Ronald A. Rader is senior director, Technical Research, at BioPlan Associates.

Ronald A. Rader

	FDA is often considered the ‘gold standard’ global regulator by many and the most rigorous and respected regulator of pharmaceutical products. Besides evaluating applications for new drugs, generics, and biologics, FDA regularly inspects manufacturing facilities for deficiencies. Because a great majority of drug substances (active agents), particularly generic drugs, are manufactured in foreign countries, primarily China and India, FDA inspections of pharmaceutical facilities manufacturing products for the US market are performed worldwide for both internal drug company manufacturing and outsourced contract manufacturing facilities.

	When evaluating the source of inspection problems, most pharmaceutical industry reports suggest that facilities in India, China, and other emerging regions are receiving a greater percentage of Form 483s and warning letters from FDA compared with US-based facilities. The problems noted in these inspections, such as data fraud or inadequate sanitation, are often more dramatic, and get more press coverage than most inspection-related problems noted in the United States, Europe, and other developed regions.  But regardless of geography, any problems noted may constitute violations of the US Food Drug and Cosmetic (FD&C) Act. FDA has less authority outside the US, such as limited ability to force halt of manufacturing, but it can halt imports into the US. The worst-case situations (e.g., Form 483s, warning letters, facility inspection-related recalls, and product withdrawals) happen in all geographies and with all types of companies, including the largest and sophisticated facilities. 

	FDA inspections can create fear and uncertainty for pharmaceutical companies when FDA finds and seeks correction of manufacturing-related problems.  Also, warning letters are published on FDA’s website, and Form 483s are available through freedom of information (FOI) requests, both of which may have an adverse impact on a company’s stock prices. Negative regulatory actions may halt mergers, acquisitions, licensing, and other business deals, and in the worst case, could result in company financial failure.

	FDA inspectors are primarily concerned that in-house quality systems are fully documented and followed. Categories of quality systems that are inspected include:

	For bioprocessing facilities, typical violations are a lack of or altered documentation, or violations of set procedures, or products not meeting quality specifications.

	Deficiencies noted in any area can trigger a Form 483; however, often, a problem can be discussed onsite with inspectors and resolved, avoiding the issuance of a Form 483. Each problem noted by inspections should be responded to specifically, including plans for remediation, generally within 15 days of Form 483 issuance.  

	Inspectional observations are cited by facility inspectors in the context violating a specific FDA regulation and generally are listed in presumed order of seriousness. FDA welcomes rapid, informal resolution of problems to avoid issuing a Form 483. After receiving a Form 483, the facility/company can use a formal two-step dispute resolution process within 30 days (1). If facility responses are found to be adequate, generally no further action is taken by the agency. If deficiencies noted are not rapidly or sufficiently fixed, a formal warning letter may be issued. 

	Warning letters are issued after significant compliance problems noted in one or more prior inspections or Form 483s have not been properly addressed and resolved. Warning letters can lead to closure of manufacturing operations; criminal charges; consent decrees potentially involving third parties assuming responsibilities for manufacturing; product recalls and seizures of products; withdrawal of approvals; or an “Import Alert” letter halting import of products into the US.

	By issuing a warning letter, FDA is serving notice that major compliance violations must be corrected, and actions taken to prevent reoccurrence of the same problems. Warning letters identify specific problems and the related regulations violated. Generally, the problems noted in warning letters are considered more severe than noted in Form 483s.

	Once the facility addresses problems cited in a warning letter, FDA will conduct another facility inspection. If unresolved problems noted are serious and affect product quality and/or safety, FDA may withdraw or recall related products, and even withdraw approvals.

	The top 10 manufacturing facility-related problems reported in Form 483s in FY2018 were, in decreasing order of frequency:

		No written stability program, improper methods, lack of testing methods, products not testing within schedule, etc.

		Calibration and testing of equipment not following pre-set written operational plans. For example, equipment that is working correctly (enough), as shown by quality-related testing, may not be tested according to schedule.

		Procedures to maintain sterility lacking or not being followed. 

		Control systems for computers and automated systems are inadequate to assure persons lacking full permission can modify manufacturing-related records; or proper systems are not in place, such as audit trails tracking by lab equipment erased or not recorded.

		Final release testing did not include full laboratory confirmation of meeting full formal specifications, or related testing data and testing are missing or inadequate.

		Set procedures for facility and equipment cleaning and maintenance not followed, or procedures are inadequate.

		Lack of standard operating procedures (SOPs) for manufacturing and process control to assure product quality, including instructions for what to do when products and procedures do not meet specs or SOPs.

		Failure to investigate and correct deficiencies/problems noted during manufacturing.

		Laboratory testing controls not scientifically sound, not appropriate, not well designed, etc.

		Quality assurance responsibilities and procedures not fully documented or followed, such as for handling of complaints, process deviations, change control, supplier qualification, and batch release.

	In general, most problems noted involve:

		Procedures not being documented or are not fully followed

		Investigations and internal resolution of problems not sufficiently followed-up

		Documentation or written procedures missing or not existing

		Lack of sufficiently sound lab controls and methods.

	Other common problems involve computer and data systems:

		Computer/data systems not ‘locked down,’ with persons who should not be allowed to view and modify records

		Critical data files manually rather than automatically saved such that they cannot be modified

		Too many or the wrong people having administrator rights to modify files and computer behavior

		Not having computer audit trails active all the time, with users potentially able to modify, delete, move, etc. key data without record of the change

		Equipment audit trails, such as from chromatography systems, not being examined and evaluated.

	These computer/data-related problems can be expected to increase as ever more data are generated and many facilities/companies move data storage and management to third-party cloud facilities.  

	Regulatory inspections frequently occur without warning; manufacturing facilities should be ready for a formal FDA inspection at all times. Conducting internal audits of quality systems for compliance with US 21

 Part 820 (Quality System Regulation) and hiring consultants for mock FDA facility inspections can better prepare facilities for the real thing.

	Relevant facility staff should be familiar with Form 483s and warning letters. Most large companies have implemented rigorous internal auditing of facilities and procedures, and maintain internal groups to monitor internal issues and trends in FDA inspections. Reviewing Form 483s and warning letters can provide insight on typical infractions.

