Maik W. Jornitz

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The revised European Union good manufacturing practice (EU GMP) Annex 1 guidance document (1), which was published on Aug. 25, 2022 and came into effect on Aug. 25, 2023, is a more detailed and comprehensive guideline that aims to enhance process understanding and incorporate new innovative tools. The updated Annex 1 also takes into account changes in regulatory and manufacturing environments. However, it is important to examine how the requirements for liquid sterilizing grade filtration within the revised Annex 1 align with technological advancements and contamination control assurance. This paper aims to review technology advances in filtration and identify areas that require clarification in the Annex 1 guidelines.

Sterilizing-grade filtration is a widely used method for sterilizing biologics, and it has become increasingly prevalent due to improvements in filter and membrane stability, advanced integrity tests, new design and chemistry features, and process validation activities. These advancements have significantly increased the reliability of aseptic processing steps using sterilizing grade filters, necessarily so; as for most biologics, sterile filtration is the only means of sterilization.

Filtration Clarification Needs in Annex 1

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Modern sterilizing-grade membrane filters are designed and built to meet the strict requirements of the biopharmaceutical industry and regulatory authorities. These filters have undergone continuous optimization and development, resulting in several important features:

 Filters can withstand high temperatures of up to 134 °C, making them suitable for sterilization by in-line steam or autoclaving even for multiple cycles. The temperature/differential pressure profile has been established, which supports the appropriate operating conditions during steam sterilization, preventing any damage.

 Single-use assemblies utilize filter capsules. These filters are resistant to gamma irradiation up to 50 kGy. The gamma irradiation method is validated to show proof the assembly is sterilized, and the assembly and filter membrane are compatible with the sterilization method, without damage.

 Even when used straight out of the box, these filters release extremely low levels of extractables, which have been published and are detailed in qualification documentation from the filter manufacturers.

 Modern sterilizing filters can withstand 25,000 pulsations at a pressure difference of 70 psi (5 bar), ensuring their durability and reliability. Such tests are performed by filter manufacturers to assure the product robustness.

 Most filters have been optimized to greatly reduce the amount of unspecific adsorption, which is of importance to avoid the retention of target proteins or other important fluid components, for example polysorbate.

 Some filters are designed to provide the highest possible volume of filtration, effectively reducing the cost per liter of filtered material. Highly asymmetric and heterogenous double layer filter designs are throughput focused filter types.

 Some filters are engineered to achieve the most efficient flow rates, which can reduce processing times or the required filtration area. In this case, the filters have a high pleat density and therefore effective filtration area and are typically single layer membranes.

 Sterilizing grade filters must be tested for their integrity using non-destructive methods such as diffusive flow, pressure decay, or bubble point tests. These tests have been successfully used for decades and are a reliable must-do test post-use.

 The filters come with comprehensive qualification documentation, which lists a multitude of tests, for example, endotoxin release, Plastic Class VI, etc., ensuring that they meet the necessary regulatory standards.

 The filters undergo process validation specific to the drug product being filtered under process conditions, confirming their compatibility, performance, and retentivity.

Every sterilizing-grade filter is individually integrity tested by the filter manufacturer, as a release criterion for the product.

The filter suppliers also recommend necessary shelf-life data for filtration and single-use assembly products and validate the packaging and transportation of these components to assure the product are not damaged.

Pharmaceutical Technology®/Pharmaceutical Technology Europe® Quality and Regulatory Sourcebook

is principal consultant, BioProcess Resources LLC

When referring to this article, please cite it as Jornitz, M. Filtration Clarification Needs in Annex 1. 

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Misalignment around liquid filtration requirements and contamination control assurance still persist despite the revisions to Annex 1.

Cleanroom or classified environmental infrastructures have been designed and constructed for decades (1) and can be either on-site framed epoxy coated gypsum wall (stick-built), on-site assembled modular wall panels (modular), or off-site prefabricated cleanroom units (podular), the last of which is a relatively recent addition. All of these cleanroom material and design modalities have benefits and limitations that require careful review when making decisions on which approach to use for constructing current good manufacturing practice (CGMP) cleanroom infrastructure. Such decisions need to be made not only with the process application needs in mind, but also with the long-term perspective on future capability and capacity. This is especially important for multi-modal or multi-product processing streams and new therapies, which may not have a clearly defined process design or require process modifications along the way, and contract manufacturers, as their client base require process modalities change.

