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.
Survey
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 Massachusetts
Institute of Technology (MIT) has conducted a survey asking in-depth
questions of product life-cycle history, current manufacturing site
characteristics, and site quality activities. The survey is part of a
larger initiative at CBI to understand the impact of globalization and
regulation on quality, both of which have increased in importance
and cost within the biomanufacturing industry (1, 2). An additional
intent of the initiative is to understand similarities and differences of
quality between biomanufacturing and manufacture of small-molecule
pharmaceuticals, the latter which has been analyzed previously from
the regulator perspective (3). The initiative is primarily funded by a
grant from the Alfred P. Sloan Foundation located in New York, NY.
Products surveyed
The survey collected information on 31 unique products, that were
diverse in the following dimensions: geographic location of current
manufacture (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 above
average complexity); and consistency in manufacturing (45% of
products regularly manufactured).
Using cross-tabulation analysis of the product-specific survey data
and statistical significance at the 0.10 level, the following quality issues
at the commercial scale of manufacture of biopharmaceuticals are
apparent:
• Life-cycle dependence: products that have had quality issues
during development are more likely to experience quality issues in
commercial manufacture.
• Geographic region dependence: products that have had critical
quality issues in commercial manufacture are more likely to be
manufactured in Asia and less likely to be manufactured in North
America than products that have not had these issues.
• Contract manufacture dependence: products that are currently
manufactured in a facility that does 40% or more of its manufacture
for others are less likely to have had quality issues in development
and are more likely to have critical quality issues in commercial
manufacture. In other words, lack of development issues is more
likely to lead to contract manufacture and contract manufacture is
more likely to lead to critical commercial issues.
Product quality issues in commercial manufacture were found to
be uncorrelated to process type, site-reported processing complexity,
and whether the product was regularly manufactured (based on the
available survey data and statistical significance levels of 0.10). An
insufficient number of the commercially manufactured products had
undergone quality by design to incorporate that into the analysis.
Sites surveyed
The products were manufactured at 15 sites. These sites were diverse in
terms of geographic location, age, and extent of contract manufacture
activity. 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 sample
average age is 12 years. Six of the 15 sites do less than 20% of their
production 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 the
drivers of quality and ongoing quality activities:
• Past drivers of quality efforts: Change initiated due to the regulator
was the top reason for a quality effort at the sites; new technology,
cost reduction, and pursuit of new markets were each identified as a
past driver of efforts by less than 25% of the sites.
• Future drivers of quality efforts: Most past drivers are expected to
continue, while new drivers are expected to be novel technology, cost
reduction, and the pursuit of new markets were each identified by
more than 50% of the sites
• Quality personnel and activities: Wide variation was evident between
the sites in the fraction of technical personnel in quality assurance
and control (15–45%); use of multidisciplinary teams in quality
initiatives (range: low/med to high); and the frequency of third-party
inspections (1–10 over past 5 years)
• Perception of inspection variation: Overall, there was no consistent
perception from the sites of strong variation between inspections
either within the FDA, within the EMA, or between the two.
Sources
1. 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 research
initiatives, and/or CBI at MIT, please contact CBI at cbi@mit.edu
or 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 of
Business, University of Prince Edward Island; Jeffrey T. Macher is affiliated
with CBI, MIT, and the McDonough School of Business, Georgetown
University; Paul W. Barone and Stacy L. Springs are affiliated with CBI, MIT;
Anthony J. Sinskey is with the MIT Department of Biology; and Scott Stern
is with the MIT Sloan School of Management.
Reference
1. PhRMA, "Biotechnology Medicines in Development,"
http://www.phrma.org/sites/default/files/1776/biotech2011.pdf, accessed Apr. 2012.
For additional resources and online exclusives on this topic, visit http://www.pharmtech.com/.
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