	Inspections are relatively informal in the sense that facility managers can and should discuss disagreements, offer explanations, and challenge inspectors as needed while they are in the facility. The facility may prudently later seek meet with inspectors to make sure all issues are resolved, giving the facility more certainty that it is properly addressing problems.    

	Most employees, including process operators, manufacturing-, quality-, and safety-associated staff should ideally be briefed on how to respond to FDA inspectors, who may ask questions during inspections.

	Drug companies have control over activities in their facilities and can respond to regulatory inspections. When contract manufacturing facilities are used, however, the drug company passes control of manufacturing control to another company, while maintaining responsibility for the quality and efficacy of the drug product. Therefore, supervision of the contract manufacturer is crucial.

 CMOs currently commercially manufacture 30–33% of commercially manufactured biopharmaceutical products. The CMO is contracted to fully comply with GMP bioprocessing standards, SOPs, and everything else specified in biologic license applications (BLAs)/new drug applications (NDAs), with this including CMO-internal critical review and oversight.  But it is ultimately the product developer, the ‘manufacturer’ in the eyes of FDA, that needs to take responsibility for control and oversight of its CMO’s manufacturing activities. It has been reported that the typical bioprocessing described in a BLA involves approximately 1200 distinct steps.  Add in variability in materials, equipment performance, environmental control, sterility, staff doing tasks different ways, and other normal variables, and a lot can go wrong at the off-site CMO.  Many aspects of bioprocessing execution and the supply chain are controlled by the CMO, not the sponsor. Obviously, this increases risks for problems in bioprocessing, and the client needs to devote a good amount of relevant staff time, effort, and expertise in oversight of its CMO. Generally, the more time, effort, and higher-level staff assigned to these tasks, the less risk of major regulatory inspection problems and failures. 

	Many more established manufacturer companies have over time learned that investing in onsite CMO quality oversight is both necessary and cost-effective, including preventing or lessening the extent of problems that may arise.  Some ‘manufacturers have ‘man-in-plant,’ with one or more staff on the factory floor and in the labs, providing oversight of the CMO’s bioprocessing and testing of its product(s). It is also prudent for relevant client staff or hired consultants to regularly review the CMO’s documentation related to its products, conduct audits, and debrief CMO staff, including on the factory floor, to ideally spot problems before they develop.  But most manufacturers rely mostly on periodic visits and increasingly on teleconferences and E-mail to keep up with project progress and problems. No matter what, the CMO client should seek to maximize the ease and amount of communications back-and-forth with the CMO and should seek a low barrier for the CMO to report problems and ask questions.

Guidance for Industry Formal Dispute Resolution: Scientific and Technical Issues Related to Pharmaceutical CGMP


	Volume 43, Number 5
	May 2019
	Pages: 62–65

	When referring to this article, please cite it as R. Rader, "Bioprocessing Facilities and FDA Inspection Problems," 

Articles

FDA inspections can create uncertainty. Supervision of the contract manufacturer 
is crucial in ensuring compliance. 


Bioprocessing Facilities and FDA Inspection Problems

	Essentially all biopharmaceutical industry-related indicators and trends are supporting continued incremental increases in outsourcing of pre- and commercial API and biopharmaceutical product manufacturing services to contract manufacturing organizations (CMOs). This is positive news for CMOs. BioPlan Associates’ survey of bioprocessing professionals overall confirms that outsourcing to CMOs is being viewed increasingly as a desirable option, with expectations for more outsourcing in the future (1).

	CMOs are already a core component of the biopharmaceutical industry, and their use and importance will further incrementally increase over time. Routine services and products with smaller markets will be outsourced more frequently, and products requiring novel bioprocessing, where expertise or capacity remain limited, will also be outsourced more frequently, such as cellular and gene therapies. Most innovator drug companies continue to retain manufacturing and development of their prospective blockbusters in-house.

	The financial outlook for CMOs is solid, with growth in revenue tracking that of the overall biopharmaceutical sector, which consistently grows at more than 12% annually. CMOs continue to expand capacity, staff, etc., to try to retain clients as their products advance in development. Total annual biopharmaceutical CMO revenue was approximately $3.4 billion in 2018 and is expected to grow to about $3.8 billion in 2019. Biopharmaceutical CMOs remain a relatively small niche, however, with chemical substance-based drug outsourcing revenue more than 10 times that of the biopharmaceutical sector. 

	Despite being just a small part of the overall biopharmaceutical industry, CMOs play important roles. CMOs currently commercially manufacture approximately 30% of marketed mainstream (recombinant) commercial products, although this remains concentrated among a few, large-capacity CMOs. Most CMOs primarily support R&D and early-phase support-and only a minority performing commercial manufacturing-so, in general, CMOs’ involvement in earlier-phase aspects of product development and manufacturing is even larger than with commercial manufacturing. CMOs also play an important role in new bioprocessing technology development and adoption, with CMOs often the first (compared with developer companies) to implement new technologies. CMOs often have much more technical expertise than developer companies, including with new technologies, with CMOs having worked on more products/projects and using a wider variety of technologies.

	A decade or more ago, Big Pharma and other well-established developer companies outsourced as much work as possible to CMOs, often without critical analysis. Most biopharmaceutical companies traditionally turned to outsourcing to control costs and/or manage their internal staff and resources. Biopharma companies are now increasingly taking a more strategic view of outsourcing and seeking to outsource as much as possible. Most companies periodically re-evaluate their core competencies and rationally decide how they will manage their R&D, manufacturing, and related outsourcing. As a result, almost every area of R&D and manufacturing is considered a candidate for outsourcing (1).

	The number of products in development continues to grow, with this carrying over to CMO outsourcing. FDA approved approximately 25 new biopharmaceuticals in 2018 (1), and the number of annual approvals is expected to increase in coming years, as new classes of products receive approvals, particularly biosimilars and cellular and gene therapies. In the next five years, the number of approved biosimilars will exceed the number of approved mainstream products.

