How Mitigation and Maintenance Protect Against Future Risk

The manufacture of biopharmaceuticals must be performed under good manufacturing practices (GMPs)—established by regulators in the United States (1), Europe (2), and other areas of the world (3)—in GMP facilities using qualified and validated equipment (4,5). Risk-based maintenance plans for both facilities and equipment can be used to follow these guidelines, as can the use of quality management systems.

Equipment must be maintained in a “qualified state,” according to Neil Bergeron, vice president, Global Engineering, Development & Manufacturing Segment for PCI Pharma Services, which he says doesn’t end with the equipment being qualified when it is placed in the facility. Stringent requalification of equipment must be performed to ensure the equipment meets current GMPs (cGMPs). He recommends establishing a preventive maintenance program that aligns with the requirements of the original equipment manufacturer (OEM) to provide the best opportunity to keep the facility properly maintained.

“While initial qualification is typically straightforward per a machine’s OEM-recommended protocols, requalification must consider a variety of factors—including any line changes since the most current qualification,” Bergeron explains. “So, clearly, qualification is by no means a ‘set-it-and-forget-it’ task, but rather an ongoing process that must be closely monitored and meticulously performed over a machine’s lifecycle.

“From a bird’s-eye view, the overarching principle is that all equipment in a manufacturing setting should remain consistently qualified, so that none becomes a weak link in the overall production chain,” Bergeron continues. “The requalification process is based upon a review of the machine/system’s performance over the previous period, including a thorough review of change controls, deviations, out of trends, and other parameters.”

How is risk mitigated in biopharmaceutical facility management?

Risk mitigations should start in the facility design stage by team members who understand the particular operating procedures of the facility, as well as the regulations involved, according to Justin Cantor, Life Sciences CQV Executive at DPR Construction. Risks anticipated at this stage can be resolved on paper before the facility is even operational.

“The risk mitigation process starts with going through how the facility, utilities, and equipment will be qualified, validated, operated, and maintained,” Cantor explains. “Any risks identified by the owner’s validation, quality, maintenance, and manufacturing representatives need to be assessed; not all risks are created equal.

“Once ranked, the high-risk items can be mitigated,” Cantor continues. “Mitigated risks need to be reassessed by the team to ensure that the mitigation strategy has effectively reduced the risk from high to low; otherwise, alternative or additional mitigation ideas may need to be explored. The team can then decide which of the medium-risk items need to be mitigated, if any. Identified risks will be monitored throughout the project to verify that the mitigation strategy is effectively implemented.”

For new facility construction, meetings should be held between the owner, architect, and contractor (OAC) to ensure regulatory compliance for each build project. “This is an opportunity to increase awareness of the general contractor and architect regarding the owner’s knowledge of the critical aspects of the facility in the design and build phases. OAC meeting time can be devoted to process reviews, risk assessments, field walks, discussion of discovered issues, and the general sharing of relevant regulatory information,” Cantor says. “Lessons learned by each party from previous projects can also be shared to understand the risks and strategies that could benefit the current project. Collaboration and open dialogue help to ensure that issues are raised in a safe environment without fear of reprisals. Additionally, team-building events often help develop relationships, which helps keep issue-resolution focused on solutions instead of recriminations or competition when challenges inevitably arise.”

What kind of maintenance schedule should be followed?

Each type of manufacturing area (e.g., sterile vs. non-sterile, analytical laboratory, etc.) has different needs, as does each piece of equipment. Instead, the goal is to meet “a regular and sufficient refurbishing and updating protocol that ensures each singular piece of equipment is fully up to cGMP standards,” according to Bergeron. “This should also include verification that the machine is properly interacting with other equipment in a holistic production ecosystem. Such consistent evaluations are necessary to prevent specification drifts, cleanliness issues, or other scenarios where one machine’s shortcomings can adversely affect the overall process.”

Evaluation protocols also depend on the specific equipment; however, Bergeron suggests that the process for equipment evaluation should be continuous and not staggered. Batch records should be examined and monitoring metrics should be leveraged to analyze a machine’s peak performance to ensure cGMP expectations are met.

Bergeron also stresses that the complex nature of biologics may require a tailored scope to fit the unique system and the number of touchpoints; however, the overarching maintenance guidelines apply.

Pranav Vengsarkar, PhD, director, process R&D and site head, Avantor, agrees that facilities that manufacture biologics are more sensitive to contamination and variability and, therefore, require more vigilant risk mitigation and maintenance. “Equipment and facilities must be maintained to minimize bacterial, viral, and endotoxin risks, as well as cross-contamination between batches,” he says. “Regulators expect biologics manufacturers to apply proactive, risk-based maintenance programs that safeguard product quality and ensure patient safety.”

Single-use systems play a pivotal role in many biopharmaceutical manufacturing processes. They can streamline facility maintenance because their single use nature eliminates the need for cleaning validation. Cleaning stainless steel equipment and then validating the equipment’s cleanliness can be costly and time consuming, says Payton Fraley, process engineering leader at Burns & McDonnell.

