Michelle Hoffman, editorial director of Pharmaceutical Technology.

Michelle Hoffman

 Otonomy has developed a formulation platform that enables local delivery of drugs into the ear to treat middle- and inner-ear conditions such as Meniere's disease*, certain forms of hearing loss, and infection. The diseases have traditionally been treated by surgical means. I understand the company had an unusual beginning. Can you tell me about that? 

The genesis of the idea for Otonomy came when Jay Lichter, a venture capitalist and the company's CEO, experienced severe vertigo while driving in January 2008. He made his way to the clinic of Jeffrey Harris, professor and chief of the Division of Otolaryngology–Head & Neck Surgery at the University of California, San Diego, in February of that year. Harris diagnosed Lichter with Meniere's Disease. Lichter, a serial entrepreneur, and Harris discussed the potential of forming a biotech company to develop targeted therapeutics specifically for ear disorders—and in April 2008, Otonomy was born.  

Otonomy's Chief Scientific Officer Carl LeBel 

 Could you describe the state-of-the-art for these kinds of therapeutics? 

 At this time, it remains a challenge to get therapeutics into the middle and inner ear. The only targeted delivery available requires a surgeon to insert a tube into the middle ear and infuse drugs through it for the treatment of otitis media. Some physicians today employ a technique in which they inject drugs 

 a syringe into the middle ear, referred to as intratympanic administration. These drugs are typically formulations approved for intravenous administration, yet no one has studied their suitability for direct access to the middle or inner ear. Beyond that, there's the additional problem of drainage. Fluid drains from the ear through the Eustachian tubes, and therefore drugs can't remain in the compartment long enough to provide much therapeutic benefit.  

Oral delivery of therapeutics had also been tried. But the doses required to ensure therapeutic benefit to the ear are sometimes so high as to risk inducing some kind of systemic toxicity. The ideal would be to deliver a drug directly to the middle ear in such a way as to reduce elimination through the Eustachian tubes, and limit systemic exposure. 

 Essentially yes. Lichter and Harris reasoned that they could overcome these challenges if they could produce a formulation that kept drugs in the middle ear, and is also safe and tolerable. The goal was to focus on an injectable formulation for intratympanic delivery and optimal retention of the drug, allowing it to diffuse through the round window membrane of the cochlea and gain access to the inner-ear fluids. 

Otonomy has developed a formulation that is essentially a mixture of copolymers (polyethylene glycol and polypropylene) combined with a steroid. Key to this mixture's suitability is its thermo-reversible properties. At room temperature, [the mixture] is a solution. After the mixture is injected into the middle ear, the temperature rises to body temperature, and the mixture transitions to a gel state. We can also manipulate the relative concentrations of the gel's components to alter the temperature at which the mixture transitions from solution to gel. We refer to our lead formulation as OTO–104, which is a steroid in Poloxamer 407 and might be useful in sinusitis surgery and laryngeal surgery to prevent scarring. 

The value of poloxamers is that one can easily draw them into a syringe while they're in solution. [One] can use a traditional 25–27 gauge, with a 4-inch needle, which is long enough to advance through the ear canal and inject the solution into the tympanic cavity or middle ear. Within seconds of encountering the patient's higher body temperature, the solution transitions to a gel. As a gel, the formulation adheres to the epithelial lining of the middle-ear space, where it can remain in place long enough to deliver the drug for a prolonged period of time to the inner-ear fluids.  

One other feature of poloxamers is that you can also adjust the concentrations of the polymers to optimally control a drug's release profile. You can develop short or longer-acting drugs by altering the relative concentrations of the polymers. 

 How long can poloxamers retain a drug in the ear cavity? 

 In animal studies, the observed duration was as short as three consecutive days and as long as six weeks. But we suspect drug can be retained for two or three months. 

 How will regulators respond to this formulation? 

 Several of these components, independently and in mixtures, are already on the US Food and Drug Administration's safe list. In addition, these components are in approved pharmaceutical preparations and are commercially available. We typically purchase poloxamer from BASF [Ludwigshafen, Germany]. We recently held our pre-investigational new drug (IND) filing meeting with FDA. We intend to file an IND later this year for the purpose of testing our first drug candidate in humans, and they seem to concur with our strategy, pending formal FDA review of our IND. 

