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State of the Pharmaceutical & BioPharmaceutical induStry 2013

2 State of the Pharmaceutical & BioPharmaceutical induSty 2013 Pharmaceutical manufacturing • www.Pharmamanufacturing.com

CONTENTSSTATE OF THE INDUSTRY 2013: AN INDUSTRY COmINg OF AgE 3It’s been 10 years since the FDA released Pharmaceutical GMPs for the 21st Century and the industry’s had some growing up to do — but with age comes wisdom and opportunity

gOOD vIbRATIONS: 2013 jOb AND SALARY SURvEY 9Respondents to Pharmaceutical Manufacturing’s 9th annual job satisfaction and salary survey find the industry is beginning to hit a few more high notes than last year

FOCUS ON EFFICIENCY: 2013 TRENDS WITHIN bIOPHARmACEUTICAL mANUFACTURINg 14Single-use systems, data analytics and downstream process at the forefront

CgmP jUDgEmENT DAY: LESSONS FROm RECENT FDA ENFORCEmENT ACTIvITIES 18A look at recent FDA enforcement activities and lessons to be learned

SANITARY CONNECTIONS IN PRESSURE RELIEF 22 Biogen Idec shares lessons learned over the past four years at its combined heat and power (CHP) plant

ADDITIONAL RESOURCES 28

AS OF Feb. 20, 2013, the U.S. Food and Drug Admin-istration’s Pharmaceutical GMPs for the 21st Century – A Risk-Based Approach is 10 years old. Originally met with a mix of relief, hope and skepticism, this blueprint for pharmaceutical development has inspired more commentary than any FDA strategy position. Like most 10-year-olds, it is very much a work in progress.

By Angelo DePalma, Ph.D.

State of the induStry 2013


coming of age it’s been 10 years

since the fda released Pharmaceutical GmPs

for the 21st century and the industry’s

had some growing up to do—but with age comes wisdom and

opportunity


GMPs for the 21st Century has profoundly influenced how drug companies manage risk, particularly but not exclusively with regard to manufacturing. The risk-based approach becomes particularly challenging given the backdrop of merger and acquisition activity and a heavier reliance on outsourcing for manufacturing and R&D. For manufacturing, this means negotiating the moving targets of productivity and supply chain demands.

While specifically covering risk, quality by design, and process analytics, GMPs have invigorated science-based process development, nudging it away from what is merely comfortable to what is possible.

QUALITY bY DESIgN Adoption of PAT and QbD, promulgated as part of FDA’s 2003-2004 GMPs for the 21st Century, was slow at first but is accelerating.

QbD required effort in terms of analytics and modeling (designing-in vs. testing-in quality), not to mention the implications of any “risk-based approach” for a risk-averse industry. Despite common belief, neither PAT nor QbD are mandated.

QbD case studies describing “home run” successes are increasing. Most involve what in many other industries would be viewed as common-sense measures for reducing cost and improving regulatory compliance.

QbD’s practical benefits to manufacturers include fewer failed batches, less regulatory friction, process understanding, more efficient control of change, etc. Each of these benefits may be broken down further, but all at some level reduce to an improved bottom line. The real benefit to patients is not necessarily improved safety or efficacy, but more reliable supply and the optimal allocation of resources to research and development.

QbD uptake has followed reasonable timelines, says Mike Thien, Sc.D., SVP for Global Scientific, Technology, and Commercialization Operations at Merck (Whitehouse Station, NJ). “QbD represents a paradigmatic shift in how companies develop products,” he explains. “It’s a framework that focuses where companies will allocate resources in developing science and methods for a product. It’s no surprise it has taken this long.”

Merck was a QbD pilot participant, and soon decided to adopt the strategy for most of its new products. Like any company facing paradigm shift, Merck first aligned its R&D, commercialization, quality and regulatory leadership, then trained everyone else to exploit the tools

of the QbD framework. After factoring in development and approval times, “10 years seems about right” to have reached this level of deployment, Thien says.

Merck’s QbD initiative resembles six sigma frameworks employed in other industries. As an early adopter, Merck management believed that if structured, risk-based quality initiatives worked for other industries, they could provide similar benefits for pharmaceuticals.

During the mid-to-late 2000s, industry leaders based their public rationalization of QbD on patient needs, which at the time seemed like a stretch. QbD was, after all, primarily a manufacturing exercise. Weren’t top companies already producing safe, effective products?

Yes, but as Thien explains, successful QbD begins rather than ends with the patient. It starts with identifying a patient’s needs, translating them into technical specifications for products and processes, and locating (and mitigating) risks that threaten fulfillment of those product/quality objectives. “We made great products in the past, but we were unable to focus resources as acutely, or immediately, on risk areas in light of specifications of patient needs. QbD enabled us to aim our best science at those highest-risk areas.”

Merck’s direct manufacturing benefits include processes that are more robust and reliable, with significantly fewer process-related deviations. For example, fewer assays are now required during release testing because quality assurance and modeling occur throughout the process, in real time, thanks to PAT. This results in lower cost of goods, a benefit that grows with product volume. “In some cases, PAT has enabled process viability, and thus led to the greener and higher-yielding processes that we now enjoy running at scale,” Thien says.

One could argue that corporate-wide initiatives like QbD are fine for well-heeled companies. That may have been true a few years into the initiative. Today, with best-in-class firms sharing their experiences at conferences, small and mid-sized manufacturers receive what amounts to a free education. Thien believes QbD’s prime benefit is its scientific, heads-on treatment of risk. “Risk assessment narrows your focus, to home in on where to invest resources to understand the process better, and the science behind it.”

Companies tend to create QbD programs in their own corporate image. At Janssen Pharmaceuticals (New Brunswick, NJ), QbD falls under the umbrella of “design to value” (DTV), a more encompassing quality initiative. According to Paul McKenzie, Ph.D., VP of Manufacturing

“We made great products in the past, but we were unable to focus resources as acutely, or immediately, on risk areas in light of specifications of patient needs. QbD enabled us

to aim our best science at those highest-risk areas.”

State of the induStry 2O13


and Technical Operations for Janssen Supply Chain, DTV assures the right mix of priorities around the “triangle” of R&D, commercial, and operations (including manufacturing and quality). “The other component is how we work towards standardizing our technology. Savings from standardization go to innovation, and further improving the QbD effort.”

Direct patient benefits are more easily ascribed to quality initiatives under the broader DTV concept than with conventional QbD, which is, after all, a manufacturing strategy. One success story involved creating a sustained-release form of an antipsychotic medication within a therapeutic category where non-compliance is legendary; the other involved a similar strategy for an anti-HIV medicine. “As patients get value, Janssen gets value,” McKenzie says.

CONTINUOUS mANUFACTURINgQuality, supply and regulatory uncertainties are the most-cited reasons for the slow adoption of manufac-turing innovations for new processes, and even slower uptake for existing ones.

Although common in other process industries, continuous manufacturing has long been shunned by pharmaceutical manufacturers. That is changing in a big way.

Novartis and the Massachusetts Institute of Technology are engaged in a 10-year program that hopes to integrate all steps of pharmaceutical production — from synthesis to dosage form — within one over-arching process. The Novartis-MIT Center for Continuous Manufacturing (CCM) hopes to replace discrete unit operations with a seamlessly continuous process.

“Continuous manufacturing will speed com-mercialization of new medicines because it does not involve interruption,” says Juan Andres, Head of Global TechOps at Novartis.

Potential advantages of continuous manufacturing include smaller production facilities, lower capital costs, energy and waste minimization, raw material economies, process and market flexibility, and the potential to incorporate process analytics and quality by design.

“Once you go to continuous, you begin to have continuous monitoring, so it’s much easier to control quality,” says MIT chemical engineering professor Klavs Jensen, a CCM participant and developer of the flow chemistry used in the project.

Continuous manufacturing could produce tablets in as little as a few days. By employing smaller systems and built-in waste minimization, continuous manufacturing has lower environmental impact as well.

CCM successfully completed a prototype process in 2011, and by 2012 had fully integrated a control system to automate the continuous manufacturing process. Researchers are focusing now on scaling up production with

the plan to ultimately implement continuous manufacturing technologies across the entire Novartis portfolio.

Writing in Industrial & Engineering Chemistry Research in 2011, Spencer Schaber and co-authors analyzed the potential cost savings for producing 2,000 tons of a pharmaceutical product through continuous vs. batch manufacturing. Although yields were somewhat lower for the continuous process under investigation, product recycling and lower equipment requirements more than compensated. Additionally, capital expenses were between 20% and 76% lower for the continuous process, while operating expenses fell by 40%. “Even when yields in the continuous case are lower than in the batch case, savings can still be achieved because the labor, materials handling, CapEx, and other savings compensate,” Schaber wrote. These savings are in line with CCM’s estimates of 15% to 50%.

