The inherent risk in establishing Biopharmaceutical production (product, process, timeline, capacity, regulatory and location) can be significantly mitigated by using a modular and standardised approach. Utilising a combination of standardisation, modularisation and use of modern process solutions such as single use equipment offers significant advantages over traditional design and construction.
Design, construction and installation of complete modular production facilities for pharmaceuticals and biopharmaceuticals have in recent years been widely accepted. According to Gilroy and Martini ?modular construction? of a pharmaceutical manufacturing facility refers to construction of all or part of a new or renovated facility built at a remote location, transported to the owner's address and re-assembled on site. Modules consist of structural frames that are fit out with all mechanical, electrical and plumbing architectural elements ? complete with all fixed process equipment. Modularisation considerably increases productivity, which is probably one of the most unpredictable aspects of a construction project. Besides bad weather conditions, conventional on-site construction labour productivity is plagued by high turn-over, changes, inexperienced contractor's workers, and the challenges of working out of position. In a modular facility project typically over 80per cent of all installations are performed and qualified in the supplier's workshop instead leaving 20per cent or lest to be performed in the field.
The pioneer in the construction of modular pharmaceutical facilities was Pharmadule AB, a Swedish company that is out of business since February 2011. Companies that offer modular facility construction include Biologics Modular, G-Con, Jacobs Engineering and Key Plants. Some traditional bioprocess equipment suppliers, e.g. GE Healthcare Life Sciences, Sartorius Stedim Biotech and Merck Millipore have begun to offer fully equipped modules for specific process steps.
Key Plants has developed an innovative approach to modular facility design and construction that is flexible, and cost efficient, while allowing for use of process equipment from any supplier. This design provides greater flexibility in the layout and design of both upstream and downstream process areas. Modules can be installed and operated within an existing building or as a separate modular building as long as a suitable power source is available.
In a recent discussion on next-generation manufacturing facilities, an author argued that bio-manufacturing facilities can be divided into process, facility, and infrastructure components. Each plays a significant role in the success of a manufacturing enterprise. A failure or weakness in either will lead to poor product quality and/or inefficient manufacturing. Improvements in manufacturing technologies and advancements in single use systems have clearly transformed bioprocesses. Hand-in-hand with those process improvements comes modular construction, which will become more and more common because modular alternatives can have smaller footprints than traditional facilities and be deployed rapidly in locations where clean-room and piping expertise may not be readily available.
Combined, modular technology and single-use technologies can reduce investment and operating costs, as well as the financial risk of building new biopharmaceutical manufacturing facilities.
Smaller, greener and more flexible facilities of the future that look to new technology solutions may also enable a key industry transition from fixed to variable cost structures to structures that follow demand. Defining and understanding the business drivers, uncertainties, and risks associated with building and operating bio-manufacturing facilities is a key first step in the development of future generation manufacturing facilities.
Success of future facility design must be measured in terms of utilisation, flexibility, and efficiency while providing a platform that supports and facilitates the operational excellence required to reliably produce high quality product, while meeting an ever-evolving set of regulatory compliance guidance. As the industry looks to make the transition from current state to the future model, new enabling technologies can provide manufacturing platforms that meet the goals of being flexible with low capital unit operations changeovers, efficient movement to new markets, and a scale-out approach with smaller increments of capacity from highly productive processes to meet lower demand markets.
Operational excellence is the fundamental driver for producing high quality product and efficiently meeting all necessary regulatory requirements. The following questions could be the starting point for identifying the best facility options to satisfy product quality, operational excellence and regulatory compliance:
In order to answer these questions, a novel design platform was developed for biologics production. Several criteria were identified as essential in order to come up with the right answers, such as a modular design, utilisation of single-use equipment, build on a well-known bio-process, and risk-based level of segregation.
A flexible layout is of importance especially for sites working with combinations of products, product classes, and host-cell types. The important issue is how we can combine single-use and stainless steel technologies to provide the most productive, cost-effective and regulatory risk-optimised process in a faster and more predictable way.