 Can you tell me about the indication you'll be filing on and more specifically about the steroid?  

 We'll be testing the use of the steroid dexamethasone in this formulation to treat Meniere's disease. 

 How did you choose that active pharmaceutical ingredient (API)?

 There have been numerous publications in the medical literature suggesting that steroids injected intratympanically provide clinical benefit in the treatment of Meniere's. Many papers report a reduced frequency in episodes of vertigo. But not everyone is in agreement about the results, and we believe that part of the problem is the issue of limited drug exposure. That is, there's some question about whether the adequate delivery of drugs to the middle ear with adequate exposure to the drug can produce a therapeutic benefit. We're hoping that Otonomy's new formulation will allow physicians to settle that question once and for all. 

Our clinical trial, which we project will start early in 2010, will look at the dose/response profile of dexamethasone in Poloxamer 407 versus Poloxamer 407 alone in patients with Meniere's disease. Our goal would be to provide a formulation that allows for sustained steroid exposure for approximately one month. 

 How do you imagine the drug will be packaged once it reaches commercial release? 

 Ideally, we'd like to offer it in a prefilled syringe or single-use vial. We don't yet know whether it will be premixed or mixed on injection. 

 Yes. The platform is very flexible and theoretically can be used for local delivery of small-molecule antibiotics to treat infections as well as small-molecule glutamate receptor antagonists to help treat certain kinds of hearing loss. In addition, we think it can be used to deliver larger molecule neurotrophic factors such as brain-derived neurotrophic factor or glial-cell line derived neurotrophic factor, which may alo be useful in treating hearing loss. We also imagine that we can combine the basic poloxamers with additional ingredients (e.g., permeabilizing agents, bulking agents, stabilizers, or solubilizers) as needed to optimize drug delivery. 

 Could this formulation be used to treat diseases in other organs? 

 Poloxamers are used in other pharmaceutical preparations to deliver drugs to the eye, gums, and abdomen. However, we're dedicated to treatments for inner- and middle-ear disorders at this time. 

 defines Meniere's disease as follows: Meniere's disease is a disorder of the inner ear that causes abnormal sensory perceptions, including a sensation of a spinning motion (vertigo), hearing loss usually in one ear, fullness or pressure in the same ear, and ringing in the same ear (tinnitus).  People in their 40s and 50s are more likely than people in other age groups to develop Meniere's disease. Estimates of the number of people with Meniere's disease vary significantly, but according to the National Institute on Deafness and Other Communication Disorders, about 615,000 people in the United States have the disease.  

Articles

Targeting Therapeutics for the Middle and Inner Ear

"Pfizer drank the [quality-by-design] Kool-Aid," commented Gerry Migliaccio, Pfizer's vice-president of quality, in his keynote address at PharmTech's annual conference last month, and then he wondered aloud why some other companies hadn't done the same. Which got me thinking that now, several years after the US Food and Drug Administration launched the initiative—how many companies actually are implementing quality-by-design (QbD) principles, and why or why not? 

We've conducted a few surveys during the past year that address aspects of that question. For example, nearly 60% of respondents to our December 2008 Innovation Survey reported that either they work on projects directly or for companies that have implemented projects incorporating QbD. More recently, about 70% of respondents to our July 2009 Bioprocessing Survey reported incorporating QbD into their processes. About 50% of those not incorporating QbD into their bioprocesses anticipated that QbD would provide no process advantage—which runs contrary to the experiences of those who do. Eighty-one percent said that the use of process analytical technology (PAT)—an important component of the QbD paradigm—resulted in better process understanding. Almost 70% credited PAT implementation with improving their manufacturing efficiency, and an additional 47% percent felt they'd improved their regulatory compliance (multiple answers were allowed, so the total exceeds 100%). 

Of those who do not incorporate QbD principles into their bioprocesses, almost 40% said they did not understand the initiative, and almost an equal number felt they lacked appropriate direction from the regulatory agencies. Which brings me to my next point—the role of the regulatory agencies in QbD, FDA in particular. 

Participants at the PharmTech conference pointed out that although QbD is not technically mandatory, there seems to be an expectation to implement QbD. This expectation may soon be more than just a feeling among industry as FDA ramps us its vigilance and enforcement.  

