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WWW.PHARMAMANUFACTURING.COM VOLUME 11, ISSUE 1
Novartis Edges out Pfi zer for Digital Buzz p.9
Working With Vent Filters: A Risk-Based Approach p.27
Can Architects and Process Developers Row Together? p.32
Ciurczak on Meaningful Sampling p.50
JAN
UA
RY
20
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Modular construction and disposable process equipment are maximizing
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Departments7. FROM THE EDITOR
Can Pharma Conquer the Culture of Arrogance?It had better start benchmarking. Analysts say 2012 could be the industry’s toughest year yet.BY AGNES SHANLEY, EDITOR IN CHIEF
9. DIGITAL INSIGHTSFor Digital Buzz, Novartis Tops Pfi zerAnd J&J re-enters the top ten despite continued product recalls.BY MICHELE V. WAGNER, SENIOR EDITOR, DIGITAL MEDIA
10. UPFRONTVirtual quality inspections; troubleshooting R&D; Funny Pharm; Compliance Quiz; pharma quotes
15. OUTSOURCING EXCELLENCEModular Gains MomentumModularly constructed facilities will aid outsourcing and emerging markets, says expert Pär Almhem.
32. FACILITY DESIGNFinding the FlowCan architects and process designers see eye to eye?BY ALAN A. LIDDY, AIA, NCARB, PMP, SSOE GROUP
41. PHARMA VIEWCan Manufacturing Be Sexy for Millennials?If not, maybe high-paying jobs will do the trick.BY PAUL THOMAS, SENIOR EDITOR
49. CLASSIFIEDS
50. THERAPEUTIC DOSESampling: Good News, Bad NewsMeaningful testing will satisfy both FDA and ASTM. BY EMIL CIURCZAK, CONTRIBUTING EDITOR
Features27. A RISK-MANAGEMENT-BASED APPROACH
TO TANK VENT FILTRATIONBest practices to ensure compliance, and avoid prob-lems during operation, installation, CIP and SIP.BY MICHAEL FELO, EMD MILLIPORE
34. TECHNOLOGY ROUNDUP: MACHINE VISION Machine vision technologies are getting simpler and cheaper, and yet tackling more varied applications.BY PAUL THOMAS, SENIOR EDITOR
37. IMAGING THE BLENDING PROCESSHyperspectral imaging can be used to optimize blend-ing, by monitoring the distribution of excipients and APIs in formulation.BY GABOR KEMENY AND GINA STUESSY, MIDDLETON RESEARCH
43. SPLIT DECISIONS: TABLET SCORING COMES UNDER SCRUTINYFDA has released new draft guidance; we summarize and talk with tableting expert Dale Natoli. BY PAUL THOMAS, SENIOR EDITOR
45. BOOSTING PRODUCTION LINE RESULTSForget about conventional wisdom and take advantage of employees’ natural working rhythms. BY TOM MCNAMARA AND SARAH HUDSON, RENNES SCHOOL OF BUSINESS,
AND SABRY SHAABAN, GROUPE ESC LA ROCHELLE
Pharmaceutical Manufacturing (USPS number 023-188) is published monthy except bi-monthly in July/Aug and Nov/Dec, by Putman Media Inc. (also publishers of Food Processing, Chemical Processing, Control, Control Design, and Plant Services), 555 W. Pierce Road, Suite 301, Itasca, IL 60143 (Phone: 630-467-1300 Fax: 630-467-1179). Periodicals postage paid in Itasca, IL and at additional mailing offi ces. POSTMASTER: send change of address to Pharmaceutical Manufacturing, Post Offi ce Box 3431, Northbrook, IL 60065-3431. SUBSCRIPTIONS: To receive a complimentary subscription go to www.pharmamanufacturing.com. Subscription rate for non-qualifi ed U.S. subscribers is $68/yr. Single copy rate is $15.00. Foreign rate is $115/yr. (surface mail) and $200/yr. (airmail). Copyright ©2012 by Putman Media Inc. All rights reserved. The contents of this publication may not be reproduced in whole or in part without consent of the copyright owner. Reprints are available on a custom basis. For a price quotation contact [email protected]. Subscriptions/Customer Service: (888) 644-1803
43
Cover Feature18. GROUNDBREAKERS
Driven by modular construction and disposable process equipment, facility designs
now aim to maximize agility and minimize risk.BY AGNES SHANLEY, EDITOR IN CHIEF, AND PAUL THOMAS, SENIOR EDITOR
18
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I RECENTLY invited a prominent figure in academia to write a commentary for this magazine on what the indus-try needs to do in the year ahead. He has been a leading advocate for manufacturing’s strategic importance, and for the need for improvement and change.
He declined, but his reasons were revealing. “I have to be careful about what I say, to avoid alienating leadership in the industry,” he said. Apparently, some previous writings had angered people at companies whose participation was critical to research.
This surprised me. Wouldn’t executives want constructive criticism from a neutral source? After all, isn’t the end goal continuous improvement? He is a professor and was discussing science, nothing more and nothing less. There was no political agenda.
This reaction has been around for a while. It started before and has continued long after the famous “potato chips and soap flakes” comment by former FDA commissioner McClellan. Sure, some pharma companies are embracing best practices from other industries. GSK, for instance, has formed a joint venture with the McLaren Group, of Formula One fame, with the goal of applying modeling, analytics, engineering and technology to drug development and manufacturing. But even with projects like this going on, and all the change of the past decade, the Not Invented Here syndrome is alive and well in the drug industry, we hear.
Apparently, back in the early days of Process Analytical Technology (PAT) and CDER’s Science Advisory meetings at FDA, at least one key executive at one of the world’s largest pharmaceutical firms openly questioned the need for the industry to change its practices or benchmark them against those of automotive, electronics or consumer goods manufacturers. “We could teach them about better manufacturing,” he reportedly said.
Now, I’m sure that drug companies could teach those industries everything about making drugs. But how about waste and cycle time reduction? In biotech ventures involving electronics giants Fuji and Samsung, we may see what happens when the best of both worlds collide.
Change is clearly coming. Fitch Ratings has predicted that 2012 will be the industry’s most challenging year ever. Can anyone afford to be arrogant, when R&D pipelines are so thin and drug manufacturing, as it is practiced today, has
been acknowledged to waste over $50 billion per year? According to Emory University professor Jagdish
Sheth’s book, The Self-Destructive Habits of Good Companies, highly successful companies lose their edge through complacency and arrogance. Perhaps the same holds true for entire industries. Sheth wrote, “The most dangerous competition comes from low-quality/low-price competitors. Utilizing price as their most tantalizing selling point, they establish a presence in the marketplace.
Their upstream competitors generally malign them as easily dismissed peddlers of ‘junk’ or just ignore them. But if these ‘inferior’ competitors improve quality while maintaining their relative cost advantage, they become irresistible value propositions to customers.” Sheth’s book came out over four years ago, and this transformation has already begun within pharma.
“Not Invented Here” needs to be torn out by its roots. The smartest companies are learning from every source possible. This new year, one of our resolutions is to include more practical benchmarking examples from outside of pharma that can be applied in your facilities. We also hope to get more case studies directly from you and from independent academic groups.
In this issue, for instance, you’ll see an article on operational improvement, written by professors at the Rennes School of Business in France. We also promise to get more input from generics manufacturers, who face competitive margin pressures closer to those of other manufacturing industries.
The future belongs, not only to the agile, but to those who know how to learn. Here’s to a good year!
Agnes Shanley, Editor in [email protected]
FROM THE EDITOR
A Culture of ArroganceAnalysts say that 2012 may prove to be pharma’s most challenging year ever.
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Processing facilities and technical service offices in the Americas, Europe and Asia
ZETA INTERACTIVE, a digital marketing agency, has published its annual end-of-year Buzz Report, recapping the most buzzworthy pharmaceutical brands’ trends and stories from 2011. Zeta uses its Buzz technology and algorithm, which scans more than 200 million blogs and online sites in real-time, and assigns a buzz ranking to each company, factoring in both volume and tone of posts each brand receives. From that, it determines digital winners and losers.
The most noteworthy finding was Novartis overcoming Pfizer, who previously held the best buzzed pharma brand in 2010, for the most positively tonal web buzz score (6.46). Novartis was not without its fair share of job cut news this year, but perhaps it was Pfizer appearing in the news for thousands of job cuts, claims of advertisements that objectify women, or shake-ups in top management that allowed Novartis to slide into the top position.
Johnson & Johnson, which finished as the #1 best buzzed pharma brand in 2008 and 2009 before dropping out of the top ten completely last year due to its recall crisis, managed to make it back on this year’s list, finishing at #6 overall. However, at just 61% positive, J&J’s tonal buzz ranking was lower than any other brand on this year’s pharma buzz list. And as expected, the product recalls of last year still continue to be featured prominently in J&J’s cluster analysis, with the word “recall” appearing among the most popular words used to describe the brand online in 2011.
Surprisingly, Bayer climbed up four spots to the #2 spot overall on this year’s list after finishing in 6th place in 2010. Additionally, at 88% positive tone, Bayer’s tonal buzz ranking was higher than any other pharma brand on the list. Other interesting Buzz Rankings to note:
Advil, as was Bayer’s with aspirin
DIGITAL INSIGHTS
MICHELE VACCARELLO WAGNER, SENIOR EDITOR, DIGITAL MEDIA
555 West Pierce Rd., Itasca, IL 60143
www.putmanmedia.com
Subscriptions/Customer Service
EDITORIAL TEAM
AGNES SHANLEY EDITOR IN CHIEF
PAUL THOMAS SENIOR EDITOR
MICHELE V. WAGNER SENIOR EDITOR
[email protected] DIGITAL MEDIA
KEITH LARSON V.P., CONTENT
EDITORIAL ADVISORY BOARD
ALI AFNAN, Step Change Pharma
JIM AGALLOCO, Agalloco & Associates
CARL ANDERSON, Duquesne University
JAMES BLACKWELL, Bioprocess Technology Consultants
JOHN BLANCHARD, ARC Advisory Group
TOM CAMBRON, P&G Pharma
JAMES CHENEY, Novartis
BIKASH CHATTERJEE, Pharmatech Associates, Inc.
EMIL CIURCZAK, Cadrai Group
ROBERT DREAM, HDR Company
ERIC LANGER, BioPlan Associates, Inc.
ROBBE C. LYON,
IVAN LUGO, INDUNIV, Puerto Rico
GIRISH MALHOTRA, Epcot International
RODDY MARTIN, AMR Research
FERNANDO PORTES, Stevens Institute of Technology
GARY RITCHIE, Consultant
DESIGN & PRODUCTION TEAM
STEPHEN C. HERNER V.P., CREATIVE SERVICES
DEREK CHAMBERLAIN ART DIRECTOR
RITA FITZGERALD PRODUCTION MANAGER
ADMINISTRATIVE TEAM
JOHN M. CAPPELLETTI PRESIDENT/CEO
JULIE CAPPELLETTI-LANGE VICE PRESIDENT
JACK JONES CIRCULATION DIRECTOR
USPS number (023-188)
Novartis Beats Pfizer in 2011 Web Buzz Rankings
BrandVolume Ranking
Tonal Ranking
Zeta Buzz Ranking
Change From Last Year’s Rankings
1. Novartis 75.1 86/14 6.46 +1
2. Bayer 71.3 88/12 6.27 +4
3. AstraZeneca 62.8 85/15 5.34 No Change
4. Merck 65.1 76/24 4.95 +1
5. Pfizer 74.8 66/34 4.94 -4
6. Johnson & Johnson 75.3 61/39 4.59 New to list
7. Bristol-Myers Squibb 51.7 87/13 4.50 No Change
8. Eli Lilly 44.5 84/16 3.74 +1
9. Teva Pharmaceuticals 35.1 80/20 2.81 New to list
10. Mylan 33.4 84/16 2.80 No Change
“It’s now part of the SOP to send the recall notice with each consignment. This may well be our best cost saving measure.” – Atul Deshmukh
Funny Pharm comics, drawn by professional cartoonist Jerry King,
appear twice a month on PharmaManufacturing.com. Readers submit
suggested captions. Above is a recent cartoon and winning caption.
FUNNY PHARMJUST HOW far has pharma R&D productivity fallen? According to three Oliver Wyman analysts, very far indeed. They’re basing their conclusion on the number of new drug approvals vs. the research dollars spent over the past several decades. But they’re also factoring the true value of new drugs launched each year.
In “Beyond the Shadow of a Drought: The Need for a New Mindset in Pharma R&D,” analysts Jeff Hewitt, J. David Campbell, and Jerry Cacciotti state: “It’s well accepted that pharmaceutical R&D productivity has fallen, with new drug approvals trending downward even as costs trend up. Companies are taking some actions: rationalizing costs, increasing outsourcing, collaborating with academic institutions, increasing their focus on specific disease areas, reconfiguring their organizations. But is that enough? We don’t think so. And neither, apparently, does Wall Street. Investors remain wary of R&D spending, rewarding companies that cut and penalizing those that don’t—a sign of limited confidence in the industry’s use of its capital.”