“We see the future of pharmaceutical manufacturing as continuous,” says Bernhardt Trout, Professor of Chemical Engineering at MIT and Director of CCM. “That includes continuous flow together with a systems approach, integration and advanced control. We can use a lot of chemistry in continuous that we couldn’t use in batch.”

The CCM project involves “new technologies across the board,” according to Trout, from new, high-yield chemistry exclusive to continuous manufacturing, to novel work-up, drying, and dose-forming technologies, including coating. “These approaches are model-based and incorporate end-to-end process control, leading to a huge reduction in total process time, greater energy efficiency and lower cost.”

Continuous processing involves a change in mindset, with significant shifts for process developers who must now view plants holistically rather than as a string of unit operations. But few limits exist, either on scale or molecule type. “It just needs to be done,” Trout says. “A key will be selecting the first molecule to process continuously.”

University-industry manufacturing collaborations are not new, but their frequency appears to be increasing.

One focus of Rutgers University’s NSF-funded Research Center for Structured Organic Particulate Systems (C-SOPS) is the efficient production of active

Even when yields in the continuous case are lower than in the batch

case, savings can still be achieved because the labor, materials handling, CapEx, and other

savings compensate



pharmaceutical ingredients. When the center opened in 2006, its director, Fernando Muzio, deemed prospects for continuous pharmaceutical manufacturing “debatable.” But much has occurred in the last seven years.

“Process Analytic Technology is now widespread, QbD is increasingly becoming part of the standard language in process development, and modeling methods are spreading rapidly,” Muzio says. “Continuous manufacturing is now identified by the FDA as a manufacturing megatrend for the next 25 years.”

Flexibility and inFlexibility One of GMPs’ most exciting after-effects has been a more flexible approach to manufacturing that encompasses the entire product portfolio, including anticipated products through mergers and acquisition activity. High-value core products should remain within large companies, advises John Linder, Life Sciences VP at Celerant Consulting (Richmond, England), while marginal product lines may be more profitably outsourced. Companies should therefore prepare for a complete reconfiguration of their

supply chain footprint.Improving manufacturing agility, while closely

managing core products and competencies, is not a new idea. Innovator firms have farmed out packaging, formulation, printing and over-the-counter (OTC) manufacturing for decades. Linder extends this strategy to reducing “SKU” creep — the proliferation of products around a specific active ingredient or set of actives, particularly for OTC medicines or off-patent molecules. Companies should view this type of redundancy in the same way as non-core activities, products and therapeutic areas: outsource, divest or partner-out.

Thus, the conflict between marketing, which seeks greater complexity, and manufacturing, which prefers streamlining. Commercial experts were taught in business school, to expand product lines horizontally, and increase the footprint as much as possible.

“But that creates unwarranted complexity for manufacturing. Rather than producing 57 varieties in various sizes, packaging and formulations, consider consolidating the footprint for groups of these products

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pharma-review-half-page.pdf 1 2/22/2013 5:13:45 PM



and consider which should be retained and which should be moved externally,” Linder advises.

On the flip side, many processes now employ platform strategies that supply consistency and predictability. Currently all the rage in biologics manufacturing, particularly for monoclonal antibody manufacture, platform processes employ identical unit operations, and often nearly identical culture media, for molecule classes.

“Platform processes help speed deployment of products from R&D out through commercial,” explains Janssen’s McKenzie, “not only from the perspectives of time and cost, but for reliability and reproduceability.”

At Janssen, platforming is not restricted to therapeutic proteins. The manufacture of Zytiga, the company’s small-molecule prostate cancer drug, is based on platform methods. So is Janssen’s ibrutinib, another non-biologic indicated for blood cancers. Ibrutinib, that has received one of FDA’s first “breakthrough therapy” designations, which accelerates development of drugs for serious diseases that show substantial improvement over existing medications.

One of Janssen’s initial QbD platforming successes

was the successful move from perfusion cell culture (how Remicade is produced) to more standard fed-batch cultures. “This enabled us to standardize the entire process, down to raw ingredients,” McKenzie says. Another improvement leading to quality and consistency was the move from animal product-derived media ingredients to animal component-free media, a move that the biotech industry has been slow to adopt.

Platforming has carried over to “visualization” of all process steps, upstream and downstream, from the number of chromatography columns to the quality bar Janssen sets for aggregates and other impurities. “Every unit operation is specified, using the same vocabulary every time. This is something I hope we can continue to expand on, not only as a company, but as an industry. We want our products, not how we run our centrifuges, to serve as our differentiators.”

m&A STRATEgYFrom a strategic standpoint, mergers and acquisitions occur to realize pipeline and therapeutic area compli-mentarity. Depending on how strategists account for the incremental production capacity such dynamics could

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affect manufacturing and supply chain strategy as well. Companies operating in advanced economies simultaneously face flattening do-mestic demand and competition for emerging markets.

Combined, these factors create moving goalposts for manufacturing-based pharmaceutical firms that must continue to meet shareholder-value goals while navigating labyrinthine regulations while minimizing supply interruptions.

Compare this situation to just 20 years ago, when everything was static and predictable, where reasonable inefficiencies were tolerable and asset utilization could hover around 50% without causing much concern.

So the conundrum for today’s pharmaceutical manufacturing and supply chain strategists is they no longer have clearly defined targets set in stone. “Technical operations, manufacturing, and engineering people have difficulty fathoming this,” Linder notes.

Mergers and acquisitions provide opportunities to optimize product footprints — as opposed to merely expanding them. From a manufacturing perspective, they force companies into consolidating manufacturing capacity (as well as other services) across locations, therapeutic areas and product groups. Lessons learned from these exercises apply to new and existing facilities as well, including those outside the merger “corral.”

You may have noticed that the last decade’s mergers and acquisitions have not all proceeded swimmingly. “Without a robust integration process to bring together thought leaders and functions, and assure that backup services are well integrated, the apparent profit and margin benefits of acquisitions can become diluted,” says Linder.

REDEFININg ObjECTIvESMany of the “seismic” shifts in the

pharmaceutical and biotechnology industries over the GMPs decade affect manufacturing either directly or indirectly: the dearth of New Chemical Entities, mergers and acquisitions, outsourcing, biosimi-lars, emerging markets, safety-related regulation, and quality initiatives, reimbursement and profitability is-sues, to name just a few.

This has led top firms to redefine their business objectives, Linder says, away from selling individual products towards fully servicing therapeutic areas through a combination of drugs, services and devices. Examples include a diabetes drug, free counseling and partnership with a device company specializing in home-based glucose monitoring, vs. simply selling the medicine.

“The analogy with IBM’s shift from hardware to hardware plus services is striking,” Linder says, although he rues that in pharmaceuticals that transition is occurring “in fits and starts.” Pharma manufacturers have a good deal of catching up to do, as they have not been as engaged as payer-providers in understanding the value of holistic value beyond selling core pharmaceutical products.

Part of the equation involves value-based pricing models, what a cynic might describe as “really, really, really expensive drugs.” The idea is actually not so sinister: Rather than pricing products based on cost and margins, charge according to therapeutic value.

Health plans already do this in effect, and in reverse, through formulary listings for both generic and branded products, which inevitably leads to a misalignment of expectations between manufacturers and insurers, and of the meaning of the term “value” itself.

“Cost-benefit is creating a different dynamic for evaluating portfolios, where companies invest, and how manufacturing should configure its supply chain,” Linder says.


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WHEN IT comes to careers, many of Pharmaceuti-cal Manufacturing’s readers made their choices early, completed their undergrad and graduate level studies then embarked on careers that offered stability, growth, first-class compensation and benefits and stability. That sounds redundant, of course, but for decades careers in Pharma were as predictable as they were stable.

Respondents to Pharmaceutical Manufacturing’s 9th Annual Salary and Job Satisfaction Survey provide demographics to support the conjecture. Of the nearly 400 respondents, 49.5% are over 40 and another 29.1 percent are over 55. Most (nearly 40%) have been employed by the industry for more than 20 years. Current salaries also point to stable, progressive careers with the majority of respondents earning more than $100,000 annually.

Unfortunately, about two-thirds of the way through their chosen profession, many in the industry experienced dramatic and sudden shifts as company after company began to restructure or consolidate to survive myriad competitive and economic pressures.

The layoff statistics for the decade past are chilling. Chicago recruiting firm Challenger, Gray & Christmas reported last year that from 2000 to 2011 the drug

industry suffered through nearly 300,000 layoffs, the high, or low point (depending on one’s point of view) reached in 2009 when some 61,000 were “adjusted” out of their positions. Fortunately for many, the statistics also reveal that overall headcount in the industry did not fall by that much. Although the industry has supported the reassignment of many of these employees, the numbers do reveal that a tremendous decade-long “churn” occurred.

