Amy Ritter was Scientific Editor, BioPharm International.

Amy Ritter, PhD

	The world of drug development is littered with early-phase failures: drugs that were shown to be safe in Phase I trials, but which failed to show efficacy later on. The failure of a drug at this early phase might not mean that there’s anything wrong with the compound. Rather, a failure might mean that the mechanism by which the drug acts was not of benefit in the disease against which it was tested.

	A handful of these drugs are being pulled from the shelves and given a second chance in a new initiative 

 earlier this month. NIH’s new National Center for Advancing Translational Sciences (NCATS) is partnering with Pfizer, AstraZeneca, and Eli Lilly, which have agreed to make select compounds available for a pilot initiative to test promising compounds for new indications.

	A total of $20 million will be used from NCATS’ budget to fund the initiative. Scientists may apply for research grants of up to three years duration for preclinical and clinical feasibility. Industry partners will supply around 20 compounds to participating researchers, as well as access to related data. The program also incorporates template agreements designed to streamline the legal and administrative process for participation, and a framework for handling intellectual property used or developed within the program.

	In times of shrinking pharma R&D budgets, this is just the type of project by which industry can capitalize on relationships with academia. In the release, Jan Lundberg, PhD, executive vice-president, science and technology, and president, Lilly Research Laboratories, sums it up. “Discovering and developing new medicines, regardless of the therapeutic area being studied, is a complex and expensive process and we look forward to collaborating with the NIH and academia for the benefit of the patients we all serve.”

Articles

The world of drug development is littered with early-phase failures: drugs that were shown to be safe in Phase I trials, but which failed to show efficacy later on.

NIH Scientists Hope to Teach Old Drugs New Tricks

At the request of FDA, the Institute of Medicine (IOM) prepared a report containing recommendations for how the agency might better monitor the safety of drugs after they have been approved. The 

Ethical and Scientific Issues in Studying the Safety of Approved Drugs

, recommends a life-cycle approach to safety monitoring. In such an approach, processes are in place to collect, assess, and act on data about a medication's benefit-risk profile from approval until it is no longer marketed.

One of the report’s key recommendations is that FDA should create a benefit and risk assessment and management plan for each drug in the form of a single, comprehensive, publicly available document. This document would serve as a central repository of information for each product from its approval throughout its entire time on the market. The report also recommended enhanced surveillance for certain categories of higher-risk drugs, such as first-in-class molecules, drugs approved through the use of several surrogate endpoints that provide conflicting evidence about likely health outcomes associated with the drug, or drugs that have a strong biological rationale for a particular side effect.

"We believe that the adoption of a life-cycle approach to drug approval and monitoring will help the agency strengthen its oversight, better tackle these complex decisions, and increase public confidence in the agency's ability to protect public health," said Steven N. Goodman, professor of medicine, health research, and policy, and associate dean for clinical and translational research at Stanford University School of Medicine, in an accompanying

. "This will become increasingly important as FDA looks for ways to safely expedite the drug approval process."

FDA notes that many of the recommendations in the report are in step with ongoing agency programs and processes. In a

  issued by the Center for Drug Evaluation and Research the agency notes, “FDA monitors a drug’s safety throughout its lifecycle, and considers the oversight of drugs once they reach the market of equal importance to the premarket review of new drug and biologics applications.” FDA also says that while the creation of a central, publicly-accessible risk management plan for each drug is a good recommendation, they are too resource constrained at this time to implement such a program. The agency says it is in the process of fully analyzing the report to determine how to implement changes that will have the largest positive impact on public health. 

At the request of FDA, the IOM prepared a report containing recommendations for how FDA might better monitor the safety of drugs after they have been approved.

Institute of Medicine Releases Report on Studying the Safety of Approved Drugs

Testing for the presence of microbes in an aseptic environment used to be a process that took weeks. Now, methods for rapid microbial testing can be used to detect the presence of mircoorganisms in the environment or in a finished drug product in hours or days. In this technical forum, experts describe different methods of rapid microbial testing and their applications. Contributors to the forum are: Anne Baumstummler, senior scientist; Renaud Chollet, head of biotechnologies and reagents; Hervé Meder, R&D project manager; Céline Rofel, cell culture and molecular biology technician; Adrien Venchiarutti, engineer; and Sébastien Ribault, PhD, director development & bioproduction, all at Millipore SAS; and Ruth Eden, PhD, president of BioLumix. 