In all cases, the need for flexibility is real (2,3,4). However, flexibility must be defined, as it is often used in general terms (5). Some claim that standardization of cleanroom infrastructure designs, faster deliveries, and lower cost of goods sold, will impede or prevent flexibility. This generalization may be inaccurate, as smaller volumes require smaller process footprints, which can be reconfigured within the available standardized space (6). Such spaces may be even more flexible if units can be scaled rapidly.

To truly determine flexibility, one needs to dissect the different flexibility needs and the available solutions. Only then can an appropriate decision be made, which will not just satisfy the short-term requirements, but also show long-term benefits.

Pharmaceutical Technology's May 2023 Trends in Manufacturing eBook

M.W. Jornitz is is Prinicipal Consultant at BioProcess Resources LLC. Sindey Blackstrom is vice-president of Business Management, Blake Williams vice-president of Operations, and Denniss Powers vice-president of Business Development, all at G-CON Manufacturing.

When referring to this article, please cite it as Jornitz, M.W. et al. The Quest for Cleanroom Flexibility. 

Pharmaceutical Technology's Trends in Manufacturing eBook 

Contextualizing what type of flexibility is needed is paramount when considering cleanroom design.

The Quest for Cleanroom Flexibility

Point-of-use sterilizing grade filtration has been used reliably for years to achieve sterile fluid fill.It is currently the only alternative for biologics, which would be damaged by heat sterilization.Over the years, the dependability of this critical aseptic processing step has been improved with the introduction of new filter materials and designs, and the adoption of single-use technology in closed unit operations.Moreover, the sterilizing grade filters and related processes are validated to test their performance under process conditions to help ensure that they perform as specified (1–3).Nondestructive tests (e.g., bubble point, diffusive flow, or pressure decay), which have been in use since the mid-1970s, are typically used for filter integrity assessments, which can be done in the following ways:

Maik W. Jornitz is CEO of G-CON Manufacturing, Inc.

Pharmaceutical Technology's Biologics and Sterile Drug Manufacturing


eBook: Biologics and Sterile Drug Manufacturing, May 2021
May 2021
Pages: 4–12

When referring to this article, please cite it as M. W. Jornitz, “Sterile Filtration: Reducing Risk, Ensuring Safety,"

 Pharmaceutical Technology Biologics and Sterile Drug Manufacturing eBook 

A task force established by PDA and BioPhorum is establishing scientific data for integrity test activities.  

Sterile Filtration: Reducing Risk, Ensuring Safety

The bio/pharmaceutical industry is experiencing a paradigm shift—not only for therapies, but for the entire support infrastructure. The process streams and surrounding cleanroom and facility infrastructures for recombinant proteins are drastically different from those for small-molecule processes. Advances in cell and gene therapies and continuous bioprocessing require a shift as well. In these cases, the scale of the processes can range from small, per-patient batches to multiple, 2000-L fluid volume streams. These different applications require in-depth review so that that the best processing and cleanroom infrastructure platform may be chosen. Decisions can no longer be based on a single parameter, such as initial cost. Rather, a matrix of different factors must be evaluated. This article addresses the different decision points behind this approach, to guide determination of the best cleanroom and technology choice.

The traditional brick-and-mortar facility is still the main type used in the industry. These constructions are typically very capital intensive, requiring lengthy design and construction phases. A project completion timeframe of two to three years is not uncommon for these types of buildings.

Shell building infrastructures with box-in-box cleanrooms are another option. Such buildings are typically high-span buildings, similar to warehouses. The benefit of this type of infrastructure is that it permits faster construction and more flexible use of space. With this approach, the entire space does not need to be planned out in detail at the outset of a construction project. Instead, cleanroom and other infrastructures can be integrated gradually.