The churn seems to be abating, with layoff statistics trending dramatically lower for the second year in a row. Challenger, Gray & Christmas reported just 1,034 layoffs for January-February 2013 compared to 4,336 layoffs during the same period in 2012. “It’s true that the pharmaceutical industry over the last couple of years went through a wave of job cuts and restructuring,” says Challenger, Gray & Christmas CEO, John Challenger. “And perhaps got out ahead of it a bit, but the industry did what it needed to do to thin down; now it is looking at the new Healthcare [Act] and what it’s going to be.”

Reading between the lines, the statistics support the supposition that companies have found the floor when it comes to staffing levels which, more often than not, translates to very lean org charts and overextended

Good vibrationsRespondents to Pharmaceutical Manufacturing’s 9th annual job satisfaction and salary survey find the industry is beginning to hit a few more high notes than last year

By Steven E. Kuehn, Editor in Chief



2013 SALARY SURvEY

employees. Survey results find the majority, just under 54%, did not take all their vacation time last year, and 19.3% (about a 2% increase over 2012) feel stressed and burnt out most of the time. When asked “Is burnout a problem among those you work with?” the majority (45.4%) responded that “Yes it’s a real issue for us and is hurting our productivity” bumping up from 38.7% from last year.

Burnout is prevalent, but how much does that impact job satisfaction? Survey responses to “What is your level of job satisfaction?” reflect that people may be getting a little more used to the new normal (see figure 1). Although “High” satisfaction is down (41.2% from 44.1%), “OK” responses were up (to 43.5% from 35%) with the “Poor” responses down 4%. “Very Poor” responses stayed about the same. What drives job satisfaction of pharma workers? About what you would expect from superbly educated, highly motivated professionals: 31.5% find “Challenging Work” brings them the most satisfaction. True, salary and benefits hold second place, but compared to other motivators those seeking job fulfillment lead. Of less concern, at least for those responding, is job security—perhaps recent experience has tempered those fears.

With staff fat long gone and some of its muscle cut to the bone, will the industry return to more robust hiring and eschew more cutting? According to Challenger, the industry is benefiting from a stronger economy: “Each year we get away from the recession there is less concern, but in some ways it’s too early to tell because of the uncertainty in the economy and the potential negative impact of the health care reform.” There might be a silver lining, says Challenger, remarking that there is real potential the Affordable Health Care Act will have a positive impact on hiring. “Yes, it just might. Potentially there will be more than 40 million new people that will have access to health care and medicines — that may not have had access — [pharmaceutical manufacturers are asking] will there be more demand for our products? Will there be pressure on pricing? How is that going to cause the structures of our organization to change?

Uncertainty breeds uncertainty, and anxiety about the prospects of keeping one’s job is generally ever present. But stress over job security is just part of the new normal for most rank-and-file employees and response to the question “Are you concerned with job security?” is 63.1% “Yes.” Relative to years past, yes responses were virtually the same as last year, revealing that anxiety levels trended lower from its peak (69.7%) in 2011 and has been stable for two consecutive years. Driving anxiety among respondents is the current state of the economy and the “External financial pressure

on my company due the current financial crisis,” and the effect of “Internal cost cutting measures.” The fear of losing one’s job to internal pressures to cut cost is what most Pharmaceutical Manufacturing survey participants fear most, up slightly to 42.8% (see figure 2). And although the term “financial crisis” may not aptly describe the current economy anymore, the responses show that about a third feel this is the other primary threat to job security. Regardless, the industry will continue to recast itself and form new alliances in response to market and economic dynamics.

Financial powerhouse KPMG recently surveyed executives from 107 pharmaceutical and life sciences sector companies with revenues of more than $100 million; the majority (45%) earning more than $10 billion. According to KPMG’s 2012 Industry Outlook Survey,” navigating the regulatory environment and investing in organic growth will be the key focus of management over the next two years. “Sixty percent of the executives,” say the report, “cite regulatory and legislatives pressures as the most significant barrier to their company’s growth over the next year.” What will drive revenue growth? KPMG survey respondents point to new therapies from their own research (52%) followed by therapies developed by alliance partners (36%) and growth from non-U.S. markets (34%). The upside here is that KPMG analysts reported that the zeal for using mergers and acquisitions to fuel growth has diminished, therefore tempering the staff consolidations and layoffs that inexorably follow such initiatives.

Although pharma executives are looking to drive revenue growth from internal growth, the responses to Pharmaceutical Manufacturing’s Ninth Annual Salary and Job Satisfaction Survey reveal these and similar business goals are likely to be earned on the backs of the current work force (see figure 3). When asked “What are the biggest changes you have had to face in the last year?” a little more than half chose “increased

.

Yes 61.4%

No 38.6%

1-3 years 34.3%

Less than 1 year 56.7%

More than 3 years 9.1%

High 41.2%

Very High 7.8%

Very Poor 1.5%

Poor 6.0%

Okay 43.5%

Most of the time 19.3%

Some of the time 53.0%

Never 3.5%

Not often 24.1%

No, it's not a significant issue.

29.9%

Yes, it's a real issue for most of us and is hurting our productivity. 45.4%

Yes, but only among workers who do not

manage their time well. 24.6%

What is your overall level of job satisfaction?

figure 1.


2013 SALARY SURvEY

workload due to staff cuts” followed by “introduction of new team or organizational structure.” “New product introductions” also attracted about a third of respondents as well. Perhaps these figures tell more about potential job security — meaning staffing levels are as lean as they can get. But that begs the question: Is hiring going to rise? KPMG respondents reveal some ambiguity. “While 33% of survey respondents noted they added personnel over last year, 42% report a decrease in head count. Executives, continues the report have similar expectations for the year ahead with 38% predicting an increase in hiring as opposed to 37% anticipating a drop in headcount.

As far as the overall economy, responses from KPMG’s surveyed executives show cautious optimism with 54% expecting modest improvements and another 38% feeling things will stay about the same. However, a strong majority (70%) feel substantial economic recovery is still in the horizon, not occurring until 2014 or later. For Pharmaceutical Manufacturing’s respondents, the effect

is more personal (see figure 4) with 57.8% percent feeling that in spite of the increase in duties and responsibilities fewer raises and promotions are being offered because of current economic conditions.

Let’s look at compensation. As mentioned, more than half of all respondents reported annual salaries past six figures. And while the upper limit for most is $150K, nearly 20% have salaries extending to over $200K (see figure 5). Interestingly, in spite of a majority responding the economy was holding employers back from doling out raises and promotions, a majority (56.7%) reported they had received a raise in the last year, representing an increase over last year’s 50.5% response. Down from last year were those responding their last raise was in the last 1-3 years, while those still waiting for a raise for more than three years edging up 9.1% from 6.3% last year. Of those getting raises, 67.3% percent say they received a 1-3% bump.

One’s professional skills, matched well to the demands of the position often spell career advancement, and responses reveal attitudes little changed from last year

External financial pressure on my company due to the current economic crisis

Continued internal cost-cutting measures

Possible plant closing.

The trend toward outsourcing

The diminished relevance of my skills due to changing technologies and industry focuses.

Personal issues with coworkers or supervisors.

2013 30.4% 42.8% 8.7% 4.8% 6.3% 6.9%

2012 29.9% 39.8% 8.3% 7.9% 6.6% 7.5%

2011 47.1% 21.3% 14.2% 8.0% 3.1% 6.2%

2010 30.3% 31.6% 13.9% 7.4% 4.3% 12.6%

2009 39.6% 32.6% 11.7% 7.8% 2.2% 6.1%

If you are concerned, what is the greatest threat to your job security?

figure 2.

What are the biggest changes that you have had to face in the past year?

Lean, Six Sigma or other Operational Excellence initiative

Increased workloaddue to staff cuts

Plant expansion

0 10 20 30 40 50 60

New product(s) introduction

Introduction of new team or organizational structure

Merger or acquisition

My skills and background are well suited to my

current position

I am being asked to do some tasks outside my skill set, but am

generally suited to my position

I am doing many tasks that are above or below my skill set

I'm in the wrong position and not doing work that

uses my strongest skills

Other

Over 200K

150-200K

100-150K

80-100K

60-80K

40-60K

Under 40K

0 5 10 15 20 25 30 35

0 10 20 30 40 50 60 70 80

What is your annual gross salary?



Plant expansion

0 10 20 30 40 50 60





current position






Other

Over 200K

150-200K

100-150K

80-100K

60-80K

40-60K

Under 40K

0 5 10 15 20 25 30 35

0 10 20 30 40 50 60 70 80

figure 5.figure 3.


2013 SALARY SURvEY

(see figure 6). According to 2013 respondents, 64.6% feel assured “My skills and background are well suited to my current position.” This may be doubly true in the biopharmaceutical space, which is experiencing its own renaissance and already recognized has a “hot” sector looking to hire the best talent to support this pharmaceutical industry segment’s tremendous growth.

