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Amy Ritter was Scientific Editor, BioPharm International.
Readers share their views on bioprocessing challenges, equipment use, and outsourcing trends in our annual bioprocessing equipment and processing survey.
Biologics continue to gain ground as therapeutics, with 11 Biologic License Agreements approved in 2011 by FDA, and a staggering 900 or so products in the pipeline according to PhRMA, including 300 monoclonal antibodies, 298 vaccines, and 78 recombinant proteins other than mAbs (1). This year's survey suggests that the great rush to enter the biologics field has given way to a slow, steady rise in new entrants, but new entrants and old hands all face production challenges. To understand these challenges, Pharmaceutical Technology asked those involved in the production of biologics about the issues that concern them most, and about their choice of equipment for bioprocessing.
The largest group of respondents to this years survey worked at biotech companies, 38%, with 24% from innovator companies, and with a scattering of respondents from contract services companies or from academia or nonprofits. Half of the respondents (51%) said their companies produced only biologics, while the other half produced both large and small molecules. When asked what type of drugs they produced, 34% of respondents said they produced branded drugs, 21% said generic drugs, and another third, 33%, said they produced neither branded nor generic, and so presumably were producing biologics still in the development phase.
Only a minority of companies were newcomers to the field—23% said their companies had started producing biologics within the past year, which is the same percentage as last year. Those just entering biologics production were more likely to be contract manufacturers: 33% of respondents who worked as contract manufacturers said they had started producing biologics within the past year, compared with only 10% of those from biotech companies.
Different products, different concerns
The product produced by the largest group of survey participants (46%) was protein products other than monoclonal antibodies (mAbs), little changed from last year's result of 51% (see Figure 1). Surprisingly, those who said they produced mAbs decreased this year to only 34%, compared with 44% in 2011. There was a clear dichotomy in the types of companies producing mAbs: only 20% of respondents from companies with revenues of less than $500 million were producing mAbs, compared with 57% of those from companies with revenues greater than $1 billion. Other classes of products manufactured by survey participants remained little changed between 2011 and 2012. This year, 10% of respondents produced nucleic acid-based products, 33% produced vaccines, and 16% produced cells for cell therapy.
Figure 1: What class(es) of biopharmaceutical does your company manufacture (multiple responses allowed)?
This years results indicate that some of the enthusiasm for biosimilars may be waning now that FDA has released its draft guidelines. The number of respondents who say that they are planning to make follow-on biologics is down slightly from 2011, 36% compared with 45% in 2011. Twenty five percent say they are not planning any follow-ons, compared with 21% last year, and 39% are uncertain if they will do so, compared with 34% in 2011.
When producers of protein-based products, including both mAbs and proteins other than mAbs, were asked about their greatest challenges during production, producing high enough protein yields and protein stability were of concern to 40% and 33% of respondents, respectively, with purification (30%) and formulation (28%) also cited as areas of concern (see Figure 2). Other aspects of protein production, such as creating efficient expression cassettes, creating working cell lines, viral contamination, and achieving correct posttranslational modification were not of great concern to most respondents, garnering responses of less than 15%. Perhaps not surprisingly, different concerns emerge if the responses are broken down according to the respondents' job responsibilities. For instance, 56% of those who identify themselves as working in manufacturing say producing high enough yields is a significant challenge, while only 27% of those in formulation perceive this to be a challenge. Those in formulation are, of course, more sensitive to formulation issues (59%, compared with 29% of the sample at large) and drug delivery issues (41%, compared with 15% of the sample at large).
Figure 2: If you produce protein-based drugs, what are your current technical challenges (multiple responses allowed)?
For purification, those who produced protein-based products used chromatography with protein A (51%), chromatography with other resins (68%), and ion-exchange chromatography (70%). The proportion of those who used membrane-based filters, 64%, is increased somewhat over last year's reported 53%.
Those who produced nucleic acid-based therapies listed purification (35%), scale-up (25%) and stability (25%) as being their most pressing concerns. Fewer than 10% of respondents indicated that analytics or automation presented technical challenges during the manufacturing process. Of those making cell-based products, 38% indicated that process development continued to be a challenge, with scale-up (35%) and costs (33%) also of great concern. Adequate bioreactor volumes were a concern for only 18% of respondents, and cell viability a challenge for 19%.