Sure, it’s hard to be too alarmed when drug companies are still seeing respectable revenue growth, but fundamental problems are masked, they say.
success. They have met many of what were formerly viewed as unmet needs, and many of these important medicines are now available in cheap, generic versions.
rein in drug prices.
conventional wisdom believes. Oliver Wyman’s own analysis suggests “the likelihood that a new drug entering Phase III will reach the market is just 50 percent, far less than the success benchmarks many companies commonly use.”
fungible. (Stated differently, pharmaceuticals do not lend themselves to substitu-tion). Companies are realizing they can’t compete in varied therapeutic areas, lessening their ability to conduct a “more shots on goal” approach to scoring with given molecules.
problems. The key, they say, is to think differently about innovation:
Focus on efficacy. “This reverses the classic approach,” they write, “which targeted the broadest population in which the drug had a statistically significant (if mar-ginal) result.”Invest more up-front. “Companies need to spend more to fully understand where and for whom their drugs work.” (Editor’s Note: Sounds like a ringing endorsement of Quality by Design.)
Even small im-provements in safety and ease of use for patients, as Merck did with Januvia, can pay off.Ultimately, the authors say, drug companies must
reconsider the importance, or definition, of “speed to
pursuing a new lipid therapy as Lipitor’s patent window was closing. In the end, Merck chose a slower approach, and produced a drug with fewer side effects and greater success. “Rather than massing investment against a single shot, could [Pfizer] have accelerated back-up molecules to determine if they had a different safety profile?” the
UPFRONT
R&D Productivity: Worse Than We Thought?Drug companies are, a new report says, victims of their own success.
10 JANUARY 2012
BY PAUL THOMAS, SENIOR EDITOR
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report asks. “More radically, could they have used their leading position to strike a partnership with Merck or Roche to share the investment and risk across CETP inhibitors, and decrease the chance that they might miss out on a major therapy breakthrough in a chosen focus area?”
For a link to the report, see PharmaQbD.com.
Drug Manufacturers Seek Remote ControlAS FACILITIES of the future become more far-f lung and distant from drug manufacturers’ home bases, and as outsourcing continues to increase, the challenge of monitoring varied and vast activities around the globe becomes greater. One obvious solution for this dilemma is to make use of remote videoconferencing capabilities. Videoconferenc-ing has long been used in boardrooms and amongst researchers, and is gaining traction as a means of ensuring manufacturing consistency and quality worldwide.
FDASmart Inc. is one solution provider banking on manufacturers’ need for greater, faster global oversight. Its SmartInspect system enables live, secure, Internet-based, mobile video transmissions between two locales. In other words, says founder and CEO Ram Balani, “complete global visibility without travel and without a boatload of money.” SmartInspect has garnered interest from Pfizer, which is testing the system for various purposes—assisting technology transfer, performing quality audits remotely, and for remote training.
The drug company has experimented with using the system for API screening at sites in China, for instance, notes Balani. Whereas Pfizer might typically send three people abroad for a lengthy trip to perform such screening, it could potentially do the entire task via videoconference.
Bristol-Myers Squibb is also doing Proof of Concept testing of SmartInspect to facilitate tech transfer for biologics—for sharing complex information between, for example, Syracuse, New York, and a contract manufacturer such as Celltrion in South Korea.
“Having a direct link to our plants and subject matter experts around the world is obviously advantageous,” says Kirk Leister, director of process analytical sciences for BMS. Part of Leister’s job is to find technological innovations that can facilitate development and manufacturing.
Leister uses the example of having spent two months troubleshooting a peptide map in a Korean facility, eventually sending an expert to the site, only to find out that the problem was related to a fairly simple setting. Being able to set up and operate instrumentation via mobile video would have made a significant difference, he says.
SmartInspect users pay a $24,000 fee upfront for the equipment and software, and may sign up for a maintenance contract as well. While BMS and Pfizer have shown interest, Balani envisions his technology being used more by small and mid-size companies with limited resources, and by clinical trial teams. –Paul Thomas
UPFRONT
12 JANUARY 2012
PHARMA REPLAY
“Most drug shortages we re-
viewed in detail were report-
edly caused by manufacturing
problems.”
– U.S. Government Accounting
Office (GAO) investigators, on the
root causes of recent chronic drug
shortages
“This limited product availability
does not foreshadow the poten-
tial for any additional supply of
Doxil in the immediate future, as
we have no further information
from BVL on when manufactur-
ing will resume.”
– A letter from Janssen to health-
care providers regarding future
shipments of Doxil following
the halting of production at Ben
Venue Labs.
“There is no proceduralized pro-
cess to notify senior management
of issues that could potentially
impact the safety or quality of
product.”
– One of many faults cited by FDA
in a recent warning letter to Ben
Venue
“We apologize for any inconve-
nience this may have caused.”
– Facebook, citing an “adminis-
trative error” that allowed the
Facebook page of the Germany’s
Merck KgaA to be used by Merck
& Co. of the U.S.
“The problem with R&D is it’s
not always consistent. It’s not
like engineering where you can
incrementally innovate and make
another version of the iPhone.”
– Merck CEO Ken Frazier, justifying
his commitment to maintaining
R&D spending
USP Proposes Guidelines for Supply Chain Integrity
THE U.S. Pharmacopeial Conven-tion has proposed a set of recom-mended best practices that will help ensure improved supply chain security and integrity. (USP is cur-rently seeking feedback; www.usp.org/USPNF/notices/generalChap-ter1083.html.)
The standards are contained within the proposed USP General Chapter <1083> Good Distribution Practices—Supply Chain Integrity. The proposal is intended to serve as general guidance for essential elements of an effective supply chain strategy.
“Th ere is incentive for all players in the pharmaceutical industry—large and small companies, regulators and standards-setting bodies—to come to some agreement on hot-button issues such as track and trace technology and, at the larger level, to codify what constitutes a solid, universal approach to global supply chain integrity,” says Praveen Tyle, Ph.D., chief science offi cer for USP. “USP has developed an initial proposal that we expect to evolve as industry, FDA and others weigh in. Our role as an independent body provides an opportunity to convene all these parties and advance this critical issue. . . . USP can move forward something more concrete than a technical report, as part of a mechanism that can be regularly updated to best meet the needs of all.”
Th e proposed standard covers four main areas:
Devicescomments submitted to USP will be discussed at a Supply Chain Integrity Workshop that USP is hosting on
UPFRONT
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Welcome to Compliance Quiz. (Find each month’s quiz,
and more details on answers, on PharmaManufacturing.
com.) January’s quiz focuses on some general rules of
good GMP compliance. For answers, see below, right.
1. Which three criteria are FDA investigators most likely
to focus on during GMP inspections?
A. Your ability to debate the broad language used in
FDA guidance documents, refreshments provided, and
your sense of humor.
B. Process validation, lab/facility operational response to
OOS results, your firm’s response to any observances
of deviations.
C. Cost savings from shortcuts in your quality system, lab/
facility dress code, the kindness of the receptionist.
2. 21 CFR Part 211.22 (d) states: “The responsibilities
and applicable to the quality con-
trol unit shall be in ...”
A. “software” & “compliance”
B. “accessories” & “arrears”
C. “procedures” & “writing”
D. “regulations” & “an electronic format”
3. Which of the following is NOT an example of an ob-
servance of a deviation?
A. “Inadequate process failure investigation.”
B. “Responsibility of Quality Control Unit not document-
ed or followed.”
C. “Laboratory controls do not include scientifically sound
test procedures to assure that drug products conform
to standards of identity, strength, quality and purity.”
D. Examination and testing of samples is not done
frequently enough to improve the likelihood that in-
process materials conform to specifications.
4. One of the most critical aspects of a successful Form
483 response is that it:
A. is quick and indicates the immediate fix (for the devia-
tion) to be implemented in the shortest amount of time.
B. comes from one single person in the firm, wherein each
observation is addressed by one person in one step.
C. goes beyond addressing the Form’s observations, but
determines root causes and underlying issues behind
the observed deviation.
D. leaves an overall impression of self-righteous indignation.
5. An effective corrective and preventive action (CAPA)
system of procedures must entail:
A. The precise details of one corrective and one preven-
tive action taken after a single defective batch.
B. An assumption that once the corrective action is tak-
en, the problem is solved for the foreseeable future.
C. A dynamic program for continuous reappraisal of pro-
cesses and test methods that will determine areas that
are at risk for producing an unacceptable product.
UPFRONT
14 JANUARY 2012
Answers 1. B 2. C 3. D 4. C 5. CCompliance Quiz
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ICH Fleshes Out Q8, Q9, and Q10
THE ICH Quality Implementation Working Group has released its final three “Points to Consider” (PtC) docu-ments, following three it released last June. The docu-ments are intended to provide further clarity in regards to
ICH Q8, Q9, and Q10. The six PtCs are:
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OUTSOURCING EXCELLENCE
PÄR ALMHEM has been involved in modular con-struction for several years, previously at Pharmadule, and, now, with the recent startup ModularPartners. As the pharmaceutical industry increases its use of modular construction, new players are entering the market. At the same time, designs are becoming more standardized, which promises to reduce project timelines even further. Will pharma embrace modular to the same extent that other industries have? Almhem recently shared his per-spectives on “mod con,” where it is today, and where it is going, in the pharma and biopharma industry.
PhM: Modular construction continues to grow in popu-larity within pharma and biopharma. How far along are we in terms of a paradigm shift?
P.A.: I think we are still in an early stage. Modular solu-tions have gone from being a novelty and something very few would consider, to now being discussed and consid-ered in many (most?) cases. However, few have started to take advantage of the real opportunities in modulariza-tion in the way that, for example, the software and elec-tronics industries do. This requires a change toward much more standardization of building blocks (not necessarily the complete process or facility), use of configurable sys-tems rather than customized systems, etc. Only when we adopt these strategies can we talk about a paradigm shift.
PhM: What’s been the most significant change you’ve seen in the past ten years in regards to the industry’s understanding and acceptance of modular construction?
P.A.: The biggest change is that in the last few years, most end users have become aware of modular solutions and more and more service provider are now saying they offer modular solutions. Modular solutions have become an established methodology.
PhM: What have been the most significant hurdles to adoption? Are there limitations to modular facilities that you didn’t foresee in the past?
P.A.: The most significant hurdles have been the tradi-tion of how projects are planned and executed. If their
full benefit is to be realized, modular solutions need to be considered in the early stages of a project. Many times, if the question about modularization has been asked, it has been too late. Modular facilities have also had a reputa-tion for being expensive. This has sometimes been true, partially because. in the past, there hasn’t been enough volume to really drive down cost. Other limitations like layouts and flexibility have, for the most part, been solved by new engineering solutions.
PhM: Modular facilities require more intense, focused initial planning. You previously wrote: “Team building, interface management, automation, and integrated validation must be incorporated into the plan at the pre-project planning phase.” Has this been a challenge for manufacturers?
P.A.: This is actually relevant for all fast-track projects, not just modular projects. It has been a challenge for owners, but there is an increasing understanding that this is mostly a matter of good project management.
PhM: Are major manufacturers gravitating towards modular design for emerging markets in particular, as a way to better standardize, control, and maintain facili-ties there?
P.A.: Yes, modular solutions are even more valuable in these markets, for the reasons you mention. However, in addition, modular constructions can mitigate risk for project quality and schedule, and can enhance security by allowing companies to keep intellectual property in house and under control.
PhM: Have you collected data on time and cost savings of modular vs. traditional projects? What specifics can you share?
Pharma Facilities: Modular Gains MomentumModularly constructed facilities are an inevitable part of the industry’s future, especially for emerging markets, says Pär Almhem
BY PAUL THOMAS, SENIOR EDITOR
PHARMA IS NOT TAKING ADVANTAGE
SOFTWARE AND ELECTRONICS ARE.
P.A.: There are case studies and some statistics, but un-fortunately very few really relevant, objective reports. CII has done benchmarking, but only members have access to this. Merck made a detailed benchmark for their Summit S6 project that was one of the ISPE Facility of the Year category winners this year. This was presented at the ISPE Annual Meeting 2009 and published by ISPE.
PhM: Have there been advances/changes in how modules are shipped and transported? Are they typically moved in the same fashion as standard shipping containers?
P.A.: Building modules are generally shipped in a fashion similar to shipping containers. The main differences are that the modules are larger and shipped with greater care (for instance, steps are taken to ensure weather protec-tion). Thousands of modules have been shipped around the world with very few incidents. Process modules are shipped in similar ways, depending on size, sensitivity, and other factors.
PhM: Finally, can you clarify the circumstances of your leaving Pharmadule and helping to start Modular Partners?
P.A.: Pharmadule AB, the Swedish parent company of the Pharmadule group, was owned by a European private equity firm. After a couple of difficult years in 2009 and 2010, they decided in early 2011 to close Pharmadule, and Pharmadule AB filed for bankruptcy in February 2011. Pharmadule AB is now closed. Pharmadule, Inc., the U.S. subsidiary that I ran, is also closed. We did not file for bankruptcy but closed. The other subsidiary, Pharmadule Oü, the manufacturing plant in the Pharmadule group, was taken over by local management in a management buyout. Pharmadule Oü is now owned partly by manage-ment, and partly by Telstar of Spain, and is core part of the ModularPartners network.
After closing Pharmadule, Inc., I started a company ModWave (www.modwave.com), with a colleague from Pharmadule, Camilla Sivertsson. From that platform, we took the initiative to form ModularPartners with KeyPlants of Stockholm, Sweden, and Yonkers Industries of Cary, NC. Please see www.modularpartners.com for additional information.
