REVIEW
`mAbs 1:5, 443-452; September/October 2009; © 2009 Landes Bioscience
`
`REVIEW
`
`Industrialization of mAb production technology
`The bioprocessing industry at a crossroads
`
`Brian Kelley
`
`Bioprocess Development; Genentech; South San Francisco, CA USA
`
`Key words: bioprocessing, cell culture, purification, economics, capacity, manufacturing, production, facility, biopharmaceutical
`
`Manufacturing processes for therapeutic monoclonal antibod-
`ies (mAbs) have evolved tremendously since the first licensed
`mAb product in 1986. The rapid growth in product demand for
`mAbs triggered parallel efforts to increase production capacity
`through construction of large bulk manufacturing plants as well
`as improvements in cell culture processes to raise product titers.
`This combination has led to an excess of manufacturing capac-
`ity, and together with improvements in conventional purification
`technologies, promises nearly unlimited production capacity in
`the foreseeable future. The increase in titers has also led to a
`marked reduction in production costs, which could then become
`a relatively small fraction of sales price for future products which
`are sold at prices at or near current levels. The reduction of
`capacity and cost pressures for current state-of-the-art bulk pro-
`duction processes may shift the focus of process development
`efforts and have important implications for both plant design and
`product development strategies for both biopharmaceutical and
`contract manufacturing companies.
`
`Background
`
`Bioprocessing technology for production of therapeutic monoclo-
`nal antibodies (mAbs) has advanced greatly since their introduc-
`tion into the market in 1986. Early murine mAbs were derived
`from hybridoma cell lines, using diverse production technology;
`the first licensed mAb therapeutic, OKT3, was produced in the
`ascites of mice.1 The development of recombinant technology
`based on cloning and expression of the heavy and light chain
`antibody genes in CHO cells enabled mAb production to take
`advantage of the common technologies already used for recom-
`binant products like tissue plasminogen activator, erythropoi-
`etin, Factor VIII, etc. These recombinant cell culture processes
`for antibody production initially had low expression levels, with
`titers typically well below 1 g/L.2
`The combination of low titers and large market demands for
`some of the first recombinant mAbs like rituximab (Rituxan),
`trastuzumab (Herceptin), infliximab (Remicade) and others
`drove many companies and contract manufacturing organi-
`zations (CMOs) to build large production plants containing
`
`Correspondence to: Brian Kelley; Email: Kelley.brian@gene.com
`Submitted: 06/18/09; Accepted: 07/16/09
`Previously published online:
`www.landesbioscience.com/journals/mabs/9448
`
`multiple bioreactors with volumes of 10,000 L or larger. Other
`products derived from mammalian cell culture in the mid-90s
`also required large production capacity (Enbrel, while not a mAb,
`is an Fc-fusion protein which is produced using a similar manu-
`facturing process), driving further expansion. In parallel with the
`increase in bioreactor production capacity throughout the bio-
`processing industry, improvements in the production processes
`resulted in increased expression levels and higher cell densities,
`which combined to provide much higher product titers.
`Today, the potential of combining high titer process tech-
`nology with the large installed bioreactor base has resulted in a
`great excess of production capacity for mAbs, far outstripping the
`increase in market demands over recent years. This has stimu-
`lated discussions of the controversial issues of the best use of cur-
`rent production capacity, the impact of manufacturing cost of
`goods (COGs), and the choice of the appropriate mAb produc-
`tion technology for emerging product candidates. Should com-
`panies choose conventional bioprocessing technologies, or invest
`in novel technologies which may lead to superior expression levels
`or lower production costs? Have process development strategies
`adjusted to this paradigm shift where nearly unlimited capacity
`and very low COGs are enabled by the current state-of-the-art? If
`not, how should process development groups respond?
`This article will analyze the current mAb production technol-
`ogy, review production capacity and demand estimates, and con-
`sider the position of these conventional technologies in the future
`of commercial mAb production for therapeutic use.