According to New Chemistry: Getting the Biopharmaceutical Talent Formula Right, a recent PriceWaterhouseCoopers (PWC’s) Health Research Institute (HRI) survey of life science company HR and R&D executives, “A talent gap in the scientific workforce has biopharmaceutical companies searching outside for fresh skills and alternate approaches to R&D staffing.” PWC’s research found 51% of executives report that hiring has become difficult and only 28% feel confident they will have access to top talent.

Perhaps supporting that conclusion, respondents to Pharmaceutical Manufacturing’s survey find that to a certain degree their companies are imposing on them to make up for said skills “gap” responding to the

question, “Do you see a skills gap or mismatch within your organization?” Some 42% answered: “Somewhat. Lately, we’ve all had to pitch in to do things outside our traditional domains.” Yet actions and intentions seem to be a bit at odds out there. Certainly the uptake of talent cast off from Big Pharma and other small molecule pharmaceutical companies over the past three years should provide a deep pool of talent from which biopharma can draw, but the PWC seems to counter that. But why the disconnect then?

Derek Lowe, who writes and edits the popular In the Pipeline blog posits there just might be demand and supply-side market dynamics at work “The whole ‘we just can’t find good people’ story does seem to be better phrased as ‘We can’t find good people for what we want to pay them.” Lowe contends that it is similar to the real estate market, when it comes to pricing: there are people on both sides who would like the prices to be other than what they are, and they’re willing to hold out to see if reality comes into line. Meaning the laws of supply and demand will balance. Until then, says Lowe, “well … if you’re willing to keep a position open for months and months because you want to save some money on the salaries, how crucial was that hire to start with? Who’s kidding whom?”

When Pharmaceutical Manufacturing revisits this survey a year from now, will things be all that different? Probably not, but there are good vibrations running through the industry and it is likely more people, not less, will be on board to support the strategic initiatives and business goals of the organizations they work for.

Lowe finds some things have gotten worse, but the cost of finding drugs the way it has always been done is unsustainable. “So unless we figure out a way to do that better, the nasty intersection of trends isn’t over yet … I’m not trying to forecast doom — people are still getting sick, and our longer life expectancies mean that we’re going to be around for a lot of things that we’ll want treatments for. There’s so much unmet need out there; we’ve only made tiny inroads into what’s possible. I’m a short-term pessimist and a long-term optimist.”

Hiring Freezes Fewer Promotions and Raises Layoffs Salary Freezes More Outsourcing

2013 39.6% 57.8% 32.9% 23.7% 23.7%

2012 37.6% 56.3% 40.9% 19.4% 24.7%

2011 49.8% 62.6% 52.7% 29.2% 33.8%

2010 52.5% 57.9% 45.8% 34.4% 24.1%

2009 50.0% 42.8% 37.3% 22.2% 19.3%

How has the economy affected your company recently? (Check all that apply.)

figure 4.

How would you rate the suitability of your skills to your current position?



Plant expansion

0 10 20 30 40 50 60





current position






Other

Over 200K

150-200K

100-150K

80-100K

60-80K

40-60K

Under 40K

0 5 10 15 20 25 30 35

0 10 20 30 40 50 60 70 80

figure 6.

Wisdom From WithinEliminate reliance on transmitters with Arc intelligence engineered into your sensor head.The Arc sensor head enables the first fully integrated intelligent sensors that do not rely on a transmitter. Arc can be integrated into existing 4-20 mA or digital environments to improve signal quality and data efficiency. Calibration statistics, usage history, and diagnostics are stored in the sensor for quality management and troubleshooting. Increase the productivity and quality of your analytical process.

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FEATURE TOPIC


THE bIOPHARmA industry’s continued focus on process efficiency is being fueled by advances in biosimilars, smaller volume drugs, shorter drug lifecycles (faster trials, development cycles), and high-volume product manufacturing issues.

To evaluate the trends that are shaping the bioprocessing segment today, BioPlan Associates recently surveyed 450 global subject matter experts and senior participants on its Biotechnology Industry Council panel of bioprocessing professionals and asked them to identify the most critical factors and trends they expect will need to be addressed over the coming year. While ‘process efficiency’ was a unifying thread, three clear sub-topics emerged: downstream processing; analytical methods development; and single-use system integration.1 This year, the industry will see an increase in multi-product facilities, selective single-use adoption (both in clinical and commercial stage), a ramping up of continuous processing, and more advanced automation and monitoring. With downstream processing continuing to lag improvements in upstream, the industry will continue to look for better performing chromatography resins and consider alternatives to protein A.

Single-use systems, data analytics and downstream process at the forefrontBy Eric S. Langer, BioPlan Associates

focus on efficiency


15 State of the Pharmaceutical & BioPharmaceutical induSty 2013 Pharmaceuticalmanufacturing•www.Pharmamanufacturing.com

Downstream ProcessingDownstream purification (separation, filtration and chroma-tography) continues to be a culprit behind facilities’ capacity constraint problems. It counts as one of the key areas that the biopharmaceutical industry believes must be addressed to avoid short- and long-term capacity constraints, and it is where a large number of industry suppliers and end-users are developing and evaluating new technologies and other options for improving production efficiency.

Biopharmaceutical manufacturing, due to the fact that it operates in a highly regulated environment, tends to be characterized by incremental improvements rather than rapid, major technology shifts associated with other less regulated or consumer-oriented industries. The problem has been that with the significant increases in protein expression levels over the past several years, pressure has shifted squarely to downstream operations, which have not seen the same degree of improvement. This, in return, has resulted in continued bottlenecks in purification and filtration operations. The issues experienced by downstream operators have remained relatively constant over the past few years. And although there are many new technologies under investigation and consideration, few as yet, are being actively implemented.

This year’s trends study revealed 24% of industry participants named downstream processing as the single most critical trend. By contrast, 5% said the same about upstream processing. Within the rather broad area of downstream processing, the research reveals several sub-trends including:• Process improvements in bioburden control in chroma-

tography columns;• Development of non-chromatographic recovery unit

operations;• Improving harvest operations through novel technologies;• Increasing protein concentration in solution, without

reducing yield; and• Purification related to impurity profiles in biosimilars.

There is a general perception that the industry needs better-performing chromatography resins. Results from last year’s 9th Annual Report and Survey of Biopharmaceutical Manufacturers2, in which more than 300 biomanufacturers were surveyed, showed that slightly less than one-third of respondents wanted suppliers to focus efforts on chromatography products, the third-most sought after new product development area of the 21 we identified.2

There appears to be some consensus that alternatives to protein A will continue to be sought and developed this year. It is worth noting that while the industry has been clamoring for alternatives to protein A purification for some time, few facilities have made such a switch. For example, last year’s

survey revealed 16% of respondents considering alternatives to protein A for existing projects, but less than half that proportion (7%) offer that they will actually be moving away from protein A for existing scale-up or commercial production units over the following 12 months.

In fact, the study found that the long-term trend among facilities interested in protein A alternatives appeared to be decreasing for new production units, while there was modest interest in switching from protein A for existing scale-up and existing production units. In general, though, interest appeared to be waning.

Using protein A chromatography media remains problematic because of the high-cost, limited life of the material and the cost of cleaning/validation. Alternative methods for purification of antibodies have been, and are being developed with longer lifetimes and therefore lower cost per unit of protein produced. However, according to most end-users, protein A “works.” While general interest in alternate purification methods to protein A remain high, actual switching behavior seems to be static or declining.

Still, the environment is ripe for innovative alternatives to emerge, and as long as downstream processing remains in the conversation, alternatives to protein A will be an ongoing topic of discussion.

analytical methoDsIn most biomanufacturing segments, it appears that improvements in assays and analytical capabilities are needed or desired. In addition to the continuing needs to assess and document product composition and quality, new demands for assays and analytical capabilities for biosimilars range from proving similarity to determining the unique differences between products. Assays and ana-lytical method improvements are also needed to increase productivity in active agent design, discovery, screen-ing and optimization, as there are too many products continuing to fail very expensively later in development. Most all can agree that it’s preferable to have products

Downstream Processing

24%

Others 30%

Single-Use: Implementing & Improving 22%

Analytical Methods 24%

Product platforms, cost reductions, materials sourcing, supply chain regulatory compliance, biosimilars, etc.

Biomanufacturers’ top trends, 2013

BioPharmaceUtical trenDs


fail fast in order to move on to the next, most promising candidate in the development pipeline.