In an August 6 address to the Food and Drug Law Institute, FDA Commissioner Margaret Hamburg threw down the gauntlet. After listing a litany of attributes of a strong FDA, Dr. Hamburg declared, "And a strong FDA enforces the law," according to a transcript of her remarks posted on the FDA website. The sentence was highlighted in boldface type.  

She went on to say that although she was impressed with the commitment that many companies have made to compliance "both in terms of their corporate culture and their investment in compliance systems," FDA's goal is for "all companies to make and implement such a commitment." A key part of this strategy, Dr. Hamburg said, is to support private-sector compliance through "effective enforcement against violations of the law." 

Under the new regime, FDA expects "companies will work quickly and thoroughly [to] correct deficiencies and ensure safety." How quickly? The timeline to demonstrate corrections seems to be very short indeed. Noting that "serious violations have gone unaddressed for far too long," Dr. Hamburg challenged industry to deliver a "prompt response," stating that a firm will "generally have no more than 15 working days in which to respond before the FDA moves ahead with a Warning Letter or enforcement action." Furthermore, Dr. Hamburg promised that Warning Letters would be issued with greater speed than before and that "FDA will no loner issue multiple Warning Letters to noncompliant firms before taking enforcement action."  

In fact, in the most egregious violations, the agency is prepared to consider "immediate action—even before we have issued a formal Warning Letter," said Dr. Hamburg. She ended her speech by saying, "The solution is a commitment to compliance backed by a strong compliance program. Now is a good time to reassess whether you have  such an effort in place."  

I strongly suspect she was talking to the 30% or so of companies not implementing QbD. Because what does that paradigm allow a company to do after all, but to understand its manufacturing processes in such detail that when a product or process does fall out of compliance, the company can address the deficiency and correct it swiftly, say within 15 working days? It's interesting to note that about 50% of respondents to our March 2009 Equipment and Machinery Survey purchase new equipment to remain GMP-compliant. This is an industry motivated most by Federal mandates. So, although FDA may not mandate QbD, it certainly seems that companies practicing it will be in a better position to respond to FDA's increased vigilance and enforcement stance. In other words, I think many more pharmaceutical companies will be serving up Kool-Aid very soon.  

After years of promomting QbD concepts, FDA's ready to take action on nonconformers.

Quality by Enforcement

Eliot Spitzer, Lehman Brothers, Richard Nixon, Ranbaxy. Don't see the pattern? The common thread here is the self-imploding career. Eliot Spitzer's was derailed by a prostitution scandal, following a brilliant tenure as New York State's Attorney General and a record-breaking election that made him the state's governor—for little more than a year.  

Lehman Brothers filed for bankruptcy in 2008, thus ending its 158-year history as one of Wall Street's most successful investment houses after CEO Richard Fuld and a handful of his executive minions made what observers call risky, even reckless investments. 

Richard Nixon's undoing was the series of events referred to as "Watergate," which started with the attempted break-in and bugging of Democratic Committee offices at Washington's Watergate Hotel by operatives connected to Nixon's reelection campaign and ultimately to the President himself. Many have speculated that the break-in was a misguided attempt to gain advantage in the election—needlessly. Nixon won the election in a landslide victory, capturing more than 60% of the popular vote, the kind of commanding lead enjoyed by only three presidents before him. He left office less than two years into his second term. 

This brings me to Ranbaxy. India's largest pharmaceutical company, and one of the top 10 generic drug manufacturers in the world, has been called out with alarming frequency for deviations from good manufacturing practices (GMPs).  According to a Feb. 26, 2009, 

 article by Lyndsey Layton, Ranbaxy's troubles first came to light in 2006, when US Food and Drug Administration investigators at the company's plant in Paonta Sahib, India, turned up "reams of laboratory tests that were inaccurate or missing information." Ranbaxy made headlines again in September 2008 after receiving warning letters from FDA citing GMP deviations. Falsified laboratory reports landed the company a spot in the news again in February 2009; and once more in May 2009, when certain lots of Nitrofurantoin capsules were determined not to be "in conformity with the approved laboratory specifications," according to a company statement quoted in a May 2 

 report. And on July 20, Erik Greb reported in PharmTech's blog that 1303 cartons of isotretinoin had to be pulled after FDA found the "product's dissolution-test results were out of specification."  