Microcolonies Fluorescent Staining Method for Rapid Detection of Microbial Contamination in Mammalian  Cell Culture 

Anne Baumstummler, Renaud Chollet, Hervé Meder, Céline Rofel, Adrien Venchiarutti, and Sébastien Ribault, Millipore SAS

Traditional testing methods for microbial contamination of mammalian cell culture require several days to detect contamination. The presence of microorganisms is typically assessed by membrane filtration and incubation on solid media or inoculation into liquid media. These culture-based methods rely on microorganisms growing and yielding visible colonies or turbidity. Time-to-result is measured in days for standard bioburden testing (1). The microcolonies fluorescent staining method (MFSM) described in this study is a robust, simple, and rapid method enabling the detection of microbial contaminants. It can be applied to cell culture samples with time-to-results that are two to five times shorter than traditional microbiology. The nondestructive feature makes it compatible with downstream identification of contaminants. 

 Many technologies and detection systems such as enzyme-linked immunosorbent assays, impedimetry, bioluminescence, flow cytometry, and polymerase chain reaction arose in the field of rapid detection during the two past decades (2–4). Fluorescent dyes have been routinely used in methods such as the direct epifluorescent filter technique (DEFT) to monitor microbial contamination (5). This technique involves the capture of microorganisms on the surface of polycarbonate membrane filters, staining, and visualization using epifluorescence microscopy. The sensitivity is directly linked to the volume filtered and the number of fields observed. A limitation of this approach is the inability to differentiate fluorescent microorganisms from autofluorescent particles. Automated and semi-automated systems have been developed to increase this discrimination and improve accuracy (6–8).  

An alternative is to combine the principles of epifluorescence microscopy and flow cytometry (9). Microorganisms retained on a polycarbonate filter are fluorescently labeled and automatically counted by a laser-scanning device that makes the differentiation between fluorescent microorganisms and particles (10). Several authors have reported the use of this solid-phase cytometry technology for bioburden testing of mammalian cell culture processes (1). Results are typically obtained within five hours of sample preparation (6). One drawback of such direct detection methods is the inability to discriminate between culturable and nonculturable organisms (11). In addition, many fluorescent-labeling techniques have an impact on the viability of colony formation, thereby making it impossible to identify organisms that are detected. This is a challenge when conducting investigations or evaluating the severity of a contamination.  

MFSM is a method that combines the widely used membrane filtration method with a fluorescence-based staining for the rapid detection of contaminants in filterable samples using microcolony formation. MFSM is based on a nondestructive fluorescent labeling of viable and culturable microorganisms present on cellulose membranes (MilliFlex Quantum, EMD Millipore; see Figure 1). The procedure consists of filtration of the sample, a short incubation on media to yield microcolonies, staining of microorganisms, and counting of fluorescent microcolonies with a light-emitting diode (LED) system. The microorganisms are labeled directly on the filter with a nonfluorescent substrate that is cleaved by intracellular microbial enzymes. Only metabolically active microorganisms with membrane integrity that retain the fluorescent product are stained. Because the staining solution is nondestructive, the method is compatible with standard identification methods. 

The objective of this study was to compare MFSM with traditional epifluorescence microscopy for its ability to rapidly detect microbial contaminants in mammalian cell culture. 

 Both methods were used to detect bacteria in Chinese hamster ovary (CHO) cell cultures. Epifluorescence microscopy was limited by filterability, media interference, and nonrobustness issues, whereas microcolonies fluorescent staining method enabled consistent detection of 

after eight, nine, and 48 hours of incubation. 

With epifluorescence microscopy, nonspiked treated CHO cells yielded a great deal of fluorescent debris and a very high background (see Figure 2A), which interferes with the detection of 

 (see Figure 2B). Because observation was difficult in the presence of cells, 

was spiked in CHO medium. The fluorescent background was removed, but it was still difficult to observe bacteria on the polycarbonate filter. The detection of the microorganisms was only possible when increasing the number of contaminants retained on the filter by tenfold (see Figure 2C). Microorganisms spiked in the mammalian cell culture were easily detected with the MFSM without any background or media interference (see Figure 2, D–F). Background noise was minimized as a result of lysing the CHO cells before the filtration using the mammalian cell lysis solution; this buffer eliminates CHO cells while minimizing the impact on microorganisms. Similar results were obtained for both methods with 

As a result of the nondestructive feature of the MFSM, stained membranes could be reincubated on culture media to yield visible colonies that can be collected for further identification using existing identification methodologies (i.e., biochemical, morphological, nucleic-acid analytics, etc.). The ability to identify the microorganism can accelerate the root cause analysis and implementation of the corrective/preventative action (CAPA) plan.  