Survey results indicated a slight shift in the type of bioprocessing equipment that is being used this year compared with 2011. Most respondents, 66%, indicated that they used a hybrid system containing both stainless and disposable elements, which is unchanged from last year's results. However, the numbers indicating that they used stainless-only systems declined slightly, from 26% in 2011 to 21.8% this year. And the number of all-disposable users inched up proportionally, from 8.4% last year to 12.2% this year. Of those using an all-stainless system, 31% indicated that they had no plans to change their equipment, but 25% said they planned to move to a hybrid system. In contrast, most users of all disposable systems (59%) said they had no plans to change their equipment and only 13.6% said they'd be adding some stainless into the mix and moving to a hybrid system.
When asked about the relative strengths and weakness of disposable bioprocessing equipment, respondents focused on a few key attributes. When asked, whether or not they used disposables, to identify the greatest advantages to using single-use components, the highest-ranking attributes were reducing contamination, time savings, ease of use, and flexibility for multiproduct manufacturing (see Figure 2). High cost was seen to be the biggest drawback to disposables, followed by high environmental impact, concerns about leachables, and limitations on size. Those who use only stainless have largely the same opinions as those who use disposables. The only concern that ranked lower among stainless-only users than the population at large was leachables: 21% of stainless-only users ranked it as a drawback to the technology, compared with 33% of the group as a whole.
Figure 3: Whether or not you currently use disposables, what in your opinion is (are) the greatest advantage(s) to disposable equipment (multiple responses allowed)?
Quality by design and process analytical technology
A solid majority of survey participants, 62%, say that their companies incorporate quality by design (QbD) into their manufacturing processes; this percentage is similar to last year's response of 65%. Those who identified themselves as working at an innovator company were somewhat more likely to employ QbD than the sample at large, at 79%. Reasons given for doing so were to gain greater process understanding (71%), improve product quality (57%), reduce product variability (53%), and to improve manufacturing efficiency (51%). Of those who do not employ QbD, 34% say that they don't see the process or quality advantages to be gained, while 27% say they don't understand the initiative, and another 27% responded that they thought it would be too costly to implement.
Respondents were evenly split on whether they used process analytical technology (PAT), 45.7% did and 54.3% did not, again, little changed from last year. Sixty-two percent of those who use PAT say they use high-performance liquid chromatography as one of their analytical technologies, with the second most popular technology being other types of chromatography, at 45%.
Capacity and outsourcing
Fifty-five percent of respondents indicated that their companies increased biomanufacturing capacity over the past year, up slightly from last year (50.5%). Large companies drove a greater share of the increase, with 69% from companies with revenues more than $1 billion indicating an increase in capacity. The most common reason for the increase in capacity was increased production of an existing product (57.5%), followed by the addition of new products (44.7%) and the internal development of new products (41%). Of those companies that did not increase production, most (71.3%) said that production was holding steady, rather than decreasing. Rather than a boom, it looks like a steady rate of increase in capacity, with those not increasing production at least holding their ground.
Only a minority of the survey respondents indicated that they outsourced the manufacture of biologics (30%), with the most commonly outsourced product being drug substances (APIs, 45%), and clinical trial materials (41%). Finished products (24%) and formulation (19%) were least likely to be outsourced. When asked about their reasons for doing so, 51% indicated that it was because their company had limited in-house capabilities, and 41% indicated that outsourcing was more cost-effective than doing it themselves.
Past and future innovation
Even though the use of disposable technology is well established, it continues to impress. When asked to identify the single most important innovation of the past year responsible for improving process efficiency, many respondents said increased number of disposable options and new types of equipment had been the biggest contributor. Some were quite specific, mentioning the development of disposable stirred bioreactors, increased disposable bioreactor size, and single-use sensors as being important innovations. In addition to disposables, others said that QbD and PAT, including a greater range of available analytical tools, had increased bioprocessing efficiency, while improved cell lines resulting in greater yields were also mentioned.
While users obviously find the disposables they have to be useful, they still feel there are improvements that could be made. Readers were asked what specific innovations could be made to improve process efficiency, and again, disposables earned prominent mention. Readers asked for harmonization among disposables suppliers, disposables for microbial culture, disposable pressure sensors, and disposables for large-scale culture of adherent cells. Others were looking for better purification techniques—an alternative to protein A, cheaper disposable tangential flow filtration equipment, or a method for decreasing the number of steps in the purification process. To improve product quality, readers asked for better monitoring tools, and a broader application of PAT.