So my question is, Why would an individual, or an organization, short-circuit its own success?  

 entitled "Explanations of Success and Derailment in Upper-Level Management Positions" lists the following qualities of the successful executive: 

3. The ability to remain cool in a crisis 

4. The ability to adapt to different kinds of bosses. 

With these four traits as a guide, let's see whether Ranbaxy has what it takes to remain on course. Is Ranbaxy able to deal with the increasing complexity of a larger more successful organization? Or is it possible that Ranbaxy's continued growth creates a level of corporate complexity that its executives and quality officers are unprepared to handle? And as a corollary, maybe it's also possible that the company is ill-equipped to adapt to the demands of the various international regulatory agencies—"bosses" of a sort—with which it has to deal to sell its products across borders. 

 How about integrity? Well, without being inside the company, it's impossible for me to assess that or the company's ability to keep cool in a crisis. But from this vantage point, it's difficult to feel that a company that has repeatedly falsified data, laboratory analytical tests, and reports is operating within a culture of integrity. The increasing frequency of these incidents suggests that someone is losing his cool.  

Here's another possibility: Ranbaxy, like Spitzer, Lehman's, and Nixon, has succumbed to the belief that its success indemnifies it from censure. If so, repeated warnings and product seizures should disabuse the company of that belief. Or, perhaps these incidents can be chalked up to some garden variety shortcuts in quality control meant to boost profits. After all, conducting careful quality control is expensive, as is discarding out-of-spec product.  

And finally, do Ranbaxy's motives really matter? All of these stories could have had very different endings. Ranbaxy still has time to rewrite theirs. Let's hope they do. 

Individuals and companies at the top seem to have no problem short-circuiting their success.

Of Hubris and Happy Endings

With so many mergers and acquisitions lately, many of life pharmaceutical companies you grew up with many have disappeared, absorbed into other companies or spun out to make their way on their own. Here, the editors of 

 trace the corporate lineages for the past 30 or so years for pharma's top 15 companies.  

View the Bristol-Myers Squibb family tree.  

View the Glaxo SmithKline family tree.   

View the Johnson " Johnson family tree.  

View the Schering-Plough/Merck family tree.  

http://www.msd.com.hk/about_us/e_history_of_merck.html

Read about the top 50 pharma companies in "

Big Pharma Tightens Its Belt in Global Manufacturing

View the corporate lineages of pharma's top companies.

The Pharma Family Tree

 Outsourcing has increasingly become the mark of good resource management on the part of modern pharmaceutical companies. Why invest in equipment, machinery, space, and human resources for a novel process or product, and why spend time slogging up the learning curve, if you can find a partner company who already has the skill and equipment to move your project forward? This realization is especially relevant for firms entering new markets, manufacturing new drug types, or using novel formulations and delivery mechanisms.   

Outsourcing can be an attractive alternative for products in any stage of development, from early-stage formulation and process development through commercial-scale production. By outsourcing, the client company maximizes efficiency—freeing up time, personnel, and equipment to do what it does best, and at the same time reduces its investment exposure and capital expenditures. The partnership can be quite reasonable, but does not come without its own challenges.  

For in outsourcing, a sponsor company is giving up a good deal of control and has to balance the risk and rewards of keeping a project in-house with those of working with external partners. This challenge, although always present in any outsourced relationship, becomes more difficult with increased complexity in the supply chain. The basic expectations and requirements for the client and the outsource service provider have not changed. On-time delivery, meeting product specifications, regulatory compliance, and product quality remain the cornerstone of any successful outsourced relationship.  

The outsourcing relationship, however, increasingly operates in a truly global pharmaceutical supply chain through the supply of raw materials, ingredients, or the delivery of the contract services themselves. And with the elongation of the supply chain comes attendant obligations and costs in securing that supply chain.  

We've heard tales from firms that the cost of their due diligence can exceed the cost of the service contract, at least for the initial project. Furthermore, it's been estimated that the pharmaceutical industry collectively performs 800,000 audits each year to ensure the quality of its suppliers in the US and abroad. That's got to use up a lot of resources (not to mention paper). 