According to the evaluation study’s results, almost one-quarter (24%) of industry experts tabbed analytical methods development as the top trend of 2013, on par with the percentage citing downstream processing. Common micro-trends within this area included: • Convenient, high-throughput assays that assess physico-

chemical properties IgG clones for high level expression and therapeutic efficacy;

• Demonstration of biosimilarity to reduce costs of biologics manufacturing, and analytics to demonstrate equivalent product quality;

• Development of better characterization tools for up-stream analysis and optimization; and

• Improved high throughput, high resolution glyco-slylation analysis.Clearly, there are multiple addressable dimensions to this

topic, and we found a similarly wide net in last year’s Annual Report study where we inquired as to which assay areas most urgently required new or improved testing methods. That is, of the 29 “areas” we identified, 10 were cited as urgent by at least 20% of respondents. These included: • Bio-assays to assess potency for release of drugs (41%), • Biophysical characterization during process develop-

ment (35%), • Glycosylation (33%), • Better stability assays (32%), and • Biotech drug comparability (in-house manufacturing

changes and biosimilars (31%).Preliminary data from our 10th Annual Report and

Survey of Biopharmaceutical Manufacturers3 (due to be released in April) indicate that the industry is looking for innovation in this area, ranking it near the top of the list in terms of new product development areas of interest among respondents.

SINgLE-USE SYSTEm INTEgRATIONAlthough analytical assays rank towards the top of bio-manufacturers’ new product development interests, single-use, disposable products are at or near the top of the list. Preliminary data from the study reveals that end-users are interested chiefly in disposable products, bags and connec-tors (49%), while also expressing a desire for improvements in disposable probes and sensors (30%), disposable bioreac-tors (29%), and disposable purification (29%). These areas have been consistently in demand for several years now.

Disposable devices continue to make advances in manufacturing and are becoming increasingly common in most areas of biopharmaceutical production. Although, as yet, there are few non-rigid single-use

devices (e.g., bioreactor bag liners) used in commercial scale GMP applications, it is likely this will change quickly as new products move through the development pipeline and out of clinical-scale manufacturing. Further, as regulators gain familiarity with the safety profiles and materials used in such devices, necessary approvals for product manufacture are apt to accelerate as well. When this occurs, the market volume for single-use devices is likely to increase significantly.

This year, 22% of the Biotechnology Industry Council members surveyed believed that single-use system integration would be the key trend for the year. Within this burgeoning area, participants identified several sub-trends. These include: • Building quality into single-use operations to further

reduce regulatory activities/oversight; • Fixing disposable bioreactors that create inconsistent

growth due to changes in resins, films, gamma ir-radiation, and cell line specificity;

• Downstream operations using membrane adsorbers;• Emergence of flexible and modular biomanufacturing

facilities;• Establishing leachables and extractables guidance for

testing;• Improved upstream contamination investigations from

a QA perspective;• Introducing single-use devices at GMP commercial

THE FUTURE OF THE bIOPHARmACEUTICAL INDUSTRY

Rutgers Business School's Annual Healthcare Symposium

Presented by Blanche and Irwin Lerner Center for the

Study of Pharmaceutical Management Issues at Rutgers

Business School, this event provided the opportunity

to share the knowledge of the bio-pharma industry

experts. Take away from those who attended was the

exchange of ideas and knowledge of the growth of the

bio-pharma industry and networking.

bIOPHARmACEUTICAL TRENDS


scale manufacturing; and• Leachables and extractables [standardization] at clinical

and commercial scale. There are two interwoven trends worth an additional

look. The first regards leachables and extractables. Last year, there were reported problems with the reliability and performance of available disposable solutions, with leachables and extractables a key factor. As Rick Johnston, Ph.D., CEO of Bioproduction Group Inc. noted, these issues “undermined confidence in the ability for … manufacturers to supply material in a timely manner to support production. This led many biomanufacturers to aggressively pursue dual-sourcing and risk-mitigation strategies like holding large inventories, both of which raise overall production costs. It is hoped that in the 2013 time period these issues can be resolved to allow the promise of disposables to be realized in the biomanufacturing setting.”

Indeed, the emergence of flexible and modular facilities, as well as the adoption of single-use devices at GMP commercial scale manufacturing (something already underway) depends in part on resolution of leachables and extractables (L&E) problems. In our 9th Annual Report, we asked respondents to identify the factors that may restrict their use of disposables in biopharmaceutical manufacturing. Fully 7 in 10 (69%) either agreed or strongly agreed that L&E problems were a concern, beating out bag breakage and single-source issues as the most common factor restricting further adoption of disposables. And when respondents were asked about identifying the single most important reason for not increasing their use of disposable technologies, concern regarding L&E headed the list again.

The debate over L&E data continues, but a major concern that end-users struggle with is that the raw material sourcing sometimes is unregulated, putting them at a disadvantage. Because vendors deal directly with raw material providers, end-users feel they are in a better position to test and provide the necessary L&E data as supporting documentation for their products. The desire for this type of data is strongest among scale up/clinical development organizations that do not have the resources to conduct such tests in-house. On the other hand, late-stage manufacturing organizations that are in phase III or commercial production are unwilling to take a chance with vendors and would rather generate L&E data themselves to minimize regulatory risks.

If the L&E problem can be addressed, then it is likely that the use of disposables in biomanufacturing will grow more rapidly. While the wheels have been set in motion, the remaining hurdles still need to be cleared. Members of BioPlan Associates expert council believe that the L&E roadblock could be addressed this year.

The trend evaluation study revealed that three topics — downstream processing, analytical methods, and

single-use systems — will dominate industry attention, both among end-users and industry suppliers. But it is important to remember that many other trends and themes are certain to shape and influence the market. Product platforms, cost reductions, materials sourcing, supply chain regulatory compliance and biosimilars will all make headlines in one form or another.

When 2013 comes to a close, the industry will be looking to answer three key questions: 1. Where were the breakthroughs in downstream process-

ing innovation to help ease capacity constraints? 2. Did we see significant improvements in assay development

that meet the current and emerging industry demands?3. Was 2013 the year that L&E problems (and related sup-

ply chain management issues) were finally put in the rear-view mirror, and a jump in single-use adoption at commercial scale emerged? Stay tuned for the answers.

References:1. BioPlan Associates’ “2013 Biotechnology Industry Council Trends Analysis Study”2. 9th Annual Report and Survey of Biopharmaceutical Manufactur-ing Capacity and Production, April 2012, Rockville, MD, www.bioplanassociates.com 3. 10th Annual Report and Survey of Biopharmaceutical Manufactur-ing Capacity and Production, Preliminary Data, Release April 2013, Rockville, MD, www.bioplanassociates.com

AbOUT THE AUTHOR: Eric S. Langer is president and managing partner at BioPlan Associ-ates, Inc., a biotechnology and life sciences marketing research and publishing firm established in Rockville, MD in 1989. He is editor of numerous studies, including “Biopharmaceutical Technology in China,” “Advances in Large-scale Biopharmaceutical Manufactur-ing,” and many other industry reports. Contact: [email protected]; 301-921-5979; www.bioplanassociates.com Survey Methodology: The 2013 10th Annual Report and Survey of Biopharmaceutical Manufacturing Capacity and Production in the series of annual evaluations by BioPlan Associates, Inc. yields a composite view and trend analysis from over 300 responsible individu-als at biopharmaceutical manufacturers and contract manufacturing organizations (CMOs) in 29 countries. The methodology also included over 180 direct suppliers of materials, services and equipment to this industry. This year’s survey covers such issues as: new product needs, facility budget changes, current capacity, future capacity constraints, expansions, use of disposables, trends and budgets in disposables, trends in downstream purification, quality management and control, hiring issues, and employment. The quantitative trend analysis provides details and comparisons of production by biotherapeutic developers and CMOs. It also evaluates trends over time, and assesses differences in the world’s major markets in the United States and Europe.

bIOPHARmACEUTICAL TRENDS


THE LAST few years have seen an increase in drug man-ufacturers’ failures to follow current good manufacturing practices (cGMP) consistently. This year’s numbers have not yet been released by FDA. But last year, the number of cGMP-related drug recalls increased substantially, exceed-ing a record set in 2009 (see sidebar).

Both Warning Letters and recalls of injectables were notably higher, with injectable recalls three times the 10-year annual average reported two years ago, according to Bowman Cox, managing editor of “The Gold Sheet,” which analyzes and reports regularly on FDA data.

“We’re seeing the same types of failures we saw in the early 1980s, when nearly 70 percent of ethical pharma was under Warning Letter or Consent Decree,” says one consultant, who asked to remain nameless.

These compliance failures have far-reaching effects, not only on corporate reputations and bottom lines, but also on patients. In discussions earlier this summer between FDA and members of U.S. Congress, manufacturing noncompliance was noted as a key reason for chronic shortages of important drugs, including injectable anesthetics and cancer treatments.

According to Jeanne Ireland, FDA’s Assistant Commissioner for Litigation, who detailed facts in a July letter to Elijah Cummings on the House Committee on Oversight and Government Reform, this year, quality control issues at drug manufacturing facilities continue to account for shortages of drugs, particularly injectables. Last year, manufacturing issues, including QC problems, resulted in nearly 70% of shortages.