	The evolving mix of biopharmaceuticals in the development pipeline is also expected to increase outsourcing to CMOs, because CMOs often have more capabilities and expertise in new areas of bioprocessing than developer companies. Product types, classes, and the underlying molecular structures of products in R&D continue to diversify.

	Rather than just familiar-type recombinant proteins and monoclonal antibodies, CMOs are often the pioneers in terms of manufacturing novel products, including antibodies with novel core structures/backbones, antibody-drug conjugates (ADCs), cellular therapies, gene therapies, RNAi, pegylated proteins, and other novel types of products. Also, lesser innovative classes of products are often outsourced; CMOs report a 15% increase in business in recent years from biosimilars projects.

	Essentially, every successful CMO is continually expanding its capacity and staff/expertise. The industry is starting to see a major trend for CMOs adding 1000–2000-L single-use bioreactor process lines for commercial manufacturing as products currently in development manufactured with single-use systems advance to approvals.

	In the past year, BioPlan has identified approximately 180,000 L of single-use systems with capacities greater than 1000 L added as CMO expansions or new facilities (2). As CMOs develop this ‘entry-level’ commercial scale single-use capacity, the number and percentage of marketed products commercially manufactured by CMOs will further increase, at the expense of stainless steel-based bioprocessing.

	Developers generally outsource a higher percentage of projects/products involving mammalian vs. microbial expression systems. The historical picture of respondents to the annual BioPlan survey reporting that they do not outsource bioproduction is shown in 

	In 2018, 30% of survey respondents reported no mammalian outsourcing, meaning that 70% outsourced at least some of their mammalian projects/products; 43% reported no (57% reported some) outsourcing of microbial work. The percent not outsourcing of any mammalian or microbial work has generally decreased (i.e., percent reporting some outsourcing has increased) since 2006. Comparable small portions, approximately 15%, report outsourcing the majority of their mammalian and microbial work. Growth and trends in outsourcing of microbial work remain somewhat unclear, with the largest CMO market, the United States, relatively lacking in microbial CMOs and GMP capacity greater than 100–200 L; Europe is the clear leader in microbial CMOs and GMP capacity.

	When developer respondents to the 2018 survey were asked about expectations for outsourcing any work (any expression system) in five years, 72.3% projected at least some mammalian and 58.3% said they expected to outsource at least some microbial work. More than 61% of respondents are currently outsourcing at least some API manufacturing.

	But this percentage was lower than for many tasks outsourced to contract research organizations (CROs), including 77.8% outsourcing some analytical testing/bioassays, and 72.6% outsourcing at least some toxicology testing. More than one-quarter of the respondents (27.7%) cited expectations/plans to outsource more biopharmaceutical API manufacturing in the next two years, increasing from 12.4% in 2010.

	The US continues to be the destination for the largest portion of outsourcing to foreign CMOs, with 30.1% of respondents citing US facilities as likely being considered for CMO work within five years. 

 shows the top 10 countries, other than their own, survey respondents said they expected to be a destination for outsourcing of their international expansions in the next five years. Among US respondents, China was the top destination, cited by more than 50%.

	Despite these industry expectations of more outsourcing to China, CMOs are not fully permitted in China; just a few select companies currently participate in government-run CMO pilot programs (3). Once China turns on its domestic bioprocessing industry, China may become a major off-shoring destination, even if these CMOs are hired to only manufacture products for China’s massive domestic market.

	BioPlan expects Chinese CMOs to capture business, potentially doing this at the expense of Indian CMOs. India appears to be focusing on serving its own and international markets for lesser-regulated biogenerics, while, according to BioPlan studies, nearly 85% of the Chinese biopharmaceutical industry targets GMP manufacture for their own domestic and Western markets (3).

Report and Survey of Biopharmaceutical Manufacturing Capacity and Production

, 15th Edition. BioPlan Associates: Rockville, MD, April 2018.

	2.  BioPlan Associates, Top1000Bio.com, 

Advances in Biopharmaceutical Technology in China,


	Volume 43, No. 1
	January 2019
	Pages: 56-58

	When referring to this article, please cite it as E. Langer and R. Rader, "The Outlook for CMO Outsourcing in 2019," 

Outsourcing of manufacturing activities is expected to increase in 2019.

The Outlook for CMO Outsourcing in 2019

	Single-use systems (SUS)-bioprocessing equipment designed for one-time use or a single product manufacturing campaign-has become the leading paradigm for pre-commercial (preclinical and clinical supplies) manufacturing of biopharmaceutical products (1). An estimated ≥85% of pre-commercial upstream bioprocessing now involves primarily or fully the use of single-use equipment for manufacturing. And the use of SUS for large-scale, commercial manufacturing is just starting.

	This article reviews some of the SUS-related results from BioPlan Associates’ 15th annual survey of biopharmaceutical manufacturing professionals worldwide, which included responses from 352 responsible individuals, including 222 working for biopharmaceutical developers/manufacturers, and 130 working for bioprocessing suppliers or vendors. Because SUS operations directly impact bioprocessing capacity and capacity utilization, this survey has long included questions concerning SUS.

	Much has been written about the benefits and disadvantages of SUS, and the biopharmaceutical industry has accumulated more than a decade of experience with the equipment and materials. Industry consensus now includes recognition that SUS enables lower up-front capital investments and operational costs compared with classic fixed stainless steel-based equipment. SUS also provide more flexibility than stainless systems, including more rapid turnovers and availability of the same process lines for manufacturing multiple products. SUS have lower operational costs due to the elimination of cleaning, sterilizing, and (re)validation of stainless-steel equipment.

	One downside of SUS, however, is the considerable recurring costs for new devices and equipment purchase for each use or campaign. Every bioprocessing facility consumes significant amounts of some type of SUS products, if only classic, legacy SUS products, such as tubing and filter membranes. In the past decade-plus, however, newer types of SUS equipment have been brought to market, and nearly all types of bioprocessing equipment are now available in SUS format. The past decade has seen rapid growth in adoption of SUS-based process lines in place of stainless steel-based equipment, to the extent that SUS process lines dominate upstream precommercial biopharmaceutical manufacturing.