The container-based approach has shell and internal infrastructure designed off site while prefabricated, container-based units are stacked on each other and interconnected to form an entire facility. This type of facility requires significant upfront design, and design is fairly inflexible. Because these facilities, to a large degree, are built off-site, they take less time to build. However, they can be relatively inflexible since these facilities are typically designed for a specific application. 

Except for off-site, container-based buildings, the other two facility types require the integration of cleanrooms and auxiliary infrastructure. Three types of cleanroom infrastructures can be used: stick-built, modular wall panels, and off-site prefabricated units (podular). These types of infrastructure can be used in a singular solution or as part of a hybrid solution that includes some or all of these approaches.

In stick-built construction, the wall material is typically gypsum or sheetrock, which is either epoxy or PVC coated. The framing and wall installation are constructed on-site, very similar to the way drywall is handled in the construction of homes. Stick-built construction is the most widely used within the pharmaceutical industry but has begun to fall out of favor due quality concerns and lack of long-term durability. Further, the construction requires a large lay-down area for supplies and a significant number of workers on site for framing construction and finish work. Such construction sites also experience high particulate load, as particles are shed when materials of construction are cut and installed.

Modular wall panels are typically honeycomb aluminum panels, which are coated with a multitude of different materials, most commonly unplasticized polyvinyl chloride (uPVC). The panels are prefabricated off-site, shipped, and installed on-site, once the framing is complete. Again, a lay-down area is required to order to supply the essential materials to the installation team. Installation is faster and cleaner than it is with stick-built systems, because the panels are precut and ready to install. Furthermore, the wall panels are robust, because the aluminum sheet underneath the uPVC coating retains structural integrity.

Off-site prefabricated units are cleanroom or auxiliary infrastructures that are fully built off-site as three-dimensional structures. These units typically have an aluminum or steel framing and use epoxy-coated walls or modular wall panels. Depending on the design and requirements, the podular units can be fully outfitted, including heating, ventilation, and air conditioning; fire suppression; and automation, and the units undergo factory acceptance testing (FAT) before leaving the manufacturing site.

Once the units get to the site, they are introduced into the building and interconnected to provide a fully functional cleanroom infrastructure. There is no lay-down area requirement because all the materials have already been assembled. Because the shell building construction or refurbishment occur in parallel with the building of the podular structure, the time-to-run is much faster than it is with more traditional approaches.

There is never a one-size-fits-all solution. Typically, it is necessary to review a multitude of factors in deciding which cleanroom solution will work best for a particular project. The application and existing building infrastructure are important. Other questions to ask include the following:

What are the long-term and short-term plans in regard to clinical processing space and final commercial site?

Will capacity need to be scaled up or down in the future?

How soon will the cleanroom infrastructure be needed?

Is the depreciation length of the site a relevant factor in the decision?

Often the first question results in a focus on cost, specifically cost per square foot. However, this is a very limited view and fails to consider other cost factors as well as the actual needs of the process and long-term plan of the site (1, 2). For example, the speed and reliability of the delivery of the infrastructure can have a greater implication than cost per square foot, creating the opportunity to delay the capital investment and de-risking the investment. Instead of looking at one cost factor, the total cost of ownership analysis should guide decisions because it is more comprehensive and representative.

, while not all-inclusive, lists many of the factors that should be considered yet are sometimes overlooked. Each factor is described in the following sections.

 When a site is refurbished, the building’s dimensional arrangement may be restrictive to some of the cleanroom types. The most flexible type is stick-built, because it is cut and installed at the site and can be used in any way needed. Since modular wall panels are prefabricated off-site, their dimensional flexibility can be restricted. The three-dimensional, podular prefabricated cleanroom infrastructure has dimensional requirements and is the least flexible of these three types.

 The lay-down area, which is the area required to store construction materials, can be substantial, up to the same size as the cleanroom infrastructure constructed. Either the building must have space to utilize as a lay-down area or an off-site temporary storage must be used. Material logistics and security are also important. With large projects, the impact of supply and transfer of materials should also be considered during the planning phase.