It is for this reason we applaud and encourage efforts such as those of the Rx-360 consortium, an industry initiative, which held its launch meeting in June, with an overarching mission of supporting product quality and authenticity throughout the supply chain. Among the group's efforts is to explore the feasibility, acceptability, and potential approaches for shared supplier audits.  

The consortium seeks to develop a system that will make audits broader and more thorough and will allow firms to share audit findings and corrective actions, making the system more effective and efficient. Each consortium member company could use this information for its own independent assessments on the appropriateness of a supplier based on their own company policies and product needs. Obviously, the needs of each client may differ, and standardizing audit information to make it useful to the greatest number of clients in the greatest number of cases won't be easy. Nevertheless, the ultimate saving in time alone could be worth its weight in—well, if not gold, at least in paper. 

As the pharmaceutical supply chain expands, sponsor companies need to weigh all their options.

Growing Pains

While on the ferry between Manhattan and New Jersey, I struck up a conversation with a fellow traveler, an investment banker who follows the pharmaceutical and healthcare industries, as it turns out. The first thing he told me was that the economy would turn around in September 2009—not too long to wait. The second thing he told me was that the rally would be led by the healthcare and pharmaceutical industries, due specifically to all the new biopharmaceutical products that would be released on the market. The timetable seems a little tight, but the expectation for new biopharmaceutical products to reignite a stalled economy is hardly news to anyone who works in—or really follows—the healthcare and pharmaceutical industries.  

Surveys conducted in this magazine and by countless accounting firms, investment houses, and marketing outfits have for some time been predicting an economic boost from the development and sale of biopharmaceuticals. And even the most cursory walk around the exhibit hall of the Biotechnology International Organization's annual conference will reveal that a great many geographic regions—from US cities, counties, and states, to entire nations—are banking on biotechnology and its drug products to lift their economies out of the doldrums.  

Over the past few years, other large industry trade shows traditionally devoted to the science of small-molecule drug manufacturing have increasingly added tracks addressing the needs of biopharmaceutical manufacturers. Equipment manufacturers are increasingly expanding their productive offerings to include equipment and consumables geared toward biopharmaceutical manufacturing. Clearly, it's not just investment bankers that expect growth in this sector of the pharmaceutical industry. 

Given all of the gathering interest in large-molecule drug manufacturing, we at 

thought it high time to survey our readers involved in some aspect of biopharmaceutical manufacturing to learn more about the products they produce, the equipment they use, and the challenges they encounter. The following is a summary of the results to our survey questions from respondents, representing the roughly 41% of our readers engaged in the manufacture of biopharmaceuticals. The values given are 95% accurate to within 6.3 percentage points plus or minus. 

Thirty-three percent of respondents work for companies that produce biopharmaceuticals only; 46% produce both biopharmaceutical and small-molecule drugs; and the rest produce equipment and/or services for the biopharmaceutical manufacturing market (see Figure 1). 

 Figure 1: Companies producing small-molecule versus large-molecule drugs. 

More than 50% of respondents work for companies that have been producing biopharmaceuticals for more than five years; 2008 was the year in which the greatest amount of biopharmaceutical manufacturing capacity was added, with 8.1% of respondents reporting the addition. Five-and-a-half percent respondents report their company added biopharmaceutical manufacturing capacity in 2007, and 5.1% said their companies added capacity this year. Fifty-nine percent of respondents reported the additional capacity was added to accommodate internally developed products; almost 29% of respondents say that biopharmaceutical capacity and products came into their companies through mergers or acquisition; and 24% reported that biopharmaceutical drugs were in-licensed (see Figure 2, multiple answers were allowed). 

Figure 2: Reasons for adding biocapacity. Total exceeds 100% because multiple responses were allowed. 

The press has been so focused on monoclonal antibody (mAb) drugs, that we were surprised to learn that a majority (56%) of respondents manufacture protein and peptide drugs other than mAbs, which are manufactured by 43% of respondents. Almost 18% of respondents manufacture nucleic-acid based drugs, and 17% of respondents manufacture cells for tissue and cell therapies—a field on which many are heaping high hopes, especially now that government funds are available for embryonic stem-cell research (see Figure 3). Thirty-eight percent expect their companies will manufacture follow-on biologics; 22% expect their companies will not manufacture follow-ons; and 39% don't know. 

Figure 3: Product mix. Total exceeds 100% because multiple responses were allowed. mAb is monoclonal antibody. 