The MIT CBI Biomanufacturing Product Quality Survey - Reuben D. Domike, Jeffrey T. Macher, Paul W. Barone, Stacy L. Springs, Anthony J. Sinskey, and Scott Stern
The Center for Biomedical Innovation (CBI) at the MassachusettsInstitute of Technology (MIT) has conducted a survey asking in-depthquestions of product life-cycle history, current manufacturing sitecharacteristics, and site quality activities. The survey is part of alarger initiative at CBI to understand the impact of globalization andregulation on quality, both of which have increased in importanceand cost within the biomanufacturing industry (1, 2). An additionalintent of the initiative is to understand similarities and differences ofquality between biomanufacturing and manufacture of small-moleculepharmaceuticals, the latter which has been analyzed previously fromthe regulator perspective (3). The initiative is primarily funded by agrant from the Alfred P. Sloan Foundation located in New York, NY.Products surveyedThe survey collected information on 31 unique products, that werediverse in the following dimensions: geographic location of currentmanufacture (48% North America, 32% Europe, 19% Asia); processing(71% by mammalian cell culture, 29% by microbial fermentation);perceived manufacturing complexity (45% perceived to be of aboveaverage complexity); and consistency in manufacturing (45% ofproducts regularly manufactured).Using cross-tabulation analysis of the product-specific survey dataand statistical significance at the 0.10 level, the following quality issuesat the commercial scale of manufacture of biopharmaceuticals areapparent:• Life-cycle dependence: products that have had quality issuesduring development are more likely to experience quality issues incommercial manufacture.• Geographic region dependence: products that have had criticalquality issues in commercial manufacture are more likely to bemanufactured in Asia and less likely to be manufactured in NorthAmerica than products that have not had these issues.• Contract manufacture dependence: products that are currentlymanufactured in a facility that does 40% or more of its manufacturefor others are less likely to have had quality issues in developmentand are more likely to have critical quality issues in commercialmanufacture. In other words, lack of development issues is morelikely to lead to contract manufacture and contract manufacture ismore likely to lead to critical commercial issues.Product quality issues in commercial manufacture were found tobe uncorrelated to process type, site-reported processing complexity,and whether the product was regularly manufactured (based on theavailable survey data and statistical significance levels of 0.10). Aninsufficient number of the commercially manufactured products hadundergone quality by design to incorporate that into the analysis.
Sites surveyedThe products were manufactured at 15 sites. These sites were diverse interms of geographic location, age, and extent of contract manufactureactivity. Of the 15 sites, five each are located in North America, Europe,and Asia. Five of the 15 sites are 10 years of age or less and the sampleaverage age is 12 years. Six of the 15 sites do less than 20% of theirproduction volume for others on contract and five do greater than 80%of their production volume for others as contract manufacturers.The survey results of the sites suggest the following regarding thedrivers of quality and ongoing quality activities:• Past drivers of quality efforts: Change initiated due to the regulatorwas the top reason for a quality effort at the sites; new technology,cost reduction, and pursuit of new markets were each identified as apast driver of efforts by less than 25% of the sites.• Future drivers of quality efforts: Most past drivers are expected tocontinue, while new drivers are expected to be novel technology, costreduction, and the pursuit of new markets were each identified bymore than 50% of the sites• Quality personnel and activities: Wide variation was evident betweenthe sites in the fraction of technical personnel in quality assuranceand control (15–45%); use of multidisciplinary teams in qualityinitiatives (range: low/med to high); and the frequency of third-partyinspections (1–10 over past 5 years)• Perception of inspection variation: Overall, there was no consistentperception from the sites of strong variation between inspectionseither within the FDA, within the EMA, or between the two.Sources1. J. Woo, S. Wolfgang, and H. Batista, Clin. Pharmacol. & Therapeut. 83 (3)494–497 (2008).2. D. Vogel, Governance 11 (1) 1–22(2002).3. J.T. Macher, J.M. Mayo, and J.A. Nickerson, Jrnl. of Law and Econ. 54 (1) 25-54 (2011).
To learn more about this ongoing survey, the broader researchinitiatives, and/or CBI at MIT, please contact CBI at email@example.com tel. 617.253.0257. About the Authors:Reuben D. Domike is affiliated with the Center for Biomedical Innovation,Massachusetts Institute of Technology (CBI, MIT) and the School ofBusiness, University of Prince Edward Island; Jeffrey T. Macher is affiliatedwith CBI, MIT, and the McDonough School of Business, GeorgetownUniversity; Paul W. Barone and Stacy L. Springs are affiliated with CBI, MIT;Anthony J. Sinskey is with the MIT Department of Biology; and Scott Sternis with the MIT Sloan School of Management.
1. PhRMA, "Biotechnology Medicines in Development,"
, accessed Apr. 2012.
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