 The time-to-completion should be reviewed for the total facility and separately for the cleanroom infrastructure within the facility. In both cases, prefabricated, off-site units can be up to 50% faster due to parallel building of the facility, utilities, cleanroom, and auxiliary infrastructure and equipment. Even when an existing facility is refurbished, off-site units have the benefit of being built in the time the facility is refurbished. Furthermore, the productivity level in off-site construction is up to 30% higher, since there are no weather, permitting, or logistics delays and no head count density restrictions. Off-site builds can also use predesigned superstructures with standard designs that are built to stock and supplied even faster.

 If a design change is required after the cleanroom infrastructure has been built, the stick-built and modular wall panel-built structures are easier to change than the podular design, if only wall structures are changed. The detailed design phase should be performed with all potential possibilities and needs in mind. However, new construction reports (3) show that turnkey facility designs, which can be chosen without going through lengthy and costly design phases, are increasingly used. Standardization may ultimately bring down timelines and costs.

 Traditional cleanroom infrastructures are designed and built by acquiring and constructing components, which means a large bill of material list is required to produce a fully functional cleanroom. Any flaws must be corrected on site, which can take time. Off-site podular units are built and assembled within the manufacturing area of the supplier and typically undergo an FAT to ensure that the cleanroom is fully functional as specified when it reaches the install site.

 The cleaning processes and single-use pallet tanks used within cleanroom infrastructures require cleanroom durability. If the wall surface is damaged and the material underneath the wall surface is hygroscopic, the processing areas may be contaminated by mold or other foreign matter. Honeycomb uPVC wall panel material or epoxy-coated aluminum wall structures are more robust than epoxy or PVC-coated gypsum walls. The stick-built construction option requires frequent refurbishment and maintenance to avoid problems caused by damage resulting from a single incident or cumulatively, over a long-term cleaning regime.

Delivery time and budgeted cost reliability.

 Many on-site construction projects overrun the given timeline and cost. In off-site prefabrication, the workforce’s size can be more easily adjusted, making the budgeting and construction timeline process much more reliable.

 When considering only the cost per square foot, inexpensive materials often win the race. However, this is a short-sighted approach. Instead, the balance between material expense and quality must be considered. Questions to consider include the following:

Does the cleanroom infrastructure and material meet the quality requirements of the application?

How durable is the specific material, and will it require frequent refurbishment?

What is included in the cost per square foot and how reliable is it?

On-site construction disruption and safety.

 The stick-built construction material and type generates the most onsite work, followed by modular wall panels and then off-site prefabrication. Any work that must take place on-site can disrupt project progress of existing processes. A high density of workers and heavy onsite traffic demands that safety be closely considered and well managed.

 Uninterrupted scalability is important, especially with newer biological therapies, such as cell therapies. Capacity expansions that require changes in the existing infrastructure or construction in the vicinity of the existing space will detract from scalability. However, a cleanroom infrastructure with its own air-handling system supports scalability.

 The ease with which cleanroom infrastructure can be moved to another location may not be a requirement initially. However, in many cases, it will prove to be beneficial. For example, in some cases, the end-user will not know whether the existing building will be used for the entire product life cycle, either because the property is leased or has not been appropriately sized for expansion. However, a prefabricated cleanroom can be moved to another location.

 Historically, repurposing traditional cleanroom infrastructures has been restricted to cases in which a different end-user has acquired the site and using it for the same or a similar application. In this case, the site and processing spaces need to be thoroughly decontaminated, including the potentially elaborate mezzanine level.

It is more difficult to repurpose stick-built options. However, podular options can be and have been repurposed. Repurposing reduces risk for companies that do not reach regulatory milestones or that no longer need the cleanroom infrastructure, which can then be reused, providing some recovery of initial investments.

The matrix presented in this article reviews some of the performance indicators that should be considered in determining which cleanroom infrastructure is best suited for one’s application. A hybrid approach that combines two or more of the infrastructures is also an option. The key in each case is to consider the need for speed and predictability of outcome. With predictability, reliable and flexible capacity planning can be possible. 