KeyPlants is a spin-off from Pharmadule AB, formed in mid 2010. Just like Pharmadule Oü, the company is owned by management and Telstar. Yonkers Industries is a privately held construction management firm.
OUTSOURCING EXCELLENCE
16 JANUARY 2012
NEWS & NOTES
Amgen and Watson Pharmaceuticals will develop and
commercialize follow-on versions of several antibody
biotech drugs for cancer, excluding Amgen’s products.
Amgen will be in charge of development, production
and initial marketing, while Watson will provide as much
as $400 million for product development and contribute
expertise in commercialization and marketing.
Baxter and Momenta Pharmaceuticals will also collabo-
rate to develop and commercialize biosimilars. Baxter
will provide expertise in clinical development and bio-
logic manufacturing, while Momenta will add expertise
in analytics and product and process development.
Soligenix has begun developing a next-generation
anthrax vaccine, a modified anthrax toxin protein, with
Harvard University.
ImmunoGen and Eli Lilly will jointly develop antibody-
based cancer drugs. Lilly will get exclusive licensing
rights to some of ImmunoGen’s cancer drugs in ex-
change for a $200 million milestone fee for each drug
licensed and additional royalties.
DSM Pharmaceutical Products has contracted with New
Jersey-based QRxPharma to manufacture MoxDuo
capsules, an opioid pain medication, to supply the U.S.
market through 2015.
Accelrys has acquired VelQuest, which specializes in
paperless lab execution systems, for $35 million.
AAIPharma Services has acquired Celsis Analytical
Services, which performs material testing services for
pharma and biopharma. The new company will feature
“an integrated development and material testing service
model,” said Patrick Walsh, AAIPharma CEO.
Ben Venue Labs will extend the voluntary suspension of
manufacturing at its Bedford, Ohio facility. The company
said it “can no longer continue to manufacture and re-
mediate simultaneously.” Ben Venue hopes to get some
manufacturing begun this winter, but said that its north
facility, which makes key sterile injectables that are in
short supply on the market, requires “major reconstruc-
tion” and will not manufacture any new products before
the fourth quarter of this year.
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2012 MARKS what some analysts are already expecting to be the most chal-
lenging year in the pharmaceutical indus-try’s history. As patent expirations and global
competition step up, and the mantra changes from blockbuster to nichebuster, manufactur-
ers are chipping away, wherever they can, at the years and millions of dollars required to launch each new product.
If they must fail, more pharmaceutical manufacturers acknowledge, they’ll need to fail fast and move on quickly. Pharma’s older infrastructure has not always allowed this to happen.
Over the past few years, the pace of pharma plant consolidations and closures has increased. In the U.S. alone, 38 drug manufacturing facilities were shut down last year, and 65 the year before, according to Pharmalot’sEd Silverman, who analyzed data from the Sugarland, Texas-based research fi rm, Industrial Information Resources, in December. However, he notes that 106 new plants and laboratories, worth an estimated $4.3 billion in contracts, are now planned or under construction.
Companies in pharma’s newest sector, biopharmaceutical manufacturing, are leading the way in harnessing technologies and methods to reduce the timeline and risk of building facilities to make
new products. Th is will be important, says BioPlan Associates principal Eric Langer, since biopharm
companies will be increasing production capacity by 25%, globally, over the next
few years. Biosimilars promise to intensify the competition,
and companies are gearing up for production in fl exible facilities throughout the world.
Enabling pharma facilities’ transformation are modular construction, which has been around for decades but is now possible in shipping-container-sized units (Box,
p. 23), as well as disposable bioprocessing equipment, standardized solutions allowing for continuous operation and quick validation.
At the same time, modeling and simulation tools are becoming more important,
particularly for training and startup, as are standard templates for IT and process control. For MedImmune’s new biopharmaceutical manufacturing facility in Frederick, Maryland, which won ISPE’s Facility of the Year competition last year, best IT and automation practices not always seen in traditional pharma led to improved results (Box, p. 20).
Th is article will look at enabling technologies, some of them already in action at existing and prototype facilities, that suggest drug manufacturing’s future.
Enablers are combining in interesting ways that promise to allow greater use of continuous processing in the plants of the future. Peter Watler, CTO of Hyde Engineering + Consulting (San Francisco), notes, “A simple 45-cm-diameter chromatography column operating continuously could replace a complex and costly 200-cm column operating once per batch,” he says. “Th is will drive a need for enhanced unit operation science and superb automation, but it will result in reduced facility footprint, complexity and cost.”
Th ey are also shrinking design-to-production timelines, which, Watler notes, have moved from 4-6 years a decade ago, to as little as 12 months and will soon shrink, for smaller facilities, to just six months. Eventually, he says, timelines will be dictated by shipping and assembly times.
18 JANUARY 2012
Modular construction and disposable process equipment are maximizing
agility and minimizing risk
By Agnes Shanley,
Editor in Chief,
and Paul Thomas,
Senior Editor
At the same time, globalization has complicated the plant construction picture. Despite progress with harmonization, there is still some “discontinuity” of requirements from global regulators and, especially in more remote locations, there are questions of local suppliers and support, says Bikash Chatterjee, president of Pharmatech Associates (Hayward, Calif), which is actively consulting in India and China.
Th ere is also a need, Chatterjee adds, to make information management a part of the plant design process from the very start. “We should take into consideration developing and applying IT infrastructure as part of facility design, assuming a global supply chain,” he says.
In addition, he says, plant layout must be optimized early in the drug development process, to foster collaboration within the company and across cultures, which can be an issue for some Asian societies. “Multicultural operations require collaboration,” he says. “In Asia, the focus is oft en on doing the opposite. Most offi ces and conference rooms have card key or key code access. Designing spaces that foster collaboration and integrate telecommunication technology that can bridge cultural diff erences requires thought.”
State of the art facilities in the future, Chatterjee says, will need:
THE FUTURE? MODULAR AND PLASTIC
spite the technology’s higher construction and transportation costs, manufacturers should continue to be attracted by the fact that it allows for smaller facility footprints and allows construction to progress
He foresees layouts becoming simpler and more standardized, driving costs down and enabling the construction of smaller, closed processing type plants in both developed and
therapeutics and vaccines unique to their regions, and small, modular facilities featuring
Working in synch with modular technology is disposable process equipment, which can help reduce investment and operating costs, and potential fi nancial risk for anyone launching a new pharma product. Howard Levine, head of BioProcess Technology Consultants, summarized some of the economic benefi ts recently at the World Vaccine Manufacturing Congress in France (Table, p. 22).
Disposables can reduce labor costs by about 30%, Levine noted, although they result in 20% higher raw materials costs, off ering a net savings, per manufacturing campaign, of about 10%, he said. However, additional savings come from the elimination of column packing and elastomer changeouts, as well as lower validation, calibration and equipment preparation requirements, as well as shorter processing time.
Th e leading edge of pharma’s new manufacturing base may be seen in vaccine manufacturing and niches such as personalized medicine, in such concepts as the pandemic-ready vaccine facilities being developed by Texas-based G-Con, LLC using its GMP-ready modular cleanroom technology. G-Con’s partners in various ventures include Xcellerex (Marlborough, Mass.) and GE Healthcare (Chalfont St. Giles, UK). GE is also collaborating with M+W Group (Stuttgart, Germany) off ering turnkey construction solutions aimed at global markets.
Initiatives driven by the Gates Foundation, WHO and GAVI will spur development of more modular vaccine
manufacturing facilities, allowing countries to tailor development to their unique regional needs, predicts Hyde’s Watler. One of the fi rst such facilities was CPL Biologicals’ vaccine plant, a partnership between Novavax (Rockville, Md.) and India’s Cadilla Pharmaceuticals, which was completed in 2010 in Dholka, India.
In the U.S., increased government investment is stimulating more research and commercial activity in modular vaccine facilities using new plant, insect or animal cell culture platforms. Working with various plant cell culture platforms originally developed by Fraunhofer USA Center for Molecular Biotechnology
20 JANUARY 2012
FUTURE FACILITIES
Last year, MedImmune received ISPE’s Facility of the Year
“Overall Winner” award for its new large-scale mammalian
cell culture-based production facility adjacent to its Freder-
ick Manufacturing Center (FMC) in Frederick, Maryland.
Brent Hill, director of automation within MedImmune’s
Global Engineering organization, and Victor Ronchetti, Sr.
VP and technical director for systems integrator Auto-
mated Control Concepts, explain how they harnessed IT
and process control tools to meet an extremely aggressive
product schedule.
PhM: What was the impetus to do something extraor-
dinary and, in your mind, what is truly groundbreaking
about the Frederick project?
Hill, Ronchetti: We had recently just fi nished a large “Pilot
Plant” project similar in nature to the one in Frederick. We
had learned that we would need to do something that was
extraordinary to meet the aggressive schedule. Therefore,
we set in motion several systems, such as the Factory Ac-
ceptance Test Process Automation Core (FATPAC) and code
control, to position ourselves for success.
As most projects go, there are unforeseen events that
involve patience and adaptability. Near the completion of
the project we were given a completely new set of built
P&ID’s. The control system had already been designed
around the design documents. We were now faced with
the task of re-coding and re-execution of the Process Con-
trol System (PCS) SAT.
Due to competing deadlines, MedImmune was now
faced with a nearly vertical schedule where the constraint
was the physical equipment in the facility. To stay on
schedule, the automation team used Rockwell Softlogic’s
software to completely replicate the process control
system in its entirety. As shakedown activities took pre-
cedence in the schedule, it was necessary for the project
team to perform activities related to the commissioning
and qualifi cation of the PCS in parallel, without interrupt-
ing shakedown runs.
Under the strain of limited time on equipment as a
result of competing project phases (start-up and debug-
ging of applications, train production operators, and
running test batches), the project team developed a
separate PCS simulator (in addition to the PCS simulator
used for operator training) that allowed them to commis-
sion and qualify major aspects of the PCS without having
to perform the work on the plant fl oor. This system,
which simulates every Programmable Logic Controller
(PLC) in the facility, provided a safe, equivalent environ-
ment to perform testing.
USING ORDINARY TOOLS IN EXTRAORDINARY WAYS AT MEDIMMUNE
Simulated training helped prepare the Frederick team in advance.
FUTURE FACILITIES
PhM: What about S-88 (aka ANSI/ISA-88) “worked” for
this project?
Hill, Ronchetti: Giving the specifi c control modules, equip-
ment modules and phases to each of the appropriate
vendors was key to the project’s success. With the regula-
tory nature of the pharmaceutical industry, companies are
becoming more informed about the value of only validat-
ing these standard modules and then using them time and
time again. We are seeing the majority of the companies
in the pharmaceutical industry going this way on most, if
not, all hardware/software platforms.
PhM: You had 44 skids from different vendors all over the
world and expected them to have common data storage,
a single domain controller, form, fi t, function, etc. Did this
prospect seem ludicrous when the project began?
Hill, Ronchetti: At the beginning of the project, we sent
out in the bid specifi cations, our requirement that all skid
vendors were to use our standard modules and our inter-
system communications specifi cation. Once the vendor
understood what we were trying to accomplish, all but
one not only accepted it, but were enthusiastic about it.
They realized how much easier it would make start-up and
integration of the system as a whole.
PhM: Explain a bit more about FATPAC, if you could.
Hill, Ronchetti: A common issue in automation projects,
especially of this size, is interfacing skidded systems
with the PCS and with each other. Using a proactive ap-
proach to solve this potential issue, the team developed a
FATPAC, a portable interface package to support FAT. This
package of servers replicated MedImmune’s high-level
process network and allowed MedImmune to test the
equipment in the appropriate environment, at each site.
The FATPAC included a domain controller used to preset
user access, a PLC, and an HMI client from the PCS system.
Communications were set up with the PCS PLC/HMI and
used in the FAT for each of the skids. Any problems identi-
fi ed during FAT were resolved and retested prior to ship-
ment. When the skids arrived onsite, minimal setup was
required to integrate them into the PCS system.
PhM: Does the simulation project provide a template that
you can now apply to most any process going forward?
Hill, Ronchetti: As discussed earlier, the PCS simulator was
a complete replication of the live PCS system. If a change
was needed due to errors found in testing or errors found
on the live system the code was changed on the live
system fi rst. Each night the code from the live system was
then downloaded into the simulator. Asset Centre was
used to maintain code equivalence between systems and
allowed for traceability. Test scripts were then generated
and the errors were then retested to insure the quality
and integrity of the codes. This process is now the stan-
dard for all of MedImmune Control system projects.
PhM: Brent has said, “Automation is always to blame for
slow startup.” Does the Frederick project change this?
Hill, Ronchetti: The very nature of automation is considered
a risk. The errors or problems in coding have an unknown
duration, which is what has historically has given automation
a bad name. By careful planning, the industry as a whole
can help make the paradigm shift. Once it is obvious that al-
though critical to the success of any project, the automation
need not be one of the greatest unknowns of a project.
are Project Greenvax, based in Texas, whose partners include Xcellerex, G-Con and Texas A&M University, and iBio, Inc. (Newark, Del), whose iBioLaunch platform was patented last October.