`
`Current State-of-the-Art: Potential for mAb Process
`Industrialization
`
`The processes for manufacturing recombinant therapeutic mAbs
`have several common features, and efforts to benchmark the cur-
`rent state-of-the-art draw upon information that is shared at con-
`ferences, but often not published. For production of purified bulk
`drug substance, i.e., the intermediate that is used to produce the
`final drug product sold to healthcare providers and patients, a
`consensus process has emerged from the major biopharmaceuti-
`cal process development groups (Fig. 1).
`Mammalian cells are used for expression of all commercial
`therapeutic mAbs, and grown in suspension culture in large bio-
`reactors. The majority of commercial mAbs are derived from just
`a few cell lines3 (Chinese Hamster Ovary (CHO), NS0, Sp2/0),
`with CHO being the dominant choice because of its long history
`of use since the licensure of tissue plasminogen activator in 1987.
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`GENENTECH 2002
`GENZYME V. GENENTECH
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`which would generate batches of 15–100 kg from 10 kL–25 kL
`bioreactors.
`Large manufacturing plants are designed with multiple bio-
`reactors supplying one (or sometimes two) purification train(s).
`The individual purification unit operations can be completed in
`under two days, and often in just one day, and therefore several
`bioreactors can be matched to the output of a single purifica-
`tion train. The increased capacity of these plants arising from the
`elevated titers will decrease the drug substance COGs, by virtue
`of the economies of scale afforded by the large bioreactors. As will
`be described in more detail below, these plants are capable of pro-
`ducing enormous quantities of mAbs with very attractive costs.
`Further, this consensus manufacturing process is amenable to
`standardization that establishes a common processing platform for
`many mAbs. Each company is likely to use a slightly different plat-
`form process, but the similarities outweigh the differences when it
`comes to the process flowsheet (Fig. 1) and the typical manufactur-
`ing plant design. The use of a platform approach reduces the invest-
`ment per mAb product candidate, streamlines development efforts,
`simplifies raw material procurement and warehousing, and reduces
`scale-up and technology transfer complexities. Several companies
`have revealed that they have very similar development timelines
`from the start of cell line development through first-in-human clini-
`cal trials, and many are using common tools such as high through-
`put systems for cell line and purification process development.
`This state-of-the-art has the hallmarks of a highly industrial-
`ized family of manufacturing processes. Many companies have
`converged on the use of very similar processes, this common pro-
`duction technology is mature and robust, and the outcomes of
`product quality, production capacity and costs are predictable.
`This standardization and maturation of the mAb process tech-
`nology has emerged relatively recently, since the early years of the
`21st century.
`Why would companies need to stray from this mature and
`convergent platform? In some process development groups, con-
`tinued advances in cell culture technology have driven mAb titers
`up steadily, putting pressure on purification technology that
`would eventually limit or bottleneck the plant’s production capac-
`ity. Concerns have also been raised about the need for increased
`production capacity, and pressures to reduce COGs further.
`These factors could drive the development and implementation
`of novel bioprocess technologies, such as perfusion technology
`for cell culture, or non-conventional purification methods like
`precipitation, crystallization, continuous processing or the use of
`membrane adsorbers.6
`Assessment of the process fit into a production facility now
`enables purification bottlenecks to be identified, and process
`designs can be adapted to enable larger batches to be purified.
`Often, new technology is not required, but instead simple adjust-
`ments of the consensus process will avoid the typical plant limits
`of product pool tank volume, unit operation cycle time or supply
`of process solutions. Overall purification yield, if allowed to drop
`a few percentage points, can often be a key degree of freedom for
`debottlenecking a plant as well. The use of current separations
`media combined with a focus on facility has shown that many
`plants can be debottlenecked to support titers of up to 5 g/L.7 If
`
`Figure 1. Consensus process flowsheet for mAb Bulk Drug Substance. A
`consensus process flowsheet has emerged for production of recombinant
`therapeutic mAbs. Suspension mammalian cell cultures bioreactors operat-
`ing in fed-batch mode provide high product titers in 10–14 days. Following
`harvest by centrifugation and depth filtration, Protein A chromatography
`captures the product, and two additional chromatographic polishing steps
`complete the purification. Two membrane steps are used to assure viral
`safety of the product, and concentrate and formulate the drug substance.
