Category: Cleanrooms

For as long as most of us can remember, the manufacture and purification of biologic drug substances has mostly been performed in cleanrooms. Recently, advances in the design, form, function and operation of bioprocessing equipment has made it possible to close — or functionally close — biological active ingredient (API) manufacturing operations. As expressed in the most recent regulatory guidelines (PIC/S 2017, Annex II), closed bioprocessing can be moved into simpler, unclassified environments and even outdoors! This strong endorsement of closed processing provides enormous opportunity and cost benefits to drug manufacturers.

Why Cleanrooms Anyway?

At the inception of the biopharmaceutical industry, with the production of antibiotics via fermentation, bioreactors were often located outside, with plumbing inside in locations that experienced colder weather. Contamination of these processes was seldom an issue during fermentation, given that the cultures in question were of a short duration and the organisms used produced antibiotics that inhibited the potential invasion of other contaminating species. In addition, the analytical tools available at the time often could not detect traces of contaminating organisms or chemicals.

Things changed with the introduction of mammalian cell-culture-based processes in the 1980s. The longer duration of the cell culture (from 24 hours to 12-180 days) and the lack of natural antibiotics produced by mammalian cells resulted in a higher frequency of detected contamination rates of up to 50%. Detected contamination rates of less than 5% were often considered acceptable or even “ideal” given the limitations of the industry’s capabilities for effective SIP, sanitary design and maintenance of an aseptic state. Today we know that the failures were largely due to the fact that the equipment was not appropriately designed for aseptic operations. The biopharmaceutical industry’s response to this deficiency was to move bioprocesses into cleanrooms, where the levels of bioburden were lower, thus reducing the level of bioburden to which our process streams were exposed. This solution was successful at reducing the frequency of detectable contamination rates to 5%-10%, so the strategy of moving bioprocesses into cleanrooms was adopted. The irony is that actual contamination rates likely remained the same. Only by improving the integrity of the equipment used can one truly mitigate the risk of contaminating a bioprocess from environmental elements. Unless one works in a bioburden-free environment (Grade A/ISO 5), the risk of contamination of an open operation cannot be totally eradicated.

Cleanrooms Will Never BE Clean Enough

The observed contamination rates were achieved because existing analytical capabilities were limited, and therefore could not detect the lower levels of bioburden. As analytical detection limits continued to improve, it became possible to detect even minute levels of contamination in bioprocess fluids.

Equipment, raw materials, airborne particles, clothing, packaging, etc., are all sources of contamination of the environment. However, personnel represent the greatest source of contamination in cleanroom environments. Unless humans are removed from the bioprocessing environment, cleanrooms will always represent a risk of contamination to an open bioprocess. Because of personnel and the bioprocess itself, the level and type of environmental contamination in a cleanroom is ever-changing and thus impossible to control. As a result, cleanrooms will never be more than moderately effective in mitigating the risk of contamination of an open system except by reducing the level of contamination.

The only real solution to prevent contamination is through the use of closed equipment. Closed equipment is equipment or systems designed to be cleaned and/or sanitized to a point where the risk of contamination from environmental sources during product contact is fully mitigated. This includes single-use equipment and equipment designed to be CIP’d and SIP’d between operations. With such an approach, a process will only fail if there is an unusual event or malfunction of the equipment. An effectively closed process cannot be contaminated because of common human failures such as a torn glove, insufficient or inappropriate gowning, a cleanroom suite door that was improperly (or untimely) opened or closed, or because too many personnel were present in the suite during critical operations. If good science and process analytical technology are implemented, equipment can be appropriately closed by CIP and/or SIP and verified as closed. Personnel errors in gowning or transitions from one cleanroom zone to another will have little impact on the quality of the drug when manufactured
in a closed system. Our regulatory agencies have recognized this, and for this reason, they are now inviting the manufacturers of biological APIs to perform these functions in unclassified environments (or “outdoors” as stated in the 2017 PIC/S regulations¹).

If good science is implemented, equipment can be thoroughly sterilized every time, without having to turn to gowning, for instance, which has little impact on the quality of the drug being manufactured. 