HYBRID FACILITIES: FINDING THE RIGHT MIXWhile mobile facilities would, by defi nition, be based on disposable equipment, it is unlikely that a large tradi-tional type facility would be built with 100% dispos-able equipment. At larger scale, their cost and effi ciency attractions diminish, says Watler. Most facilities on the ground today are opting for a hybrid approach, com-
bining biodisposables with traditional stainless steel equipment. Th e challenge that manufacturers will have is determining the right ratio of each and where disposables can convey signifi cant cost and operational advantages over traditional equipment.
Finding the right mix has been a challenge for DSM Biologics as it builds a major new facility in Brisbane, Australia. Th e new site has a six-story shell in place that is being fi t out in 2012. Th e second and third fl oors are empty for the time being, available for future build-out. Nevertheless, when it goes online some time in 2013, DSM Brisbane will become by far the largest biopharma
contract manufacturer down under, says Ben Hughes, senior process engineer for DSM who is overseeing much of the project work.
All upstream processes at the site, from media and buffer preparation through to bioreactors, are anticipated to be single-use, Hughes says. “We’ve shrunk the process suites by keeping all media and buffer concentrates outside of the controlled areas. The product and all solutions will be pumped through the walls into 500-liter bag-lined totes awaiting transfer or directly to the process equipment.”
“Downstream, we envision single-use for all of the filtration steps,” he says. “Chromatography will be more of a hybrid approach.”
“Single-use has all sorts of advantages in a CMO environment,” he continues. “It’s also really nice for us in terms of future-proofing the site. It’s extremely adaptable, with plug-and-play skids and so forth, so it’s easy to roll in new single-use technologies and roll out the older ones.”
It’s also about sustainability, Hughes notes, especially as single-use eliminates CIP and SIP procedures and significantly reduces consumption of water, cleaning chemicals, energy and other resources.
SENSE AND SUSTAINABILITYThe Brisbane facility is also a sign of the times in that it is the product of tight collaboration between DSM and the Queensland State Government and the Commonwealth of Australia,
who provided financial assistance for the project. Around the time of the BIO annual meeting in 2009, BioPharmaceuticals Australia (BPA) requested expressions of interest to operate a major new bio contract manufacturing facility. It was fortu-itous timing for DSM, says Hughes, as the manufacturer was looking to expand its biologics capabilities. DSM was selected as BPA’s partner and work began in 2010.
FUTURE FACILITIES
22 JANUARY 2012
FACILITY COSTS FOR A BIOREACTOR(Stainless Steel vs. Disposable) Stainless Steel Single-Use
Construction time 16 months 14 months
Process area 6,372 ft2 6,781 ft
Class C 1,109 ft 667 ft
Class D 5,231 ft 3,315 ft
CNC 0 2,745 ft
Total area 12,153 ft 2,745 ft
Piping length 2,854 ft 886 ft
Process equipment cost 4 million Euros 3 million Euros
Total equipment cost 17.3 million Euros 15 million Euros
Source: Levine, H., “Vaccine Manufacturing in the Coming Decade,” presented at the World Vaccine Manufacturing Congress, 2011, Lyon, France, October 11-12, 2011
continued on page 26
A mockup of
a production
space in the
DSM Brisbane
facility.
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FUTURE FACILITIES
24 JANUARY 2012
MODULAR MOMENTUM
Malcolm McLean is a name that few people in pharma
know, and yet his 1956 invention is helping to revolutionize
drug facilities today. McLean is the father of the modern
day shipping container, which is inspiring a modular facili-
ties boom in our industry. The shipping container provides
a convenient size for, say, a cleanroom or facility production
add-on, and of course can be easily, quickly transported to
anywhere in the world. Modular facilities:
emerging markets
tent practices between sites
Founding its business on the shipping container concept
is Biologics Modular, headed by Clark Byrum, president
and CEO, and Chris Wernimont, VP of Engineering and
Operations and formerly of Eli Lilly. This past September,
it fi led for several patents related to manufacturing clean-
room and biologics production space within the shipping
container confi nes.
Byrum. But they soon realized there was potential for GMP
manufacture, and Biologics Modular produced its fi rst
Biologics Modular works with outside consultants to com-
plete the process-related work, which could mean building
as many as three or four production steps in one container.
Their fi rst order was a stem cell processing company that
required a GMP facility as well as an analytical lab.
Still, the industry is just warming to the idea of modular
One of the pioneering forces in pharma modular con-
struction was Pharmadule. That fi rm has gone bankrupt,
but many of its assets are now part of ModularPartners,
from being a novelty and something very few would
consider, to now being discussed and considered in many
to take advantage of the real opportunities in modular-
ization in the way that, for example, the software and
cant hurdles have been the tradition of how projects are
planned and executed. Modular solutions need to be
considered in the early stages of a project in order to get
the full benefi t of them. Many times, if the question about
Modular facilities have also had a reputation for being
The ModularPartners modules are also shipped is a fash-
ion similar to shipping containers. The main difference,
of this issue.
Exterior and interior (left) views of a
Biologics Modular cleanroom.
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Section J of the Australian Building Code, enacted in 2010, calls for advanced greening of all new buildings, including, for example, significant increases in thermal insulation, window glazing and shading, rainwater collection, and high-efficiency equipment (e.g., HVAC and piped services with variable speed drive motors). A sophisticated Building Management System provides detailed operating and energy consumption data. The facility will be oriented to the north for optimal solar design, is convenient to public transport, and has a large area for bicycle storage.
Any of these requirements alone is not groundbreaking, says Hughes. But together, they signal a new way of building drug sites—“heartening to see,” he says.
All of this comes in a smaller building than would have been imagined in the past—a mere 8,000 square meters. DSM’s proprietary technologies for productivity—for example, for ramping up mammalian cell culture or expanded bed chromatography yields—will allow it to achieve in single-use bioreactors what would have required stainless steel bioreactors with 10 to 15 times greater capacity. “We’ve achieved a footprint that is much smaller than facilities built in the past but will still maintain the required output,” Hughes says.
Facilities of the future will be green, experts agree. According to estimates from the design and construction firm CRB, bulk biotech manufacturing facilities of the future can realize green savings in the neighborhood of:
When considering a hybrid installation, Hyde’s Watler says, the first question to ask is, is the single-use system designed from the ground up, or is it simply a modification of a conventional system? If it is simply a modification, did the workaround result in follow-on issues which must be addressed?
He uses the rectangular disposable bag in bin as a good example of a ground-up design. It is not a mere modification of a round stainless steel tank, Watler says, but rather, is rectangular, stackable, fits easily against a wall, has an open top and side panels for access—quite different from a conventional tank, and it works.
In contrast, buffer preparation tanks have been challenging. “There are no baff les so mixing is not as rapid, solids can settle in corners and crevices and it is a challenge to insert sensors into the tank,” Watler says. “The competition stainless steel mix tank, of proven design, with an optimized CIP cycle can be changed over in 15 minutes. At larger scales, this conventional tank may be the best option, operationally and cost wise.”
He recommends using FMEA and PHA risk analysis to sort through the mix of single use and conventional equipment. As facility design evolves and disposable systems become further incorporated, Watler says, there will be similarities between different sites, but not to the extent of standardization of hybrid facility designs.
What’s clear from talking to facility experts is that the drug manufacturing plants of the future are already here, being designed and built worldwide. They will only become more affordable, flexible, green, and commonplace in the coming years.
FUTURE FACILITIES
BIOPROCESSING
MANY BIOPHARMACEUTICAL applications require vent filters, the hydrophobic sterilizing-grade filters that are used as air vents on processing tanks. These filters maintain near-ambient pressure in the tank while ensuring sterility. In addition, the filters remove viruses and micro-organisms from the gas as it flows into or out of the tank.
To ensure its proper operation and sterility, a bioreactor, for example, may have a number of vent filters including those for the tank vent, the sparge gas inlet, and the overlay gas inlet.
Understanding the diverse applications of vent filters is critical to their proper implementation and use.
Following best practices can help ensure compliance, and avoid problems during operation, installation, CIP and SIP.
By Michael Felo, EMD Millipore
A number of factors must be considered in advance of vent filter implementation, including filter sizing, housing and piping design, condensate control, regulatory requirements, and operational considerations such as clean- and steam-in-place (CIP, SIP) and integrity testing. Employing best practices for vent filter use can avoid common problems during installation, CIP, SIP, integrity testing and operation.
This article will describe an application-based approach to vent filter sizing, in situ integrity testing of the filter design, best practices for housing design and vent filter operation, and a risk management approach to implementation and replacement of vent filters.
VENT FILTER SIZINGAir flows in and out of a process tank commonly for two reasons: the first is to replace a volume of liquid as it is pumped in or out of the tank. Sizing the tank vent filter for pump-out or fill rate is relatively simple, as the air flow rate will be equal to the
pump-out or fill rate. With flow rate and pressure determined, a flow/pressure change (ΔP) curve can be used to determine sizing.
The second reason air will f low into a process tank is to compensate for the volume change associated with steam condensation. At the
end of a tank SIP procedure, steam in the tank will cool and undergo a phase change to liquid water. There is more than a thousand-fold difference in volume between water in the gas phase and water in the liquid phase. During cooling, sterilized ambient air must be allowed into the tank to prevent vacuum. Sizing the vent filter for steam collapse requires knowing the vacuum rating of the tank and the convective cooling rate. These can be calculated based on the
tank dimensions including height, diameter, and wall thickness.
Improper tank vent sizing can result in low pump-out rates, loss of sterility due to a ruptured disk or filter failure, or worst case, tank implosion. Fortunately, proper sizing is not difficult, as long as the
flow requirements and driving force are understood.
Tank venting can be static or dynamic, with each requiring filters that are sized slightly differently. For static venting, the air outside of the tank is assumed to be at ambient pressure, so the driving force for airflow is determined by the pressure difference between the inside of the tank and the atmosphere. For dynamic venting, compressed air is fed to the tank in order to minimize any difference in pressure that occurs between the tank and atmosphere.
Static tank venting is commonly used for buffer tanks and intermediate storage tanks. To determine the proper size for a static tank vent filter, four basic steps should be followed:
1. Determine the maximum flow rate for venting that the vent filter will need to provide. This will be either the process flow rate or steam col-lapse rate after an SIP cycle.
2. Select the maximum pressure drop that you want the filter to experience. The pressure drop is typically less than 5 psi and should be dictated by the vacuum rating for the tank or rupture disk vacuum rating. Clearly, it is important to avoid pulling a
BIOPROCESSING
28 JANUARY 2012
2.6
0 bar
2.6
0 bar
2.6
0 bar
2.6
0 bar
CompactionInstantaneous
flowmeasurement
Time
Flow
Crosssection
Stabilization
Patm
Figure 1. Hydrocorr water flow integrity testing process.
strong vacuum on the tank that might cause collapse.
3. Calculate the number of filters or filter area required to meet f low rate and pressure drop requirements.
4. Ensure an adequate safety factor (~1.5x) and select the appropriate filter configuration for the tank or application.
Table 1 shows the vent sizing process for a static vent. This example represents a hold tank used for ambient temperature water storage with a maximum pump-out rate of 400 liters per minute. No SIP is necessary and the tank has no vacuum rating.
Common uses for dynamic tank venting include bioreactors and other applications where steam is replaced with compressed air after an SIP cycle. In this case, the process for sizing a filter varies slightly from the static model and is as follows:
1. Select the desired pressure drop. Pressure drop is typically less than or equal to 2 psi, especially when calculating for bioreactors where minimizing vacuum is key to maintaining a sterile environment in the tank.
2. Calculate the air flow rate neces-sary to replace the steam during steam collapse post-SIP.
3. Calculate the number of filters or filter area needed to meet flow rate and pressure drop requirements.
4. Ensure an adequate safety factor (~1.5x) and select the appropriate filter configuration for the tank or application.
Dynamic vent sizing can be significantly more complex than static venting since the steam collapse rate needs to be calculated
BIOPROCESSING
30” x 18” Ametek Centrifuge Hastelloy C-276
Parameter Value
Maximum flow rate 400 liters / minute (~13 SCFM)
Maximum pressure drop ΔP 1 psi (due to no vacuum rating on tank)
Filter size 5” Aervent® filter (EMD Millipore)
provides 20 SCFM at ΔP = psi
Table 1. Vent sizing process for a static vent.
for the specific tank and process conditions being used. In this case, it is recommended that available software programs be used to calculate the proper dynamic vent filter sizing.
IN SITU INTEGRITY TESTING OF FILTERSVent filters are typically tested using a process such as the Hydrocorr water flow integrity test (Hydrocorr Valida-tion Guide, MM document VG050) [1]. The test measures the resistance of the filter to water intrusion (Figure 1). A filter is placed in a stainless steel housing which is flooded with water. Under a pressure of 40 psi, there is compac-tion of the filter. Over time, the compaction stabilizes and the flow decreases. Once stabilization is complete, an instantaneous flow measurement can be taken; if the measurement is below the specification of the vent filter, it is considered to be integral.
In situ water-based testing can be conducted when the filter is attached to the tank using a manual or fully automated process. With the manual process, the filter is flooded, the Hydrocorr integrity test is conducted, and once a passing value is achieved, the vent filter housing is drained. The same steps are used in the fully automated process, which can be a more efficient way of testing when in a commercial operations setting.
