Involve your manufacturing team in the planning process, sweat the details, and get smart about how your cleanroom functions
BY STEVE SMITH
In the face of emerging technologies, high costs of research and development, and intense competition facing biopharmaceutical companies, a successful get-it-right-the-first-time design requires input from both the company and the contractor, as well as documented expectations and monitoring, anticipating rather than reacting to manufacturing trends, and getting smart about cleanroom operation basics.
For example, when Hyaluron Contract Manufacturing of Burlington, Mass. (HCM; www.hyaluron.com) was looking to design a new sterile manufacturing facility for its syringe and vial-filling aseptic processes, they faced the challenge of establishing a unidirectional flow of equipment, supplies and people through the cleanroom while seeking maximum, high-yield production for preclinical and small commercial manufacturing. For biopharmaceutical contract manufacturers like HCM, keeping contamination under control while maximizing the amount of fill/finish work is the greatest challenge when considering new construction.
 Photo courtesy of Hyaluron. |
“As the life-science industries explore further into the nanolevel of materials and submicrobial levels of organic structures, biopharmaceutical facility requirements resemble those that previously occurred in the semiconductor industry,” observes Thomas Hansz, president of Facilities Planning and Resources (www.fprinc.com), an architectural firm specializing in the planning of advanced technology facilities. “Incorporating a cross-industry pollination of design ideas is proving to open opportunities for better controlling of costs and maintaining flexibility.”
Critical control of airflow, temperature, relative humidity, ESD and vibration are among the areas where biopharmaceutical facility companies and designers are learning and borrowing from “clean” semiconductor manufacturing. But at the same time, semiconductor facility expertise doesn’t necessarily completely translate into effective biopharmaceutical design, and as Scott Mackler, principal consultant for Cleanroom Consulting LLC (www.cleanroom-consulting.com), points out, a cleanroom contractor needs to “gain a meaningful understanding” of what will be taking place in the biopharma manufacturing process.
Designing for emerging technology
“Often, the attitude is ‘a cleanroom is a cleanroom’; but that is as naïve a statement as ‘a vaccine is a vaccine,’” cautions Mackler. While both semiconductor and biopharmaceutical cleanrooms may have specific contamination-control requirements that are above and beyond that of a cleanroom designed for general industrial use, their design issues are often entirely different.
“While the requirements for an aseptic processing suite are well-defined and well-known, biopharmaceutical facility design requires judgment based on experience, as in many cases we are dealing with emerging technology,” Mackler adds. “In this regard, biopharmaceutical and nanotechnology both offer requirement challenges to the designer and constructor that are many times more difficult to clearly define. Contractors need to be diagnostic and ask questions regarding time, susceptibility and contamination.”
One of the best ways to help companies and contractors ensure a clear understanding of the application and its critical needs is to welcome insight from employees involved in the manufacturing processes, and even the customers who purchase the product or services.
“They are usually the most knowledgeable of what past problems have been,” explains Ken Christie, senior director of consulting services at VTS Consultants (www.vtsconsultants.com), a company servicing validation and regulatory requirements of pharmaceutical, biotechnological, and medical device companies. “People accustomed to working on manufacturing lines also are very aware of typical design issues and, if listened to, can eliminate many of the common problems encountered.”
This was the approach taken by Hyaluron during its recent design and construction of a new 5,500-square-foot biopharmaceutical cleanroom that includes two sterile formulation/fill suites, and several ISO Class 7 processing/packaging rooms (see Fig. 1). Company president Dr. Shawn Kinney commissioned Paul L. Mahnen and Associates Inc. (Scarsdale, N.Y.), a consultant group with more than thirty years of experience in facility design. Mahnen’s consultants drew up engineering diagrams and blueprints for the cleanroom design, which included input from Hyaluron clientele on the design and flow of equipment and personnel through the cleanroom space. Construction was carried out by Clean Air Technology (www.cleanairtechnology.com) of Canton, Michigan.
“The facility flow at HCM is unidirectional, with personnel and equipment having completely separate entry airlocks,” says Hyaluron Vice President of Business Development, Dr. Andrea Wagner. “This is a cGMP requirement, but many fill/finish facilities nonetheless do not have this unidirectional flow or separate dedicated airlocks. Contamination is more likely to be an issue if these protections are not in place.”
The most significant breakdowns in biopharmaceutical contamination control, says FPR’s Hansz, is in the interface between facility design and process operations. Effectively controlling contaminants requires a high degree of coordination between the facility systems design and the operational requirements and clean protocols that are in place.
Appropriate system design
Biopharmaceutical “system designs are not as much the issue as appropriate system designs,” says Hansz. “This applies to high-purity systems as well as to airflow, air filtration and cleanroom layout.” As with Mahnen and Associates’ approach to the Hyularon facility design, Hansz says his company makes it a practice to “interview selected representatives from every department within the company, beginning with the corporate management, prior to the start of design.” Depending upon the scale of the design project, Hansz says a typical week of predesign interviews may involve as many as sixty employees.