Pharmaceutical Technology, Bioprocessing and Sterile Manufacturing Supplement, pp. 12-18 

M.W. Jornitz, P. Makowenskyj, and S. Backstrom, 

McKinsey & Company, “The Next Normal in Construction. How Disruption is Reshaping the World’s Largest Ecosystem,” 

Maik Jornitz is CEO, G-CON Manufacturing, Inc.

Volume 45, No. 1
January 2021
Pages: 36–39

When referring to this article, please cite it as M. Jornitz, “Choosing a Cleanroom Infrastructure Technology," 

Consider a matrix of factors when choosing what type of cleanroom facility to construct.

Choosing a Cleanroom Infrastructure Technology

For pharmaceutical and biopharmaceutical manufacturers today, a key success factor is time to market (1–4). When it comes to processes and manufacturing facilities, time to the first product run is crucial. The faster a drug moves through the development pipeline and the faster a facility is up and running, the higher the return on investment. In addition, a fast-moving facilities project can allow capital expenditures to be delayed until later in the development cycle, minimizing risks and maximizing the amount of cash on hand until needed.

	Traditional facility designs and infrastructures do not permit such fast-track implementation (5). It takes months to generate designs and even longer to build these manufacturing sites, and construction proceeds sequentially. 

	The process generally follows this pattern: a building shell is built first, followed by utilities, then ancillary and cleanroom spaces, and finally production equipment is installed. Typically, this approach means a time-to-first-product run of 24–48 months, depending on the size of the facility. The same is true for smaller projects such as laboratories.

	Modular construction onsite involves building processing space at the ultimate production location using modular wall panels. Many companies provide such panels. This approach differs from traditional construction in that the panels are rigid and therefore do not require framing material. The panels also come in a variety of sizes, reducing the amount of cutting required onsite.

	The panels also reduce the amount of finishing work that is required, because they are supplied as finished pieces such as coving at the wall-to-ceiling and wall-to-floor connection points. The use of standardized components can shorten the design phase for modular panel projects, compared with the time required by traditional approaches.  Significant engineering knowhow is still required, however, to make modular construction work.

	Because this approach reduces the amount of onsite construction required, these projects can be completed faster than a traditional construction approach, with project timelines that can range from 18 to 36 months depending on the size of the project.

	Prefabricated cleanrooms are modules that are built offsite that provide clean space including floors, walls, ceilings, windows, and doors in appropriate finishes. In some instances, such modules include their own mechanical space where automation equipment such as programmable logic controllers (PLCs), heating, vacuum and air conditioning (HVAC) equipment, fire suppression systems, utility connections, etc. are housed. 

	The cleanrooms are built entirely at a vendor’s manufacturing site. At the close of the manufacturing process, they are factory tested. After this testing, they are shipped and moved into the ultimate host facility. Due to the utility infrastructure within the cleanrooms, connections to the host facility are minimal,  and infrastructure within the host facility is also minimal. High level advantages include being able to build the modules rapidly without the need for special permits, the lack of required infrastructure at the ultimate destination, the ability to move and repurpose the cleanrooms, and depreciating the cleanrooms on an accelerated basis as process equipment, as opposed to the traditional facility timeframe (6). 

	Engineering expertise is required both for the cleanroom and the outer structure. Compared with the fairly standard cleanroom approach in most cases, however, there is less to engineer using this approach. 

	A leading architecture and engineering firm considered the amount of time required to build a 2000L monoclonal antibody (mAb) facility. The study considered three types of facility options: traditional, modular wall panel, and prefabricated cleanrooms. 

, the time differences among the three models are substantial, with prefabricated systems being much faster. For one manufacturer, using the prefabricated approach allowed the facility to be ready for operation 16 months after the start date (1) compared with 25 months for the paneled approach and 27 months for the stick-built approach. Construction of the prefabricated system solution was faster due, in part, to the fact that the cleanrooms were built in parallel with the building or refurbishment of the host facility (

). Such an approach is not possible with the other construction options, because the structures must be constructed after the host facility is substantially complete.
	

