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Manufacturing biopharmaceuticals in an aging facility may create quality issues such as equipment breakdown and contamination risks.
Mitigating and containing contamination of drug products manufactured under sterile conditions is an essential part of quality control in a pharmaceutical facility. This is particularly true for biologics. A facility that is aging may contribute to the challenges of ensuring the quality of drug products. But how long do biopharmaceutical manufacturing facilities last and what is considered aging?
According to Francesca A. McBride, director of Regulatory Compliance, and John Chapman, senior architectural technologist and subject matter expert, both at Jacobs, the original facility design, material, and personnel flow in facilities that date back to the 1990s and early 2000s may not be to the same standard as newer facilities and, therefore, may be perceived as obsolete.
The lifespan of a facility, however, depends on a variety of factors that include the date the facility was built, the type of products manufactured, preventive maintenance performed, and the flexibility to adapt to new purposes, according to industry experts. “Some facilities go offline if a product becomes obsolete or demand has diminished. [Whereas], if demand stays strong, the lifespan can be quite long. While the average life span of a facility is in the region of 12–18 years, there are facilities that have been in operation for over 20 years without a shutdown, thanks to strong market demand,” says McBride. “The lifespan of a facility can also be extended by switching processes, or if required, retrofitting the facility to manufacture an alternative product than it was originally designed to manufacture.”
Maik W. Jornitz, president and CEO of G-CON stresses that facilities may be viable for 20 or more years with constant preventative maintenance. “In addition, the question is whether the facility has the flexibility to be repurposed in case the product lifecycle runs out and a new product entity is admitted,” he says.
A commitment to maintain a facility is key to its longevity, notes Susan J. Schniepp, distinguished fellow at Regulatory Compliance Associates. This maintenance includes equipment replacement, updating process validation, and using appropriate analytical methods for new therapies.
Manufacturing biopharmaceuticals in a facility that is older may create quality issues such as equipment breakdown and contamination risks. Older facilities may use older technology not in alignment with the advances of biopharmaceutical products, according to Schniepp. “Challenges in using an aging facility to produce new products could include difficulty in performing suitable process validations for the product due to antiquated manufacturing equipment. Another impact is the availability of change parts. Older manufacturing lines tend to break down more frequently and replacement parts may not be available
due to discontinuation. If we take a broader approach to aging facilities, we would also include antiquated methodology for analyzing the new biopharmaceutical products for patient safety and product quality,” she says.
For quality control, facilities must be able to adapt to changing requirements, according to McBride and Chapman, including staying up to date with automation and key process operations. “From a control standpoint facility operators need to also consider if there are risks related to environmental cleanliness that put the product at risk. This will vary depending on whether it is an open or closed process. For example, for solid dosage manufacturing, some of the steps are open with the addition of raw materials, so failure to maintain environmental cleanliness would put the product at risk. Self-culture operations, on the [contrary], is a closed process, so environmental contamination is lower risk,” says McBride.
“If the facility [is] not maintained frequently, the PDA [Parenteral Drug Association] aging facility survey found that the facility utilities, including wall finishes and air filtration, and the processes start causing problems,” says Jornitz.
According to a study performed by a PDA task force, the investment in post-approval changes may inhibit an organization’s interest in investing in new technologies (1). “Respondents agreed that the time required for post-approval changes can be considerable, 32% described time frames of up to two years, 62% said that they can take from two to 10 years, and 3% related that they take more than 10 years. A total of 92% of respondents estimated the regulatory costs for such changes to be below $110,000” (1).
This lack of upkeep or modernization can impact cleanrooms especially. A quality control risk assessment should consider the materials used to construct the cleanroom, according to Jornitz, because traditional construction materials can elevate the risk of mold contamination. “As has been experienced, some of the older cleanroom materials are hygroscopic and when damaged can cause major mold contamination issues, so much that in instances the infrastructures had to be either refurbished or were shut down,” he says. “Other experienced contamination risks in utilities could be biofilm formation in water systems or contamination within the duct or mezzanine levels. Key to avoid such contamination potentials is preventative maintenance and equipment upgrades.”
Risk assessment should be performed if a facility produces more than one product on a line, explains Schniepp, to minimize the potential for cross contamination. “In addition, the product flow (how the product moves through the manufacturing line) may not be ideal for the product and could expose it to potential viable and non-viable particulate contamination,” says Schniepp. “In some cases, the actual construction materials in the cleanroom may be degrading and difficult to clean, which also impacts the product. Manufacturing lines not using current protective barrier technology or single-use systems offer more exposure to the product through human interface.”
Schniepp stresses that aging facilities may cause more concern regarding microbial contamination. “This is generally because the materials of construction are not state of the art and could be degrading. Some of this degradation may go unseen or undetected during cleaning, creating areas that might harbor microbial growth. The cleaning regimen for the facility should be reviewed and effectiveness tracked through the microbial monitoring program,” she says. Microbial monitoring programs may also need to be more robust.
Jornitz also points to outdated aseptic filling lines as a potential problem for quality control in aging facilities. “If the fill line breaks-down or is not functioning as specified, the impact on quality can be detrimental. This critical processing step needs the highest attention level,” he says.
Adhering to a well-planned maintenance strategy can reduce the impact on cleanrooms, say McBride and Chapman. “Wear and tear and the reliability of older systems such as HVAC [heating, ventilation, and air conditioning], purified water/steam, and clean-in-place (CIP) systems are also a consideration in aging facilities,” says Chapman. “For cleanrooms, HVAC is a critical component, providing a reliable source of clean air. Durable, easy-to-clean finishes are also essential to maintaining a valid cleanroom. As the finishes age, tiny voids can begin to occur, making cleaning more difficult. The joints and seals between dissimilar materials will need more scrutiny and maintenance to ensure viability. There is also now increased regulatory focus on airlocks going into and out of process suites and the operations in the clean areas. Therefore, the facility design and operational strategy in aging facilities may no longer meet the regulations,” he stresses.