We queried respondents about the challenges they face manufacturing their respective products, and among manufacturers of protein-based drugs, we found something of a schism. Fifty percent—fully half—of those producing protein drugs, including mABs, said that they had difficulty producing high enough product yields. And yet 44% reported that purifying protein products was a challenge because yields were so high. Product instability was a problem for almost 40% of respondents, while contamination was a problem for 20% (see Figure 4). 

Figure 4: Technical problems reported in protein manufacturing. Total exceeds 100% because multiple responses were allowed. 

Stability seems to be a problem confronting 56% of producers of nucleic-acid based drugs, with another 50% reporting difficulties with purifying these products. Thirty-six percent have formulation problems, and almost 28% find it a problem to produce adequate yields. 

Industrial-scale cell manufacturing is still in its relative infancy, as evidenced by the fact that 62% of respondents said that developing a manufacturing process posed a challenge to them. Forty-three percent reported difficulties maintaining product stability and uniformity, while 32% said that formulating cell-based therapies posed a challenge. Almost 30% have difficulty finding bioreactors of adequate volume to accommodate their product yields. 

We were especially curious to learn how manufacturers were purifying their protein-based products. We learned that 72% use ion-exchange chromatography, 62% use membrane-based filters, and 52% use Protein-A-based chromatography, often thought of as the standard for mAb purification (see Table I). 

Table I: Purification technologies used for protein-based drugs (multiple responses allowed). 

There has been an ongoing debate among equipment vendors about the merits of disposable, often plastic, versus stainless-steel equipment for biopharmaceutical manufacturing. Vendors tend to cite cost, ease of use, and reduced opportunities for contamination as advantages of disposable equipment.  

We thought it would be interesting to learn what equipment people are actually using and their attitudes about the equipment classes they're not using. The results were illuminating. Only 7.5% are using all disposable equipment, 19% are using all stainless steel, and the vast majority—74%—use a combination of stainless-steel and disposable equipment (see Figure 5).  

Figure 5: Stainless-steel versus disposable equipment use. 

Next, we wondered whether equipment classes in any way followed the type of product manufactured. For instance, do protein manufacturers have a preference for a particular equipment class compared with manufacturers of nucleic-acid-based drugs. We found that regardless of product type, the choice of equipment used tracked very closely to the group as a whole. Eighty-one percent of mAb producers use a combination of stainless-steel and disposable equipment; 4.2% use all disposable equipment; and 15% use all stainless-steel equipment. Among producers of proteins other than mAbs, the results were similar: 80% used a combination; 5% used all disposable; and 15% used all stainless steel. All-disposable use was highest among manufacturers of nucleic-acid-based drugs (10%) (see Table II). 

Table II:  Type of equipment used to manufacture biopharmaceuticals. 

Interestingly, users of stainless-steel equipment are most inclined to switch to disposables and not the other way around. Of those currently using all stainless-steel equipment, 21% are considering switching to disposable equipment, and 52% are not. Yet, among those using all disposable equipment, 65% report that they will not go back to stainless-steel equipment, while the remaining 35% do not know. 

Figure 5A: Perceived advantages of disposables (all biopharmaceutical manufacturers, regardless of equipment used). Total exceeds 100% because multple responses were allowed. 

We noted some marked disparities in perceptions and realities about various types of equipment, depending on what manufacturers are currently using (see Figure 5A). Specifically, the perceptions of disposable equipment among users of stainless-steel equipment were more negative than among those who actually use disposable equipment. For example, among manufacturers using all stainless-steel equipment, only 7.3% think that process reproducibility could be an advantage to all disposable equipment. In contrast, 53% of those using all disposable equipment cite process reproducibility as an advantage. Only 68% of those who use stainless-steel equipment believe that contamination could be reduced by using all disposable equipment, versus 82% of those who actually use all disposable equipment (see Table III). Only 39% of stainless-steel equipment users think disposables would be easy to use, as opposed to 71% who use disposables and find them easy to use. Only 10% of stainless-steel equipment users think it would be easy to incorporate process analytics into a disposable-only facility; 24% of those who actually use disposables say that it's easy to incorporate process analytics into their facilities. Finally, about 20% of stainless-steel users believe regulatory bodies will accept the use of disposables; 35% of those that actually use disposables cite regulatory acceptance as an advantage. 