	Downstream bioprocessing has seen less adoption of SUS compared to upstream. It still is difficult, expensive, and rare to implement a fully or even mostly SUS downstream processing stream, as chromatography and other purification technologies to date resist cost-effective adaptation to SUS formats. Due to excessive costs, chromatography columns and separation media/resins continue to be recycled. SUS has been adopted-nearly exclusively-for mammalian cell-culture applications; microbial bioprocesses have resisted adoption of SUS.

	Microbial bioprocessing compared with mammalian, requires higher temperatures, pressure, use of special atmospheres, and more energetic mixing and aeration. Some microbial SUS product lines are now marketed, but do not appear to have gained traction in the market. On the other hand, most cellular and gene-therapies bioprocessing involves use of SUS, and despite adoption of plastic systems, a capacity crunch is expected in these sectors (2).

	In the early 2000s, a few single-use systems, such as simple WAVE bag bioreactors (now from GE) on rocker platforms, and a few primitive fixed-wall SUS bioreactors with plastic liners, were available; these systems were limited in size, such as a few hundred liters. Late-stage clinical and commercial manufacturing, however, requires larger capacity. Today, a variety of single-use bioreactors and other products are available, with most product lines going up to 2000-L scale.

	Some suppliers are pushing this limit (e.g., ABEC now offers 4000-L SUS bioreactors). Each 1000 L of bioprocessing fluid weighs approximately 2200 lbs., making SUS with capacities above 2000 L unwieldy, difficult to install and move, not practical, or cost-effective for many facilities. Stainless steel still dominates commercial manufacturing, which thoroughly dominates all bioprocessing capacity-wise; precommercial manufacturing is only done as needed and involves much smaller quantities than needed to supply world commercial markets.

	Currently, 1000-L and 2000-L SUS bioreactors-with multiple bioreactors used in parallel if needed-are on track to become the industry standard for new large- and commercial-scale manufacturing, eventually replacing larger stainless-steel units and facilities. Thus far, there are few such facilities, but a trend for building SUS-commercial manufacturing facilities is starting, and growth in adoption of SUS for commercial manufacturing will be dramatic in coming years, albeit from a very low baseline. However, much commercial manufacturing, particularly at the largest scales, remains more cost-effective when using large, fixed stainless-steel equipment-based process lines/facilities. Most commercial manufacturing, in terms of new facilities and total capacity, will continue to be stainless steel-based for at least the next five years.

	A major trend supporting growth in adoption of SUS has been the steady increase in bioprocessing productivity, particularly upstream, in the past three decades since the introduction of recombinant products in the early 1980s (1).

	Bioprocessing productivity, especially upstream titers, has increased, essentially doubling about every five years, going from just a few tenths of a gram/L to the 3.2 grams/L that is now reported by BioPlan’s survey respondents as the average titer being attained at both clinical and commercial scales. This trend is expected to continue in the near term. Larger volumes of biopharmaceutical products can increasingly be manufactured using smaller or the same scale equipment. Only a decade ago, a facility producing several 100 kg/year of monoclonal antibodies would have required multiple dedicated ≥10,000-L stainless steel bioreactors and other comparably-scaled equipment. Today, the same amount can be manufactured with a few or even just one 500–2000-L SUS bioreactor faster and at lower cost.

	The survey also found outsourcing of bioprocessing has remained steady, if not slowly increasing, with companies now taking a strategic approach to outsourcing versus seeking to outsource everything they possibly can.

	Contract manufacturing organizations (CMOs) use more SUS equipment and use it more frequently compared with developer/manufacturer companies. As shown in 

, survey respondents from CMOs reported increased use of SUS products vs. developers/manufacturers in nearly every product category surveyed.

	This increased use of SUS by CMOs is fully expected, with CMOs needing the flexibility that SUS offers to rapidly switch over process lines or suites to manufacture different products at different scales. CMOs are highly motivated to get a facility or project up and running as quickly as possible; they do not have time to construct and validate stainless-steel process lines. CMOs, compared to developers/manufacturers, have more products to manufacture for clients and generally at non-commercial scales.

	The past 12-year increases in the adoption of different types of SUS as reported by surveyed bioprocessing professionals, in terms of first use at facilities, are shown in 

. There have been approximately 50% increases in first use/adoption of major, big-ticket, SUS equipment, including bioreactors, mixing systems, membrane adsorbers, and perfusion devices.

	Figure 2: Twelve-year percentage-point change in first-usage of disposables,

	2006–2018 (selected data). Note: Not growth in sales, this is growth in application

	Some problems and issues involving SUS still inhibit its adoption. For example, when asked in the recent annual survey to cite the most important reason for not increasing their use of SUS, 25% of CMO respondents (vs. 17% with developers) cited high cost; 25% said “leachables and extractables are a concern” (vs. only 10% with developers); and 13% of CMO respondents cited a “lack of disposable equipment that meets process requirements”, and “breakage of bags and loss of production material were a concern”, compared to 9% and 8% of developer respondents, respectively. Fully 70% of CMOs cited some factors limiting their adoption of SUS. But CMOs do what clients want, and clients increasingly want to adopt SUS for commercial manufacturing of products in development.

	As other parts of the annual survey regularly show, end-users identify improvements in SUS at the top, or among the top areas, where suppliers need to focus their R&D and bring new technologies to market.

	CMOs have extensively adopted SUS-based bioprocessing over the past decade-plus, and CMO bioprocessing in terms of the number of process lines, facilities, and products manufactured, especially at clinical scale-is now primarily SUS-based. Stainless-steel equipment still dominates in terms of total overall capacity; commercial manufacturing scales often are using legacy stainless-steel facilities or are producing at volumes where SUS is not a viable approach.