HOUSING DESIGN AND VENT FILTER OPERATIONBest practices for the implementation of vent filters include selection of the proper housing. Three housing options are available (Figure 2):
C-line. Offers the best condensate trapping capacity on the upstream side of the filter. If the stream is in an es-pecially moist or humid environment, the C-line format allows excellent removal of condensate.T-line. While this format is popu-lar, it is not optimal for vent filtra-tion, as the housing has to be tilted for proper condensate drainage.In-line. This format allows the downstream condensate to drain directly into the vessel.
In all cases, a vertical mounting of the housing is always required to enable the most effective drainage of condensate.
The life cycle of the vent filter includes installation in the housing on the tank, CIP, SIP, and operation. Adopting best practices at each step can help ensure proper functioning. During installation, filter o-rings should be pre-wetted for easier installation in filter housings. Code 7 tabs at the bottom of the cartridge
should be locked in to their housings as venting occurs in the reverse direction and, if there is pressure pulsing, the cartridge may be ejected from the filter housing.
During CIP, the sprayball direction should be adjusted so that CIP liquids do not reach the filter as caustic solutions can impact the strength of the membrane. A heat jacket, blanket, or trace should be used to minimize condensate buildup in the filter housing during the CIP cycle. CIP creates a moist, humid environment so it is important to avoid instantaneous release of high pressure, moist gas through the vent filter, which can cause damage.
SIP is the most mechanically strenuous step that a vent filter will experience. A number of best practices can be employed to prevent damage to the filter:
high temperature as the filter can be-come weaker at elevated temperatures.
-tion from the tank to ensure conden-sate removal from the core of the filter.
until after the tank heating phase is complete.
drain and not the vent filter during the heating phase.
During the operation phase, it is best to avoid fouling of the filter from entrained liquid in the tank especially
potential exists for moisture build-up.
BIOPROCESSING
30 JANUARY 2012
Figure 2. Vent filter housing options.
MECHANICALLY
RISK MANAGEMENT As shown in Table 2, regulatory authorities have addressed the implementation of vent filters. All advocate a risk-based approach be used to establish filter re-use and integrity testing policy.
A typical risk assessment and process validation plan should consider the criticality of the process and application of the vent filter, the number of re-use cycles, process implications, and the impact on filter lifetime.
Regulatory documents establish two types of applications for vent filters: critical and moderately critical applications. Critical applications are those in which filtered gas is in direct contact with the sterile final product. In this situation, the sterilization cycle must be validated and performed before each use of the vent filter. The filter must be integrity tested upon installation and following each use.
In moderately critical applications, the filtered gas is not in direct contact with the final product. In these applications, sterilization and integrity testing frequency should be established based on the following risk assessment parameters:
It is common practice to reuse vent filters over mul-tiple cycles. A risk-based assessment should help guide reuse and change-out criteria. The assessment should consider the following:
-turer or internally set limit)
-
-uct strains
traced housing
References1. Jaenchen, R., Schubert, J., Jafari, S., and West, A. Studies on the
theoretical basis of the water intrusion test (WIT). European Jour-nal of Parenteral Sciences, 1997, Vol. 2, No. 2, 39–45.
2. Technical report no. 40: Sterilizing filtration of gases. PDA Journal of Pharmaceutical Science and Technology, 2005, Vol. 58, No.S-1.
3. Pharmaceutical Inspection Convention, Pharmaceutical Inspec-tion Co-Operation Scheme. Recommendation on the Validation of Aseptic Processes. Section 9.6.1, January 2011.
4. EC guide to GMP Annex 1: Manufacturing of sterile medicinal product, 2003.
About the AuthorMichael Felo is an Applications Engineer Consultant in the Merck Millipore Biomanufacturing Sciences Network (BSN) whose focus is optimization, implementation, and troubleshooting of late-stage clinical and commercial scale manufacturing processes for the tech-nologies of clarification, aseptic filtration, and single-use systems. Mr. Felo has over 12 years of experience in process development, technol-ogy transfer, and clinical and commercial GMP manufacturing of monoclonal antibody and recombinant protein therapies.
BIOPROCESSING
PDA TR40 “ No single approach applies to all applications, and an appropriate testing fre-
quency and rationale should be selected using risk analyses considering impact on
product quality and regulatory compliance.”
PIC/S Section 9.6.1
“ It is important that the integrity of critical gas and air vent filters is confirmed im-
mediately after the filling and if it fails, the disposition of the batch determined.
In practice vent filters fail the integrity test more frequently than product filters,
as generally they are less robust and more sensitive to pressure differentials during
steam sterilization.”
European Commission“ Results of these checks should be included in the batch record. The integrity of
critical gas and air vent filters should be confirmed after use. The integrity of other
filters should be confirmed at appropriate intervals.”
Table 2. Examples of regulations addressing vent filter implementation [2,3,4].
DESIGNING A new or expanded manufacturing facil-ity with a new or modified process requires two sets of knowledge—that of process-flow architects and that of the manufacturing production experts.
Together, process-flow architects and manufacturers possess key components of the knowledge required to find a better process. A manufacturer understands the process flow of a current facility, has adapted it over the years to better fit the existing facility and site constraints, knows what will and won’t work in an existing facility and, perhaps most importantly, understands the imperatives of the current market for its product.
A process-flow architect possesses an overview of how manufacturing processes in different industries have maximized quality and efficiency. He or she can, for instance, pluck an idea from a plastics manufacturing process and plug it into a pharmaceutical process.
At the beginning of a project, however, neither side has a comprehensive understanding of what knowledge or insights the other can offer to this specific project. Designing a more efficient manufacturing process begins with each side telling the other enough about what it knows to create a common body of knowledge that can be shaped and molded—by both sides—into a new and improved process and product. While all of this may seem like common sense, it is difficult for manufacturers and process-flow architects to generate a mutually beneficial planning relationship.
It is similar to the situation that a home seller and homebuyer find themselves in. The seller resents the comments that the prospective buyer makes about repainting or adding a room here or changing a room there. The prospective buyer views the homeowner as a small thinker. But if the home seller finds a way to like the prospective buyer’s ideas and if the prospective buyer focuses on what he or she likes about the existing house, both sides are much more likely to find common ground and, perhaps, a sales contract.
The same dynamic can improve the results from process-flow architects and manufacturers. Both sides must identify the common goal: an improved process. They must resist the natural resentments that can crop up, and focus on answering each other’s questions until someone has an insight that makes everyone shout, “That’s it!”
WHAT IF YOU CUT A HOLE IN THE CEILING?Consider the case of a pharmaceutical manufacturer working through the question of how to increase the production of tablets. The existing production process uses forklifts to deliver powder to a compactor, which compresses the powder into a solid ribbon of material that could be processed into tablets.
In discussions with the process-flow architects, the manufacturing team indicated that the key to increasing
production was to move more powder into the compactor. The forklifts couldn’t keep up. Adding more forklifts wouldn’t work because the existing floor did not have enough space to permit more traffic.
“How about an addition?” asked the architects. The manufacturer had already considered that option in detail. One area of the plant offered plenty of space for the addition, but it was so far away from the post-compaction production line that the time required to transport the material wouldn’t produce a measurable improvement.
The expansion would have to go in near the existing compactor, but that option raised structural issues related to supporting walls and the second floor area of the plant.
Both the architectural team and the manufacturing team worked the options over, searching for the answer to what had become the key question: How do you design an addition to the building in the area of the compactor?
Finally someone asked, “Can we cut a hole in the ceiling?” That question unleashed more questions and the ultimate answers. As it turned out, the floor above the compactor had been abandoned some time ago. There was nothing up there. A vertical expansion could include a tall lift system that would raise a product-filled tote and dispense it directly into the compactor feed tube.
The lift could be designed to eliminate the time-consuming docking and maneuvering that the current compactor assembly required of the forklifts. The forklifts could feed more powder to a larger compactor, which
FACILITY DESIGN
Finding the FlowDesigning a new pharmaceutical manufacturing facility requires that architects and manufacturers collaborate to improve process flow.
32 JANUARY 2012
BY ALAN A. LIDDY, AIA, NCARB, PMP, SSOE GROUP
WHEN ARCHITECTS AND PROCESS
INGENUITY RESULTS.
could, in turn, feed enough ribbon to the final production line to increase production as necessary.
The concept posed several challenges. The most significant involved removing a portion of the existing roof, reinforcing the roof framing and constructing a roof penthouse to accommodate the new equipment. Lesser but still significant challenges included determining the most cost-effective approach to the suite renovation that would still accommodate the equipment; coordinating the equipment suppliers during design as equipment design and assembly occurred simultaneously; and maintaining production operations during the renovation, which would have to be carried out in an adjacent space.
These challenges all required close coordination between the construction phasing and production phasing. At the same time, the architects worked to keep the owners fully informed about the complex design solution. This was essential because the owner could not be expected to visualize what the renovation would look like and how it would function from the construction documents. The architects continually elicited questions from the owner and provided explanations to ensure that the owner understood and approved of what was being built.
ADDING A NEW AND POTENT POWDER PRODUCT, SAFELYRegulations also wield great influence over the design of a plant. FDA, for instance, requires that manufacturing lines producing injectables meet an ISO-5 cleanliness standard, which affects the HVAC design by requiring more air changes than normal. ISO-5 also requires spe-cialized packaging procedures handled by people wearing personal protective equipment (PPE).
One manufacturer recently satisfied these regulations while incorporating a new, potentially dangerous product into an existing manufacturing facility. The simplest solution, from a logistical point of view, was to expand through the back wall of the plant. Behind the wall, however, were offices and a primary connecting corridor, which could not be moved efficiently. The plant manufactures a pharmaceutical product by formulating and batching ingredients. So the plant managers and employees were familiar with batching work. With the back wall of the plant eliminated as an option, the architects had to figure out how to fit the new process into a limited space on the already crowded manufacturing plant floor.
A downdraft booth seemed like the solution, but that would require coming to terms with three challenges. First and most importantly, the design would have to
control the cost of construction—downdraft booths can be prohibitively expensive to purchase and install.
Once again, the concept required a lot of discussion to ensure that the owner had a complete understanding of a complex concept that design drawings probably couldn’t convey in satisfactory detail to people unaccustomed to reading plans. By the time construction began, the architects and the owners had been through many more review meetings than would be expected for a relatively small project. The architects were also careful to involve the owners and other stakeholders as construction proceeded.
Second, the design would have to control the cost of heating, ventilating and cooling the space—downdraft booths require 100 percent air changes all the time.
Third came the problem of where to put the booth within the existing facility. The new facility had to be big enough to do its job and small enough to hold down costs and stay out of the way of existing processes. The plant already contained a half-dozen dispensing suites, and one or two could be converted to a suite for potent drug dispensing without requiring major modifications to the other suites to maintain the original production lines. Still, the booth would have to be small yet allow sufficient space for dressing rooms and airlock entries for employees plus the airlock intake areas for the product.
The architects whittled the booth itself down to an 8- x 8- x 10-foot box. The small booth made it possible to accommodate the support spaces for employees and materials, while limiting the expense of the HVAC system and its operating costs. As with any plant renovation, the work had to be carried out without interrupting plant operations. In the end, simplicity and efficiency were the keys to the downdraft booth design.
Indeed, simplicity and efficiency are always the keys to designing successful pharmaceutical plants, which number among the most sophisticated manufacturing facilities in the world. They cost thousands of dollars per square foot to construct. The simpler the process, the smaller the plant and the lower the cost. While pharmaceutical plants must embrace practical design considerations over aesthetic desires, they are, in the truest architectural sense, the result of form following function or process flow, and then going with the flow.
About the AuthorAlan A. Liddy, AIA, NCARB, PMP, is a Senior Project Manager at SSOE Group (www.ssoe.com), an international engineering, procure-ment, and construction management firm. With 23 years of experi-ence, Alan specializes in pharmaceutical and nutraceutical projects. He can be reached in SSOE’s Raleigh-Durham, North Carolina office at 919.361.9606 or [email protected].
FACILITY DESIGN
TECHNOLOGY MOVES fast, and it seems even subject matter experts, aka SMEs, can have trouble keeping up with their subject matter. Machine vision is one such technology that keeps moving ahead—in-creasing the applications to which it can be applied in pharma, for instance. Those trying to follow along may wish to visit LinkedIn and join in the “Machine Vision in Pharmaceutical Industry” group. It’s small by Internet standards—just 176 members at last count—but has some good discussions, updates on new products, and can be a helpful forum to get your questions answered by, yes, SME’s in pharma machine vision.
The group is managed by Kasra Ravanbakhsh, who specializes in machine vision and industrial automation. A couple other LinkedIn groups—“Machine Vision” and “Machine Vision Group”—are oriented towards various industries but are larger and should also be interesting for vision enthusiasts.
What are drug industry end users looking for in their machine vision systems today? One thing is user traceability, says Bob Ochiai of the machine vision group at Keyence. That is, who’s using the system, when are they doing it, and who is authorized to make changes? Keyence
has upgraded user functions related to permissions and changes for its XG Series (bottom, left) with more sophisticated User Accounts and Modification Log options, he says. These changes reflect the increased importance of overall corporate accountability for all systems and processes, Ochiai says.