Closed and Functionally Closed Equipment

The solution of removing bioprocesses from classified cleanrooms can be achieved with closed or functionally closed equipment as defined in the International Society of Pharmaceutical Engineers (ISPE) Baseline Guideline.² A closed system is validated to show that there are sufficient layers of protection to mitigate the risk of contamination from the environment. Importantly, the environment housing the system is not a critical aspect of the process, because the product is never exposed to the outside environment. Thus the risk of contamination in a closed system cannot be mitigated by housing the process in a bioburden-free environment, so why put it there?

A functionally closed system is a system that is routinely opened, but then returned to a closed state via cleaning, sanitization or sterilization prior to product contact. The process, when run in a closed manner, does not expose the raw materials, in-process materials or bioprocessing fluid to the operators or environment. The cleaning and/or sanitization/sterilization process must be validated to confirm the return of the system to a functionally closed state.

The American Society of Mechanical Engineers (ASME) Bioprocessing Equipment Standards Committee (BPE) is charged with developing a standard covering the design, materials, construction, inspection and testing of bioprocessing equipment such as vessels, piping and related accessories, such as pumps, valves and fittings, for use in the biopharmaceutical industry. The ASME BPE standard³ establishes requirements for the design of bioprocessing equipment and addresses the design features required for effective cleaning and sanitization of that equipment. The BPE is working to establish design standards for equipment for all biopharmaceutical unit operations that are single use or can be cleaned and sterilized/sanitized for the purpose of effectively closing the system in which this equipment is used. With current technology available, it is possible to eliminate the environment as a factor for the contamination or adulteration of virtually all bioprocesses.

Unfortunately, some unit operations that have always traditionally been performed in open systems continue to be performed in this manner. Today, most — if not all — of these processes can be performed in closed or functionally closed systems. If the goal of 100% closed processing can be achieved, the need for cleanrooms can be eliminated completely. Doing so is not only safer for the operators, the manufacturing process and ultimately for the patient, it can also significantly reduce the cost of a unit operation from both OPEX and CAPEX perspectives. A cleanroom typically carries a capital cost of approximately $2000-$3000 per square foot, compared to $200-$400 per square foot for a high-quality unclassified environment suitable for housing a closed operation.

Closed processing can be achieved either by designing closed equipment or placing the open process inside a closed system such as an isolator. Whether using traditional stainless-steel tanks that are functionally closed by CIP and SIP or using single-use (SU) systems that are closed by gamma irradiation or by housing a process within a properly conditioned isolator, these options all represent a more cost-effective strategy that represents much lower risk to the patient.

Risk Assessment and Validation of Design

The key to successful implementation of closed or functionally closed systems is good overall design. Good design includes the use of connectors that are designed, installed and used correctly, effective sterilization/sanitization procedures, appropriate validation, effective monitoring and compliant documentation. Until all of these criteria are met, a system should not be considered closed.

CRB has developed a risk-assessment tool that helps its clients assess the potential for ingress of environmental contaminants into their processes. We have also created methodologies to mitigate these risks. As part of the ASME BPE, we are actively involved in the design of functionally closed solutions for existing open processes that can be readily cleaned and sanitized.

With current technology available, it is possible to eliminate the environment as a factor for the contamination or adulteration of bioprocesses.

Societies/Standards/Guidelines/ Technical Reports and the Regulatory Agencies

Among the challenges facing biopharmaceutical manufacturers are the numerous regulations, standards and guidelines applicable to bioprocessing. In addition to the ISPE Baseline Guidelines and the ASME BPE standard, the Parenteral Drug Association (PDA) has issued a series of technical reports with guidance on how to clean, sanitize and sterilize systems. And a consortium of biopharmaceutical manufacturers called the BioPhorum Operations Group is testing and challenging some of the former legacy paradigms and approaches (many of which have become folklore) and presenting new concepts to be considered in a series of white papers. Current good manufacturing practices issued by the USFDA (laid out in the Code of Federal Regulations, CFR) and the European Medicines Agency (EMA, laid out in the Eudralex in Annex I for drug products and Annex II for drug substances), as well as similar regulations in Japan, China and many other countries, must be complied with by producers of biologic APIs and formulated products. 

