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 process¹.  As expectations for manufacturing efficiency increase, we are likely to see more events like Amgen’s recent reduction in manufacturing operations by 23%, and its plans to cut up to 15% of its manufacturing and R&D workforce. This, and similar cuts are evidence of the pressure on manufacturing operations, such as for media and buffer preparation. Companies expect to produce more efficiently, with fewer people, and at lower cost.

This increased outsourcing has been clearly demonstrated in the shift in budgets over the past five years; according to our 11th Annual Report on Biopharmaceutical Manufacturing, outsourcing budgets have grown much more rapidly than any other major area of bioprocessing².  This signifies a long-term strategy shift to eliminate in-house bioprocessing of less core activities; particularly when specialists can do a unit operation better, faster, and cheaper.

To quantify these general trends, and the degree of interest in outsourcing, specifically media and buffer preparation for biologics, we initiated a short survey among 50 decision-makers and members of our Biotechnology Industry CouncilTM (BIC) panel of experts3.  The objective was to determine industry interest in outsourcing large-scale liquid culture media and buffer prep operations. Nearly half of the respondents, 47%, indicated that large scale media and buffer prep outsourcing was an option they would actively consider.  Respondents interested in outsourcing these services assumed that they would be carried out locally, in a cGMP, audited facility with production, logistics, and validation expertise.

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. The make-vs-buy decisions are beginning to favor buying prepared liquid culture media and buffers instead of end-users preparing their liquids to cGMP standards from powders in-house. Cost is just one factor. Other issues include: Regulatory issues, documentation, integration of inventory management, space availability, utilization of classified space, staffing, training, preferences for flexible and lean operations and demand for bioprocessing sterility.

Current Situation
About 90% of current sales of culture media and buffers are for powders that require end-users to hydrate and mix with highly purified water.  This is followed by filtration to form the final reconstituted liquids.  Today, about 10% of culture media and buffers are purchased as bulk liquids from distant manufacturers’ facilities, requiring relatively high delivery costs for what is mostly water.  Increased adoption of single-use equipment for bioprocessing⁴  has also affected the economics of buying bulk liquid culture media and buffers.

As bioprocessing is scaled up, most facilities switch from small-scale liquid media and buffers to powdered forms.  Media and buffer powders have long been a core bioprocessing chore and until recently were rarely critically examined. Facilities are beginning to assess their media and buffer preparation costs and options. BioPlan, in collaboration with end-users, has developed a cost analysis model to assess the value of in-house vs external media and buffer prep. This model is available from BioPlan for evaluation.

Alternatives to Powder Media and Buffers
Alternatives to current in-house preparation of media and buffers from powders include outsourcing liquids preparation to distant original manufacturers.  However, shipment of bulk dilute or even concentrated liquids is a major expense, and assuring product quality in transit is not easy. Alternatively, outsourcing to local “hydration centers” that prepare finished liquids from manufacturer-provided powders offers just-in-time, local delivery of cGMP materials. 

Such local hydration centers would be based in geographic clusters of biopharmaceutical companies, which would form a regional consortium of customers that reserve capacity available in an off-site facility.  Primary users would include companies that are manufacturing at commercial scales, in both single-use and hybrid facilities, biosimilars manufacturers, and even manufacturers in emerging countries that require cGMP process fluids.

Older, legacy facilities, for example, very large facilities with ≥10,000 L bioreactors, may choose to continue to prepare their fluids from powders in-house. However, outsourced finished liquid culture media and buffers might appeal to newer facilities, those that are being upgraded, biosimilar facilities focusing on efficiency, and facilities that are adopting single-use strategies.

The purchase of bulk liquid media and buffers can free capital in facilities construction, capacity, inventory and staff overhead. On the other hand, facilities planning to use prepared liquids may need larger refrigerated storage areas, stronger floors, broader halls, etc. to accommodate the movement of large liquid-filled vessels.  As more cost analysis and in-use case studies define benefits, the inherent advantages of outsourced liquids preparation will likely drive increasing adoption.