	CMOs now rarely implement stainless-steel process lines for client product manufacturing. By using single-use vs. stainless steel systems, CMOs can save on facility, campaign and operating costs, and capital investments, while gaining needed flexibility, including rapid process line turnover, enabling manufacture of more products more rapidly at diverse scales. The differences in views and adoption of SUS by CMOs vs. developers reflects the business models of each, with CMOs needing speed and flexibility, and taking a transactional approach. Developers have fewer products to manufacture at larger scales and seek more long-term and cost-effective commercial manufacturing approaches; using large stainless steel-based process lines still generally fits that bill. But with more products in development having smaller, even orphan markets; titers and bioprocessing productivity continuing to increase; and product potency increasing, volumetric needs for commercial manufacturing are decreasing, with this facilitating an increasing percentage of new commercial manufacturing using SUS.

15th Annual Report and Survey of Biopharmaceutical Manufacturing Capacity and Production


	Vol. 42, Issue 11
	November 2018
	Pages: 52-56

	When referring to this article, please cite it as R. A. Rader and E. Langer, "Single-Use Bioprocessing Equipment Trends and Adoption by CMOs," 

The growth in adoption of single-use systems for commercial manufacturing will be dramatic in coming years.

Single-Use Bioprocessing Equipment Trends and Adoption by CMOs

	Since 2003, BioPlan Associates, Inc. has published an extensive annual survey of bioprocessing professionals. Since the first survey, which was started in collaboration with the American Society for Microbiology, critical bioprocessing issues have grown. The annual report has expanded to include 60 questions with nearly 500 pages of analysis and data (1,2). Manufacturing capacity issues have always been at the core of the annual survey, but as the industry has matured, the factors impacting capacity have become more complex.

	This article highlights some of the significant changes in biopharmaceutical manufacturing (bioprocessing) that have occurred from 2003 to 2018. Most all of the changes in bioprocessing that have occurred over the past 15 years have generally been for the better. Examples of these changes can be found in 

, which compares 2003 and 2018 survey data.

	In retrospect, many of these trends were not always predictable, and some have gone counter to expectations at the time. Predictions of periodic capacity crunches, for example, have not materialized as the industry has matured. The industry has also become fairly effective at addressing production costs by developing efficient, more flexible processes.

	Trends in adoption of diverse mammalian expression systems have also not materialized, as Chinese hamster ovary (CHO) cell lines have become the dominant expressions systems. In fact, nearly 80% of respondents now report their organization has mammalian manufacturing capacity, up from 54% in 2003. The percent reporting use of microbial has not increased much in 15 years. As discussed in the current annual report, companies prefer to concentrate on one or a few platforms to be applied to as many products as possible. Most have or are moving to adopt mammalian systems as their primary manufacturing platform. This move toward single-platform manufacturing is continuing, even when alternatives have been shown to be more cost effective.

	Also unpredicted 15 years ago was the rate of adoption of single-use devices. While 15 years may seem a long adoption cycle, in the bioprocessing industry, where regulators are involved in most decisions, change comes slowly. At present, pre-commercial bioprocessing is now dominated (approximately 85%) by single-use systems. And much of the current growth in capacity involves single-use adoption at commercial scales.

	Geographically, 15 years ago, the industry did not predict the rise in bioprocessing in developing regions such as China and Latin America. In a BioPlan survey of 100 participants at the BIO conference 10 years ago, China was noted nearly universally as an unacceptable potential partner in biopharmaceuticals due to the lack of intellectual property protection and the virtual absence of quality management systems. Today, many Chinese companies are expanding through biosimilars, contract manufacturing organization (CMO) partnering, and other means to reach Western markets. For example, China’s WuXi Biologics, a contract development and manufacturing organization (CDMO) with global reach, is investing $60 million to build a manufacturing operation in Worcester, MA, in addition to its plans to build a $392-million biologics facility in Dundalk, Ireland (3,4).

	BioPlan has also reported data and trends for bioprocessing titers and yields over the past 30 or more years (5). Average commercial-scale titers have increased from estimated 1.1 g/L in 2003 to current 3.2 g/L, a nearly 300% increase. Also, during this period, the number of FDA-approved recombinant therapeutics has increased by approximately 400% (6,7). In 2017, FDA set a record for the number (31 approvals) and percent (93%) of approved biopharmaceuticals being recombinant-based compared with 18 approvals in 2003 and 69% for recombinant products (with 2003 a relative outlier in the early 2000s, with higher number of approvals).

	Industry outsourcing views and practices have changed significantly in the past 15 years (8). Outsourcing or the use of CMOs or contract research organizations (CROs) has significantly increased. The percent of respondents citing any current outsourcing of manufacturing task has doubled, from 35% in 2003 to 70% in 2018. Similarly, the percent reporting outsourcing mammalian manufacturing tasks has increased 164%, from 44% in 2003 to 72% in 2018.

	Back in the early 2000s, a significant shortage in capacity, a “capacity crunch,” was a major concern. With commercial manufacturing capacity then being tight, and in high demand, facilities were generally operating at much higher levels of capacity utilization rates than currently-79% overall in 2003 compared with 2018 rates of less than or equal to 60% overall and 63% for mammalian manufacturing. As discussed in the current report, having a lower-but still greater than 50%-capacity utilization rate is much healthier for the biopharmaceutical industry versus operating at high rates (e.g., the 79% reported in 2003). Process lines and facilities tend to become bottlenecked, and bioprocessing limited, when utilization rates approach and exceed 80%. The percent of respondents currently reporting severe or significant capacity constraints at their facility has fallen dramatically in 15 years, from 44% in 2005 to 20% in 2018. In 2018, lower percentages of severe constraints were projected as expected in five years, with this now falling from 44% in 2003 to 19.6% in 2018. This “future projection” is also an indication of the level of comfort many in the industry now have for managing their facilities, projecting operational needs, and dealing with intermittent capacity problems.

	Bioprocessing lines/facilities need some downtime, including for switchovers, maintenance, new equipment installation and validation, staff training, and cleaning and sterilization of stainless steel facilities. Current survey data continue to show that downstream operations still are struggling to keep up with improvements in upstream output, so downtime with upstream versus downstream equipment is normal.