Consider the critical anesthetic injectable Propofol. Serious

contamination issues at its manufacturer’s, Teva Pharmaceutical’s facility in Irvine, Calif., led to a shutdown of the facility, resulting in chronic shortages. The plant was reopened this spring.

Problems involved endotoxin contamination of Propofol emulsion. The company had failed to test for endotoxin in its lot samples, had been unable to find the reason for out of trend results in endotoxin

A look at recent FDA enforcement activities and lessons to be learned

By Agnes Shanley


level, and failed to maintain cleaning and sterilization equipment effectively, FDA said.

In this brief overview, observers and experts share insights into some of the industry’s most chronic recurring cGMP noncompliance areas, citing lessons that manufacturers might learn for the future. Some consultants refused to be interviewed, while others asked to remain anonymous because they work with some of these manufacturers to help them resolve these issues. However, the companies and the problems involved are in the public record.

What’s notable, one consultant says, is the fact that many of Big Pharma’s recent cGMP failures have involved fundamental quality principles and are coming from companies that know better. “Many of these companies were the shining example of compliance in their day,” he says.

Among the most glaring recurrent problem areas that FDA inspectors have noted (sidebar) is a failure to validate processes. In addition, many drug manufacturers today are inconsistent in documenting or systematizing QC operations, says Ken Reid, publisher of “Validation Times and Food and Drug Inspection Monitor,” both of which track FDA enforcement activities very closely. There is also frequently a failure to establish adequate laboratory controls or to get to the root “out of specification” (OOS) problems, he says.

Former FDA inspector Dennis Moore, now managing partner of AUK Technical Services, has seen this misunderstanding of Quality Systems first hand. During a recent visit to a company with a good compliance record and sophisticated approach to quality, Moore asked for a copy of the company’s Quality Policy, and, at one site, was presented with 20 different versions.

Pharma is still at a relatively early evolutionary stage in its quality and risk management systems, said Mike Long, Director of Consulting at Concordia Valsource, during a November webcast (visit pharmamanufacturing.com to hear the archived version). In addition, Moore says, many companies are using HAZOP for risk management, but driving processes to their critical control points. This can lead to turf battles over which process is more critical. He suggests that drug manufacturers embrace the modern spirit of medical device quality management systems guidance. In fact, he says, ICH Q9 refers directly to this guidance and FDA inspectors are being trained in its principles.

Corrective and Preventive Action (CAPA) programs, and failure to trace patient complaints in the field continue to dog manufacturers, based on a cursory look at FDA enforcement records. As Rick Friedman, Associate Director of FDA’s CDER’s

Office of Manufacturing and Product Quality has said, manufacturers still emphasize the C in CAPA, when they need to focus on the P. It was just this failure to investigate serious adverse effects in patients that led to the inspection and closure of Teva’s Irvine facility.

CAPA is never directly spelled out in the cGMP code, says Moore. He suggests that drug manufacturers refer to the QSIT guidance on FDA’s website, as well as ISO 14971, both of which are medical device-oriented, for best practices.

WINNERS AND SINNERS?When asked for examples of proactive corporate quality systems, consultants cited biopharmaceutical manu-facturers as the best examples. Biopharma has had its problems with contamination, which led to one recent consent decree at Genzyme’s Allston facility. However, one consultant says biopharmaceutical manufacturers are generally more proactive about compliance and quality. He cites Genentech’s use of intermediate modeling and

REASONS WHY DRUg

mANUFACTURINg PLANTS FAIL FDA INSPECTIONS

1. Failure to document, in writing, and/or follow QC

responsibilities and procedures

2. Lack of process validation to assure proper identity,

strength, purity and quality of drug

3. Insufficient laboratory controls

4. Lack of investigation into Out-Of-Spec batches, and

complaints, or batch-to-batch variation

5. Insufficient GMP training and written procedures

6. Written SOPs and production procedures aren’t be-

ing documented and/or followed

7. Lack of written procedures for equipment cleaning

and maintenance

8. Insufficient cleaning and maintenance

9. Lack of testing to assure the specs of API

10. Lack of in-process monitoring of critical process

parameters that validate the performance of man-

ufacturing processes that might cause variability.

Source: Sharon Toma, FDA Inspector, ORA from a presentation at the International cGMP Conference, March, 2012, summa-rized in Validation Times, March 2012


design of experiments to ensure process understand-ing when compounds reach commercial stage. He also mentions Amgen, which is currently studying how to use ASTM 2500 in qualification and validation efforts.Another consultant praises Abbott’s approach to CAPA. At least before the restructuring, he says, the company used one standard CAPA system for its multiple product lines. In most cases, he notes, pharma companies are using different systems, or developing their own home-grown approaches, which can lead to confusion.

There are no real “winners” and “sinners” in this story. Today’s sinners are often the compliance models of the future. But here are some case studies in compliance from FDA’s recent inspection and enforcement records:

• NovartisThe company’s recent GMP problems showed a failure to investigate consumer complaints of foreign products in its

oral solid dosage forms. There were more than 160 such complaints since 2009, but a root cause was never found. The company also failed to extend investigation into all potentially affected product batches. In addition, FDA noted that complaint investigations took up to 100 days, and there was no attempt to retrieve suspect material from the marketplace.

There was a mixup in packaging so that the wrong product was placed in the wrong package. “Line clearance is a core quality element of any manufacturing organization,” says an anonymous consultant. There were also failures to address root causes of contamination and repeated analytical and procedural failures.

• Johnson and JohnsonThree sites move toward remediation since being cited by FDA. All three were cited for failing to investigate complaints and establish root cause of quality problems.

Contamination issues drove drug recalls

to record levels in 2011 and contributed

to yet another increase in FDA warning

letters that year, according to analysis

by “The Gold Sheet,” a publication

from Elsevier Business Intelligence that

focuses on drug manufacturing quality.

Analysis of this year’s recalls and

warning letters will appear in “The

Gold Sheet” early next year.

RECALLSU.S. drug recalls last year soared past

the record set in 2009 due to a spike

in contamination-related recalls.

As in 2009, most of the spike was

from a single repackaging incident.

Much of the rest was from potentially

contaminated antiseptic swabs, pads

and wipes sold by H&P Industries

Inc., Hartland, Wis., and distributed

through its Triad Group Inc. unit.

Of last year’s 2,329 drug recalls,

1,024 resulted from a single incident,

in which Aidapak Services LLC, Van-

couver, Wash., realized that penicil-

lin could have cross-contaminated

numerous products repackaged in its

facility. The incident mirrors previous

repackaging failures that inflated re-

call numbers in 2000, 2006 and 2008.

Aside from the Aidapak and Triad

recalls, there were another 248

contamination-related drug recalls

in 2011, still four times the prior

decade’s annual average.

Of those 248 contamination recalls,

33 involved issues related to glass

containers such as cracked syringes or

the presence of glass flakes. An-

other 10 involved malodorous plastic

bottles tainted with 2,4,6-tribro-

moanisole (TBA), a degradant of the

chemical wood preservative 2,4,6-tri-

bromophenol (TBP).

Contamination Drives spike in reCalls, Warning letters in 2011 By Bowman Cox, Guest ContriButor and

manaGinG editor, “the Gold sheet”

Potency

Dissolution

Other

Contamination

Labeling

NDA/Monograph

Manufacturing/Testing

Figure 1. Rising Number of Drug Recalls and Their Root CausesSource: Gold Sheet March 2012


• HospiraThe company’s Austin and Rocky Mount facilities received warning letters for problems with injectables, CAPA and sampling.

• Ben Venue The company’s Bedford plant recalled 10 products due to sterility assurance problems, particulate contamination and low-fill volume. In addition, the company was sited for poor maintenance, staff training and building problems such as mold.

• Sandoz CanadaCrystalline material was found in sterile injectables; foreign matter and broken tablets were found in opiate products produced in Nebraska.

As one consultant points out, these failures aren’t intentional, but may ref lect corporate cultures

where greater value is placed on the creation and dissemination of systems and processes, rather than the content of these systems. “CEOs can talk the talk, but if they do not reinforce the concept that high quality will ultimately equate to bigger and better profits, it is just lip service,” he says.

Editor’s Note - Pharmaceutical Manufacturing will be increasing its coverage of compliance in 2013, and will also be launching a new e-newsletter focused exclusively on this area.

ReferencesQSIT Audit Guide Summaryhttp://www.fda.gov/downloads/ICECI/Inspections/UCM142981.pdf

Kerr, M., ISO 14971 and ICH Q9, http://www.pda.org/Chapters/Europe/Ireland/Presentations/Quality-Risk-Management-ICH-Q9-ISO-14971.aspx

There were also a number of

cases involving foreign tablets, a few

involving precipitation or crystalliza-

tion, and a variety of cases of par-

ticulate contamination of injectables

involving stainless steel, polyvinyl

chloride, rubber and food grade gas-

ket materials or unspecified materials.