“Our process is to communicate the project objectives from management to all participants and, in turn, convey the issues and programmatic solutions from the staff back to management,” Hansz continues. “We encourage our clients to bring the construction manager on board during this time [to] participate as well as hear ideas firsthand.”
Clearly communicating workflow and essential environmental control issues, however, is not merely to ensure that a biopharmaceutical cleanroom is built right the first time, but that quality and safeguards at every turn will help achieve validation quickly so that new manufacturing and yields are not delayed.
In Hyularon’s case, a well-thought-out design involving expert input from employees and customers alike helped it achieve validation within four months of completion. Last July, the sterile manufacturing facility completed both ISO and FDA aseptic processing validation of its Inova syringe/vial line, where filling capacity is 40,000 units per day.
The completed cleanroom fully met Hyaluron’s requirements for unidirectional flow of equipment and workers: a one-way flow of traffic as well as separate pass-throughs for materials and personnel. Cleaner areas are closer to the beginning of the clean corridor, while dirtier areas are nearer to the corridor’s exit.
Hyularon’s design/construction success and rapid validation of its biopharmaceutical facility, however, is in contrast to other projects that have been delayed because FDA cGMPs had not been carried out thoroughly in the design stage. Mackler recalls a number of similar unidirectional-flow, aseptic-fill cleanrooms that, once built, proved unable to meet FDA validation requirements. “In most of these situations,” Mackler points out, “the aseptic-fill application was treated as if it were simply a Class 100 [ISO Class 5] particle count requirement, without regard for the critically important airflow patterns required to ensure that exposed products and components are protected from contamination.”
Basis of design
One of the best ways to get it right the first time, quickly and cost-effectively, is to compose a Basis of Design (BOD), which a company can use to put qualified, competitive design/builders on a consistent footing. A BOD is a descriptive guideline for design and construction that includes the project’s scope, terminology, conceptual design, and structural analysis.
For mission-critical projects, such as biopharmaceutical cleanrooms, Mackler says minimum criteria for a BOD should include:
- Process description and process flow diagrams;
- cGMP floor plan and general equipment arrangement;
- Sized major process equipment list with utilities requirements/consumption;
- Sized process support services utilities list (such as water for injection);
- Functionality flow diagrams (processes, people, product, material, components, waste, directionality, and airflows);
- HVAC zoning and room classifications, including microbial limits;
- Budget-quality (+/-20 percent) cost screening estimate with preliminary “scope of work” matrix (identifying explicitly who is responsible for every element of the project);
- Realistic project schedule, from start through validation;
- Listing of appropriate/applicable regulatory authorities and jurisdictional venues for which the facility will have to be validated.
Having established design criteria in writing, however, isn’t enough. “There should also be routine reviews of the contractor’s work to ensure design specifications are adhered to throughout the project, and that any changes are recorded for possible review later on,” adds Christie.
And when meeting tight budgets, Hansz advises, “It is as important to avoid over-designing to meet [FDA] regulation as it is to avoid noncompliance.” Future costs, he says, can be better controlled when modifications in the manufacturing processes are considered during the design/planning phase.
For Hyaluron, careful planning and foresight have enabled the company to install a state-of-the-art environmental monitoring system, which is crucial for its present biopharmaceutical production, while at the same time make plans for future expansion (see Fig. 2). The environmental system continuously monitors airflow, particulates, temperature, humidity, and microbial presence. “This system, though expensive, is critical to ensuring that our clients’ products are not affected by changes in the cleanroom environment during filling or processing,” says Wagner.
Hyaluron executives were also attentive to opportunities for expansion in the years ahead, especially with the aseptic contract-manufacturing industry growing at 11 to 20 percent per year. One goal is additional expansion to a large-scale, commercially sized facility. Even now, says Wagner, the company is in the process of adding a third aseptic-fill suite, which will house a lyophilizer and a next-gen version of their proprietary Inova vial filler.
Kinney adds, “We’ll keep our current, state-of-the-art facility for preclinical through small commercial syringe and vial fills, but we intend to build a larger, commercial, sterile contract-manufacturing facility to handle higher-volume fills that current and future clients will need.”
Disposable manufacturing
Biopharmaceutical companies such as Hyaluron realize that planning for the future means sailing into uncharted waters where critical next-gen processing needs don’t always have an immediate solution. For Hyaluron, one such issue is disposable manufacturing. The advent of biobag systems, which are useful for final product housing and clean or sterile formulation and mixing, are increasingly in demand by clients who would rather do away with hard-to-clean stainless-steel tanks and vessels.
“Facility design is only part of the puzzle when manufacturing product for [our] clients,” says Wagner. “The ability to have completely disposable and contained mixing, blending and filling systems is the trend.”
One-use bioprocessing equipment, adds Wagner, continues to gain traction in the aseptic manufacturing market, particularly for cell culture and fermentation. “And in constructing a new facility, one must [also] consider the advantages and limitations of barrier isolator technology,” she says. “Isolators have the advantage of limiting or eliminating personnel interaction with exposed product, but they are difficult to clean and impossible to retrofit with existing filling equipment.”