	The “capacity crunch” perceived in the early to mid 2000s was largely resolved by industry responding with construction of many new facilities, including many for commercial manufacturing, combined with incremental technology improvements. These have included the rather steady increase in titers (5). In 2003, 79% of respondents reported planning for facility expansion in five years. In contrast, less than 30% overall (32% mammalian, 24% microbial) now report planning facility expansions in five years. The percentage of respondents reporting no current capacity constraints at all has increased significantly from 10% in 2003 to 28% in 2018.

	The factors cited as the primary causes of facility capacity constraints have changed somewhat over the past 15 years. Lack of experienced production and scientific staff were the top issues in 2003. In 2018, “facility constraints” has become the primary bottleneck factor, suggesting another round of industry capacity expansions may be coming, while inability to hire staff moved to second place.

	Survey respondents now report that downstream, compared with upstream, operations are where most bottlenecks in their bioprocesses are continuing to occur. The advances in upstream titers are reflected in survey responses regarding the top areas industry needs to address to avoid future capacity constraints, with developing better continuous and better overall downstream purification technologies now the top two most-cited responses. In contrast, upstream concerns, “optimizing cell-culture systems,” was number one in 2003.

	Exciting technologies have come and gone over the past 15 years. For example, back in 2003, transgenic animals for 

 manufacture of recombinant proteins was considered a “hot” topic, with fully 73% of respondents then citing this as likely to become a viable manufacturing alternative in the future. Transgenic animals are now a relatively ignored area of bioprocessing. Today, cellular and gene therapies, many of these involving both technologies (genetically-modified cells), are shaping-up as the next big biopharmaceutical manufacturing trend and also problem area in terms of capacity issues. BioPlan has reported an ongoing ‘capacity crunch’ in cellular/gene therapy areas (9). This includes a significant shortfall in capacity (e.g., five times the current capacity could be used if available).

Advances in Large Scale Biopharmaceutical Manufacturing and Scale-Up Production: A Survey of Industry Capacity

 (BioPlan Associates in conjunction with the American Society for Microbiology), Nov. 2003).
	2. E.S. Langer, et al., 

Fifteenth Annual Report and Survey of Biopharmaceutical Manufacturing Capacity and Productio

n (BioPlan Associates, 2018).
	3. WuXi Biologics, “WuXi Biologics to Invest $60 Million to Establish a Biologics Production Facility in the United States,” 

, June 11, 2018.
	4. WuXi Biologics, “WuXi Biologics to Invest €325 Million to Build Largest Biomanufacturing Facility Using Single-Use Bioreactors in Ireland,” 

, April 30, 2018.
	5. R.A. Rader, E.S. Langer, BioProcess Intl., 13 (3), p. 10-14 (February 2015).
	6. R.A. Rader, 

BIOPHARMA: Biopharmaceutical Products in the U.S. Market

, 2nd edition (Biotech. Info. Inst., June 2003).
	7. R.A. Rader, BIOPHARMA: Biopharmaceutical Products in the U.S. and European Markets, online database (www.biopharma.com).
	8. R.A. Rader, E.S. Langer, 

, Genetic Engineering & Biotechnology News

 Survey Methodology: The 2018 Fifteenth Annual Report and Survey of Biopharmaceutical Manufacturing Capacity and Production yields a composite view and trend analysis from 222 responsible individuals at biopharmaceutical manufacturers and contract manufacturing organizations (CMOs) in 22 countries. The methodology also included over 130 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 major markets in the United States and Europe.


	Vol. 42, No. 7
	July 2018
	Pages: 56–59

	When referring to this article, please cite it as R. Rader and E. Langer, "Fifteen Years of Progress: Biopharmaceutical Industry Survey Results," 

This article highlights 15 years of changes in biopharmaceutical manufacturing.

Fifteen Years of Progress: Biopharmaceutical Industry Survey Results

	Modern bioprocessing and antibody manufacturing are mature fields; however, challenges remain, and the advances themselves often bring new challenges. This is the nature of progress. The current challenges are exemplified by the ongoing advances and industry adoption of technologies such as continuous processing, the importance of modeling bioprocesses, increasingly seamless downscaling of processes, and other factors that are expected-and even required-by regulatory agencies. 

	Over the past 15 years, the industry has evolved into a mature, productivity-oriented segment. Of the dozens of trends evaluated in the annual BioPlan Associates survey (1), productivity continues to show the highest focus as an industry objective (See 

). This suggests that other operational aspects must address industry challenges around improving productivity and efficiency. 

	But to achieve successes, operational challenges must be worked out. As an example, continuous bioprocessing is one of, if not the most, challenging area for process development. Continuous processing-including both upstream perfusion and downstream continuous purification processing--remains rare and elusive despite the fact these technologies have been established for some time. These challenges particularly stand out when continuous and conventional batch processing options are compared. 

 shows survey results when bioprocessing professionals were asked to indicate issues with adoption of upstream perfusion that are much or somewhat bigger.

	Bioprocessing professionals clearly see a number operational problems remaining with upstream perfusion versus conventional batch processing. In 2017, a number of concerns were cited by more than 50% of respondents to BioPlan’s survey: 

		Upstream [process] development and characterization time 

		Process development control challenges.

	This daunting collection of concerns about perfusion persists despite it being in use and marketed for multiple decades-including for commercial biopharmaceutical manufacture-notably for Factor VIII. In many respects, perfusion may be viewed as a technology adoption model in bioprocessing that demonstrates the slow nature of adoption of rational, effective technologies. BioPlan market research studies (1) have shown that approximately 5% of bioreactors use perfusion, with many of these being feeder and not production bioreactors. Further, while perfusion is seen by users as highly productive, often better and cheaper versus batch processing, most using it in early manufacturing continue to avoid its use in commercial manufacturing, viewing the challenges as high and the risks significant, in terms of regulatory approvals. One challenge for perfusion process adoption is that single-use perfusion units only recently became available. This lack of familiarity could be a factor in the reporting of high levels of concerns with--and even fears of--perfusion versus batch bioreactors likely among those not using the technology. Many challenges remain before the industry gains experience and confidence in this option for continuous upstream processing.