The Pharmaceutical Inspection Convention (PIC) is working to address this issue through the development of harmonized regulations. The PIC consists of 52 participating authorities from all over the world. The group has created a new series of guidelines based on the European regulations but updated in more user-friendly language. Together with the societies stated above, the regulators are helping paint a clearer picture of what the real standards should be for the manufacture of biopharmaceuticals.

Death to Cleanrooms

Biologics manufacturers should be investing in process closure in lieu of investing in outdated, heavily customized, non-sustainable cleanrooms. The transition of our biopharmaceutical industry from open processing in cleanrooms and into closed processing is encouraged by regulators as well as other organizations responsible for publishing key bioprocessing guidelines. This strong endorsement of closed processing provides enormous opportunity and cost benefits to drug manufacturers. Simplifying the design and construction of a biopharmaceutical facility and the operation of an unclassified manufacturing environment results in huge capital and operational cost savings, and therefore fewer deviations and failures. The use of closed integral equipment also results in lower risks to the patient. May the next five years lead to improvements in equipment design, and ultimately to the death of cleanrooms in ”Back to the Future Facilities™” for biopharmaceutical manufacturing.

Cell and gene therapy manufacturing must be performed under aseptic conditions and with good aseptic handling practices to ensure patient safety. The use of isolators can help address this critical need, but designing isolators for advanced therapy medicinal product (ATMP) processes can be challenging. 

Rich Pipeline Driving Market Growth and Capacity Demand

The cell and gene therapy segment of the pharmaceutical market is evolving at lightning speed. Only a few years ago, these treatments comprised the smallest fraction of products in the clinical pipeline. At the end of the second half of 2019, the Alliance for Regenerative Medicine (ARM) counted more than 930 companies — from emerging biotechs to major international biopharma firms — that were pursuing cell and gene therapies, with more than 1,000 clinical trials underway around the world.¹ 

Meanwhile, the U.S. Food and Drug Administration (FDA) expects 200 cell and gene therapy IND applications each year by 2020 and 30–60 approvals by 2030.² Not surprisingly, the cell and gene therapy market is predicted to expand at a CAGR of greater than 36%, rising from approximately $1 billion in 2018 to nearly $12 billion by 2025.³

With so many candidates reaching late-stage clinical development and nearing commercialization, demand for cell and gene therapy manufacturing capacity is rapidly increasing. Despite heavy investment by contract manufacturers to expand their capabilities, they cannot possibly meet the growing needs of the sector; many cell and gene therapy developers are, therefore, establishing in-house facilities.

Facility Design Challenges

Designing new facilities for cell therapy manufacturing is a challenging task. Commercialization remains in the nascent stage, with only a few facilities constructed to date. Production experience thus far has largely been limited to the laboratory scale, and, particularly for cell therapies, most processes involve highly manual operations. The current equipment, technologies and techniques require significant modification for practical scale-out (for autologous therapies) or scale-up (for allogeneic therapies).

In addition, the potential demand for any given new therapy is typically not well understood at the earliest stages of commercialization. Lead times for key raw materials are also often unknown. The significant complexity of the supply chain — most notably for patient-specific cell and gene-modified cell therapies — further complicates the situation.

As a result, facility designers and engineers are challenged to develop robust solutions while facing uncertainties including plant footprint, the types and quantities of equipment, the required staff, and the flow of people and materials.

Moving to Isolators

All cell therapies cannot be terminally sterilized. Therefore, very rigorous quality control is essential in their production, regardless of the batch size — whether it is a patient-specific autologous therapy or a large-volume batch of an allogenic, off-the-shelf product. The entire production process must be performed aseptically, including extensive in-process and final product quality control testing, in a manner that ensures sterility and efficacy with a high degree of certainty.

The traditional approach has been to perform processes in biosafety cabinets within cleanrooms. However, these processes are not closed but are open to the environment. As such, the cleanroom must be Grade A or B, and with a Grade A biosafety cabinet in an environment that is very tightly controlled. Product purity is heavily reliant on operator procedures, and the risks of contamination can be high, the training and qualification is costly, and the process is highly unforgiving for a human “having a bad day.”

Isolators, when used as primary containment, provide a closed environment in which the process is performed, allowing the use of a lower HVAC classification cleanroom. This typically leads to reduced facility capital expenditure and lower operating costs due to the reduced need for gowning and airlocks. The facility footprint is often smaller as well.