`
`CHO cells have attractive process performance attributes such
`as rapid growth, high expression, and the ability to be adapted
`for growth in chemically-defined media. Typical production pro-
`cesses will run for 7–14 days with periodic feeds when nutrients
`are added to the bioreactor. These fed-batch processes will accu-
`mulate mAb titers of 1–5 g/L, with some companies reporting
`10–13 g/L for extended culture durations. Production bioreactor
`volumes range from 5,000 L (5 kL) to 25,000 L (25 kL).
`The antibody purification process is initiated by harvesting
`the bioreactor using industrial continuous disc stack centrifuges
`followed by clarification using depth and membrane filters. The
`mAb is captured and purified by Protein A chromatography,
`which includes a low pH elution step that also serves as a viral
`inactivation step. Two additional chromatographic polishing
`steps are typically required to meet purity specifications, most
`commonly anion- and cation-exchange chromatography.4 A virus
`retentive filtration step provides additional assurance of viral
`safety, and a final ultrafiltration step formulates and concentrates
`the product (the step order of the virus filter and two polishing
`steps is somewhat flexible, and may vary among company plat-
`forms).5 Overall purification yields from cell cultured fluid range
`from 70–80%, and the concentrated bulk drug substance is
`stored frozen or as a liquid, and then shipped to the drug product
`manufacturing site. While the purification processes developed
`in the 1990s using the separations media (chromatographic resins
`and membranes) available at the time were not capable of puri-
`fying 2–5 g/L feedstreams, improvements in separations media
`make it possible today for many facilities to purify up to 5 g/L,
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`Figure 2. Model mAb production plant design and capabilities. A model large scale mAb
`production plant employs multiple bioreactors configured to supply a single purification
`train. A plant having six individual 15 kL bioreactors is potentially capable of supplying
`10 tons of purified mAb per year using conventional technologies, or 4–5 products with
`1 ton demands. This enormous capacity per plant would result in a marked decrease in
`drug substance production costs, and results in significant excess capacity throughout the
`biopharmaceutical industry.
`
`these conventional platform technologies can gen-
`erate 50–100 kg batches from existing facilities, is
`there a driver for larger batch sizes? This question
`can be put in context of product demand in the
`subsequent sections.
`It is valuable to conduct a critical assessment
`of these drivers for higher production capacity or
`reduced COGs and determine the validity of the
`arguments that the bioprocessing status quo is not
`sufficient. This has fundamental implications for
`important aspects of process development, facility
`management, capital investment and broad future
`trends in mAb production technology. This analy-
`sis will focus on commercial operations, as the
`clinical stages of the product lifecycle have differ-
`ent objectives that could benefit from flexible and
`lean operations, capital avoidance strategies and
`minimal upfront investment. The optimization of
`clinical process development strategies is a separate
`topic, but the design of clinical processes should
`reflect the key elements of the eventual commercial process.
`
`Analysis of Drug Substance Production Capacity for
`mAb Products
`
`An analysis of the production capacity for mAb drug substance
`is relatively straightforward, as much of the information on plant
`capabilities is available to the public. Both internal and exter-
`nal databases8 were used to develop estimates of mammalian cell
`capacity and demand. While the number of bioreactors and their
`volumes are known, details of the purification train capacities are
`generally not. It has been reported that some facilities can purify
`up to 5 g/L titers and potentially generate a 100 kg batch from a
`25 kL bioreactor, yet it should not be assumed that all facilities
`could purify such large batches. It would be safe to assume that a
`2 g/L titer should be easily supported, however, and that a 5 g/L
`titer would fit in some, but possibly not all, facilities.
`It is useful to examine the production capacity of a single
`plant, which could be described as a model plant for the purposes
`of this article. The model plant would have six 15 kL bioreactors,
`for an installed base of 90 kL capacity (the largest plant in opera-
`tion today has 200 kL of capacity), and be supported by a single
`purification train (Fig. 2). If this plant ran a cell culture process
`with a titer of 5 g/L and had no purification limitations, it would
`offer a capacity of 10 tons of mAb drug substance per year. The
`design basis for this model plant has been described in the litera-
`ture,9 and would use conventional purification technologies that
`are available today.
