Risk Considerations for Aging Pharmaceutical Facility Cleanrooms

Pharmaceutical facility cleanrooms are designed to reduce and control particle contamination and to minimize the ingress and retention of microorganisms. Such risks typically are easy to control in well-designed, modern facilities. But risk mitigation is more difficult in older facilities.

The former Idec Pharmaceuticals site on Torreyana Road in San Diego was closed in 2011 after the company merged with Biogen. Four years later, it became home to the Biocom industry trade group’s California headquarters. Photos circa 2004, courtesy of Biogen (https://www.biogen.com)

There is no exact definition of what constitutes an aging facility (or what are sometimes euphemistically called legacy facilities). For example, a facility established 100 years ago to manufacture a simple tablet can continue to operate perfectly well with careful upkeep and an eye on developing regulations. By contrast, a biomanufacturing site that was established 10 years ago can become out of date if it doesn’t receive necessary process adjustments because of changes to product formulations or to meet new regulatory recommendations (e.g., for viral inactivation) (1, 2).

Often, older facilities are maintained or even upgraded for commercial and compliance reasons. Plants that predate modern thinking (e.g., quality by design, QbD) might not be able to adapt to future opportunities or threats. Such facilities might be facing risks of microbial contaminations and thus require careful management during shutdown and start-up (3–5).

Extent of Aging Facilities and Regulatory Concerns
The number of aging facilities is not easy to determine (6). As many pharmaceutical companies seek to establish manufacturing facilities for new product lines in emerging markets (e.g., China, Eastern Europe, and Asia), some established sites in regions such as North America and Europe are getting older and possibly needing maintenance. Those facilities also might have difficulty with meeting good manufacturing practice (GMP) requirements. As an example of architectural concerns within GMP, 21 CFR Part 211.42 (§211.42 Design and Construction Features) states

(a) Any building or buildings used in the manufacture, processing, packing, or holding of a drug product shall be of suitable size, construction, and location to facilitate cleaning, maintenance, and proper operations.

(b) Any such building shall have adequate space for the orderly placement of equipment and materials to prevent mix-ups between different components, drug product containers, closures, labeling, in-process materials, or drug products, and to prevent contamination.

An aging pharmaceutical facility is associated with different risk considerations, some of which are described below. These risks are not universal. Some facilities continue to function effectively without the need for extensive modifications. However, some older facilities require additional checks and assessment. Regulatory inspection trends have shown that aspects of aging facility are being cited with greater frequency.

Risk Factor 1: Cleanroom Fabric
Older cleanrooms, especially if they have been poorly kept, can have damaged vinyl, cracks in walls, weak construction joints, peeling paint, and/or torn lagging. Degradation leaves opportunities for microbial contamination. Unclean areas can expose cleanrooms to contamination, and microorganisms can reside in cracks. Risks are more acute for spore-forming organisms such as Bacillus and related bacterial genera as well as fungal spores. Where cracks appear, cleaning solutions often will be unable to penetrate. Weakened or broken joints can cause high airflow velocities that can drag unsuitable air into cleanrooms from different facility areas. That can lead to turbulent mixing and potentially contamination, which can be assessed with airflow visualization.

Nonideal surfaces can be difficult to clean. Some older cleanrooms have nonvinyled outer surfaces that might not be compatible with commonly used disinfectants.

Risk Factor 2: Cleanroom Air
Cleanroom air-supply systems in aging facilities might not supply as much air volume as they did when the cleanroom was designed. That affects not only air-supply volumes, but also air-exchange rates and clean-up times. Those parameters are essential for keeping particles (viable and inert) in suspension and for removing them from cleanrooms. This risk can be overlooked because most cleanroom-monitoring systems assess pressure differentials rather than air-supply volumes.

Risk Factor 3: Void Spaces
Voids between adjacent cleanrooms or between a cleanroom and an outside environment accumulate dust that contains spore-forming microorganisms. Contaminations arise when facilities are modified (e.g., knocking down a wall to expand a cleanroom), and that dust spreads. When such changes are made, control measures should be in place, including partitioning off areas, vacuuming dust, and regular cleaning followed by sporicidal disinfection. With all modifications, it is important to ensure that facility drawings and plans have been updated and that they remain representative and accurate.

Risk Factor 4: Scope Extension
One area of operations that can pose difficulties for facilities relates to scope extension or “drift.” It comes with improving aging sites because of an expansion of operations in terms of scale or new product pipelines. Such work could require modifications, repairs, and alterations to procedures and efficient ways of responding to more frequent breakdowns and mishaps.

One example of drift is the case of a small, sterile manufacturing facility built in 1970 in the United Kingdom. It began with a workforce of 50, a maximum batch size of 200 L, and 20 standard operating procedures. After only one year of operation, the site had raised 20 change controls and 25 deviation reports. By 2020, the facility had grown. Staffing had increased to 130 people, and the batch size had extended to 900 L. The number of procedures had risen to 80. As a consequence of capacity and staffing rising above what was originally designed and the need to maintain what was now an aging facility, the site reported 5,100 change controls and 6,200 deviations.

