EU GMP Annex 1 updates with a focus in sterile production, having a robust and documented CCS isn’t just best practice — it’s a regulatory expectation,” Perracino said. “But beyond compliance, it’s about protecting patients. That’s the ultimate goal of any CCS.”
Future of CCS
As the fastest-growing segment of the pharmaceutical market, sterile injectables are more important than ever. Fueled by the need for biologics and vaccines, the global sterile injectable drugs market is expected to expand significantly reaching $1.4 trillion by 2030, with a compound annual growth rate of 9.7%.
A new collaboration between Eli Lilly, Merck, and Purdue University is focused on sterile injectables. Purdue’s Young Institute for the Advanced Manufacturing of Pharmaceuticals is looking to advance AI-driven automation, robotics, and novel aseptic processing methods to improve efficiency, quality, and safety in the manufacture of injectable drugs.
Elizabeth Topp, director of the Young Institute, makes the case that robotics could remove human operators from sterile environments, reducing contamination risks and ensuring operator safety.
“Ideally, what we want to do is create an environment in which there are no humans present,” Topp said. “We want the fill-finish line to be completely free of humans. Humans are full of germs. We are little germ factories.”
To address the problem, Purdue is working with the pharmaceutical industry to try and create what they call a hands-off, gloveless, sterile, injectable fill-finish line. “So, we only have robots in the environment,” she said. “It’s an exciting thing to try and work on.”
In this completely robotic environment, Topp’s vision is for a fill-finish line that fixes itself.
“If something falls off the line or a widget falls off of a piece of equipment, a human doesn't have to go in and repair it,” she said. “The industry does not have fully gloveless fill-finish lines, but we have great mechanical engineers at Purdue.”
Another contamination control-related project Purdue’s Young Institute is working involves environmental monitoring. Topp notes that “one of the most old-fashioned and common ways of monitoring” is simply putting a Petri dish next to a fill-finish line and waiting to see what lands on it.
However, it is a slow and time-consuming process that can lead to false positives, according to Topp, with incorrect information resulting in a loss of product for pharma manufacturers. “We need to switch to those other methods that involve contamination detection, using methods other than waiting for the stuff to grow,” she said.
When it comes to air monitoring of the manufacturing environment, there are cone-shaped collectors that are used to actively sample air but “they also have their problems and are ultimately limited by the same kinds of analytical challenges,” Topp lamented.
One promising area of technology involves automated visual inspection of vials coming off the line, potentially replacing a cumbersome method of manually inspecting them.
“The way that that’s done currently is there are a bunch of people who are sitting in a room, and they look at the vials of liquid — say injectables that are coming off the line — and they hold them up in front of a screen,” Topp said.
Purdue and its pharma partners are working on a better way of looking for particulate or other abnormalities in products through automated visual inspection. “We have cameras. We have AI. Why can’t we have a better way of examining these?” Topp asked.
The Young Institute’s 10,000-square-foot pilot-scale manufacturing facility is under renovation in West Lafayette, Indiana — an innovation space to “monitor what’s going in fill-finish lines and develop some of these technologies,” Topp said.