Perhaps most importantly, using an isolator protects both operators and the product, because the process environment is aseptic, contained and closed. The product is separated from the operators who are manipulating the process, which significantly reduces the potential for contamination.

The Need for Customization

The use of isolators presents its own set of challenges, however. Isolators have traditionally been designed for aseptic fill-finish and non-aseptic potent compound manufacturing operations, not for small-volume, manual cell and gene therapy production. Typically, aseptic isolators have been associated with automated equipment, such as a vial or syringe fill line. For cell and gene therapy production, several different pieces of equipment must be contained within the isolator.

Isolators for cell and gene therapy production are very complex. Considerations must be made for ergonomics to ensure that operators can easily perform necessary manipulations and material can be moved smoothly from one unit operation to another. Transfer in and out — as with the removal of waste and the collection of samples — are generally more complicated. Other issues that must be addressed in the isolator design include the heat load it will need to support and the electronic connections necessary to automate the equipment and for data transfer.

Decontamination of the isolator also requires a special approach. Much of the processing equipment used in cell and gene therapy manufacturing cannot be sterilized using vapor phase hydrogen peroxide (VPHP), the most common agent used to decontaminate traditional isolators. It is often necessary to wipe down the individual pieces of equipment and then protect them so the isolator chamber can be treated with VPHP. Development of a robust decontamination cycle and validation of an aseptic environment within the isolator is, in fact, a key component of the overall process development activities for cell and gene therapies produced in isolators. The components associated with the isolator design can have a significant impact on these efforts. The isolator is more than just the metal and glass box that surrounds the process.  The elements used to transfer materials in and out of the isolator, as well as the monitoring of the strict microbial and particulate control of the isolator, are a large part of designing an isolator for a higher ease of operation and higher quality of product.

Complicating the situation further is the fact that much of the equipment used in the cell and gene therapy field to date has been designed for research applications, and not all options on the market are sufficiently robust for use in cGMP manufacturing with respect to CFR Part 11 compliance and other regulations.  In addition, no two cell and gene therapy production processes are alike, which adds to the difficulty. Processes can vary dramatically from company to company and even from product to product.

Isolator modules must be customized to fit the particular pieces of equipment and the operation steps used for each process. In addition, because most of the equipment was originally designed for use in a research or clinical environment, it is often not sized appropriately for conventional isolators, leading to even greater need for customized solutions.

The infrastructure for GMP cell and gene therapy manufacturing continues to evolve, with vendors of tubing, bags, bioreactors, etc. working hard to catch up to the demands of developers of these next-generation medicines.

Regulatory Uncertainty

Given the nascent nature of cell and gene therapies, regulatory agencies have only begun to focus on the specific requirements for these products with respect to development and manufacturing. The majority of efforts have been directed toward development aspects, notably the data required to prepare INDs for clinical studies and rules and guidance for conducting clinical trials.⁴

The FDA, European Medicines Agency (EMA), the Pharmaceuticals and Medical Devices Agency (PMDA) in Japan, and other regulatory bodies, have issued several draft guidances regarding cell and gene therapies, including a limited number recommending manufacturing practices. Early in 2019, the FDA announced that it was working on several additional guidance documents covering clinical development through manufacturing, with the intention of fostering innovation and advances in manufacturing and enforcement to promote efficiencies and address the complexities of cell and gene therapy manufacturing.⁵

The FDA, along with other government agencies, has also encouraged the formation of new public/private consortiums such as the National Institute for Innovation in Manufacturing Biopharmaceuticals (NIIMBL) and the Advanced Regenerative Medicine Institute (ARMI), which are supported by the National Institute of Health and the US Department of Defense, respectively. The Standards Coordinating Body, an independent non-profit 501(c)(3) organization spun out of an initiative of the ARM’s Science & Technology Committee is working to promote coordination of standards activities, including those for manufacturing.

There remains significant debate regarding whether the guidelines proposed to date are sufficiently strict for the manufacture of ATMPs.

The Ultimate Goal: Closed Processes

While there is much that can be done to standardize equipment use for cell and gene therapy within an isolator environment, which would then allow for more standardization of isolator designs, the use of isolators is not the ultimate goal for ATMP production.