Another difficulty comes when a facility needs to increase production output with different staffing levels (or a move to 24/7 operations) and different types of equipment. The facility could suffer increases in equipment breakdowns and incidents of mechanical and electrical components wearing out. Such aging facilities experience increasing risks of not meeting regulatory requirements.

When considering whether the scope of a facility can be increased and when considering process changes, the questions listed in the “Assessing Operational Scope” box can prove useful during initial assessments (3). Those points can form the basis of an inspection checklist.

Risk Factor 5: Personnel Increases
Contamination risks can arise with increasing personnel or when shift patterns change. That is especially true if a facility was designed for a specific number of personnel and the operational level increases. Contamination control could become problematic, especially when cleanroom occupancy rates increase (given that people are the primary contamination source within cleanroom environments) (7).

Risk Factor 6: Additional Equipment
Changes to production equipment and layouts can affect airflow direction, especially for aseptic processing. Adding equipment to a working space can generate more heat, placing a greater heat load on an air conditioning system. Reducing the spatial distribution within a cleanroom also can increase particle concentrations. Areas with added equipment can be difficult to clean and disinfect because operators must maneuver around the equipment footprint. Poor air circulation brings other contamination concerns, including niches with undetected fungal growth.

Former Idec Pharmaceuticals facility in San Diego Photo circa 2004, courtesy of Biogen (https://www.biogen.com)

Risk Factor 7: External
Environmental Impact
The operation of utilities and infrastructure depends on their performance throughout their service life. Deterioration can be accelerated under adverse environmental conditions (e.g., heat, precipitation, changes in the soil structure). When subjected repeatedly to such external elements, structures can deteriorate over time because of corrosion and fatigue. Given that structural conditions change over time, evaluating the extent of deterioration should become part of a building-reliability assessment supported by cost-based optimization. Some facility managers use a deteriorating model to predict the influence of an external environment on a building and its supporting utilities. It is important to factor in such deterioration within the lifetime assessments of a facility, especially its manufacturing space.

Risk Factor 8: Aging Equipment
Aging equipment can be problematic because it requires frequent maintenance. That creates both downtime and contamination risks (through surface abrasion and discoloration), which raise the question of whether older equipment systems meet current requirements for cleaning validation. For a cleaning process to remain “anchored” to the original validated state and to prevent drift, operators should ensure that cleaning remains consistent over time. That is not straightforward for older equipment that has not been maintained well. For such cases, it is important to account for variables such as changes in personnel, training, equipment damage (including surface abrasions), and so on. Equipment damage might be more apparent with manual cleaning than it is with automated processes.

Abrasions to surface finishes can lead to process soils or embedded microorganisms. As equipment ages, repeating some aspects of cleaning validation might be needed to verify that soiling and microorganisms still can be adequately removed and whether extended cleaning cycles must be developed.

Assessing cleanliness can be difficult. For both automated and manual cleaning processes, many manufacturers require postcleaning visual inspections. Cleanliness can become harder to detect visually over time because of the discoloration of stainless steel. That comes from repeated contact between equipment and products, chemicals, or water for injection (WFI, which is an aggressive solvent). Repeated contact produces surface or internal weathering, which can generate particles and create rouging.

Risk Factor 9: Obsolescence
As facilities age, processes and analytical procedures can become obsolete and lose key performance parameters. The original equipment manufacturers might no longer stock spare parts or have engineers available to make necessary repairs. That can be problematic especially for computerized systems such as for cleanroom air and pressure control and for building management. Data retrieval can be problematic when operating systems are upgraded.

Risk Factor 10: Recovering from Facility Shutdowns
Contamination risks to equipment and/or cleanrooms can increase when biopharmaceutical facilities undergo shutdown for repairs and maintenance. Shutdowns are required for planned preventative maintenance, emergency maintenance, modifications to room design, and for installation of new equipment (8). Shutdown activities can apply to individual cleanrooms, a suite of rooms, or to an entire facility. Some biopharmaceutical sites undergo an annual shutdown to complete modifications, calibrations, installations, and/or replacements of equipment. There are often commercial and compliance reasons for continuing to maintain or even upgrade older facilities.

