By Eric Langer, President and Managing Partner, BioPlan Associates, Inc.
Facilities are evaluating bottlenecks, risks, logistics, and inventory as part of cost modeling.
Amgen’s recent slashing of manufacturing operations by 23 percent is the latest example of how operational pressures are affecting biomanufacturers’ decision making. Now, even previously “core” operations such as media and buffer preparation are being scrutinized as biomanufacturers seek more efficiency with fewer people and lower costs.
Large-scale preparation of liquid-cell culture media and buffers for biopharmaceutical manufacturing has been discussed for decades, but only recently have the economics changed enough to warrant outsourcing of this process. This signifies a long-term strategy shift leading to the elimination of in-house bioprocessing of less “core” activities.
We surveyed 50 biopharma decision makers about their interest in core outsourcing, specifically media and buffer prep. We found that 47 percent would consider outsourcing large-scale media and buffer prep.
Large-scale Outsourcing of Media and Buffers
Outsourcing of culture media and buffer preparation primarily involves hydration of media or buffer powder ingredients under GMP conditions. Today’s economic currents are changing the make-vs.-buy equation and are beginning to favor buying prepared liquid culture media and buffers vs. end users preparing their liquids to cGMP standards from powders in-house. Of course, economics is just one of many factors. Others include regulatory, documentation, integration of inventory management, space availability, utilization of classified space, staffing, training, preferences for flexible and lean operations, and demand for bioprocessing sterility.
"We found that 47 percent [of respondents] would consider outsourcing large-scale media and buffer prep."
About 90 percent of current sales of culture media and buffers in bioprocessing are for dehydrated powders that require end users to hydrate and mix with highly purified water. Media and buffer powders have historically been used in large-scale bioprocessing. Powders have long been a core bioprocessing chore and have rarely been critically examined until recently.
There is room for greater scrutiny of traditional in-house media/buffer preparation from powders, and signs point to facilities beginning to assess their media-and- buffer preparation costs and options. With that in mind, BioPlan, in collaboration with end users, has developed a cost-analysis model to assess the value of inhouse vs. external media and buffer prep.
Alternatives to Powder Media and Buffers
Outsourcing to local “hydration centers” that prepare finished liquids from manufacturer- provided powders offers just-in- time, local delivery of GMP materials. These facilities would form a regional consortium of customers that reserve capacity in an off-site facility. Primary users would include companies manufacturing at commercial scales, including single-use and hybrid facilities, biosimilars manufacturers, and even manufacturers in emerging countries that require GMP process fluids.
The purchase of liquid media and buffers can potentially free up capital, capacity, inventory, and staff overhead:
- Facilities Implications: Today’s bioprocessing facilities include up to 20 percent of space and operational costs going to culture media and buffer prep from powders. In-house powder hydration requires utilities, dedicated staff, inventory, QA, GMP storage space, prep rooms, holding tanks, WFI (water for injection) operations, mixing equipment, and bulk liquids cooling or heating.
- Variability in Media and Buffer Prep: Differences between bulk liquid media and buffers prepared by suppliers vs. end users are not generally tested. Anecdotal data suggests that freshly delivered, expert facility-prepared liquid media may provide more productive and consistent bioprocessing. End users often use nonspecialized, less-than-optimal equipment in preparing powders.
- Costs Implications: Outsourcing of bioprocessing liquids can provide cost savings and flexibility for some facilities. Although existing facilities have invested in equipment, protocols, and staff, some are not designed to handle large volumes of bulk liquids, and few culture media and buffer suppliers promote bulk liquids over powders. Outsourcing liquid preparation can reduce a company’s risk and provide more efficient testing and comprehensive cGMP documentation, warehousing, inventory, and management.
- Safety Implications: Culture media and buffers are one of the last key parts of bioprocessing that are not expected to be, or treated as, sterile. Powder ingredients are ground into powders, packaged, and handled in nonsterile environments. Culture media-associated virus contamination is capable of damaging companies. Consider Genzyme, which experienced facilitywide culture media feed-linked animal virus contamination.
- Improvements in Technology Creating New Expectations for Safety: Many large biopharmaceutical companies are implementing technologies like high-temperature, short-time (HTST) UV light and other culture media sterilization methods. Once large facilities implement HTST or other sterilization, the rest of the industry will be expected to follow.
Regional Bulk Media and Buffer Prep
In our recent study of demand for local outsourced services, we evaluated media or buffer prep facilities. We asked which attributes would need to be offered, and cost-effectiveness topped the list at 38.7 percent. Nearly as many (35.5 percent) indicated quick turnaround, on-time/ just-in-time delivery.
We then asked which critical attributes a media and buffer prep hydration facility must possess to be considered an outsourced supplier. Effective outsourcing will require a highly competent, service- and logistics-driven organization capable of addressing documentation, regulatory, and analytical challenges in a GMP environment.
Economics Point to Outsourced Service
To support the economic analysis and potential for outsourced media and buffer prep, BioPlan established an advisory board of experts in cGMP documentation and quality management, modular facility design, inventory/logistics, services management, client services and logistics, media and buffer reagent manufacturing, and single-use operations. The board defined cost-effective approaches to ensure high-quality, documented, just-in-time delivery of liquid media and buffers. This group has initiated a core facilities network analysis to service key biopharmaceutical manufacturing centers. The design includes a core-facility approach:
- facilities located within 20 miles of biofacility concentrations
- modular, flexible design to produce culture media and buffer powders
- either stainless or single-use equipment, sized to the largest required scales
- parallel/shared utilities, WFI, warehousing, storage, IT systems
- clients reserve capacity and order just-in- time (as needed) local preparation and delivery of bulk culture media and buffers
- operated by experienced dedicated managers, includes expertise from each media supplier, oversight from regional end users
- warehouse core facility, expandable to meet changing needs
- materials and methods fully documented and auditable
- end-user access to inventory systems for real-time data on liquids manufacturing
- logistics include just-in-time delivery and integrated LIMS (lab information management system) and IT systems
- full supply chain information and quality control testing
- regional facilities identical in design and documentation for consistency and efficiency
- cloned facilities enable the “same” fluids preparation at any facility to provide redundant backup manufacturing options
- core facility network to enroll established local CMOs, outside the U.S. to support global production.
Regional hydration centers are just one example of economics-based outsourcing. When a service supplier can provide better products more quickly and with better control, then even core operations become viable outsourcing candidates.
Survey Methodology: The 2014 Eleventh Annual Report and Survey of Biopharmaceutical Manufacturing Capacity and Production yields a composite view and trend analysis from 238 responsible individuals at biopharmaceutical manufacturers and contract manufacturing organizations (CMOs) in 31 countries. The methodology also included over 173 direct suppliers of materials, services, and equipment to this industry. This year’s study covers such issues as: new product needs, facility budget changes, current capacity, future capacity constraints, expansions, use of disposables, trends and budgets in disposables, trends in downstream purification, quality management and control, hiring issues, and employment. The quantitative trend analysis provides details and comparisons of production by biotherapeutic developers and CMOs. It also evaluates trends over time and assesses differences in the world’s major markets in the U.S. and Europe.