Options: Powders vs. Liquids
Facilities Implications:  Today’s bioprocessing facilities include up to 20% of space and operational costs going for culture media and buffers preparation from powders.  In-house powder hydration requires utilities, dedicated staff, inventory, QA, GMP storage space; prep rooms; holding tanks; bulk liquids cooling, or heating, in-house WFI operations; mixers, vessels and other equipment; and experienced, dedicated staff. Even some clinical-scale facilities report having up to three full-time liquids preparation staff. 
Large facilities already having in-house preparation equipment, where no facility changes are planned, and where capacity utilization, storage and staffing are not problems, may find externally-prepared liquids are not economical.  For example, in some large facilities, in-house liquids preparation has been rationalized as “busy work” needed to keep technicians occupied.

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 non-specialized, less-than-optimal, equipment in preparing powders.  They are less aware of such problems as contamination, denaturing and breakdown products, as well as cross-reactions, effects of process conditions, etc.  As yet, studies of quality and performance differences between external expert facility-prepared finished liquids vs the same liquids prepared by end-users have not been carried out.

Costs Implications:  Outsourcing of bioprocessing liquids can provide cost-savings and flexibility for some facilities.  Yet 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.  Outsourced liquid preparations assume risks, provide more efficient testing and comprehensive cGMP documentation, warehousing, inventory, and management, so the economic scale can tip toward outsourced options in many cases.

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 end-user handled in non-sterile environments (powders open to the air, non-sterile equipment for powder withdrawal, weighing, mixing). But this ‘sterile’ filtration only removes cellular-scale material, not most viruses. Similarly, problems due to non-sterility of buffers are generally controlled by buffer formulations being less hospitable for microbial growth.  These up- and downstream filtrations, combined with tight controls of materials handling and testing have been successful, to date, in allowing industry to avoid pathogenic microbial contamination of marketed biopharmaceutical products.

However, end-user mixed liquid culture media prepared from non-sterile, potentially virus-contaminated, culture media powders can pose significant risks to facilities.  Genzyme, for example, experienced facility-wide culture media feed-linked animal virus contamination. This required closing the facility and halting for several years manufacture of several replacement enzymes critically needed by patients.  This not only resulted in shortages, patient health problems, and loss of product sales, but loss of the company, with a devalued Genzyme acquired by Sanofi.  As a result, biopharmaceutical executives are now even more concerned with facility contamination risks.

Improvements in Technology Creating New Expectations for Safety:  To prevent such contamination, many large biopharmaceutical companies are implementing such technologies as high-temperature, short-time (HTST; followed by rapid cooling), 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.  Regulators, the health care community and consumers will begin expecting full(er) bioprocessing sterility.  In addition, advances in diagnostic technology are enabling ever-lower detection of all viruses, including those never even identified. Once these methods come to market, biopharmaceutical manufacturing facilities will be expected to adopt them, to meet regulatory expectations.

The need for full sterilization of culture media in the future may adversely impact the use of powders. Powdered culture media are difficult and impractical to sterilize. Their solid form requires longer heating to attain consistent temperature, and many formulations can degrade significantly if heated for any length of time.  Liquids have better heat conduction, mixing, transparency, and ability to be rapidly heated and cooled. These are more conducive to HTST and UV sterilization. HTST or other sterilization is expected to be expensive to implement, requiring specialized equipment, and likely cost-effective only for those operating at larger scales, for example, commercial-scale manufacturers and hydration centers. 

Logistics and Efficiency in Regional Bulk Media and Buffer Prep
In our study of demand for local outsourced media or buffer prep facilities, we asked decision-makers which attributes such an outsourcing facility would need to offer.  We found that cost-effectiveness, not surprisingly, topped the list, with 38.7% noting.  Nearly as many, though, (35.5%) indicated Quick Turnaround; On-time/Just-in-time delivery was critical.

We then asked them to indicate which critical attributes the media and buffer prep hydration facility must possess to be considered for outsourcing. Based on the responses, it is clear that this service would require a highly competent, service- and logistics-driven organization capable of addressing documentation, regulatory, and analytical challenges in a cGMP environment. Needs include:

• Documentation and cGMP compliance standards / regulatory filing expertise
• Analytical lab support for release and characterization testing
• Investigation support for full scale manufacturing challenges
• Local delivery of freshly-prepared liquid culture media/buffers.