	Downstream continuous operations, particularly chromatography, has more challenges; suitable hardware with built-in data systems are just starting to become available from suppliers. Downstream continuous bioprocessing was cited as the second single-most important bioprocessing trend or operational area on which the industry must focus its efforts. In BioPlan’s study, perceived need for improvements carries over to facility budgets with interviewees reporting an average increase of 8.8% in their 2017 downstream technology budgets vs. 7.7% for upstream; 33.8% cited continuous chromatography as a “top area where suppliers should place their efforts on.” 

	Adoption of continuous chromatography, generally involving use of multiple interfaced columns with integrated controls, is growing more rapidly than perfusion adoption; however, adoption has only recently started from a near zero baseline and is low. Combined with other downstream advances (e.g., increasing use of membranes in place of resin-filled columns, automated in-line buffer dilution and column packing, better resins, and more single-use and recyclable columns), downstream processing is in many respects changing and evolving more rapidly than upstream, but the adoption and integration into actual bioprocessing remain slow. When asked to cite the top downstream areas where suppliers should focus their development efforts, disposable purification systems were cited by 35.9% of respondents, followed closely by continuous purification cited by 33.9%. Geographically, European respondents are much more interested in continuous purification compared with those in the United States (44.4% vs. 25.3%).

	But basic problems remain with broader adoption of both upstream and downstream continuous bioprocessing, including the inability to integrate related manufacturing systems. Currently, implementation of end-to-end continuous bioprocessing, or even upstream or downstream segments, remains rare or nonexistent, with at best one or a few unit processes implemented as continuous. 

	Bioprocessing modeling and understanding of implications of changes in scale remains another challenging area. The industry has naturally concentrated on scale-up, as drug product volumetric requirements increase as products advance in development. More is known about scaling up versus scaling down. But the importance of scaling down is rapidly increasing, including the ability to model and predict what happens in research and development by using smaller scales, rather than having to run experimental studies at various scales, including full scale. Having scale-down capabilities and understanding is increasingly expected, if not required, in FDA and other major market regulatory filings, particularly for product approvals. Being able to scale down and have related models and knowledge are now key parts of process analytical technology, quality by design, and other regulatory/quality initiatives. In addition, validated process down-scaling methods often are required for cost-effective design and refinement of bioprocessing. This is exemplified in the use of down-scaled bioprocesses to validate process biosafety, including reduction in virus titers from virus filtration and chromatography steps. The costs of validating virus removal and inactivation would be too expensive and time-consuming if run for full-scale processes. 

	Bioprocess system designers also want the ability to conduct computer-based modeling to scale up and scale down a process using bioprocessing equipment from the same product line. 

	This particularly applies to purchases of bioreactors, mixers, chromatography, and other major bioprocessing systems, but also extends to filters and other equipment. Scalability, particularly including scale-down ability, is a top equipment/technology selection factor cited in bioprocessing supplies-related market research studies. Many facilities will not purchase equipment unless reasonable scalability is known and documented among products throughout a product line, particularly for bioreactors and chromatography and filtration systems. Bioprocessing professionals regularly cite an expectation that bioprocessing systems will seamlessly scale up and down. In addition, the users want to model or predict the operation of the systems at scales higher than anticipated use to provide better assurance of actual scalability throughout the range of scales they actually will use, such as from mini/desktop to 2000-L or larger production bioreactors. 

	To move forward, industry and its investors need to recognize this segment has historically been one of the slowest, but also the most persistent, in terms of adopting the advances that the industry requires. To achieve success, operational challenges must be worked out, but in this regulated, high-stakes environment, the timelines for development and adoption of new technologies create challenges that, sometimes, require years to resolve. 

, 13th Annual (BioPlan Associates, 2016).


	Vol. 42, No. 3
	March 2018
	Pages: 64–65

	When referring to this article, please cite it as R.A. Rader, "Current Challenges in Bioprocesses Development," 

Development and adoption of new technologies create challenges that may take years to resolve. 

Current Challenges in Bioprocesses Development

The biopharmaceutical industry is dynamic and complex, and in addition to the overall consistent 14-15% industry growth, data from BioPlan Associates’ 2017 

14th Annual Report and Survey of Biopharmaceutical Manufacturing 

(1) shows that key trends are affecting this growth. These include the following: 

		Growth of international biomanufacturing centers, including China

	These general trends are also impacting more specific aspects of the industry. For example, current and future capacity and production are already being hit by the inability to hire and train staff-in fact, more than 50% of bioprocessing facilities are experiencing capacity problems this year due to difficulties hiring certain operations staff. Hiring problems will continue to increase as the industry expands. These human resources issues may ultimately also create quality problems, and are already increasing demand for technologies that reduce staffing, such as automation and single-use device applications. Even outsourcing to contract manufacturing organizations (CMOs) may well be challenged if CMOs continue to experience growth and hiring problems. 

	The biopharmaceutical industry is continuously demanding new and improved bioprocessing technologies to reduce costs, increase efficiencies, and improve weak development pipelines, especially in developing economies. Some of the ongoing biopharmaceutical trends support a future vision that includes:

		More biological products, but often each targets smaller markets

		More multi-product and flexible manufacturing facilities

		More efficient bioprocessing-titers and yields

		More use of continuous processing, including for downstream processing

		More automation, monitoring, and process control.

	The following is a summary of a few of the top 15 trends affecting biopharmaceutical manufacturing from the BioPlan 2017 study. This year’s survey included responses from 227 bioprocessing professionals, 131 industry equipment and services suppliers; and data from more than 150 bioprocessing professionals in China and India. 

	Trend number one: Greater demand for manufacturing efficiency and productivity

	Many of the trends in the bioprocessing industry are being driven by perceived needs for improved efficiencies, quality, and cost reductions in manufacturing processes. Companies invest in technology and innovation so they can more with less. To remain competitive, better ways are needed to: 

		Make bioprocessing more efficient and less expensive

		Decrease new products’ time-to-market (increase speed)

		Streamline new technology testing and adoption, make adopting new technologies less painful. 