The ideal objective is closed processes — manufacturing equipment and systems for cell culture, harvest, viral vector production, downstream purification and all other unit operations involved in cell and gene therapy production that preclude the need for an isolator environment. The development of such systems is occurring in parallel with advances in isolators and their attendant technology. 

Applying Decades of Experience

CRB has been providing consulting services services in aseptic processing, in biological therapeutic production, and in regenerative medicine for over 30 years. CRB has even been instrumental in facilities in the cell and gene therapy manufacturing space for over a decade. We have been involved in the forefront of manufacturing systems and facility development, largely with academic and research institutions with candidates advancing through clinical development.

CRB has been involved in more than 215 different cell and gene therapy projects ranging from feasibility studies to the design and construction of entire manufacturing facilities. Our engineers and designers listen closely to our clients and work to truly understand their needs. With this understanding, they are able to guide clients from the research scale to processes that are commercially robust and performed in facilities that are designed to garner acceptance by regulatory agencies around the world.

We are also actively engaged with vendors of cell and gene therapy manufacturing equipment and isolators to identify areas for improvement and advances that will enable more efficient design and installation of isolators — and ultimately closed processing systems. We are committed to staying abreast of developments in the field in order to be able to anticipate how cell and gene therapy processing may evolve over time.

References

1. 2019 Q2 Global Regenerative Medicine Report. Alliance for Regenerative Medicine. 2019. Web.
2. Cross, Ryan. “FDA prepares for huge growth in cell and gene therapy.” Chemical & Engineering News. 16 Jan. 2019. Web.
3. “Global Cell and Gene Therapy Market to Reach $11.96 Billion by 2025.” Markets Insider. 6 Aug. 2019. Web.
4. Mendicino, Michael, Yong Fan, Deborah Griffin, Kuty C. Gunter and Karen Nichols. “Current state of U.S. Food and Drug Administration regulation for cellular and gene therapy products: potential cures on the horizon.” Cytotherapy. 21: 699–724 (2019).
5. Macdonald, Gareth. “FDA pledges to support cell and gene therapy manufacturing innovation.” Bioprocess Internationa 3 May 2019. Web.

A cleanroom project starts with a design concept that is centered around a biopharmaceutical manufacturer’s strategic goals. Ideally, a cross-functional team will work with the design firm following a structured process to develop a comprehensive compliant design that addresses the current needs while providing flexibility for future requirements. With its Compass™ Program, AES Clean Technology provides crucial design compliance and a project management structure that enables biopharma companies to stay on a forward path to a right-the-first-time, optimum cleanroom achieving operational and regulatory expectations.

Rising Demand for Additional Cleanrooms

Growth in the biopharmaceutical industry is driving the need for greater capacity facilities. Many manufacturers are seeking to expand their capabilities, whether that means scaling out to treat more patients with autologous therapies or scaling up more traditionally to produce more doses of the same product.

As a new therapy candidate progresses through clinical trials, sponsors must prepare for advancement to the next phase, and ultimately commercial production, on the basis of early and ongoing data generated from those studies. License sponsors are compelled to anticipate study success with proactive patient drug supply planning, which in a “make” (vs. buy) scenario requires considerable capital investment.

As such, ideally the decision to design and construct a new cleanroom often comes in early phase III of the development lifecycle, which is 24–36 months before FDA approval, because of the realities of clinical trials and the complexity of biopharmaceutical projects. As a biopharmaceutical innovator approaches a critical milestone and prepares to move to the next level, they not only need to add more manufacturing space; they need to do so as rapidly as possible.

For cleanroom designers, a comprehensive understanding of where clients are and where they want to get to is critical to the foundation of the design and necessary to ensure that the design and/or integration of a highly regulated aseptic manufacturing facility is conceived and built specifically to meet the drug product processing needs.

Factors Driving Cleanroom Design

A cleanroom project begins with a design concept guided by the biopharmaceutical manufacturer’s goals. Better project parameter inputs yield better outputs, so it is imperative to gather as much information as possible before any drawings are made. The greatest cause of failure for these complex projects is the lack of a robust conceptual design and project planning, which is the foundation for project cost and schedule estimates. Schedule alignment, budget estimate, design compliance, building fit, and FDA review content are all conceptual design outcomes that can be generated in a matter of weeks — well before large capital fund outlays (and risk) are necessitated.