`In 2007, the installed capacity for mammalian cell processes
`was 2.3 million liters, and is projected to rise to 4 million liters
`in 2013 based on current plans for capacity expansion for both
`CMOs and biopharmaceutical companies (Table 1). There will
`be at least 25 plants with the same or greater capacity of the model
`plant described above by 2013, with many other smaller plants
`in operation as well. A conservative estimate can be taken, such
`that each bioreactor generates 20–24 batches per year, which is
`
`2007
`
`500 kL
`
`2,300 kL
`
`Table 1. Production capacity estimates for mammalian cell-derived mAbsa
`Year
`CMO
`Product
`Total
`Capacity
`Capacity
`company
`at 2 g/L
`at 5 g/L
`1,800 kL
`70 tons/yr
`170 tons/
`yr
`255 tons/
`yr
`300 tons/
`yr
`
`2010
`
`700 kL
`
`2,700 kL
`
`3,400 kL
`
`100 tons/yr
`
`2013
`
`1,000 kL
`
`3,000 kL
`
`4,000 kL
`
`120 tons/yr
`
`aCapacity estimates from ref. 8.
`
`consistent with a 12–14 day production culture cycle and a short
`plant shutdown. When combined with a purification yield of
`75%, this equates to 300 tons/yr if the process titer averaged 5
`g/L, or 120 tons/yr for a titer of just 2 g/L (Table 1). These theo-
`retical capacities need to be compared to current and projected
`market demands to provide the appropriate context for implica-
`tions to facility utilization.
`While the estimates for drug substance production capacity
`should be corrected for overage required for drug product man-
`ufacturing, the losses in mixing vessels, filling lines, filters and
`ancillary equipment decrease with filling volumes, and diminish
`at very large production scales that require large filling volumes.
`Stability and testing requirements will also impact overall yields.
`Because these losses are a function of scale, facility and configu-
`ration, they are not accounted for in this analysis, but typical
`losses could be 10–30%, and are not large enough to change the
`primary conclusions of the capacity analysis.
`
`Analysis of Drug Substance Demand for mAb and
`Fc-Fusion Products
`
`The estimates of the drug substance market demand rely on a
`combination of several publically disclosed factors, and cannot be
`considered a precise value. By using the annual product revenue
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`in 2013 (data not shown). This value
`would correspond to an annualized
`growth rate of 37%, which seems an
`aggressive value for growth of this
`sector, which has shown a revenue
`growth rate of 11%.11 This demand
`is still small compared to the pro-
`duction capacity of the industry as
`a whole, even at modest titers of 2
`g/L.
`These analyses of production
`capacity and demand strongly suggest
`that there will be a significant amount
`of excess mAb production capacity
`throughout the biopharmaceutical
`industry in the foreseeable future.
`Even if several blockbuster products
`are licensed which far exceed the cur-
`rent maximum demands of approxi-
`mately 1 ton per year, they will not
`give rise to a production challenge if
`multiple plants can be accessed for
`production, which has been the pat-
`tern of the production lifecycles for bevacizumab (Avastin), etan-
`ercept (Enbrel), rituximab and trastuzumab, or if their titers are
`sufficiently high (2–5 g/L). Access to large production facilities
`can be assured through the contracts with CMOs, or by partner-
`ing with the biopharmaceutical companies that hold the majority
`of mammalian cell production capacity.
`Often, arguments which state that a new technology is
`required to meet growing therapeutic mAb demands assume that
`many products will reach blockbuster status and the highest peak
`product demands in industry are likely to grow in future years.
`Still, the forces of competition from other biologics or small mol-
`ecules for common indications, and improved mAb character-
`istics such as selection for extended pharmacokinetic profiles or
`lower dose will likely combine to cap demands below 2–4 tons
`per year for all but the most unusual products. It is important to
`note that even in the case where a landmark product commands
`10 tons per year, a single one of the model plants could cover this
`demand. Further, as cell culture titers increase in concert with
`movement of today’s molecules through the pipeline and on to
`becoming commercial products, a smaller number of batches will
`be required to satisfy the demand.