Injectables recalls were three times

the prior 10-year annual average due

to the same combination of factors

that drove them to record levels in

2010 and that have contributed to

shortages of critical drug products.

WARNINg LETTERSThe number of drug GMP warning

letters increased 6 percent from 49 in

fiscal year 2010 to 52 in FY 2011, just

six letters short of the 58 letters in FY

2002, the last Clinton year.

There was a huge increase in

warning letters to injectable drug

manufacturers in FY 2011, which cor-

responded to the increase in recalls

for injectable drugs.

FDA inspections also found more

problems with sterility assurance for

injectables. The number of warning

letters going to injectables manufac-

turers shot up from four in FY 2010 to

13 in FY 2011.

Also, FDA inspections last year

identified more problems in the

global supply chain. Of the 52

warning letters issued in FY 2011,

17 went to active pharmaceutical

ingredient manufacturers, up from

eight in FY 2010.

An analysis of the 52 warning letters

by “The Gold Sheet” found that pro-

duction record review, which includes

batch failure investigations, was the

most common deficiency cited during

the last fiscal year. This deficiency was

noted in 28 of the 52 warning letters

issued, or about 54 percent.

The increase in warning letters

going to sterile drug manufacturers is

reflected in the higher number of de-

ficiencies noted in the microbiological

controls area.

The full analysis of FY 2011 FDA

recalls and warning letters is available

at the elsevierbi.com website.

Figure 2. Warning Letter Trends: Injectables, APIs and Oral SolidsSource: Gold Sheet, April, 2012

Injectable

API

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FEATURE TOPIC


sanitary Connections in Pressure relief

white Paper

PIPE CONNECTION designs have been a challenge for most design engineers working in the sanitary industries. To achieve clean processes and/or easy to clean piping arrangements a wide range of “standard” industry fittings and connectors have been introduced. With the focus on cleanliness and cleanability a variety of process fittings have also emerged. This paper ad-dresses some of the issues which may affect an installa-tion’s conceptual design and its “fit-for-purpose” level, especially when integrating specific process equipment such as rupture (bursting) disc devices. Specifically, we will address an installation’s sanitary level, optimiza-tion of the performance level of critical safety devices and Good Manufacturing Practice (GMP).

HYgIENIC DESIgNWhen designing/operating a process plant or piece of equipment intended for food, beverage, pharmaceuti-cal or biotech industries, a primary concern is the control and maintenance of the critical hygiene level. The consequence of an improper level of cleanliness or cross-contamination between batches, may create an even higher risk of potential casualties than from overpressure or explosions.

• Different approaches or solutions have been used/introduced, depending on the specific industry or application:

• Food — including standard consumer foods, healthcare nutrition, dietary & sports/energy foods, medical or “orphan” foods

• Pharmaceuticals• Cosmetics • Biochemical products• Beverages• Other

Historically, designers and equipment suppliers have worked to create process equipment and installations which limit areas where bacteria can grow. In addition, the cleaning and inspection ability has often been optimized through the design and use of specific piping connections. These connections allow operators to easily disassemble, inspect and clean the piping elements prior to the start of production. As a result, various industry fittings have been designed and are in use throughout a wide number of industry applications. Because there are so many “standard” connection types, certain compatibility issues may exist and go unnoticed, affecting both production efficiency and product quality.

CONNECTOR DESIgN & SELECTION ISSUESTo achieve acceptable performance and throughput within critical process plants, there are a number of is-sues to be addressed, each with a potential impact on the expected level of cleanliness and cleanability.

Good Manufacturing Process

The main strategy applied in these indus-tries is known as “Good Manufacturing Practice”(GMP), or production and testing practices that help to ensure a quality product. Many countries have

legislated that pharmaceutical and medi-cal device companies must follow GMP procedures, and have created specific GMP guidelines that correspond with their legislation. Basic to all of these guidelines remains safeguarding the health of the patient, as well as producing good quality medicine, medical supplies or active pharmaceutical products.

In the U.S. a drug may be considered adulterated if it passes all of the specification tests, but is found to be

FEATURE TOPIC


manufactured in a condition which violates current good manufacturing guidelines. Therefore, complying with GMP is often considered as a mandatory aspect in pharmaceutical manufacturing. GMPs are enforced in the United States by the U.S. Food and Drug Administration (FDA), under Section 501(B) of the 1938 Food, Drug, and Cosmetic Act (21 USCS § 351). The regulations use the phrase “current good manufacturing practices” (cGMP) to describe these guidelines. Courts may theoretically hold that a drug product is adulterated if the process was not performed according to industry standards, even if there is no specific regulatory requirement that was violated. As of June 2010, a different set of cGMP requirements apply to all manufacturers of dietary supplements.

The European Union’s GMP (EU-GMP) enforces similar requirements to the U.S. FDA and the World Health Organization (WHO) version of GMP is used by pharmaceutical regulators and the pharmaceutical industry in over one hundred (100) countries worldwide (primarily in the developing world). Similar GMPs are used in other countries, such as Australia, Canada, Japan, Singapore and others having highly sophisticated GMP requirements.

CLEANAbILITYThough there are specific requirements by industry, a common baseline is “no contamination.” The risk for contamination stems from a variety of sources such as: bacteriological, viruses, cross-contamination between subsequent batches, allergy-enhancing components, etc. Therefore, the ultimate objective of piping and equip-ment designers is to create products/systems which have no crevices or pockets where such contamination can initiate, and to have good cleanability and/or sterilization geometries.

Standard operation for most of these industries is the highly efficient cleaning or sterilization of the surfaces and connections

exposed to the media. “Clean-In-Place” (CIP) and “Steam-In-Place” (SIP) are terminologies often used to refer to the process geometry configurations offering such enhanced cleaning & inspection features. CIP is a method of cleaning the interior surfaces of pipes, vessels, process equipment, filters and associated fittings, without disassembly. When the cleaning involves steam as the cleaning/rinsing media and the exposed equipment is also sterilized – the operation is then referred to as SIP.

Compliance and suitability of equipment for the intended use is generally covered for the U.S. markets by design validation through organizations such as 3A (American Aseptic Association, www.3-a.org ). In Europe the EHEDG (European Hygienic Engineers Design Group, www.ehedg.org ) provides design guidelines and validation testing for cleanability of equipment. Equipment found to be in compliance with the relevant requirements, bear these compliance symbols.

Some standards, such as ASME BPE, provide useful information with regards to recommended configurations of connections and piping, drainability and suitable L/D ratios. The EHEDG-certification guidelines provide evidence of suitable design and cleanability of approved components.

INSPECTIONTo assure that the installation is fit for use, an opti-mal inspection of the equipment’s internal surfaces is required. Therefore, the pipe connectors need to be easy to disassemble, inspect and, where appro-priate, clean and re-assemble. As a result of these requirements, the market has seen the emergence of a large variety of pipe connectors: Tri-Clamp or

ASME BPE, DIN, SMS, ISO, NA-connect, etc. To the layman, some of these connectors (also called ferrules) may look identical, but there are minute differences in

An example of a sanitary rupture/bursting disc,

Fike’s Axius SC is specifically designed for the

stringent aseptic requirements of these applica-

tions. The Axius SC is free of indentations,

crevices, or other design features that may

trap process contaminants.

3A-Symbol EHEDG-Symbol

FEATURE TOPIC


dimensions making it necessary to assure the correct combination is selected.

COmPATIbLE mATERIALS Furthermore there are existing and emerging require-ments with regards to suitability of the used materials of construction, in regards to the intended purpose.

For the U.S. markets: • FDA (Food & Drug Administration) – mainly dealing

with acceptance of materials

• USP (United States Pharmacopeial Convention) - sets standards for the identity, strength, quality, and purity of medicines, food ingredients, and dietary supplements manufactured, distributed and consumed worldwide.

For the European markets: • European Regulations (such as Regulations

1935:2004 and 2023:2006) - deals not only material acceptance, but quality and traceability systems applied in the manufacturing of components and complete assemblies. Regulation 2023:2006 is also referred to as the European GMP document.

In general, most metallic parts manufactured from stainless steel or nickel alloy, are accepted for use in sanitary processes. The use of non-metallic parts (such as gaskets), coatings or active substances is often a more challenging issue; not only is compatibility required, but the traceability of the manufacturing process and used compounds must be validated. This is critical not only for high-risk pharmaceuticals or orphan drugs, but is standard for food and beverage products to avoid contamination (such as with Bovine spongiform encephalopathy, also know as BSE- or “mad cow” disease). The unwanted risks related to migration of substances or active components are also addressed in order to reduce the risks for allergic reactions and other health issues.