  6.  J. Moldenhauer,  (2008) "Overview of rapid microbiological methods" in 

Principles of Bacterial Detection: Biosensors, Recognition Receptors and Microsystems

 M. Zourob, S. Elwary, and A. Turner, Eds. (Springer New York, 2008) pp. 49–79. 

 10. K. Mignon-Godefroy, J.G. Guillet, and C. Butor, 

Growth-Based System for Rapid Microbial Testing

Currently available growth-based rapid microbiological methods provide either a quantitative cell count, estimation of viable cell concentration, information regarding the presence of a specific microorganism, or a microbial identification. However, the ability of these rapid microbiological methods technologies are limited in scope in that they cannot be used to perform all the required assays using a single technology platform. A new automated growth-based system simultaneously detects microbial growth, provides an estimation of viable cell counts, and identifies the presence of specified micro-organisms. 

 The system is based upon detection of optical variations due to microbial metabolism in liquid medium within a two-zone ready-to-use test vial. An optical sensor monitors optical changes within the vial's reading zone, which is physically separated from the incubation zone. This two-zone approach prevents masking of the optical pathway by product or microbial turbidity and, therefore, eliminates product interference. Separate test vials are used to automatically detect the presence of viable microorganisms and to estimate the concentration of viable counts by monitoring changes in CO

 production during cellular growth. The CO

  sensor is composted of a matrix of a polymeric material that is transparent to light and contains an indicator agent sensitive to CO

  gas generated by micororganisms, changing the indicator color from blue-green to yellow. Alternatively, the hydolysis of fluorogenic synthetic substrates by bacterial enzymes can cause an increase in fluorescence. Also, pH changes can be monitored calorimetrically. Each of these applications can be simultaneously performed using the same instrumentation and at the same time.  

The sensitivity of the system is a single viable cell per sample vial; when a single cell replicates to a specific detection threshold level, a positive response is recorded. The threshold level is ~100,000 cells/mL for bacteria and ~10,000 cells/mL for yeast and molds. Additionally, the system yields significantly faster results than the plate count method; one bacterial cell is usually detected within 8–18 hours, a single yeast cell is detected in 20–30 hours, and mold cells require 35–48 hours.   

The system creates dynamic patterns as the microorganisms grow in the medium. As shown in Figure 1, the green curve shows a pattern where no growth had occurred. The curve is flat without any significant increase in the signal and no detection time (DT) is observed. The blue curve shows the pattern generated when the microorganism grows in the vial (a DT of 11 hours is observed). 

In highly contaminated samples, bacteria are typically detected in 8–12 hours, yeast in 16–24 hours, and mold in 24–35 hours, providing timely warning of contamination. 

 Each BioLumix instrument has a capacity of 32 sample locations with a single incubating temperature. Multiple instruments (up to 32 instruments) can be attached to a single computer with Windows-based program that controls the operation of the instrument(s) and is barcode capable. The software is validated to meet 21 

 Part 11 requirements, provides an audit trail, operator identification (log in and log out), trend analysis, and provides various data reports. Detection events are automatically displayed. 

A critical element of the technology is the two-zone detection vial with an upper incubation zone where the sample is added and a lower reading zone that remains optically clear and free of turbidity from microorganisms and sample components. This two-zone vial design eliminates interference of the optical pathway during color and fluorescence monitoring by the sample and microbial growth.   

The data generated for the comparison of the growth-based rapid method to 

Microbial Examination of Nonsterile Products: Microbial Enumeration Tests

, is summarized in Table I. The table shows the specification ranges tested, the number of samples, and the percent agreement between the new method and the 

 plate count method using soybean casein digest agar. 

(i) Naturally contaminated samples: Two hundred and one nonsterile over-the-counter medicine samples such as vitamins, antacids, suppositories, laxatives, ibuprofin, and aspirin were tested. All noninoculated samples were below the detection level by both methods. There was 100% agreement between the two methods in classifying samples as above or below the specification levels. This indicates the ability of the BioLumix system to yield equivalent results to the plate count method when detecting growth over the range of 10 cfu/g to 1000 cfu/g.   