The standardised drug substance manufacturing suite?s configurable modules have adequate space based on a MAb process on the basis of a CHO cell line and bioreactor train 1x 50 litre ? 1x 200 litre ? 1x 1000 litre, The downstream process consists of preparation of equipment, buffer preparation of buffer solutions, tangential filtration and concentration of the uterine culture fluid, and subsequent depth filtration of the concentrate, affinity chromatography, cation-exchange chromatography, anion exchange chromatography, concentrating tangential diafiltration and viral inactivation of the concentrated MAb obtaining the active pharmaceutical ingredient (API),formulation and sterile filtration of the API followed byaseptic filling in vials. The estimated productivity of the cell line 4-6 g MAb from 1 liter of culture. The total loss initially estimated in the upstream and downstream process is 70 per cent.
The API has a concentration of monoclonal antibody (MAb) 10 mg / mL, titer concentration 5g. Annual output from 80 kg Mab, annual output approximately 50 batches(300 working days, batch duration 18 days including change-over time), 16,000 vials per batch, filled in 10 ml vials (100 mg/vial).Filled during three shifts.
The utilisation of single-use equipment is optimised for the process. This can be adjusted to the end user?s needs, and the level of stain less steel equipment increased to meet each application.
The standard facility is equipped with single use seed and production bioreactors. In addition all media and buffers were prepared using single use systems consisting of powder transfer bags, disposable bags with a disposable internal agitator, external mixing system, weighing station, and a disposable path (pump, tubing, filters, etc.) for transfer of the prepared media or buffer into a disposable bag system for storage. When necessary, buffers are prepared in concentrated solutions to accommodate the transport in disposable bags at a maximum volume of 500 L, which is a typical volume limitation for transport within the facility. In-line dilution skids were utilised at point of use for the concentrated buffers. Media is prepared at the start of each production batch. Similarly, buffers are prepared in advance and stored within the facility until used. A new batch of media or buffer is prepared for each production batch. For each of the chromatography steps included in the purification process, 630 mm diameter columns packed to 200 mm bed heights are used, with each column being used for multiple cycles per batch. For the Protein A affinity column, five cycles per batch is required. For the cation exchange column, three cycles per batch is used and for the anion exchange column, two cycles per batch is assumed. CIP/SIP for column packing is included.
Important to consider is the level of segregation based on regulatory requirements, product, closed/contained processing steps and user corporate standards. Starting from an open design, it is possible to increase the segregation level by adding walls and airlocks, e.g. to divide cultivation and initial purification areas into two rooms. Also the media and buffer preparation and hold works in the same way. In order to choose the appropriate level for a certain product/multi-product facility and the risk for cross-contamination or contamination from adventitious agents is to use a risk-based approach. Rios makes the same conclusion at a recent conference ?One well-recognised challenge in multiproduct facilities is minimising or eliminating cross contamination. For that, industry and regulatory experts have advised manufacturers to take a risk-based approach. Such strategy can prove beneficial in flexible layouts in sites working with combinations of products, product classes, and host-cell types.?
To further ensure segregation within the facility, the design includes multiple air handlers located on an upper level. The level of segregation is based on a risk assessment and includes the following:
ICH Q9 II.4: QRM for facilities, equipment and utilities recommend the use of a Risk Acceptance Profile (Figure 2). EMA 5.19 EU GMP Guide states that cross contamination should be avoided by appropriate technical or organisational measures.
In addition, separate processing areas are provided for downstream processing operations pre- and post-virus removal by nan-ofiltration. Wherever possible, fully closed and contained processing is used, generally within a Grade D environmental classification. Open processing areas, such as those required for innoculum preparation, final purification, and bulk filling are designed to be Grade C with specific open operations being performed in suitable bio-safety cabinets with laminar air flow.