A conceptual design is an imperative and necessary business investment that is often less than 1% (yes, <1%!) of the project finished costs. Factors that impact cleanroom design include the overall size and layout of the manufacturing facility, the number of desired cleanrooms, the type of product and process, the production scale and number of needed operators, and the types of equipment needed. Also important is ensuring that the design complies with current regulatory and industry expectations. Anticipating future needs is also important, as predictions of the likely uses for the cleanroom in the future — whether the current program succeeds or not — will determine the level of flexibility that must be incorporated into the design.

At the start of a project, design firms like AES must ask a lot of questions to gather this information from their clients. Those questions take into consideration the manufacturing process, current compliance, quality controls, and capacities while also thinking of costs, as well as state and local building codes. Biopharmaceutical clients are science based and are not architects, engineers, or builders, and they often do not have a full appreciation of the multitude of cleanroom options that enable speed to market, durability, and flexible facility value.

In our experience, in about half of projects, biopharmaceutical clients have preconceived ideas of what they want — or think they want — for their cleanroom designs. In many cases, owing to regulatory constraints or engineering practicalities, it is not possible or advisable to fulfill those expectations. The best approach is to take a step back and reconsider the overall goals and needs for a project. Then, by leveraging their fundamental expertise, extensive experience gained working on hundreds of previous projects, and proprietary tools, firms like AES can create an optimal, fit-for-purpose design.

There is no substitute for experience in designing and constructing complex cleanroom facilities. It’s often the biggest capital investment in a company’s history. The stakes are high for patients, providers, and shareholders. Project success requires a unique combination of experience, including cleanroom design firms who have team members who have directly been employed with biopharma companies and have held operational roles, comprehending the realities between manufacturing and quality when producing a cGMP drug product.

A Multiphase Process

Prior to selecting a qualified cleanroom design firm, the concept design is the first step in a multiphase cleanroom capital project methodology. Three or four different cleanroom layouts with classification drawings, a preliminary mechanical design, material and people flows, and other details are typically generated. Ideally, cross-contamination assessment is completed for a given design to offer the highest standard of product quality control understanding. The process architect determines the specific square footages and confirms that the cleanroom fit-out is congruent with the greater building envelope. The last step is the provision of specific deliverables, including scheduling and cost estimates associated with each layout, so clients can discuss how the project fits into their strategic plans and their budget. In all, this process takes approximately 8–10 weeks.

However, it cannot be stressed enough that concept design cannot occur without understanding the specific needs and drivers of the project, and gathering that information generally requires conversations with the client’s technical and capital project executive teams. Ergo, the concept design deliverables are only as good at the inputs that go into them. 

Scope, Team, and Process Definitions

Scope definition involves understanding what the overall goals of a project are and the client’s preferences for how the project should be executed, including who has what responsibility. AES uses a charter to help define the various aspects, including objectives, in/out scope, key contacts, deliverables, and general concept design timeline. For some projects, clients want an active role in hiring general contractors and managing administrative details, while others want AES to handle the entire project. AES uses additional tools to clearly segregate the roles of a multi-contractor project arrangement.

Team definition relates to which people from the client organization with relevant expertise and experience will work closely with the design firm on a project. Having an effective decision-making body is probably one of the most important contributors to the success of a project, but establishing a good team is often overlooked. The design firm, for instance, may not know the strategic objectives of the client or their approval process for capital projects. Having people with the relevant knowledge to advocate for to the needs of the project across all aspects — from design to GMP manufacturing, quality, and regulatory — is invaluable, especially when considering that this key design information is needed in a product license application (e.g., BLA).

Process definition relates to the manufacturing processes which will be performed in the cleanroom. This includes information about the materials and their key attributes, such as potency; the type of process, such as cell culture or fill/finish, and the protocol; equipment needs; the current development stage and expectations for the next several years; and any other specific constraints that must be considered. This step will also identify key high-risk operational steps that must be quality controlled with the aid of the facility’s design features.