`Thus, it seems that production capacity and cell culture titer
`will not be drivers for process design targets for almost all pipe-
`line mAb products. Arguments that improved process technolo-
`gies are needed to debottleneck today’s mAb production to satisfy
`market demand appear to be largely unfounded, but for very
`exceptional circumstances.
`
`mAb Drug Substance COGs Evaluation and Sales
`Prices
`
`Data on the production COGs for pharmaceutical products
`are not typically available in the public domain, but there are
`
`Figure 3. Estimated demand for therapeutic mAbs and Fc-fusion products in 2009. The total demand
`for the top 15 mAbs and Fc-fusions in 2009 is estimated to be approximately 7 tons, with the four largest
`volume products requiring approximately one ton per year. More than half of the products were estimated
`to require less than 200 kg per year (reviewed in ref. 8).
`
`provided in annual reports, and an average wholesale price from
`public and private databases,8,10 combined with a modest pro-
`cess yield loss and fill overage upon drug product manufactur-
`ing, a rough estimate of the annual drug substance demand can
`be generated. Both mAb and Fc-fusion proteins such as Enbrel
`are included in this analysis, as they would share the production
`capacity given their use of similar production technology. Some
`Fc-fusion proteins do not accumulate to titers as high as mAbs,
`and therefore would require proportionately more production
`capacity. In addition, other recombinant proteins not included in
`this analysis will also require mammalian cell culture production
`capacity. A survey of these products is beyond the scope of this
`review, and their total mass and volumetric demands are much
`lower than mAbs.
`Again, both internal and external databases8 were used as
`sources of information. The total estimated demand for thera-
`peutic mAbs and Fc-fusion proteins in 2009 will be 7 tons. The
`median demand for the 15 licensed products in the database was
`approximately 200 kg/yr (Fig. 3). It is useful to note that this
`median product demand would be satisfied by just four batches
`from the model plant described above if the titer was 5 g/L, and
`only nine batches if the titer was just 2 g/L. It is not uncommon
`for some companies to have Phase III mAb processes today with
`titers as high as 4–5 g/L. Even titers of 2 g/L for very late stage
`products that reflect older cell culture processes will provide suf-
`ficient supply for nearly all pipeline products, given access to the
`large excess capacity in the industry.
`Future demand estimates are even less certain, and are a com-
`plex combination of the factors that drive mAb clinical develop-
`ment: the probability of clinical success, competition from other
`pipeline or commercial products, development and regulatory
`review timelines. Several consultants provide estimates of the
`demands, which could increase to as much as 25 tons per year
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`indications that mAb drug substance costs
`have dropped significantly in the last decade
`as larger plants came on line and process
`improvements increased titers. Published
`estimates for COGs have shifted from
`approximately $300/gm12,13 to $100/gm14,15
`with a potential minimum as low as $20/gm
`for the model plant producing 10 tons per
`year.9 Note that these are only projections,
`not actual costs, and may reflect the ideal sit-
`uation where a plant is operated at full capac-
`ity. The cell culture titers increased from <1
`g/L, to 1–2 g/L, and then 5 g/L for these
`estimates. Several other COGs estimates
`from conference presentations and publica-
`tions range from $50–100/gm for current
`processes with titers ≥2 g/L, as economies of
`scale serve to reduce costs.
`Raw material costs are estimated to be
`less than $8/L for cell culture media (with
`an 75% purification yield, this becomes a
`small cost element for high titer processes, as
`it may be only $2/gm for a process with a
`5 g/L titer) and approximately $4/gm for the
`purification process. It appears that COGs reduction provided by
`reducing raw material costs further will only be a significant ben-
`efit for very large products with very large production scales. For
`the median mAb, a savings of 25% of raw material costs (25% of
`$6/gm x 200 kg/yr) would only result in a $0.3 M savings per
`year, and likely not recover the investment necessary to develop
`the improved process using cheaper raw materials, considering
`the fully burdened labor cost for development staff of $0.3–0.5
`M per year.