The facility also includes suitable staging areas for raw materials, consumables, and equipment and appropriate locker rooms and airlocks for personnel changing and entry and exit from the facility. Media and buffer preparation areas are located in the centre of the facility to allow the most possible adjacencies to processing areas. Wherever possible, buffers are stored in closed containers in controlled but unclassified space to minimise the environmental burden and lower the overall HVAC requirements for the facility. The result of the design of the layout within the product processing area is a general U-shape design for the product flow being unidirectional from one end of the facility to the other. The facility includes a thorough and optimised equipment positioning in order to minimise the tubing or piping needed for product and material transfer.The tubing components are delivered gamma irradiated and can be connected by tube welding. The layout has one single access point for all production personnel and one exit point. Included in the bulk drug substance area are also functionality such as Storages for raw material, consumables and equipment. The buffer and media preparation is centralised in order to minimise the adjacencies between the media hold bags and the process equipment respectively. In order to maximise the ease of transporting the different bags the largest hold bag is 500L. There is also included an in-line dilution skid for the buffer preparation for the Protein A Chromatography step to even further reduce the amounts of buffer that needs to be prepared and stored. In the Grade C area for Final Purification, an Aseptic Filling (Crystal? closed, pre-sterilised vial technology) L1 Robot Line has been placed, to meet a filling capacity of up to 600 vials/hour. Typical batch size around 5,000 vials, on a single shift basis.
The standard MAb manufacturing facility (Figure 3) has a total floor area of 1208 m2, including the mechanical space on the second floor.With the 1,000 liter bioreactor train, the process area is less than 740m2.The time schedule to build the facility is less than 12 months for the standard layout. The price for the ?plug-and-play? two storey facility described is estimated to be well in line with conventional clean-room installation. The facility may be connected to an existing building as well as being used in an indoor concept and built in an already existing building or a rapidly constructed shell.
In-door modules (Figure4) can be placed on a concrete slab in a building with pipe-racks and connections installed under, over or parallel to the modular process facility. HVAC and utility systems (mechanical areas) can be placed over or next to the modular building. An out-door(Figure 5) modular building can be placed on foundation of concrete-pillars, a slab or on top of basement or building. The main difference is the fa?ade/roof system for the out-door building, which is insulated and weather proofed.
Clean-rooms are constructed utilising an integrated panel system for walls, ceilings, doors, windows etc. Walkable ceilings create mezzanine space with service access above the clean-rooms for AHUs and other utilities such as piping, electrical and ductwork distribution. It may also be used for electrical rooms and clean utility generation. Support systems (electrical, piping, HVAC, etc.) will have the main distribution in the mezzanine. Each pre-fabricated module will have distribution integrated in the module with only one hook up point for the support systems. This will create minimal hook-up installation and each module will work as a plug and play unit. Utilities have access points into process rooms either with ceiling panels lowered into the process room or integrated wall panels. Other systems included aredata communication ? ethernet, grounding system, telecommunication, security system, air lock interlocks, fire alarm, etc. Sprinklers and alarm systems are installed according to local codes and requirements. Functional modules can be designed to incorporate any kind of process with automation as an integrated solution.
One key advantage of modular construction for biopharmaceutical facilities is the off-site construction of modules. The benefits of this approach include enhanced quality control, reduced waste, reduced impact on current operations, and simplified site logistics. Transferring labour hours away from the construction site also reduces risk and overall cost for a facility construction project. Building multiple modular elements in parallel without,for example, weather impact, can reduce the construction schedule for a facility project by 50per cent. The ability to leverage factory acceptance testing (FAT) at a module construction facility will often significantly shorten the time for start-up and commissioning of a new facility. Once modules are delivered to the construction site, they are assembled into the complete facility so that final testing and qualification can be completed.
Jamesonhas discussed in detail the cost benefits of the Modular Facility Technology. Comparisons of project cost components were discussed to help potential users of this technology gain a better understanding of cost allocations and expected differences between a modular approach and a conventionally executed project. While this example indicated an initial 9per cent cost premium for the modular concept at the conceptual design phase, the risks involved with a conceptual design were quantified, which in turn shows that the modular approach is actually in the range of5per cent more cost effective. This comparison does not include consideration for the potential loss of sales revenue due to delays in market launch (every day of lost sales revenue will be substantial considering a per dose price of certain MAb products of around US$ 1,000). With the new standardized modular concepts, also the first cost of a modular alternative is typically competitive to conventional design and construction. Adding the lower risk in the project, and the shorter time to market, a modular project many times offers a significantly higher Net Present Value.
References are available at www.pharmafocusasia.com
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