“By discarding product contact pathways after each run, [single-use systems] can reduce contamination risks and enhance product safety, particularly in multi-product environments [versus stainless steel equipment],” Fraley explains. “These systems also lower maintenance demands, with fewer valves, instruments, and calibrations required, while offering faster turnaround and improved accessibility. Pre-sterilized pathways also reduce reliance on expensive support utilities like clean steam and water for injection. Although supply chain dependencies remain a consideration, facilities often benefit from increased facility uptime, improved control, and footprint efficiency when using single-use technologies.”

“[Single-use systems provide] flexibility [that] is especially valuable in multi-product or multi-modality facilities,” Dr. Vengsarkar agrees. “However, single-use assemblies must still meet GMP requirements to ensure consistent performance. When applied effectively, these systems reduce maintenance burdens [compared with stainless steel] while enhancing compliance and operational agility.”

“While various types of equipment obviously bring differing maintenance needs, regulatory authorities rely on manufacturers’ best judgments to develop and implement maintenance programs for each critical piece of equipment, and to ensure their alignment and synchronization with other machinery categories,” Bergeron explains.

These tasks should be performed not just by the dedicated quality control department but also by engineering experts and others in the organization, says Bergeron. “Each of a product’s or project’s stakeholders—from OEMs to end users, and all players in between—have valuable insights that enrich and inform ongoing machine evaluation,” Bergeron stresses. “Of course, floor-level operators play an outsized role, as they become the on-the-ground eyes and ears that help ensure consistent cGMP standards. Automation comes into play as well, with control systems like alarming communicated via both individual machine [human machine interfaces] and other supporting touchpoints to keep everyone abreast of functionality and performance.”

What proof of maintenance do regulators want to see?

Inspectors from FDA, the European Medicines Agency, and other regulatory bodies require evidence that biopharmaceutical manufacturers are following GMPs. This includes facility and equipment maintenance. Documentation is imperative.

“Proof of maintenance is a routine request during GMP inspections,” Dr. Vengsarkar explains. “These records should be complete, organized, and easily accessible, ideally in electronic form. They should detail the date, personnel, service performed, and verification that equipment was returned to a compliant state. A lot of companies tend to outsource their calibration and maintenance needs, which makes clear stakeholder review of these documents necessary to support compliance requirements. Strong documentation not only satisfies inspectors but also demonstrates a robust quality system—reinforcing both regulatory compliance and an organization’s commitment to operational excellence.”

Bergeron suggests using a computerized maintenance management system to oversee and document maintenance events. “The expectation is that multiple relevant personnel are documenting, reviewing, and collaborating work orders to provide proof of maintenance to cGMP standards,” he states.

What common mistakes do manufacturers make?

According to Bergeron, biopharmaceutical manufacturers often fail to follow OEM recommendations. “Generally, equipment manufacturers are the most well-informed on how best to maintain their products,” he stresses. “Especially when a piece of equipment is new, following OEM guidelines is crucial; only when a piece of equipment has been integrated into a manufacturer’s environment for several years—a period that yields sufficient data regarding performance and maintenance needs—should a manufacturer consider modifying those standards. Naturally, such modifications should adhere to a company’s established change-control process.”

Being reactive instead of proactive when it comes to equipment maintenance is a common mistake seen by Dr. Vengsarkar, as are incomplete records. He also points to poor personnel training and inadequate cleaning procedures that can cause risk. These risks should be prevented by implementing robust cleaning practices that are consistent and by updating procedures when processes evolve.

How can facility and equipment problems be avoided?

Anticipating future problems using risk-based approaches can help prevent facility and equipment problems. Especially in biopharmaceutical manufacturing facilities, contamination control is key (6). Designing facilities that take into account requirements for cleanrooms and separate manufacturing areas for different types of products can keep costly contamination errors from happening…and help prevent drug shortages (7).

Being proactive and not reactive with equipment maintenance is key to successfully complying with regulations in a GMP environment. GMPs are designed and enforced to keep patients safe, but they can also keep pharma companies from finding themselves offline.

References

1. FDA. Current Good Manufacturing Practice (CGMP) Regulations. FDA.gov. Updated Jan. 21, 2025. https://www.fda.gov/drugs/pharmaceutical-quality-resources/current-good-manufacturing-practice-cgmp-regulations (accessed Oct. 27, 2025).
2. EMA. Good Manufacturing Practice. ema.europa.eu. https://www.ema.europa.eu/en/human-regulatory-overview/research-development/compliance-research-development/good-manufacturing-practice (accessed Oct. 27, 2025).
3. WHO. Health Products Policy and Standards. WHO.int. https://www.who.int/teams/health-product-policy-and-standards/standards-and-specifications/norms-and-standards/gmp (accessed Oct. 27, 2025).
4. ICH. Q7 Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients (ICH, 2000).
5. ICH. Q8(R2) Pharmaceutical Development (ICH, 2009).
6. Haigney, S. and Guidi, S. Ask the Expert: Adventitious Contamination Control. BioPharmInternational.com. June 26, 2025. https://www.biopharminternational.com/view/ask-the-expert-adventitious-contamination-control
7. Penko, A. Design Quality in Pharmaceutical Design: A Primer for Facility Executives. Pharmaceutical Technology 2025 49 (2).

About the author

Susan Haigney is lead editor for BioPharm International®.