Jornitz warns that an HVAC system that does not function properly can impact the entire cleanroom infrastructure because of the centralized nature of HVAC systems. “Maintenance of the centralized HVAC system means also shut-down periods to start up the facility afterwards with time consuming requalification efforts. New cleanroom infrastructures see a higher segregation level all the way to autonomous HVAC units for individual cleanroom units,” he says.
Ductwork in the HVAC system can degrade over time, specify McBride and Chapman, impacting filter supply. “It’s important to perform routine maintenance on these systems including regular inspections and annual rebalancing and checking of the HVAC system. HEPA filters also need to be replaced regularly—the frequency will depend on usage and the fan systems,” McBride says.
Considerations must be made when adapting facilities previously utilized for small-molecule drugs or other types of manufacturing, to produce biopharmaceuticals. “A full risk assessment is conducted to examine and ensure suitability. Once approved, these facilities are adapted to ensure they fully comply with all relevant requirements and regulations related to biopharmaceutical manufacturing to ensure optimum quality control. This method prolongs the lifespan of a facility and expedites access to life enhancing medicines and therapies,” says McBride.
Chapman points to quality risks when adapting certain types of facilities, such as warehouses. “The building exterior envelope is typically less robust for excluding exterior elements, and the structure is rarely robust enough for the loads imparted by suspended larger HVAC, piped services, power and data, etc. Furthermore, the use of pre-manufactured cleanroom wall and ceiling systems is very prevalent, and these ceilings can be used to support nominal foot traffic, imparting additional structural loads. Either the systems are bolstered or compromises in distribution or maintenance would be introduced,” he says.
Cutting and patching of floors to install liquid waste systems and other underground services presents problems, according to McBride and Chapman. “Subsequent application of monolithic floor finishes [is] more susceptible to cracks or distress over or along the resulting concrete joints. Exposing the earth inside a space that will eventually house classified cleanrooms introduces additional risks to the cleaning and validation,” Chapman says. HVAC design as well as power, data, ceiling height, and liquid and/or gas services are other considerations.
In addition, continue McBride and Chapman, older buildings may have gypsum board wall systems that generate a significant amount of dust when built, modified, or repaired. “Care must be taken to seal HVAC systems and thoroughly clean following each instance to avoid contamination,” Chapman stresses.
Preventive maintenance and recapitalization are important factors for ensuring quality control in aging facilities, points out Jornitz. Upgrading equipment can limit the number of surprises and keep processes in control. Equipment should be updated when it shows weakness or is breaking down, Jornitz points out, and outdated equipment should be replaced if it cannot be maintained. “Some process technologies can function for decades when well maintained, but if one cannot get the spare parts any longer, one runs into the risk [of having] a break-down without a possibility to fix it. It is essential to have frequent site and process analysis and reviews on the equipment used to create capital investment plans and keep all equipment up to date,” he says.
Older systems may need more attention and maintenance, according to McBride and Chapman, especially pressure seals and joints between materials. “Durable, monolithic surfaces provide easily cleanable conditions. As a facility ages, it is normal for natural settling and movement from use and weather to create openings and cracks which can harbor contaminants. Facility finishes such as flooring can also experience wear and tear over time. This can diminish their robustness and ability to uphold the required level of cleanliness. In this case, the surface must be replaced to eliminate the risk of contamination. Newer materials provide inherent chemical defenses; however, these would not be available on older facilities without retrofit. Air pressure differentials between spaces of differing classifications is another line of defense; as the room envelope ages, the gaps and seals naturally lose pliability and effectiveness,” Chapman says.
Equipment, such as parts washers, autoclaves, restricted access barrier units, or isolators, should be assessed and maintained to ensure quality, adds McBride. “Naturally, wear and tear occur over time, whether that’s on surfaces or pressure seals, and on occasion, certain equipment may be deemed beyond further repair, and must instead be replaced to ensure optimum quality.”
Updating equipment should depend on the type and the process it’s being used for, explains McBride. Updates to software and sterilization procedures also impact the need to update equipment. “For any biopharmaceutical products manufactured on a commercial level, a license application must be submitted to FDA which describes in detail the equipment used. FDA must be notified of any changes made to equipment that have direct impact on the product manufacturing,” says McBride. She stresses that equipment upgrades, however, are not always sufficient. “Upgrading equipment in an aging facility can often present problems with facility infrastructure. A full facility upgrade after a 15-year timeframe will ensure both infrastructure and equipment are up to scratch and reduce the risk of non-compliance with new requirements.”
When dealing with manufacturing of biopharmaceuticals in an outdated facility, good manufacturing practice procedures must be in place, emphasizes McBride, and manufacturers should develop a 15-year lifecycle program. “Regular employee training and swiftly and coherently communicating any procedural updates or changes are also key steps to ensuring all individuals are aligned on best practices. Frequent maintenance assessments within an aging facility are also encouraged,” she says.
“Another part, not to be forgotten, are the people who run the facility and processes, as they also age and new people require the proper training to have the same capabilities as the experienced team members. Too often the human factor is forgotten and that can add a major risk to the processes whether well maintained or not,” agrees Jornitz.
Susan Haigney is managing editor for BioPharm International.
Vol. 35, No. 12
When referring to this article, please cite it as S. Haigney, “Controlling Quality in Aging Facilities,” BioPharm International 35 (12) (2022).