The Biopharmaceutical Manufacturing Survey

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 Pharmaceutical Technology 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.

Products and processes

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.

Production challenges

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.

Equipment

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.

Outsourcing

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.

Quality by design

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.

Spending

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.

Respondents profile

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