Who Should Operate it?
Existing CMOs are likely candidates to manage and operate such hydration facilities, but their business models typically demand much higher margins, and require staff with broad technical expertise (vs focus on narrow operational expertise and superior logistics services).  Media and buffer suppliers would also be likely candidates.  But their expertise often involves product innovation and manufacture; this is a services-driven operation. Perhaps most importantly, in our survey, 68% of industry decision-makers indicated that media suppliers would not be an acceptable option, since that would involve single-sourced management of a critical operation.  Rather, the majority, 77% indicated the facility should be independently operated, and provide service for all media suppliers’ products.

Regional Media and Buffer Hydration Centers:  Economics of Outsourced Service
To address these industry trends, BioPlan established an Advisory Board5 which includes expertise in cGMP documentation and quality management, modular facility design and engineering, inventory/logistics, services management, client services and logistics, media/buffer manufacturers, and single-use operations experts.  The Board’s mandate is to define the most cost-effective approach to ensuring high-quality, documented, just-in-time delivery of liquid media and buffers.

This group has initiated the development of a Core Facilities Network to service key biopharmaceutical manufacturing centers (see also www.top1000bio.com).  The design includes a core facility approach, including:

• Facilities located within 20 miles of centralized 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 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, ex-US to support global production

In these logistically driven cGMP manufacturing operations, clients will hold long-term reservations for capacity, and order just-in-time (as needed) local preparation and delivery of their bulk culture media and buffers.  Regional hydration facilities are designed to provide better finished liquid products, rapid turnaround and delivery, with more and better supply chain control, and more and better testing and documentation vs. the same liquids prepared in-house by end-users.

BioPlan Associates has available cost-benefit estimates and studies, including comparisons of in-house vs. hydration center bioprocessing fluids preparation. It continues to seek end-user input and individuals interested in this consortium.  Please contact us for information and operational data on hydration centers. 

According to a number of industry experts, Media and Buffer prep outsourcing is a rational approach… Trent Carrier, VP Vaccine Technology at Takeda Vaccines (Deerfield IL) – “Buffer prep, in particular, can be a logistical problem as facilities execute their manufacturing plans. Delays in this relatively straightforward operation can affect overall production schedules. Further, support functions such as buffer prep and storage can become a capacity limitation. Manufacturers are constantly looking for sourcing strategies that can improve reliability, simplify logistics, and provide flexible capacity to manage demand surges and yield improvements.” Pat Larrabee, President, Facility Logix – “As facility planners and owners representatives, we’ve seen bio-manufacturers, particularly in higher-cost regions, increasingly complain about capacity problems. Media and buffer prep are often done in classified space that could be converted to higher value production space. Storage, logistics, and inventory needs for liquids and buffers add to the problem of not using classified space for its best purpose.” Jeff Craig, VP and GM, MEDIntegrity, Pall Corp. – “Media and buffer prep outsourcing validates the convergence of two powerful bioprocessing trends: Outsourcing to reduce overhead, and the adoption of single-use technologies. Both are in full swing, and it seems natural that they are coming together in places like media and buffer preparation. Tim Lee, Director of Process Sciences, Allergan – “Just-in-time rehydration of media and buffers combines both process efficiency and compliance, while reducing labor in the overall manufacturing process. The outsourcing concept will result in a leaner approach.”

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Eric S. Langer
BioPlan Associates, Inc.

Eric S. Langer is president and managing partner at BioPlan Associates, Inc., a biotechnology and life sciences marketing research and publishing firm established in Rockville, MD in 1989. He is editor of numerous studies, including “Biopharmaceutical Technology in China,” “Advances in Large-scale Biopharmaceutical Manufacturing”, and many other industry reports.  elanger@bioplanassociates.com  301-921-5979.  www.bioplanassociates.com

References

1. Langer, E.S., Rader, R.A., “Powders and Bulk Liquids:  Economics of Large-Scale Culture Media and Buffer Preparation are Changing,” BioProcess Intl.,  12(3), March 2014, p. 10-16.
2. 11th Annual Report and Survey of Biopharmaceutical Manufacturing; BioPlan Associates, Inc. April 2014, www.bioplanassociates.com/11th
3. Market research undertaken June 2014 among 50 mid- and large-scale bioprocessing decision makers, and participants on the Biotechnology Industry Council™ panel of experts.
4. Rader, R.A., Langer, E.S., “Upstream Single-use Bioprocessing Systems:  Future Market Trends and Growth Assessment,” BioProcess Intl., 10(2), Feb. 2012, p. 12-18.
5. PureSolutions Bioprocessing, LLC