Solutions
Solutions to the aging facility conundrum will vary. They can include transitioning to closed systems (if possible) to minimize risks of product exposure. Microbial risks can be reduced with the use of sterile single-use technologies, which provide improved asepsis (notwithstanding that such technologies have challenges related to different designs and with assessments of extractables). Implementation of disposable technologies can be hampered by an inadequate facility layout, structure, and supporting services. Application of single-use technologies should be embraced holistically. For facilities with serious design flaws, modular cleanrooms can provide superior environments for operations — as either new cleanrooms constructed within an older cleanroom or as extensions to a facility. Modular cleanrooms come with their own heating, ventilation, and air conditioning (HVAC) systems, and localized high-efficiency particle air (HEPA) filters can minimize contamination. Such clean spaces readily can be fitted with the necessary utilities (e.g., air, water, steam, and electricity) to enable biopharmaceutical processing to take place. With sterile manufacturing, use of closed systems and isolators provides a high level of contamination control (6).

When planning an aging facility upgrade, ask the following (6):

You also should review changes and consider the significance of those changes to equipment, supporting systems, and the entire facility. Single-use technologies also can be used when equipment no longer can be cleaned to required levels.

The future of an aging facility should be risk assessed, and the risk considerations should be documented. With aging facilities, regular inspection and a sound repair program (including the fitting of high-quality seals such as compressed rubber gaskets) can prevent some problems. At times, new procedures will be needed to help maintain an aging facility. Increasing equipment breakdowns, for example, might require that new procedures be designed to keep equipment running. Resources should be put into planned preventative maintenance (the level and type of which can be different to what was required a decade ago).

Contamination risks associated with aging facilities can be minimized through a robust contamination control strategy to assess material and personnel flows and to trace product paths in search of hazards. Those can arise when facilities undergo incremental changes such as the random placement of production areas, destruction of cleanroom walls to create larger spaces, increased demands on cleanroom supply air, and lack of integration into existing workflows and product paths. A risk assessment tool such as hazard analysis critical control points (HACCP) can be effective. HACCP also can indicate where cleaning and disinfection frequencies might need to be increased. If contamination controls are weak, HACCP can help you find appropriate monitoring locations to assess cleanroom controls (such as pressure monitoring) or for microbiological monitoring (as with the environmental monitoring program).

Complexities of Risk Mitigation
Although risk factors have been listed individually herein, often such risks are multiple and interrelated. Aging facilities rarely show just one problem area. Dealing with one problem can be difficult, but when multiple issues arise at once, the risks become considerable.

Risks of contamination are seemingly greater with facilities that predate QbD, which directs quality to be built into a product. The approach includes understanding of a product and the process by which it is developed and manufactured. QbD also requires knowledge of the risks involved in product manufacturing and how best to mitigate those risks. Upkeep and modernization efforts can be expensive, and they might be impossible to meet regulatory requirements. In some cases, redesign is possible, but that requires a “root-and-branch” review of processes and operations, which in turn will require expenditure and the incorporation of modern solutions (e.g., modular cleanrooms, supported by the adoption of closed processing and single-use technologies), and extensive cleaning and disinfection procedures.

References
1 Davda P. Developing a New Pharmaceutical Facility in Eastern Europe. Pharm. Eng. 24(3) 2004: 1–9; https://www.ispe.org/pharmaceutical-engineering/may-june-2004.

2 Zhuang C, Wang S. Uncertainty-Based Robust Optimal Design of Cleanroom Air-Conditioning Systems Considering Life Cycle Performance. Indoor and Built Environment 29(9) 2020: 1214–1226; https://doi.org/10.1177/1420326X19899442.

3 ICH Q10: Pharmaceutical Quality System. EMA/CHMP/ICH/214732/2007, European Medicines Agency: Brussels, Belgium, 2008; https://www.ema.europa.eu/en/ich-q10-pharmaceutical-quality-system.

4 Jornitz MW. A Review of the Aging Process and Facilities Topic. PDA J. Pharm. Sci. Technol. 69(4) 2015: 553–556; https://doi.org/10.5731/pdajpst.2015.01061.

5 Sandle T. The Risk of Bacillus cereus to Pharmaceutical Manufacturing. Am. Pharm. Rev. 17(6) 2014: 1–6; https://www.americanpharmaceuticalreview.com/Featured-Articles/169507-The-Risk-of-em-Bacillus-cereus-em-to-Pharmaceutical-Manufacturing.

6 Sandle T. Risk Consideration for Aging Pharmaceutical Facilities. J. Validation Technol. 22(2) 2016: 11–20; https://www.ivtnetwork.com/article/risk-consideration-aging-pharmaceutical-facilities.

7 Sandle T. People in Cleanrooms: Understanding and Monitoring the Personnel Factor. J. GXP Compliance 18(4) 2014: 1–5; https://www.ivtnetwork.com/article/people-cleanrooms-understanding-and-monitoring-personnel-factor.

8 Hart KJ. Compliance By Design. BioProcess Int. 3(5) 2005: 18–20; https://bioprocessintl.com/business/regulatory-affairs/compliance-by-design-5120052.

Tim Sandle is head of microbiology at BPL and a visiting tutor at University College London and the University of Manchester; [email protected].