Process definition is only fully realized if the scope of the project is adequately defined and the client’s project team is staffed appropriately and is accessible. If there is a gap in a sponsor’s team experience, this can easily be mitigated with supplemental subject matter expertise via the cleanroom design firm. Cleanroom designers have a vast network of SMEs that can supplement client representation in every modality, process, and product and are invaluable to consult on conceptual design projects.

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The Consequences of Operating Without Structured Teams

Unfortunately, many biopharmaceutical companies do not understand the challenges that can arise when a multimillion-dollar project is pursued without having the right team in place. It is often the case that the recommended structure and team do not exist. Limitations remain in terms of what the design firm can achieve when design details are not agreed upon and information is not provided in an orderly and timely manner.

Without a structured client team, gathering information and making decisions can become painful. A lack of communication is often the result, which can lead to a frequent need for change orders, which are accompanied by budget increases and derailed schedules. It is therefore essential to work with cleanroom design firms that can manage projects even when these critical components are not available.

With licensed process architects and experts that have come from within the biopharma industry, AES offers an understanding of both the client and technical perspectives. When clients are not in a position to drive project management, AES can step in and become involved in structuring the team and in the decision-making process. We also have experience working on projects led by industry leaders who have decades of specific experience working, designing, and commissioning complex cleanroom projects.

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Building in Flexibility

Often, when constructing cleanrooms, the initial intended use is well understood, but drug makers often have additional products in their pipelines for which the cleanroom might also need to be used at some point in the future. The rate of change in biopharmaceutical technologies and equipment is extremely high, and it is difficult to predict what will be needed in even just five years. A cleanroom design company must be familiar with equipment and technologies that are in development in order to help pharmaceutical manufacturers to prepare for the future. A well-qualified cleanroom design proactively anticipates process change improvements and the facility changes potentially accompanying them. Strategic design planning of placing knockout walls, sizing air-handling units (AHUs), and creating flows that minimally impact ongoing operations when implemented requires design firm experience when interpreting client long-term requirements.

It is important in these instances to take a case-by-case approach, as each project and each client are different. AES follows a process that includes eliciting information from clients about potential future requirements. The key is to first understand the short- and long-term facility needs before trying to establish a potential pathway for reaching them, which requires a structured design approach.

Different Needs for Cleanrooms in Greenfield versus Existing Sites

A key difference between constructing a cleanroom in an existing facility and a new site is that, in the former, the cleanroom must fit into a certain stop, while in the latter it is often the heart of the facility. In a greenfield site, it is possible to design an optimal cleanroom that fits well within the overall facility, allowing for the highest levels of efficiency, compliance, and cost-effectiveness.

Fitting a cleanroom into an existing site can be quite challenging. The cleanroom is just one of the areas needed for manufacturing drug products, and designing a cleanroom that will fit into an existing building and also be compliantly situated with respect to the utilities, material receiving, warehousing, waste management, and other key activities often requires sacrificing efficiency, contributing to higher costs.

If an existing site is to be used, it is generally better if clients ask for an optimal cleanroom design and overall layout with associated cost and scheduling estimates and then look to find a suitable existing building. An architectural “test fit” is a short and cost-effective day trip exercise with selected engineers that can be completed when considering different buildings sites for a production facility. This proactive engineering exercise can confirm structural, power grid, and foundational appropriateness, as well as basic flows that could otherwise increase cost if not a good fit for the bioproduction building use. Experts at the design firm can visit potential sites to determine whether they will be a good fit, ensuring a good outcome. When adjustments to the project are needed — and they inevitably are when constructing a cleanroom in an existing building — there is a design basis to work from, and clients can be quickly provided with the necessary changes and their impacts.

The Role of Critical Path Assessments

Capital project risk assessments based on critical path project schedule analyses help identify the best approaches to implementing a cleanroom design. Such analyses can involve consideration of modular versus traditional approaches to construction and the choice of HVAC system.

Modular design is inherently a fast-track process because the panels are the unit building blocks constructed in a factory while the site is being prepared. There are still risks, however, owing to reliance on the preliminary design. HVAC systems that do not recycle air are more expensive but are an inherent necessity from a compliance and flexibility perspective, and some clients want to consider the risk of not choosing such a system with respect to facility approval. When the client is a CDMO, they may also consider the attractiveness, access, auditability, and exceeding compliance standards for risk-averse clients.