Speed and resolution are also critical needs for end users, he says. Just as consumers of digital cameras and computers are demanding greater camera and processor speeds and higher resolutions, so are drug manufacturers demanding more robust machine vision systems.
Festo is focusing on simplicity and affordability, and yet enhanced functionalities, says Frank Langro, a manager for Marketing and Product Management. Traditional systems with a master controller, sensor interfaces, and various drives often result in complicated and costly systems that place heavy demands on operators, he says. In response, Festo’s compact vision system SBOC-Q utilizes familiar vision tools for parts inspection. These include Blob, ROI, and Ray tools. In addition, the vision system supports OCR (optical character recognition) and code scanning for barcodes and data matrix—for monitoring blister packs, bottle caps, and label coding, for example.
In addition to its inspection capabilities, the SBOC-Q has an embedded CoDeSys PLC plus a “CANopen” master interface to increase potential applications. The system can inspect, but also control actuators to reject failing packages, reorient items such as catheters, or take other physical actions. All necessary information from code reading to OCR can be passed back to a supervisory system via an embedded Ethernet port.
TECHNOLOGY ROUNDUP
34 JANUARY 2012
Pharmaceutical machine vision technologies are getting simpler and cheaper, and yet tackling more varied applications.
By Paul Thomas, Senior Editor
End users have used SBOC-Q to measure the diameter of glass ampoules for conformance to specifications, Langro says. In the same application, the system used backlighting principles to ascertain the presence of printing. For blister checking, the vision system was used to count pills and to assure that there were no empty spots in the pack. If there were empty blisters, the vision system identified the coordinates, made the information accessible to operators, and then withdrew the pack from the line.
In a syringe inspection application, the system was used to identify missing or broken parts such as rubber plunger head, auger flange, thumb rest, and needle hub. A personal care application required the SBOC-Q to check dental floss containers for the presence of the internal roll of dental floss, threads coming out from the correct hole, and threads correctly located on the cutter.
Banner Engineering has added the Q26 Series (below) to its line of clear object detection sensors. While Banner offers several sensors for reliable clear object detection, the Q26 Series is optimized for the task with its polarized retro coaxial design. The Q26 delivers both the sensitivity required for reliable clear object detection and the robust rejection of light from mirror like objects to prevent a false detection. The coaxial optical design delivers the additional benefit of precise leading edge detection, making it useful for many high speed applications in bottling, pharmaceutical and biopharmaceutical industries.
Primary applications are for pharmaceutical vials or bag filling machines, Banner says.
In-Sight Track & Trace is a new software package for Cognex’ In-Sight vision systems. The software makes it easy for manufacturers to set up a complete identification and data verification solution for package labels, says John Lewis, the company’s market
development manager. Customers choose the In-Sight model that best meets the performance and price requirements of their application, and then add software, he says.
One key application is reading an ID code and verifying the accuracy of printed text—for example, date/lot code information. If the label contains GS1 data, In-Sight Track & Trace can verify that the data is formatted correctly, and that it matches the printed text. Mismatched or incorrectly formatted data would indicate a process or database problem demanding immediate attention.
Another key application is that the software can assess the quality of the Data Matrix codes on labels while the system is operating in production mode. This process check helps to make sure that the print quality hasn’t degraded in a way that will cause readability issues downstream, Lewis explains. Equipment can be mounted anywhere on the packaging line—at the item level, carton level, case level, or at the pallet level. According to Lewis, the most strategic area for deployment is actually at the printing or marking station. If a manufacturer is marking bad codes or poor quality text—or worst of all, printing the wrong information—it needs to catch it immediately, before it causes disruptions downstream in the supply chain.
PPT Vision recently agreed to be purchased by data capture and industrial automation firm Datalogic S.p.A., says PPT’s president and CEO Bob Heller. PPT will continue to operate as a separate company, with headquarters in Minneapolis and a center of excellence there for the Italian parent company. “The partnership provides both organizations with stronger global sales channels, additional product development resources and industry leadership positions in automation and machine vision,” Heller says.
Finally, in other news, Begapt Solutions-India is partnering with Microscan-USA, with an emphasis on solutions such as its Online 2D barcode reading system.
TECHNOLOGY ROUNDUP
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BLENDING OPERATIONS
BLENDING, ONE of the most basic of pharmaceuti-cal unit operations, can also be one of the most chal-lenging to control. Solid formulations contain mul-tiple ingredients beyond the active pharmaceutical ingredients: fi llers, tabletting agents, disintegrants, and absorption enhancers or agents that slow down
and control absorption. Ingredients from diff er-ent vendors may behave diff erently due to their
particle size and shape and other factors, and their tendency to form aggregates.
Th ere are strong economic drivers for optimizing blending. Reinforcing
these is the pharmaceutical Quality by Design (QbD)
framework advanced by FDA, which requires a deeper understanding of pharmaceutical manufacturing processes, how ingredients blend and how blending progresses through diff erent stages.
Traditionally, formulation scientists and technologists have used destructive analytical methods, such as dissolution followed by HPLC or UV, to optimize blending. Th is requires running the process, pulling and analyzing samples, which can lengthen the time required for development.
Recently, hyperspectral imaging (HSI) has been applied to study the behavior of solid particles in various unit processing steps
as well as during multistep continuous processes. Th is nondestructive method generates thousands of spectra per second, providing more compositional information than conventional methods.
Th is article summarizes the results of blend monitoring studies using a new HSI device, in situ without stopping the blending and pulling samples. In this case, a batch-type blender was equipped with a computer controlled drive mechanism capable of imaging blending through a window mounted on the blender. Th e push-broom HSI camera is timed synchronously with blender rotation. Spectral information acquired at each rotation was used to assess whether the nominal composition is achieved, to reveal blend uniformity, and to avoid incomplete blending, large aggregates or re-aggregation.
A COMBINATION OF SPECTROSCOPY AND DIGITAL IMAGINGHyperspectral imaging (HSI), or chemical imaging (CI), is the combination of spectroscopy and digital imaging. A hyperspectral image contains many spectra, one for each individual point on the sample’s surface. Th e image contains information about the spatial distribution of the materials within the sample.
A hyperspectral camera (Figure 1) integrates an imaging spectrograph with a matrix array sensor. In these studies, we applied near infrared (NIR) spectroscopy, using NIR hyperspectral imaging to analyze the average composition, and the distribution of ingredients. Hyperspectral camera literature refers to the full 1000-2500 nm range as short-wave infrared (SWIR).
A special lens images the sample onto a slit of a transmission spectrograph. Th e spectrograph produces a spectrum imaged on a focal plane array detector, preserving the location of respective points on the slit and thus the points of the line on the sample.
In push-broom HSI, successive lines on the sample measured over time form a complete HS dataset. Th is data from a HS camera is called a “hypercube,” containing information in two spatial dimensions and one spectral dimension. Th e hypercube is typically
Imaging the Blending ProcessHyperspectral imaging can be used to optimize blending, by monitoring the distribution of excipients and APIs in formulation
BY GABOR KEMENY AND GINA STUESSY, MIDDLETON RESEARCH
PHARMACEUTICAL MANUFACTURING JANUARY 2012 37
ratioed with similar hypercube measurements of a highly reflective white reference material and with the residual background signal, the latter of which is measured when no light is falling on the focal plane array.
The resultant corrected spectra are produced in transmittance, reflectance, or absorbance similar to traditional spectroscopic measurements. The results can be further processed, scaled, smoothed, and eventually compressed to produce the information sought from the measurements.
PUSH-BROOM IMAGING One of the significant differences be-tween HSI and conventional single-point spectroscopy is the very large amount of data generated. Processing software and hardware are necessary to keep up with the data stream and provide compressed and processed data, thus producing composition maps and other technologically meaningful information.
Push-broom HS cameras gather a complete spectrum of each point on one spatial line at a time [1]. The area of the object is scanned, one line at a time in rapid succession. To image the whole sample, either the sample or the camera must move. The hypercube is collected by compiling the optical data from each spatial line. Since push-broom imaging detects one line at a time, the spectral data in the hypercubes correlate with the same sample point, thus push-broom HSI cameras are used with the samples moving, which is the case in many pharmaceutical manufacturing lines, schematically shown in Figure 2.
OPTICS VARY WITH NEEDSIn pharmaceutical production, there are many points where the increased amount of spectral information and the spatial information could
BLENDING OPERATIONS
38 JANUARY 2012
spectrograph
flattening filter
lens
order blocking
filtersensor
Spec
tral
Axi
s [�
]
Down Web / T
ime
Across Web
Hypercube data collection along moving manufacturing line
Different sizes and types of blenders
SWIR camera source and optics module
Motor, power supplies, camera controller module
Line, switch,
fuse
LVDS/Control cables IN
Computer interface
LVDS/Control cables OUT
Figure 3. imMix system block diagram
Figure 2. Push-broom HSI for continuous monitoring of manufacturing process
Figure 1. Simplified Hyperspectral (HS) camera components diagram.
provide additional insights, such as during transdermal manufacture, tablets, capsule filling, and blend-ing [2-6]. For different magnifica-tions, required by the different pharmaceutical applications, the same type of push-broom camera can be used with different optics. In this research project, for instance, a larger magnification was used to resolve the aggregates of the various pharmaceutical ingredients found in solid formulations.
For these studies we used the inMix system, which consists of a push-broom SWIR HS camera (Specim Ltd., Oulu Finland), which is positioned to view the blend inside the rotating blender (Figure 3). The blender is rotated by a computer-controlled motor. For the collection of HS data on all or certain specified rotations, the blender is slowed down and the camera is programmed to scan the blend covering the window. HS data collected through the optical window on the blender is turned into composition maps (indicating
spatial dispersion), which are used to predict ingredients throughout the blending process. The very large amount of imaging data is condensed to a limited number of useful micromixing parameters.
The camera is protected in a stainless steel housing; the motor, power supply, and camera controller and other electronics are housed in another stainless steel module. The instrument is compatible with different sizes and different types and sizes of blenders, as the camera position is adjustable. To empty the blender, the front housing including the camera module can be easily slid out from under the blender. A white reference for background measurements and devices to establish proper focus and help measure pure components or smaller quantities of materials can be attached to the blender.
The SWIR (Short Wave Infrared) HS camera, with a wavelength range of 1000-2500 nm, is equipped with an OLES Macro SWIR HS lens (Specim Ltd., Oulu Finland),
viewing approximately a 1 cm line with 30 μm optical resolution. A stationary directing mirror is used to direct the reflected light 90 degrees back to the camera lens. The blender with a window is illuminated with two quartz halogen lamps which are protected by another glass window. The height of the camera and optical parts can be adjusted. This is necessary to bring the blend into sharp focus, as well as adjusting for the differences among the different types and sizes of blenders used.
The blender is a one liter IBC (intermediate bulk container) blender, with filling and emptying ports, and whose emptying port is equipped with a removable 1-inch diameter sapphire observation window. The blender is attached to a rotating shaft, which is rotated by a computer-controlled motor. For frequent filling and emptying of the blender, the camera and optical parts of the blend monitor are mounted on a base plate, attached to a slide mechanism to move the entire front housing out of the way of the emptying port.
The data collection software allows the user to view live camera data, store white and dark references, and adjust camera settings such as exposure time and frame rate. The blend speed and measurement resolution can be selected, and blend rotations, where the image should be measured, can be specified.
The analysis software allows the prediction of the composition of any of the ingredients for any of the blender rotations using the Science-Based Calibration (SBC) [7] or partial least squares (PLS) methods. The SBC method requires the input of the pure analytes’ spectra which can be collected with the system or imported as a single spectrum obtained from other instruments.
BLENDING OPERATIONS
Figure 4b. Mean lactose aggregate size for acetaminophen blend
(Outlier if > 1.25 x Prediction Image Nominal %)
Turn 5 Turn 50 Turn 100 Turn 200
Figure 4a. Lactose prediction images
(Rotations)
The large amount of HS data is automatically collected, sequentially arranged by blender rotation, and analyzed. The composition maps provide the first level of data compression, resulting in the images of the predicted compositions of each ingredient. In subsequent analysis, the images are compressed into parameters that are meaningful for the blending process and displayed as a function of blender rotation.
Various image analyses can be performed with the prediction images, including standard statistical measures such as image average, standard deviation, relative standard deviation, and the fraction of pixels above/below/within a certain threshold, and spatial uniformity measures such as the distribution of aggregate sizes. The analysis software allows the prediction images for selected rotations and components to be viewed, compared, and saved.
In one blending experiment, 20% acetaminophen was blended with 39% methyl cellulose, 39% lactose, and 2% magnesium stearate. The blending was monitored at every rotation of the blender up to 200 rotations (Figure 4a). It can be observed that lactose is evenly blended by about 30 rotations of the blender, and that there is some evidence of re-agglomeration in the 80-90 rotation range. Even though there is some statistical variability from turn to turn, in this experiment, lactose seems to break up again over the consequent hundred rotations.
From the various image-processing options, the fraction of pixels that are within range of the nominal composition as shown in ranging from zero to one (Figure 4b).