Clamp & Ferrule Type Connectors

(ASME BPE, DIN 32676, ISO 2852, etc

Overview of Critical Dimensions for Common Ferrule TypesASME BPE Dimensions DIN 32878 Dimensions ISO 2862/8MS 3008 Dimensions

Nominal Inside Diam-

eterFerrule OD

Gasket Cen-terline Nominal

Size

Inside Diam-eter

Ferrule ODGasket Cen-

terline Nominal Size

Inside Diam-eter

Ferrule ODGasket Cen-

terline

mm mm mm

1 22.10 50.39 43.64 32 32.00 50.50 43.48 38 35.59 50.50 43.48

1.5 34.80 50.39 43.64 40 38.00 50.50 43.48 40 37.59 63.98 55.49

2 47.50 63.91 56.34 60 49.99 63.98 56.49 61 48.59 63.98 55.49

3 72.90 90.91 83.34 80 80.98 105.99 96.98 70 66.78 90.98 83.49

4 97.38 118.92 110.34 100 100.00 119.00 110.01 76.6 72.90 90.98 83.49Standard connections can be safely used within the pressure/temperature boundaries as specified for the subject connection type.


Ferrule Product Information: Typical Ferrule Surface Finishes

OTHER ISSUESThe objectives of connector standardization are clear: Provide a way forward to design and offer standard instrumentation and valves with suitable characteristics for use under the required operating conditions. How-ever, due to historical developments, specific industry requirements/preferences, and lacking harmonization, nearly identical “standard” fittings have been developed, oftentimes with only minute differences, whereas others will look dramatically different from others.

In all installation geometries, a smooth, crevice-free transition between the ferrule inside diameter

and the gasket needs to be achieved. A common misunderstanding with specifying engineers or users is to refer to the sanitary tube specification used (SMS3008, DIN 11850, ASTM A270, etc), while addressing the ferrule. The pipe intended to be welded to the ferrule must have identical dimensions (inside and outside diameter) to the but-weld end of the corresponding ferrule in order to achieve a smooth transition between ferrule and pipe. However, ferrules from several executions and standards have been designed to fit with the same tube dimensions. Therefore it is essential that the correct ferrule is clearly selected and specified.

Finish CodeMaximum Surface

Roughness Media Contact Surface Polishing Method

Non-Media Contact SurfacesAlfa-Laval Tri-Clover

ASME BPEMicroinches Micrometers

(m-inches) (mm)

#1 UnpolishedUnpolished

#3 32 0.8 Mechanically Polished

#7 32 0.8 Mechanically Polished Polished to Ra 32 m-inches, 0.8 mm

PC SFF1 20 0.5 Mechanically PolishedUnpolished

PD SFF4 15 0.4 Mechanically Polished & Electropolish

PL SFF1 20 0.5 Mechanically PolishedPolished to Ra 32 m-inches, 0.8 mm

PM SFF4 15 0.4 Mechanically Polished & Electropolish

Nominal Size 1” & 1 1/2” 2” 3” 4”

13MHLA Clamp Screw Tightened to Maximum

at 70°F/21°C 150 psig/10.3 barg 100 psig/6.8 barg

at 250°F/121°C 125 psig/8.6 barg 75 psig/5.1 barg

13MHHM Wing Nut Tightened to 25 in.lbs/2.82 Nm Torque

at 70°F/21°C 500 psig/34.48 barg 450 psig/31 barg 350 psig/24.1 barg 300 psig/20.6 barg

at 250°F/121°C 300 psig/20.6 barg 195 psig/13.4 barg 150 psig/10.3 barg

13 MHHS Wing Nut Tightened to 25 in.lbs/2.82 Nm Torque

at 70°F/21°C 600 psig/41.3 barg 550 psig/37.3 barg 350 psig/24.1 barg 300 psig/20.6 barg

at 250°F/121°C 300 psig/20.6 barg 275 psig/18.9 barg 175 psig/12 barg 150 psig/10.3 barg

13 MHP Bolts Tightened to 20 ft.lbs/27.1 Nm Torque



Maximum Recommended Operating Pressure Rating

FEATURE TOPIC


CRITICAL ISSUES RELATED TO PRESSURE RELIEF DEvICESIn today’s markets, equipment and components are often designed and manufactured in various global re-gions. The integration of such sub-systems may easily lead to unwanted misalignments with immediate impact on the hygienic aspect of the total sys-tem. Such “correct-fit” issues are often considered minor when it comes to rigid process equipment such as valves and manifolds.

For more sensitive devices, such as rupture/bursting discs, where the pressure sensitive membrane needs to be clamped directly into the ferrule in order to create a leak-tight, hygienic seal, the alignment issue becomes more critical. The improper combination of ferrules and rupture disc, can lead to sanitary misalignments. If the disc becomes damaged, there can be degrading effects with regard to the performance of these pressure safety devices. Improper alignment can also deteriorate the vacuum rating or the opening pressure of the rupture disc device. When there is doubt, the manufacturer should be consulted.

To avoid these potential installation issues, safety authorities and users in some regional markets require that all such devices be marked and certified with appropriate and clear references to the holding device (ferrule standard) for which the subject part is certified. There is an emerging requirement to mark the relevant piping components – such as the rupture discs – with the type designation of the ferrule (ASME BPE, DIN 32676, ISO 2852) in which it is to be used. For use in the European Economic Area, a written compliance statement is required with regards to the European food safety regulations 1935/2004 and 2023/2006. This is to ensure that the components and equipment are in compliance with their intended use, without infringing on their safety performances.

SUmmARYIn order to provide best performance and cleanability, the users and designers of sanitary installations must

positively specify the intended ferrule connection for the piping system. It is essential to ascertain that all piping components and valves intended to be used are designed and certified for use in the specified ferrule connectors. In addition, all selected valves and fittings must be certified and marked for use in the specified ferrule. The satisfactory performance of critical pres-sure relief devices such as rupture discs can be ex-pected where clamping arrangement specifications are aligned. By aligning the individual specifications, the clean processing and cleanability of the process piping and connections, will be as expected.

REFERENCES:http://www.asme.org/products/codes---standards/bioprocessing-equipment-(2)

http://www.fda.gov/Food GuidanceComplianceRegulatoryInforma-tion/CurrentGoodManufacturingPracticesCGMPs/default.htm

http://ec.europa.eu/health/documents/eudralex/vol-4/index_en.htm

http://www.who.int/medicines/areas/quality_safety/quality_assur-ance/production/en/

http://ec.europa.eu/food/food/chemicalsafety/foodcontact/frame-work_en.htm

Clamping configuration of bursting disc device in ferrule type connection

http://www.asme.org/products/codes---standards/bioprocessing-equipment-(2)

http://www.asme.org/products/codes---standards/bioprocessing-equipment-(2)

http://www.fda.gov/Food/GuidanceComplianceRegulatoryInformation/CurrentGoodManufacturingPracticesCGMPs/default.htm

http://www.fda.gov/Food/GuidanceComplianceRegulatoryInformation/CurrentGoodManufacturingPracticesCGMPs/default.htm

http://ec.europa.eu/health/documents/eudralex/vol-4/index_en.htm

http://www.who.int/medicines/areas/quality_safety/quality_assurance/production/en/

http://www.who.int/medicines/areas/quality_safety/quality_assurance/production/en/

http://ec.europa.eu/food/food/chemicalsafety/foodcontact/framework_en.htm

http://ec.europa.eu/food/food/chemicalsafety/foodcontact/framework_en.htm

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ADDITIONAL RESOURCES


http://solutions.3m.com/wps/portal/3M/en_US/3M-Purification-Inc/3MPI-US/Filtration-Solutions/Life-Sciences/

http://solutions.3m.com/wps/portal/3M/en_US/3M-Purification-Inc/3MPI-US/Resources/Seminar-Series/

http://multimedia.3m.com/mws/mediawebserver?mwsId=SSSSSufSevTsZxtUNY_xOx_xevUqevTSevTSevTSeSSSSSS--&fn=70-0201-8676-6.pdf

http://www.camo.com/industry/pharmaceutical.html

http://www.camo.com/downloads/resources/useful_guides/Infosheet_Biotech.pdf

http://www.camo.com/downloads/resources/useful_guides/Infosheet_Biotech.pdf

http://www.camo.com/resources/index.html

http://www.fwc.com/publications/focus.cfm

http://www.fwc.com/GlobalEC/Pharmaceuticals/pharmaceuticals.cfm

http://www.fwc.com/GlobalEC/Pharmaceuticals/pharmaceuticals.cfm

http://www.fwc.com/publications/tech_papers/files/Delft%20Uni%20Symp%2015Apr2011.pdf

http://www.fike.com/explprot.html

http://www.fike.com/pressurerelief.html

http://www.youtube.com/embed/kmXB_e4bwuA

http://www.hamiltoncompany.com/products/sensors/c/1008/

http://www.hamiltoncompany.com/Apps/downloads.php?r=7

http://reg.accelacomm.com/servlet/Frs.frs?Context=LOGENTRY&Source=source&Source_BC=32&Script=/LP/50172900/reg&

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