Table III: Perceived advantages of using disposable equipment. 

It also happens that stainless-steel equipment users underestimate some of the challenges inherent in disposable use. Among those who use all disposable equipment, 44% cite leaching of disposable components into cell-culture medium as a challenge, compared with 28% of all-stainless-steel users. A higher percent of disposable users—38%—find inadequate bioreactor volumes a challenge, versus 26% of stainless-steel users (see Table IV). 

Table IV: Perceived challenges  to using disposable equipment. 

We hear that, in general, pharmaceutical manufacturers are outsourcing more, so we wondered how much biopharmaceutical manufacturing is outsourced. Among our respondents, 30% outsource biotherapeutic manufacturing, and 50% do not. The remaining 20% do not know whether their company outsources. But among those who do outsource, 63% outsource both active pharmaceutical ingredient (API) and finished product manufacture; 18% outsource API manufacture only, and the remaining 19% outsource finished products only (see Figure 6). Fifty-nine percent of those who outsource say they do so because their companies have no or limited biopharmaceutical manufacturing capacity, and 45% say it is simply more cost effective to outsource. Nineteen percent say their companies outsource because they lack the technical expertise to manufacture biopharmaceuticals (see Table V). 

Figure 6: Types of projects outsourced. API is active pharmaceutical ingredient. 

So much of the focus on quality by design (QbD) has been directed toward small-molecule manufacturing, so we wondered how QbD initiatives were playing out for biopharmaceutical manufacturers. Fully 70% of biopharmaceutical manufacturers incorporate QbD principles into their process design. Among those who don't, 48% say they don't see any advantages to be gained by using QBD; 38% say they don't understand the initiatives; and an equal number—38%—say they lack direction from regulatory authorities. Seventeen percent say QbD initiatives are too costly. 

Table V:  Reasons for outsourcing biotherapeutics manufacturing  (multiple responses allowed). 

Fifty-two percent of respondents use process analytical technology (PAT) in their biopharmaceutical manufacturing operations, while 26% don't, and 23% don't know. Of those who do incorporate PAT, 81% claimed they gained better process understanding; 67% report increased manufacturing efficiency; 47% say they've achieved better regulatory compliance; and 38% say they've reduced costs as a result of PAT implementation. Sixty-seven percent incorporate chromatography into their process analytics; 42% use spectroscopy; and 13.5% use other technologies, including various forms of infrared spectrometry (see Figure 7). 

Figure 7: Process analytical technology techniques used. Total exceeds 100% as multiple responses were allowed. 

Finally, we asked about past and future plans to spend on equipment for biopharmaceutical manufacturing. Although half of the respondents did not know how much, as a percentage of sales, their companies spent on biopharmaceutical manufacturing in 2008, 34% said their companies spent up to 8%. An additional 11% thought their companies devoted more than 10% of sales revenues to biopharmaceutical manufacturing equipment. Thirty percent of respondents expect their companies to allocate up to 8% of 2009 sales on the purchase of equipment related to biopharmaceutical manufacturing. Eight percent expect their companies' 2009 spending to exceed 10% of sales; 58% don't know. Twenty-nine percent of respondents think their companies will increase their spending over 2008 on biopharmaceutical manufacturing in 2009. Who knows? Maybe that investment banker was right after all.  

 Biopharmaceutical Manufacturing Survey targeted individuals who work for companies engaged in biopharmaceutical manufacturing. Thirty-five percent of respondents work for innovator pharmaceutical companies, 29% work for biotechnology companies; 12% work for contract manufacturers; and 3% work for generic drug manufacturers. Respondents' companies mean annual sales revenues are $11.8 billion. 

Twenty-six percent of respondents are engaged in research; 24% work in production management; and 19% work in QA/QC analysis. The total mean biopharmaceutical experience of respondents is 16 years, and their mean age is 46.5 years. Eighty-nine percent of respondents work in the United States, including Puerto Rico; 4.2% work in Western Europe; and 3.3% work in Canada. The survey was developed by 

and Advanstar's corporate research department and reflects the responses of 239 participants. 

A Pharmaceutical Technology report looks at trends in biopharmaceutical manufacturing. This article contains bonus online-exclusive material.