Adapting to the growing use of disposables and isolators, says Wagner, will require careful examination by Hyaluron and any company planning for new or retrofitted facilities. “New facility designs will have to take into account changes like these in the drug development market,” Wagner continues. “And these changes will undoubtedly impact [future] sterile contract manufacturing.”
Fortunately, the biopharmaceutical equipment industry is addressing many of these and other manufacturing challenges that must be considered in the design phase. “The elimination of operator interactions and the ability to effectively clean product-holding equipment are focusing the industry on equipment designs that minimize operator contact, as well as clean-in-place and steam-in-place equipment designs,” says Christie.
Mackler agrees that both isolation technology-including restricted access barrier, or RABS-and disposables are key issues to be addressed in biopharmaceutical facility design. “There are in excess of 150 of these [isolation] systems currently approved by the FDA,” notes Mackler, “and with a properly developed BOD, both the capital and operating costs of a barrier isolation-based aseptic-fill cleanroom will be less than for an equivalent production capacity, ‘conventionally’-validated Class 100 [cleanroom] facility.”
Companies considering new clean facilities may also find long-term cost savings by selecting disposable process equipment. Disposables offer lower installation costs compared to stainless-steel systems, eliminate cleaning and cleaning validation, and also reduce the risk of cross-batch contamination and worker exposure to biohazards.
“As disposable technology is more widely deployed,” predicts Mackler, “I expect that we will start to see this have an impact on facility design similar to that already experienced [with] the implementation of isolation technology.”
Continuous monitoring
Another future-thinking design consideration, Mackler says, is a continuous monitoring system, which detects contamination in real time and at levels that allow correction before it impacts a product. And to be consistent with FDA recommendations, Mackler notes, continuous monitoring should be built in by design, “using a system for designing, analyzing, and controlling manufacturing through process measurements of critical quality and performance attributes of materials and processes, with the goal of ensuring final product quality.”
The trend toward automation in biopharmaceutical manufacturing in companies such as Hyaluron, notes Hansz, is also creating new demands on old spaces. “One trend we see is the reduction of workers in the manufacturing areas and the increase in the size and types of support functions, with the resultant increase in employees in these areas,” he says. “Facility layouts that were successful twenty or thirty years ago are not appropriate for today. The renovation of existing facilities requires finding ‘new spaces’ within an old context, and this places a huge amount of pressure on balancing space allocations with workflow and keeping within budget restrictions.”
Knowledgeable management, trained personnel
Being alert to emerging nanotechnologies, planning wisely with a Basis of Design, and building automation and contamination monitoring into the process up-front are all practical essentials for today’s biopharmaceutical facility design. But the onus is not entirely on the contractor to make sure it all comes together. As with nearly all aspects of advanced life-science technologies, company owners and key personnel are being urged to stay abreast of the technologies that go into their contamination-controlled facilities.
It’s an ongoing challenge that Hyaluron acknowledges, especially when training personnel and choosing next-gen equipment for the cleanroom. “Extensive education about the newer technologies is difficult to obtain, and good personnel with adequate skills and training have always been difficult to find in the aseptic contract-manufacturing industry,” says Wagner. “The introduction of newer technologies, while exciting and likely to ultimately enhance end-user safety, also introduces new challenges in training of personnel.”
But Mackler says that company owners, in particular, have no choice-especially when it comes to the technologies within their own cleanroom. “Owners need to get better educated on the physics of cleanrooms, as they often lack a basic understanding of airflow dynamics and what a cleanroom actually does,” advises Mackler. “For example, [the fact] that a cleanroom does not keep things clean; rather, exposed product simply gets dirty more slowly in a cleanroom.”
Specifically, facility owners can benefit from a better understanding of their cleanroom HVAC design because of the technical challenges involved in effectively delivering HVAC to a clean facility. “Very few facilities, if any, start up without any [HVAC] difficulties,” Mackler claims. “It must be understood that unlike a simple modular cleanroom-most times with no thought given to HVAC-a sophisticated, new facility designed to provide predictable and reliable control over pressure, temperature, relative humidity, ESD, EMI, and vibration will require time to ‘dial in,’ and that it may be necessary during the commissioning and start-up phase to make physical changes to already installed major components.”
Testing is another area where biopharmaceutical facility owners place high expectations on contractors, but again, a little self-education will go a long way in preventing problems and speeding validation.
“The challenge with qualification is to do an accurate risk assessment of the facility, utilities and equipment,” says Christie, “to determine those that have direct product impact and thus require full testing, versus noncritical items that can be dealt with by commissioning activities only.” Mackler concurs, “Owners need to be clear on what tests will be required, what criteria will be used, what will constitute pass/fail, and what testing the owner will have to perform.”
Forethought, not afterthought
In the end, Mackler says, the two most important keys to biopharmaceutical facility design success are a well-defined scope of project and early, extensive planning. “It is in this conceptual stage when we have the best opportunity to establish design criteria and a solid Basis of Design, so that the project will benefit from accurate budgets and a firm execution plan,” Mackler explains. Such a diagnostic approach minimizes project risk and can prevent costly and unforeseen ‘adders’ once the construction begins.
Mackler emphasizes: “Quality must be built into the design of an FDA-validatable facility, not added afterwards.”