`The 2008 average sales prices for the top 15 mAbs and Fc
`fusions range from $2,000–20,000/gm, and the median sales
`price is $8,000 (Fig. 4). The fraction of the sales price associ-
`ated with the drug substance COGs for a process with a titer of
`2 or 5 g/L would be very small (approximately 1–5% at most). It
`may not be widely recognized or reported that because of these
`increase in titers and economies of scale, mAbs will be a class of
`biological products with relatively low production costs, although
`this calculation does not account for many other expenses, such
`as royalties incurred for accessing either the necessary process
`technology, or for the antibody sequence or target, in addition to
`the burdens of the cost of research, sales and failed projects in the
`research pipeline. This will have critical implications for process
`development, manufacturing and product lifecycle strategies.
`Thus, it appears that drug substance COGs will not be a sig-
`nificant driver for process technology decisions for pipeline prod-
`ucts as long as reasonable titers (>2 g/L) can be achieved; titers
`greater than 5 g/L are very unlikely to have a meaningful impact
`on either capacity or COGs, and even higher titers could have no
`impact on costs as the bioreactor output would exceed the puri-
`fication process capacity. For nearly all mAb products, with the
`exception of blockbusters with a very low sales price, there will be
`no direct link between mAb drug substance production costs and
`
`Figure 4. Distribution of average wholesale prices for mAb and Fc-fusions in 2008. The average
`U.S. wholesale prices per gram for 15 commercial mAbs and Fc-fusions are shown. The minimum
`is approximately $2,000 per gram, and the median is approximately $8,000 per gram. Note that
`a significant price erosion (50% of the minimum shown here) for a product with modest demand
`(100 kg/yr) could result in an unprofitable market, as revenues for the therapeutic product ($100
`million/yr) may never provide a positive return on investment.
`
`sales prices in the future, as companies are able to take advantage
`of the economies of scale provided by large production capacities
`and increasing titers. However, the current slate of mAb products
`may have very different cost bases given that their process titers
`are likely to be much lower, as a consequence of earlier technolo-
`gies used to establish their cell lines, media formulations and bio-
`reactor management strategies.
`A summary of COGs components for the final product vial
`is shown in Table 2. Cell culture titer is a strong influence on
`COGs, but the difference between 0.5 and 2 g/L is much larger
`than between 2 and 5 g/L. The rough cost of the upstream
`process is inversely proportional to titer, while the downstream
`costs are in direct proportion to the product mass purified. As
`the titer increases from 0.5 to 5 g/L, the majority of the drug
`substance COGs shifts from upstream to downstream unit
`operations, as has been described by other models.16 The clear
`benefit in increasing product titers for these large-scale produc-
`tion facilities is evident, as the 10-fold increase in titer decreases
`the drug substance COGs by over 85% ($124/gm to $16/gm).
`The cost of manufacturing the drug product is estimated at
`$10 per vial, which represents a reasonable average for a par-
`enteral product, but will depend upon many factors including
`configuration, batch volume and testing requirements. The fill-
`finish costs could become a larger component of final product
`costs than drug substance COGs in some cases, although this is
`largely dose and product titer dependent. When drug product
`device or delivery technologies are employed, the proportion of
`costs associated with drug substance production will be reduced
`even further, sometimes dramatically. Recognizing that drug
`product manufacturing costs may exceed drug substance costs
`for some high titer mAb processes emphasizes the diminishing
`returns of increasing titer further.
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`Table 2. Sensitivity analysis of mAb drug substance COGs for the model plant (six 15kL bioreactors)
`Titer (g/L)
`Plant capacity
`Raw materials ($/gm)
`Depreciation &
`Fill/Finish costs
`(tons/yr)
`labor ($/gm)b
`per vial ($)
`
`Cell culturea
`100
`20
`1
`0.5
`25
`4
`4
`2
`10
`2
`10
`5
`aAssumes medium cost of $8/L. bBased on the model plant ($500 M capital investment + 250 staff = $100 M per year).