	The largest portion of survey respondents, 16.4%, noted that “Manufacturing Productivity/Efficiency” was the “single most important biomanufacturing trend or operational area on which the industry must focus its efforts, 2014–2017.” Essentially, all of the top three-and most other cited trends or operational areas-are related to cost savings though increased efficiency and productivity (see 

		Average reported titer for commercial-scale biologics (for new monoclonal antibodies [mAbs]) this year was 2.80 g/L, with yearly data back to 2008 showing overall consistent year-to-year incremental increases to the present.

		Average reported upstream titers have been growing rather steadily over the past three decades from a baseline of at best a few tenths of a gram/L back in the 1980s.

		Average reported titer for clinical-scale biologics was 3.29 g/L, with these data also showing an overall consistent incremental growth. 

	Trend two: Downstream processing remains the major bioprocessing bottleneck

	Downstream purification including chromatography continues to be the area cited as requiring the most technological improvements. Yet, other recent BioPlan studies confirm that downstream yield improvements remain much more resistant to change. This year, 74.3% of respondents reported their facility was experiencing at least some capacity bottleneck due to downstream processes. Overall, respondents are experiencing a higher level of bottlenecks than seen in 2011–2015. Approximately 10% reported that their facility is currently experiencing “serious” downstream bottleneck problems. CMOs perceive downstream bottlenecks as more serious, with 60% of CMO respondents reporting either “Serious” or “Some” capacity constraints due to downstream processing. “Serious” capacity constraints were also reported much more frequently by European vs. US respondents, 11.5% vs. 5.7% (see 

	Chromatography remains the top-cited downstream (or any) bioprocessing problem area. This included 48.3% of respondents citing “Chromatography columns” as causing them “Moderate constraints” or worse; with 80.8% reporting “Minor constraints” or worse. 

	Trend three: Biosimilars are bringing more competing biopharmaceutical products (competition) and players

	Biosimilar product development continues worldwide, and appears to be accelerating now that the US biosimilars’ market is coming online. The 

 (2) reports nearly 850 biosimilars (including biogenerics) in development or marketed worldwide, including approximately 125 in clinical trials; and more than 515 biobetters in development or marketed worldwide, including more than 200 in clinical trials. With such a healthy development pipeline, within approximately five years, biosimilars will outnumber reference and other innovative products, including in the US market. This increase will change the underlying nature of the biopharmaceutical industry, as biosimilar products eventually affect overall sales. CMOs are also reporting increased business, about 15% increase in revenue, attributed to biosimilars development projects.

	Biosimilars are resulting in a number of new players entering the biopharmaceutical industry. Established drug companies, including Big Pharma, startup and virtual companies, foreign companies, generic-drug companies, and others are working to develop portfolios of biosimilars. The United States remains a primary location for biosimilar R&D and the largest market for biosimilars. Europe, India, and China are the other major centers for biosimilars development and marketing. A good portion of the new bioprocessing facilities and process lines have recently come online or under construction and will be solely or largely devoted to biosimilars manufacture. 

	Trend four: Single-use systems in demand, use still growing

	Approximately 90% of respondents currently use single-use bioprocessing equipment, with “Tubing or disposable operations” cited the most. More than 80% reported use of single-use bioreactors. In contrast, the highest rate of reported downstream single-use systems use was “Disposable chromatography devices,” reported by 55.6% and membrane adsorbers at 49.6%. The rates of usage of diverse disposables in biopharmaceutical manufacturing have remained relatively steady in recent years, with the market nearing saturation, for smaller, clinical-scale operations. BioPlan estimates that approximately 85% of pre-commercial biopharmaceutical manufacture is done using single-use systems, particularly upstream. Sales of single-use systems will further increase as more manufacturers advance to commercially manufacture their products using single-use systems. 

	And the industry itself expects to see continued adoption. A significant majority (66%) expect their own facility to involve at least 50% of its substantial unit operations to be done using single-use system devices (see 

	Trend five: International growth in biomanufacturing; China and India are maturing

	India, China, and other regions are rapidly increasing their domestic manufacturing capabilities; however, most of the current products are developed for home markets, including biogenerics (i.e., non-GMP biopharmaceuticals for lesser-regulated markets). While these are fast-growing geographic areas for biopharmaceutical R&D and manufacturing, little (as yet) involves innovative products. Growth in capacity and  new and expanded facilities coming online are most rapid in China, India, Korea, and Singapore, but some of these countries’ capacities are growing from low baselines. 

	BioPlan’s analysis of China’s bioprocessing facilities, Top 60 Biopharmaceutical Facilities in China, (3) found that China holds approximately 2.4% of the total worldwide estimated 17 million L capacity for recombinant protein/mAb bioprocessing capacity. And nearly all growth in China is domestically financed, with foreign investment in Chinese biopharmaceutical manufacturing remaining relatively low.  

	Most biogeneric developers aspire to bring their products as biosimilars into major highly-regulated markets. But it will take years for developing country-based facilities (aside from a few outliers) to develop major market-friendly GMP manufacturing capabilities. Besides physical plant and needed staff expertise, improvements are needed in business culture, including aspects that have fostered persistent fraudulent data manipulation. 

	This year, the BioPlan survey includes data from interviews with 50 Chinese and more than 100 Indian bioprocessing professionals. Among the attributes noted as most required in Chinese facilities to enable international sales/competition are: 

		More innovative biopharmaceutical pipeline (58%)

		In terms of citing the weaknesses, 52% cited “Scientific/technical expertise” and the same percentage noted “Compliance track record/expertise.” 

		From Indian bioprocessing professionals, the core competencies noted as being lacking in Indian biopharmaceutical manufacturers included: 

	Bioprocessing industry trends and innovation speeds discovery and can drive down costs and improve productivity. The current situation in biopharma is exciting, with new technologies, biosimilars, cell and gene therapies, and opportunities in emerging markets.

14th Annual Report and Survey of Biopharmaceutical Manufacturing Capacity and Production

 (BioPlan Associates, April 2017).
	2. BioPlan Associates, 

Top 60 Biopharmaceutical Facilities in China

, 2nd edition (BioPlan Associates, February 2017). 

The biopharma industry is growing at 14-15%, but efficiency demands and lack of skilled labor may impact performance.