	An additional factor that also saves time, which this study did not consider, is the fact that prefabricated cleanrooms use standard designs. Instead of creating new designs from scratch, these standard designs can be used to reduce the design time and cost effort. 

	As noted, some standardization of cleanroom options can reduce the time required to build out a facility, using a prefabricated approach. But could standardization also lead to other advances as it has in other industries, enhancing speed to market without sacrificing quality or utility? 

	Procter and Gamble showcased an example of what might be possible for pharma at the International Society for Pharmaceutical Engineers’ (ISPE’s) 2014 Annual Meeting. The presentation discussed the use of standardized shell buildings that could be erected in weeks. Parallel to the construction of the building shell, prefabricated manufacturing modules were assembled and then added into the shell when it had been completed. 

	Mixing and matching, in synch with demand

	The prefabricated manufacturing modules were standardized and could be mixed and matched into the shell building. Depending on demand, they could also be exchanged, in case regional demand for one product rose or fell. Standardizing the system created budget and timeline robustness, as well as scaling effects to reduce costs (7).

	Another example comes from the automotive industry. In automobile manufacturing today, the core product is standardized, but also configurable, with options that are related to aesthetics or performance. Standardizing the core product keeps costs low and delivery times short, and adding options to that core does not increase either factor significantly. 

	If carmakers sought to design each vehicle anew, with no standard platform in place, costs would be astronomical and the efficiency of production and delivery would be exceedingly low. The question is: Can the biopharmaceutical industry mirror these two examples, especially in the cell and gene therapy space? Why shouldn’t it be possible to standardize these processes, unit operations, and surrounding cleanroom infrastructures all the way to the facility platform? 

	Why has such standardization been achieved, or even become the norm, in other industries but not the biotech industry? Is it because the engineering or processing needs are that much more sophisticated than other industries, or is it because the supplier infrastructure in the biotech industry prefers self-preservation to innovation? 

	More to the point, couldn’t a prefabricated, standardized but configurable cleanroom infrastructure solution be provided much like a car, bioreactor, or filler? Shouldn’t such infrastructures be available from a catalogue where they can be chosen for delivery? And is there any reason why that cleanroom couldn’t be delivered in 48 hours? 

	Amazon and FedEx deliver hundreds of thousands of items in two days. Mobile homes can be ordered. Contractors build and sell “spec” houses every day. So why can’t biotech companies choose from available options instead of re-inventing the wheel every time they have to build a new manufacturing facility? 

	The goal for the industry should be to configure a cleanroom on-line or at a showroom and get it delivered consistently with the same quality at a fixed price and timeline. End-users who adopt this standardization approach will gain desired speed, with tremendous flexibility and greatly reduced costs. That can only be good for the industry and, ultimately, for the patients it serves. 

Efficient, Flexible Facilities for the 21st Century

Continuous Solid-Dosage Manufacturing Platform Nears Prototype Installation

www.pharmamanufacturing.com/articles/2012/008/

, 2 (1), pp.12-14 (2013).
	5. P. Almhem, “

, July/August, pp. 28-30 (2014).
	6. M.W. Jornitz, “

Podified Manufacturing Facilities and Risk Mitigation of Aging Pharmaceutical Facilities


	Supplement: Outsourcing Resources
	Vol. 42
	August 2018
	Pages: s26–s28

	When referring to this article, please cite it as S. Backstrom and M. Jornitz, " Reducing Cleanroom Complexities and Cost," 

Pharmaceutical Technology Outsourcing Resources Supplement

	Sidney Backstrom is vice president of business development (sbackstrom@gconbio.com), and Maik Jornitz is president and CEO, G-CON Manufacturing, Inc. 

Why shouldn’t biopharmaceutical manufacturers be able to leverage standardized construction practices to improve time to market?

Reducing Cleanroom Complexities and Cost

Flexibility now guides cleanroom design and plant construction. This article examines the changes now taking place, and what the future might bring.

This article examines the changes now taking place, and what the future might bring.