`
`10
`
`Purification
`
`4
`
`Total Drug Product Cost
`($/vial)
`
`100 mg
`22
`13
`12
`
`1 gm
`134
`43
`26
`
`Although not indicated in Table 2, the largest potential cost
`driver is the drug substance plant occupancy or utilization. A
`single product plant running a 5 g/L titer process that is capable
`of producing 10 ton/yr, but which only needs to produce 1 ton/yr
`to satisfy demand, will have a cost structure that cannot take
`advantage of the high titer process. This is the major driver for
`the design and licensure of facilities for multiple products, which
`will benefit from standardized processes. While this impact of
`excess capacity can dwarf the drug substance manufacturing
`costs, there is little influence that the process design could have
`on managing this cost. It is interesting to observe that the origi-
`nal motivation for a proposal to establish a consortium model
`with shared mAb production capacity17 was the ability to satisfy
`peak demands for blockbuster products when production capac-
`ity was limiting. Today, as a result of excess capacity, the new
`driver would be to distribute plant overhead among several prod-
`ucts and bring new molecules to existing facilities.
`Future pricing trends are difficult to predict, and certainly
`there will be cost containment pressures on biopharmaceutical
`products. The development of personalized medicines to sat-
`isfy smaller markets could become a larger sector of the mAb
`market, but these products will only require a reduced product
`demand and will likely command prices per gram that are at
`least as high as current mAbs, but almost certainly not lower.
`Consider a small market with only a 50 kg per year demand. A
`sales price of just $2,000/gm would result in revenue of $100
`M per year, which is unlikely to recoup the company’s invest-
`ment, which averages $1.2 B by some estimates.18 For innovator
`companies, the main cost driver of product development and
`subsequent commercial production is the clinical development
`costs of the many failed products that never generate revenues,
`and not the manufacturing cost of the successful mAb prod-
`ucts. Even price erosion that may arise from competition from
`follow-on biologics or biosimilars in the mAb sector, which
`many would estimate as only amounting to 10–30% reduction
`in sales price, would not markedly shift the production cost as a
`percentage of sales for a high-titer mAb process.
`
`Critical Evaluation of Very High Titer Processes and
`Alternate Production Technologies
`
`Much attention has been focused in recent years on improving
`mAb production technologies. This has enabled the current state-
`of-the-art, with debottlenecked processes capable of handling up
`to 5 g/L titers. What could happen if this current technology
`were in competition with an even more efficient technology of
`
`the future? The potential for high titer cell culture processes
`operating in existing facilities has identified what appears to be
`a futile cycle: In the drive for higher titers which generate ever
`larger batches in the large-scale production facilities, one will
`eventually exceed the plant’s purification capacity (even with
`new separations media, bottlenecks will be reached), potentially
`requiring the development of new technologies. Implementation
`of these new technologies would require more capital investment
`and retrofitting of the facility to accommodate the non-standard
`unit operations, which then generates a challenge to managing
`a multiproduct facility and product changeover. Why spend
`additional capital, and complicate plant operations, including a
`potentially expensive shut-down phase to conduct the retrofit?
`An increase in titer above the purification capacity of a large pro-
`duction plant that then drives development of new purification
`technology could be counterproductive.
`This has led to the proposal for future production facilities to
`be designed for lean and flexible operation, but at relatively small
`production scale. Disposable bioreactors have been used at up to 2
`kL scale, and a plant with disposable cell culture technology would
`require less capital to build.19 It has been proposed that these plants
`could still enable production at high capacities, which isn’t trivial
`with 2 kL bioreactors because the capacity equivalent to the model
`plant would require 45 bioreactors operating in parallel, and could
`potentially be operated with reduced labor, although a high degree
`of automation would be required, hence reducing the COGs fur-
`ther. While the production cost would be reduced, this is unlikely
`to be a competitive advantage, given the low production costs for
`mAbs as described above. A reduction of a product’s COGs that
`ranges from 1–5% of the sales pric