(ii) Inoculated products: Fifty-nine products were inoculated with all the organisms cited in 

 <61>. Ten inoculated samples had counts below the specification level and all were correctly classified as the challenge organism by the BioLumix system. There was 100% agreement between the two methods in determining whether samples were above or below the specification level.  

As shown in Table I, similar data were obtained for yeast and mold as well as Gram negative bile-tolerant bacteria. The data indicate the ability of the system to yield equivalent results to the plate-count method over the range of 10–1000 cfu/g for both of these assays. 

The method has good specificity in detecting target organisms and excluding nontarget flora, and the detection limit for the system equals or is slightly better that the limit for the plate count method. High precision or repeatability was obtained for all three assays tested. It can be used to detect the presence or absence of organisms, total aerobic count, the presence of yeast and mold, enterobacterial count, and absence of objectionable organisms in 10 grams of product. By encompassing both 

types of testing, the system offers a complete screening solution, making the existing microbial testing simpler, faster, and automated.  

In this technical forum, experts describe different methods of rapid microbial testing and their applications.

Rapid Microbial Testing

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, 

 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. 

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%. 

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. 

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.

The 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.

The 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.

1. J. Woo, S. Wolfgang, and H. Batista, Clin. Pharmacol. & Therapeut.

 (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. 

To learn more about this ongoing survey, the broader researchinitiatives, and/or CBI at MIT, please contact CBI at cbi@mit.eduor 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," 

For additional resources and online exclusives on this topic, visit 

Readers share their views on bioprocessing challenges, equipment use, and outsourcing trends in our annual bioprocessing equipment and processing survey.

Bioprocessing Trends: Annual Survey Results

 to FDA, requesting that the agency not consider any applications for biosimilar versions of its monoclonal antibody therapeutic, Humira. Abbott’s legal team argues that the Biologic License Agreement (BLA) for Humira contains trade secrets, and even if FDA does not directly divulge any of those secrets to companies seeking to copy Humira, the agency cannot help but use those secrets when deciding whether a competitor’s application should be approved. Furthermore, they argue that the use of those trade secrets to advance a competitor would constitute a taking of Abbott’s property. The BLA for Humira was approved before the Biologics Price Competition and Innovation Act (BCPIA) was enacted, and Abbott argues that it submitted its BLA without any expectation that the contents would eventually be used to approve another company’s product. Therefore, no biologic approved before the enactment of the BCPIA should be the basis of a biosimilar approval.

	Will this fly? It’s hard to imagine, given the precedents set by the generic drug approval pathway, and the reality of how FDA approves drugs. But it reads as a shot across the bow to those coming along behind with biosimilar versions of Abbott’s products. Be prepared to discuss the matter further in court.

Abbott Laboratories submitted a Citizen’s Petition to FDA, requesting that the agency not consider any applications for biosimilar versions of its monoclonal antibody therapeutic.

Abbott Requests Indefinite Protection from Biosimilars Competition

	Apr. 16, 2012 marked the closing date for submitting comments on FDA’s draft guidance documents clarifying the approval process for biosimilars. More than 35 pharmaceutical companies, trade associations, and patient advocacy groups submitted public comments on the guidance documents, which are available 

	A careful slog through the comments, revealed a few common issues, but also some topics that reflected the commentator’s industry outlook. Both BIO and PhRMA, industry trade groups, commented on the importance of protecting the innovator’s data until the period of exclusivity had expired, and also requested that the criteria for granting exclusivity be further clarified.

	More than a few of the commentators asked for clarification around interchangeability. The guidance document has little detail on the topic, other than defining it as an approval designation permitting free substitution with the innovator product. Companies including Elan, Bayer, and Novo Nordisk asked that the agency provide more detail around the requirements for interchangeability, both in terms of product characterization and the sequence of steps to follow to obtain that designation.

	While the abbreviated biosimilars pathway is intended to reduce the amount of clinical testing required for approval, there was a call from several commentators, including Elan, Novo Nordisk, the Alliance for Safe Biologic Medicines, and Amgen to preserve some requirements for clinical studies to ensure patient safety. According to Elan, there should be no cases where biosimilarity to a reference product, particularly for a monoclonal antibody, should be demonstrated by analytical means alone.

	FDA will convene for a public hearing on May 11, 2012 to hear further commentary on the guidances, and I’m looking forward to hearing more on the topic. For those who don’t live near the FDA campus, the event is being webcast: more information 

Apr. 16, 2012 marked the closing date for submitting comments on FDA’s draft guidance documents clarifying the approval process for biosimilars.