Each pixel is much smaller than the unit dose and is even smaller than the usual aggregate sizes, thus it is a good metric to show the progression of the blending. Of the main ingredients, cellulose and
lactose reach their best uniformity at around 25 turns, whereas the acetaminophen breaks up more slowly (Figures 5 and 6), improving until about 160 turns. These differences would not have been revealed using single-point near-infrared monitoring, which obtains one average spectrum for each rotation of the blender. It can also be observed that in this example the cellulose and lactose are both slowly getting less homogeneously blended, although these changes probably do not affect the quality of the blend as much as the API getting more uniformly distributed.
References1. Hyvärinen, T., et al. (2007). High speed
hyperspectral chemical imaging.2. Kemeny, G., et al. (2009). Hyperspectral
monitoring of moving process samples. FACSS Poster.
3. Kemeny, G., et al. (2010). Hyperspectral monitoring of continuous pharmaceutical manufacturing. Transdermal Magazine.
4. Kemeny, G., et al. (2010). Pharmaceutical blend homogeneity. AAPS Poster.
5. Kemeny, G., et al. (2011). Micromixing analysis for formulation developers. AAPS Poster.
6. Ma, H. & Anderson, C. (2007). Optimi-sation of magnification levels for near infrared chemical imaging of blending of pharmaceutical powders. Journal of Near Infrared Spectroscopy, 15, pp. 137-151.
7. Marbach, R. (2007). Multivariate Calibra-tion: A Science-based Method. http://www.pharmamanufacturing.com/Media/Media-Manager/ralf-marbach_PATI061207.pdf
AcknowledgementsThanks for helpful discussion and feedback from Steve Hammond, Mojgan Moshgbar and Jun Huang of Pfizer’s Process Analyti-cal Sciences Group of Pfizer, Inc.; Juan G. Osorio and Prof. Fernando J. Muzzio of Rutgers University, and John Bobiak of BMS’ Analytical and Bioanalytical Research and Development Group.
BLENDING OPERATIONS
40 JANUARY 2012
Figure 5. The fraction of pixels within a threshold increases for acetaminophen as blending
progresses.
Figure 6. Acetylsalicylic acid blend with magnesium stearate added at turn 100.
Fraction of Pixels Within +/- 0.25 Prediction Image Nominal %
Median Aggregate Size (Outlier if > 125% x Prediction Image Nominal %)
(Rotations)
(Rotations)
UNEMPLOYMENT REMAINS high in the U.S. and other countries, and yet manufacturers struggle to find the skilled workers they need. It’s a maddening paradox.
There’s a clear skills gap out there. Young people especially—“millennials”—aren’t gravitating towards manufacturing careers and don’t see the work as sexy.
“Manufacturing has a PR problem with young people,” said John Nesi, VP of Market Development for Rockwell Automation, speaking recently during a panel discussion at his company’s annual Automation Fair. Millennials don’t have an appreciation for the high-tech nature and diversity of careers in manufacturing today, he said.
It’s not just in the U.S., said another panelist, Tom Duesterberg, a manufacturing expert at The Aspen Institute. “In both India and China, the quality of engineers and those going into jobs as line workers and so on is not adequate. In the U.S., we’re not training enough scientists and engineers. We are going to have to focus on immigration as one solution. But also, basic literacy and numeracy skills and the ability to be trained are missing.”
“Skill is a combination of education and experience,” said Mary Isbister, president of the metal fabrication firm GenMet. Most younger workers she sees “don’t have experience, and they don’t have basic math and science, and even the basic work-readiness skills of arriving to work on time!”
Irving McPhail, president of the National Action Council for Minorities in Engineering, bemoaned the “Engineering Awareness Conundrum.” “There are just not enough young people aware of the excitement in STEM careers,” he said. “Not a lot of young people know people who work in these fields. And we need K-12 educators who can impart enthusiasm in these fields.”
The end result, said McPhail: “We are not producing the number of engineers required to give the U.S. the ability to participate in the flat, global world.”
Duesterberg said that the U.S. must, as Germany and Japan have, place more emphasis on technical colleges and technical tracks in high schools, with support from government and industry. (North Carolina got this message long ago. It is a model of collaboration between educators, government, and industry. Other regions are catching on as well.)
But two things stand in the way, Duesterberg said.
First, the U.S. as a society places an inordinate emphasis on the “entrepreneurial” rather than the “industrial.” (Are they mutually exclusive?)
And, despite evidence to the contrary, many of our most influential thought leaders say “the future of our economy is in the service sector.” As Duesterberg and others have pointed out, successful economies need diversity—including a healthy manufacturing sector.
But making manufacturing sexy is an uphill climb. A
better approach would be to tap into a trait that all of us, millennials included, have in spades: greed.
If sexy just won’t work, maybe greedy will. In the National Association of Colleges and Employers (NACE) report on the best paying jobs for 2011 college graduates, engineering dominated the list. Here are the first 10 (with average starting salary in parentheses):
1. Chemical engineering ($66,886)2. Computer science ($63,017)3. Mechanical engineering ($60,739)4. Electrical/electronics and communications engineer-
ing ($60,646)5. Computer engineering ($60,112)6. Industrial/manufacturing engineering ($58,549)7. Systems engineering ($57,497)8. Engineering technology ($57,176)9. Information sciences & systems ($56,868)10. Business systems networking/telecommunications
($56,808)
These jobs top even those in finance, accounting, and human resources. The good salaries, of course, have something to do with the fact that there are not a lot of qualified candidates out there. But one would think that a starting salary of $60K and a wealth of open job positions would be enough to raise the eyebrows of even the most dour and discriminating millennials.
PHARMA VIEW
Can Manufacturing Be Sexy for Millennials?If not, maybe greed can help overcome manufacturing’s PR problem WITH YOUNG PROFESSIONALS.
BY PAUL THOMAS, SENIOR EDITOR
A STARTING SALARY OF $60K SHOULD
MOST DISCRIMINATING MILLENNIALS.
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TABLETTING
TABLET SCORING has long been used by oral solid dosage manufacturers—originally as a means to prevent tablet stress fractures, but recently as more of a cosmetic feature [1]. Bisects, of course, present manufacturing challenges. Th ey “may be aff ected by the tablet cup depth, band thickness and the intended tablet hardness. As the tablet size increases or changes, so do the size and type of bisects that may be placed” [2,3].
A score is a useful feature for the patient who, for instance, wants to switch from a name-brand to generic product and may need to halve tablets to maintain a consistent dosage regimen. By some accounts, this is happening more oft en, as insurance companies and doctors are increasingly recommending that patients split tablets for proper dosing or even cost savings.
Scoring has also been an issue in determining whether a generic drug is equivalent to its reference product. Whether or not a tablet is scored (and scored properly) can play a role in the cat-and-mouse game that originating manufacturers play with would-be generic competition. A reference drug may have a well-defi ned score while a generic product may only have a cosmetic breakline—in such a case, is the generic truly equivalent?
As one consultant recently stated on a LinkedIn conversation, scoring is “a door to patient non-compliance.” FDA has taken this to heart and has
conducted its own research, fi nding that scoring can lead to discrepancies in tablet content, weight, disintegration, or dissolution. (If you’ve split tablets yourself at home, how oft en have you gotten a good, clean split?)
Last fall, the Agency established draft guidance for tablet scoring [4]. (See PharmaManufacturing.com for a link.) Th e guidance is intended to provide “consistent and meaningful criteria by which scored tablets can be evaluated and labeled by: (1) providing a harmonized approach to chemistry, manufacturing, and controls (CMC) reviews of scored tablets; (2) ensuring consistency in nomenclature (e.g., score versus bisect) and labeling; and (3) providing information through product labeling or other means to healthcare providers.”
Th e draft guidance’s fundamental guidelines and criteria are:1. Th e dosage amount meant to be achieved aft er splitting
the tablet should not be below the minimum therapeu-tic dose indicated on the approved labeling.
2. Th e scored dosage form should be safe to handle and not pose risk of unintended drug exposure.
3. Modifi ed release products for which the control of drug release can be compromised by tablet splitting should not have a scoring feature.
4. Th e split tablet, when stored in standard high-density polyethylene pharmacy bottles and caps (no seal),
FDA provides more direction as questions
arise about dosage consistency.
By Paul Thomas, Senior Editor
Split Decisions:
should meet established stability requirements for a pe-riod of 90 days at 25º C, plus or minus 2º C/60 percent Relative Humidity (RH), plus or minus 5 percent RH.
5. The split tablet portions should meet the same finished-product testing requirements as for a whole-tablet product with equivalent strength. A risk assessment should be provided to justify the tests and criteria for product with the proposed functional score.
6. The scored tablet should be tested using the indicated patient population to ensure patients can split the tablet correctly, as labeled.
7. The scoring configuration of generic drug products should be the same as the reference drug.
8. New study data on tablet splitability should be pro-vided during postapproval for any product changes per FDA’s SUPAC guidances.
For more clarity on this “divisive” topic, we sought out Dale Natoli, president of Natoli Engineering, who has 35 years of experience in tabletting and has written extensively on oral solid dosage forms.
PhM: From an equipment standpoint, what are the lat-est in improvements in tablet scoring or bisecting?
D.N.: There have been recent improvements to a bisect de-sign commonly referred to as the “Pressure Sensitive” bisect to help reduce edge chipping and edge attrition. The new design requires a facet or radius eliminating the sharp edge on the tablet at the bisect and the beginning of the punch cup. The Pressure Sensitive bisect design is more common to the European pharmaceutical industry due to an earlier adoption of the European Pharmacopeia standards pertain-ing to uniform dose of a split tablet presented in 2002.
PhM: FDA wants to ensure good “splitability” for scored tablets. What are some of the keys or best practices for manufacturers in this regard?
D.N.: A key practice to adopt is establishing good com-munications regarding tablet requirements, powder and compression idiosyncrasies with your tooling supplier. When a tablet is required to be split providing equal dose, then careful consideration should be given to the tablet design. Proper tablet configuration, tablet thickness, hard-ness, bisect type, and placement play a tremendous role in achieving a uniform dose of a split tablet. Most tablet designers have the capability to create a digital model of a tablet with details of the bisect in relationship to the tablet thickness. Take advantage of these services when develop-ing new products or when redesigning an existing tablet.
PhM: How about the monitoring and Quality Control of scored tablets? Have there been advances?
D.N.: I am not a tablet analytical expert but from my point of view there have not been advances related to equipment or testing protocol to assure that a bisected tablet will yield a uniform dose. On the other hand, from recent interviews with product development and QA professionals, achieving a uniform dose of a split tablet has recently gained more attention to assure com-pliance to the EU Pharmacopeia and the new proposed FDA Guidelines to comply with export regulations.
A recent development by Accu-Break Pharmaceuticals is a unique patented process and tablet design consisting of two layers. The first or bottom layer is a non-drug layer and is compressed f lat and is used primarily as a base for the second layer consisting of the active powder. The top layer is compressed using an upper punch with a bisect or bisects engineered to precisely divide the active second layer and compress until the bisect slightly penetrates to the first non-drug layer, assuring a precise and uniform dose with each segment of the split tablet.
PhM: Finally, one consultant has said, “Scoring is just a door to patient non-compliance” and should be done away with. Your thoughts?
D.N.: There is no question that taking a whole tablet opposed to a split tablet provides the most accurate dose of a prescribed medicine. As a patient, I would feel more comfortable knowing that I am taking the proper dose of medication by only consuming a whole tablet. But unfortunately, I don’t think we will see tablets designed to be split leaving us any time soon. It now becomes the responsibility of regulators to assure that if a tablet is to be split that it splits evenly and doses the proper amount of medication.
References1. Rowley, F. Minimize Tablet Bisect Risk: Part I. http://
www.pharmamanufacturing.com/articles/2006/188.html2. Rowley, F. Minimize Tablet Bisect Risk: Part II.
http://www.pharmamanufacturing.com/arti-cles/2006/234.html
3. Tableting Specifications Manual, 7th edition, APhA Tableting Specification Steering Committee, APhA Publishing, 2005.
4. FDA. http://www.fda.gov/downloads/Drugs/Guid-anceComplianceRegulatoryInformation/Guidances/UCM269921.pdf
TABLETTING
44 JANUARY 2012
OPERATIONAL EXCELLENCE
DESPITE THE cautious optimism following the recent economic crisis, people who design, manage and main-tain production facilities are still facing tough decisions. Competition from emerging economies such as the BRIC countries (Brazil, Russia, India and China), slow consum-er response, rising prices for raw materi-als and uncertainty about the immediate economic future, are just a few of the issues that are continuing to challenge production managers today.
In this context, what can managers do to ensure the continued viability of their operations? A certain number of companies have gone for off -shoring and outsourcing to low-wage countries. But with production and quality issues becoming more and more of a concern, this option is beginning to lose
some of its shine, and some managers are hesitant to take this route as it can complicate an already complex and over stretched supply chain. Another popular option is cost cutting, but it would appear that most of the “low hanging fruit” has already been picked, with the danger
now being that companies will be trimming muscle instead of fat.
For pharmaceutical fi rms the picture might be a little more complicated in that, for many, the primary concern is the development of new products, which soaks up huge amounts of research and
development. Th e actual production is either the last step in an intricate series of events or outsourced altogether. An already complicated process would have an added dimension of complexity in that one is oft en dealing
By Tom McNamara and Sarah Hudson,
Rennes School of Business, and Sabry Shaaban,
Groupe ESC La Rochelle
There might be another way to increase output, reduce idle time or lower the average amount of material in a given linked set of processes.
with heightened safety and quality standards, far more stringent than those found in most other industries.