AES has developed matrices for evaluating projects on the basis of the process architecture and preliminary mechanical designs that make it possible to demonstrate the risk relative to the engineering design, process architecture, compliance hurdles, costs, safety considerations for potent compounds, and potential issues for the future. In addition, clients can be shown the consequences of different tradeoffs in space, equipment, and other factors with respect to scheduling and costs. The goal is to facilitate the decision-making process when considering different cleanroom designs.

The Value of Staying on the Right Path

A methodical approach to cleanroom design and construction is essential to keep projects on track, particularly if no structured client team is provided and the scope and process definitions are slow in coming and less clear than desired.

AES’s approach begins with a proven inquiry approach comprising multiple specific cleanroom design-influencing factors of compliance and costs. The goal is to find out as much needed information as possible and determine which aspects clients do not yet know. When information is not available, a more conservative design is initially adopted. If the client expects to generate the information soon thereafter — such as equipment lists and process flow diagrams, which are part of the CMC requirements for NDA and BLA filings — waiting a day or two is generally the best solution.

If clients push hard to get designs on paper, AES will begin preparing drawings while still gathering the necessary process, equipment, and other information. Running these phases in parallel can help to prevent projects from getting too far ahead of themselves. That should be avoided at all costs, because it often results in large numbers of change orders with negative impacts on schedules and costs.

The best way to ensure that projects stay on the right path is to follow a structured process that begins with collecting all of the necessary information from a team of experts from the client with knowledge about the company’s strategic goals and specific project requirements. Concept designs can then be drawn that take all of the necessary factors into consideration, thereby minimizing the need for changes that can contribute to scheduling delays and higher project costs.

Defining, Designing, and Delivering the Perfect Clean Solutions

The key to our success has been focusing on the goals and needs of the client’s production process in order to identify the ideal solution. AES is committed to maintaining as balanced an approach as possible to provide the most efficient design that encompasses cost and floor space. We are very flexible. We have experience integrating the AES modular systems in all multi-contractor design/build arrangements. We do what’s best for each client and the client’s patients.

We also are not afraid to have difficult conversations with clients and tell them what they need to hear rather than what they might want to hear. Our team is nimble, highly experienced, and service-oriented. Throughout the cleanroom design process, AES always looks for ways to reduce project timelines and cut costs, providing additional options that help to balance both. We have 30 years of proven designs that are accepted as the standard of excellence by regulatory authorities. A major component of our approach is transparency and open communication to ensure that the client has the information needed to make informed decisions.

AES often builds modular cleanroom systems, and we take the opportunity during the concept design stage to highlight the advantages of modular solutions for clients. These benefits are not only linked to our specific cleanroom system, but to the advantages afforded by pre-piped piping systems and pre-run electrical systems, among other fit-for-purpose cleanroom trademarked products that raise the bar on design compliance, installation speed, and cost effectiveness. The modular approach is the standard of excellence for state-of-the-art advanced medicinal science and patient supply through the application of current technologies and/or methodologies in contact materials, fabrication, and installation of modular cleanroom methods.

The AES Compass Program

The Compass Program at AES is a cleanroom design methodology that combines fit, form, and function objectives by defining the relationship between product, process, and facility requirements — all with transparency about process architecture and compliance aspects.

The objective is to keep the process as simple as possible so that the client only needs to convey the specific project goals and needs and the information that AES requires to confidently develop relevant cleanroom designs. Our experts bring their decades of experience on both the engineering and manufacturing sides to bear on each project. We are thorough in asking experienced cross-functional questions, yielding the optimal cleanroom design. Templates also provide clients with guidance and examples.

AES Compass Program surveys have shown this approach has well received by clients:

• “… Very thorough package of information…”
• “… the process forced us to define portions of the process we had not considered yet.”
• “The knowledge of the design team as a whole was invaluable.”

AES has completed over 3,000 projects, many of them multi-million-dollar designs that received approval from regulatory authorities and are used today to produce lifesaving and life-changing medications. In the initial years of the COVID-19 pandemic, the vast majority of vaccine product was produced in AES cleanrooms.