Many drug manufacturing procedures involve large amounts of raw material passing through a series of processes. Invariably done as a batch operation, this activity could also be thought of in terms of a flowline. The material flows in one direction. There are a series of precedent constraints. At each step some “work” takes place until the material in process has passed through all stages.
In pharmaceutical production, quite often the focus is on scheduling and capacity planning, with the goal being to get the most output out of a given facility, given a limited amount of resources. But our research has shown that there might be another way to increase output, reduce idle time or lower the average amount of material in a given linked set of processes.
FROM STARVING TO BLOCKINGThe aim of this article is to high-light possible ways for improving the performance of facilities having unpaced production lines, where operators are allowed to work at their own speed without the aid of an automated moving belt. We also take into account that these lines will necessarily suffer breakdown at times. Such lines usually have some storage spaces allotted in between the individual stations, referred to as buffers, for storing work-in-progress (WIP) units. This permits smoother production by avoiding stoppage of work due to an operator not having a work piece available (known as “starving”), or not being able to pass an item on to the next station due to lack of space (termed “blocking”). The importance of buffers should not be underestimated since they allow workers to process items relatively in-
dependent of each other. This type of production is called “asynchronous.”
There has been a considerable amount of attention paid to achieving a “balanced” line, where every workstation along the line completes its task at equal rates, and passes the unfinished piece on to the next station. Some firms have made substantial investments in time, money and effort to bring balance into their lines, but is a balanced line desirable, or even possible?
If we want to be realistic and flexible in our line designs, it needs to be recognized that different people work at different speeds, so perfect “balance” is a nigh on impossible dream. There are several reasons for this. One is the type of work performed—sometimes, because of pre-existing technological or precedence restrictions, it might be impossible to break down an individual job into a number of simpler tasks where each one has the same average completion time. We can imagine, say, a process where a series of chemical reactions are followed by centrifuging, drying, crystallization, and so on until the final packaged product
is manufactured. We can’t simply run one of the reactions for half the necessary time in order to maintain a balanced line.
THE HUMAN ELEMENTAnother reason in these manual lines is human nature. Different people have different levels of training, education, skill, ability and motiva-tion. For these reasons, the amount of time it takes for different opera-tors to complete the same task will never be equal. Contrary to popular opinion, this is not necessarily a bad thing. Studies have shown that an unbalanced line where people work at different speeds can actually outperform a perfectly balanced line. By deliberately having at least one station slower than the rest (a bottle-neck), higher production rates than those attainable by a corresponding balanced line were possible. An oper-ations management approach known as the “Theory of Constraints” views bottlenecks as a normal everyday occurrence. By identifying the con-straining bottleneck station and pro-viding it with additional resources, better on-time delivery and overall performance are possible.
OPERATIONAL EXCELLENCE
46 JANUARY 2012
Figure 1. The patterns of worker speeds
1. ASCENDING ORDER OF MEAN TIMES 3. INVERTED BOWL SHAPE
2. DECENDING ORDER 4. BOWL SHAPE
SlowSlow Slow
SlowSlow
Fast
Fast
Fast
Fast Fast
Even the slightest improvements in efficiency and operating costs can result in sizeable savings when considered over the anticipated useful life of a facility. So how can we design our unpaced lines to take best advantage of the natural working rhythms of our employees in so-called “unreliable” lines that can break down at any time?
SIMULATED CASE STUDYWe conducted a computer simulation investigation into production lines having five and eight stations. We in-corporated station failure, to duplicate real-life operating conditions as closely as possible. We assumed that indi-vidual workers fell into one of three categories according to their mean (average) service time; that is to say an op-erator could be fast, medium or slow. Four configurations of employee arrangement were looked at (Figure 1):1. the fastest worker is located at the front of the line,
followed by slower and slower operators—an ascend-ing order (/).
2. the fastest worker is placed at the end of the line, pre-ceded by progressively slower workers—a descending order (\).
3. the slowest operator is positioned in the middle, with workers getting faster as we go towards both the front and back of the line—an inverted bowl shape (/\).
4. the fastest worker is stationed in the middle, with operators getting progressively slower as one moves outward in both directions—a bowl shape (\/).Another factor that we considered was the percentage
degree of imbalance, i.e. the difference in speed between any two successive operators. Three degrees of line imbalance were viewed: 2% (slight), 5% (medium), and 12% (high). In addition, inter-station buffer capacities were set at 1, 2, 3 and 6 units.
Our objective was to find out which pattern (if
any) of worker allocation would provide the greatest enhancement in performance by way of: 1) an increase in the throughput (output) rate; 2) a reduction in the overall amount of worker idle time; and 3) a decrease in the average buffer level.
Some of our results were surprising and might run contrary to prevailing wisdom concerning production line management (Figure 2). We found that the best configuration resulting in increased throughput rates and lower average worker idle times was a bowl-shaped arrangement (fastest worker placed in the middle).
The biggest improvement, in certain cases, when compared to a balanced line, was nearly a 2% increase in output rate and an almost 6% reduction in average idle time. These might not appear to be significant, but when taken over the expected lifetime of an assembly line, higher revenues and increased savings could prove to be substantial. As for the average buffer level (Figure 3), the best pattern turned out to be a descending order (\) of mean service times (i.e., workers get progressively faster). It was observed that, on certain occasions, a reduction in average buffer level of almost 83% was possible—a huge amount of saving.
LESSONS FOR MANAGERSOur findings offer some useful insights into how managers can improve the efficiency of their facili-ties. They indicate that a line manager who chooses to reap the benefits of unbalancing his or her line is faced with a decision making situation. Would he or she like to increase output and lower idle times, or prefer to reduce average buffer levels? This decision will most likely depend on the type of operating environment involved. Is product demand high? Is this a technical product for which highly skilled (and paid) workers are needed, where specific or complex scientific, legal
OPERATIONAL EXCELLENCE
Figure 2. Best Idle time and throughput results: An eight-station line with a slight (2%) bowl-shaped imbalance in mean time and a buffer capacity
of one unit
= Pattern of average service time imbalance
SlowSlow
Fast
or health and safety knowledge is required? Here we may feel that throughput and idle time are of primary concern. In these cases a bowl arrangement of workers (\/) would likely provide the best benefits.
Alternatively, managers might fi nd themselves operating in an industry with extremely short product life cycles, or chemical compounds that are not very stable at certain steps of the process. Here the goal might be to keep as little material waiting in buff ers as possible, and correspondingly, a descending order of workers (\)—i.e. workers get faster as you move down the line—would be the preferred allocation
It should be noted that only a few of the almost unlimited number of possible alternatives for unbalancing a line were examined. Caution should be taken in that if a line is imbalanced in the “wrong” way, adverse performance could be the result. In spite of the caution needed, this is undoubtedly an attractive proposition to production managers, since the line can be redesigned simply by reassigning workers along the line at no extra cost. Th e fact that the diversity in working speeds can actually be taken advantage of means that every line worker can off er something to the whole process and can feel of value to the company—a motivating exercise indeed.
About the AuthorsTom McNamara and Sarah Hudson are professors at the Rennes School of Business, Rennes, France, in the Department of Finance and Operations. They can be reached at the following email addresses, respectively: [email protected] and [email protected]. Sabry Shaaban works within the Department of Economics Strategy and Organization at Groupe ESC La Rochelle, Cerege, France, and can be reached via email at [email protected].
OPERATIONAL EXCELLENCE
Figure 3. Best average buffer level results: A five-station line with a high (12%) descending mean-time order imbalance and a buffer capacity of six
units
Slow
Fast
MEAN TIME DIFFERENCE 12%
= Pattern of avereage service time imbalance
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LAST YEAR marked the release (escape?) of FDA’s Pro-cess Validation guidance, which outlines what is needed for “proper” manufacture of a pharmaceutical product. Many manufacturers have been saying, “Oh sure, we would love to do PAT/QbD, but how?” Guess the “whist- ling past the graveyard” is over now. The essence of the Guidance is simply stated (the italics are mine):
“A successful validation program depends upon information and knowledge from product and process development. This knowledge and understanding is the basis for establishing an approach to control of the manufacturing process that results in products with the desired quality attributes. Manufacturers should:
Understand the sources of variation
Each manufacturer should judge whether it has gained sufficient understanding to provide a high degree
to justify commercial distribution . . . After establishing and confirming the process, manufacturers must maintain
”Currently, companies without a working PAT (QbD)
program are relying on the 1960s approach to product control, namely, testing a 10 or 20 sample set and either selling or discarding the product. After-the-fact product testing, of course, is ineffective in managing the process. Numerous people have suggested more samples (cGMP does call for “a statistically significant number,” after all), but the question of how many is “significant” has been up in the air. However, that may have changed.
Recently, I was made aware of a new(ish) ASTM standard, E2790-10, for calculating the proper sample sizes of lots of materials. While I was waiting for a greater mind (Howard Mark) to examine the standard, I considered an older, simpler approach: the √n for a batch of 106 would be 103 and be quite expensive to perform under the current paradigm of “all HPLC, all the time.” My friend and super-statistician, Howard Mark,
explained the application, and I will paraphrase:Three key parameters are needed: the fraction of
samples OOS, the fraction of OOS tablets captured, and the confidence level. One million tablets is a good approximation of infinity, allowing assumptions about Normality and other properties (as the number approaches infinity, tolerance and confidence limits become the same). Confidence intervals for the normal distribution for large numbers of degrees of freedom
allows an approximation to the much more complicated formulas otherwise needed. It shows that 99.99% of the readings are within 3.7 standard deviations and 99.999% of the samples are within 4.2 standard deviations. Take that number as 0.1%.
That means, in a batch of one million tablets, 1,000 of them would be OOS. To a first approximation, one tablet per thousand would be at or beyond the 0.001 probability point of the Normal distribution, corresponding to 3.15 standard deviations. That corresponds to (0.001 x 1,000,000) = 1,000 tablets. Measuring 1,000 tablets allows a chance to capture one of the OOS tabs. Since the actual number of tablets that would be beyond the 3.15 std. dev. value are distributed according to a Poisson distribution, measuring only 1,000 tablets gives only a 50% chance that one of the OOS tabs will be found. To increase the probability of including at least one OOS tablet among those measured, more than 1,000 samples need be measured. That means a true statistician would laugh hysterically if told ten or twenty samples are representative of a 1,000,000-5,000,000-unit batch!
Unfortunately, business as usual would dictate using HPLC. Changing from the status quo to meaningful (non-destructive, information-rich) testing will satisfy both FDA and ASTM. Therefore, the good news is that we now have blueprints for QbD; the bad news is that manufacturers have run out of excuses for notrunning QbD.
THERAPEUTIC DOSE
Sampling: Good News, Bad NewsChanging from the status quo to meaningful testing will satisfy both FDA and ASTM.
50 JANUARY 2012
BY EMIL W. CIURCZAK, CONTRIBUTING EDITOR
A TRUE STATISTICIAN WOULD LAUGH
REPRESENT A MILLION-UNIT BATCH.
April 16-18, 2012JW MARRIOTT DESERT RIDGE RESORT • PHOENIX, ARIZONA
The 2012 PDA Annual Meeting is the meeting place this April. The distinguished Program Planning Committee, made up of your peers, is hard at work to bring you the best content in the industry. They know what you are concerned about, what you want to hear and who you want to hear it from.
The Best Content in the IndustryConference Highlights Include:
• Two Great Opening Plenary Topics: • Future Benefits for Patients: From Discovery
to Commercial Products, Cellular and Gene Therapies, David Shanahan, President, Mary Crowley Research Center and President, CEO and Founder, Gradalis
• The Future of Personalized Medicine – Challenges Ahead, Ted Love, MD, Executive Vice President, R&D and Technical Operations, Onyx Pharmaceuticals
• Plenary Session Two: • The Future of the Biopharmaceutical Industry,
David Urdal, Chief Scientific Officer, Dendreon• Financial Analyst Perspective on the
Pharmaceutical Industry, Barbara A. Ryan, Managing Director, Research Analyst, Deutsche Bank Securities, Inc. (invited)
• Student Call for Posters – Abstracts Due February 6, 2012
• Closing Plenary Topics: • Manufacturing
Opportunities and Challenges in the Next 10-20 Years, Matt Croughan, Professor, Keck Graduate Institute of Applied Life Sciences
• Emerging Regulatory Expectations, Emily Shacter, PhD, Chief, Laboratory of Biochemistry, CDER, FDA
• New this Year: A breakfast Session on Career Development Strategies
• Networking Receptions & Events like the 6th Annual PDA Golf Tournament at the Wildfire Golf Club & the PDA 6th Annual Walk/Run (benefiting the Phoenix Children’s Hospital)
• Post-Conference Workshop: PDA Single Use Systems Workshop on April 18-19
• PDA’s Training and Research Institute (PDA TRI) will be offering eight courses on April 19-20
• Hotel activities for the entire family!
www.pda.org/annual2012EXHIBITION: April 16-17 | CAREER FAIR: April 16-17
POST-CONFERENCE WORKSHOP: April 18-19 | COURSES: April 19-20
The Parenteral Drug Association presents...
Also: Post-Conference
Workshop on Single Use
Systems!
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