Some of the news reports that followed FDA's recent approval of the blood-thinner Lovenox suggested that it was the Agency's first approval of a biosimilar, or follow-on biologic. (Here's one example.) In a recent interview with Ed Silverman of Pharmalot, Jonathan Pan of Scientia Advisors disputes that Lovenox is a true biosimilar (as vague as that definition may be). Says Pan, "Lovenox is not a biologic like a protein or antibody.

From Chemical Engineering Progress, Girish Malhotra presents his prescription for the pharmaceutical industry----QbD, PAT and control all play a key role, and chemical engineers will make it happen. The ultimate goal will be entirely new business models for pharma. Mr Malhotra discusses a new "Open Lab" open source R&D initiative in India that involves Sun Microsystems.

In its neverending fight against both poor manufacturing practices and the manufacture and marketing of unapproved drugs, FDA has filed a Consent Decree and expects courts to prohibit Activis’ Totowa, New Jersey facility from further production.

Any crime covered by the press inspires a wave of copycats.  So, it seems, the global heparin supply chain will have to be closely monitored for some time.  Both 2-D NMR and capillary electrophoresis have been recognized as the best ways to assess the purity of heparin. Both are beautiful techniques, and yield a lot of information, but they also require highly experienced analysts and expensive equipment. 

A nice, if brief, Q&A appeared today in India's Business Standard, featuring a conversation with Arun Kumar, CEO of generics maker Strides Arcolab.

Forget about championing one side or another. The politically charged "generics vs. namebrand drug" debate offers an opportunity to study the impacts of process and ingredient variability on drug manufacturing and on clinical effects in patients.   (For material to analyze, click here). At IFPAC 2008 in January, FDA's Dr. Janet Woodcock noted the fact that the industry still cannot definitively trace clinical issues in patients to specific manufacturing challenges or problems. 

Quality of excipients and other ingredients may meet basic specifications and yet vary from batch to batch. Cost-pressured generics manufacturers may have to use alternative ingredients and tests (e.g. for bioequivalence).

But couldn't a "Quality by Design" framework, even for developing generic drugs, eliminate these problems?

Yesterday, ConsumerLab.com reported results of its investigation of generic versions of the blood pressure medication, Toprol XL, which, according to consumers, may raise blood pressure rather than lower it and cause side-effects. ConsumerLab found that certain generic brands, such Sandoz's, contain ingredients not found in the original and do not necessarily dissolve like Toprol XL. These differences can potentially to trigger chemical sensitivities and result in differences in absorption.

ConsumerLab, citing previous studies of generic Wellbutrin XL last year, suggests that generic "inequivalence" affects a wide range of generic drugs. ConsumerLab.com and The People’s Pharmacy are jointly calling on the FDA to disclose inherent differences between generics and originator drugs. The FDA has yet to release findings from its investigation of generic Wellbutrin XL, but new information from both the USP and an FDA official corroborate ConsumerLab.com’s findings

What do you think? 

If the recent Science Board report on science within the Agency wasn't enough and you needed more evidence of the urgent need for better IT infrastructure, staffing and other resources for FDA, the Wall Street Journal released this bombshell this morning. Click here to read.

Baxter's recalled generic Heparin may be linked to API manufactured by a Chinese manufacturer that was "supposed to have been inspected." What happened? Human error and inadequate IT, the Journal reports, so a pre-approval inspection was never performed (although the Cherry Hill, N.J. plant where the finished version of the drug is packaged had been inspected).

Some suggestions? Have the Agency focus only on drugs and build up its data management capabilities and give it the funding ( a lot more funding) to hire more inspectors. As API manufacturing has stepped up in China and India, FDA has become the de facto police for API and drug manufacturing around the world, and it simply doesn't have the resources to do this job properly. How could it? Have you read the FDA budget allocations?

Dr. Janet Woodcock touched on the issue of resources lightly in this recent interview with Emil Ciurczak.

Schaumberg, Ill.-based heparin manufacturer APP was quick to jump in and announce production increases. As the WSJ blog pointed out, that company also sources its API from a Chinese manufacturer, although a  spokesperson says the company has not heard of any adverse reactions.

Heparin is a critical and widely used drug. Regardless of the outcome of this particular story, it is sure to heighten scrutiny of foreign API plant inspections. Perhaps it will also prompt more discussions in Washington about increasing the funding and staffing to allow more of those inspections to take place, and establishing the IT needed to track inspection data and information on adverse reactions. What do you think?

AMS

We love the progressive thinking that's going on in pharma. That's why I enjoy my job and what makes covering this side of the industry so much more interesting and positive than looking at the financial side and all the marketing scandals. As we do every year, we've covered this year's IFPAC process analytics conference, a hotbed for some of that thinking, and promoted it on our web site.

Only this year, thanks to our talented multimedia director Scott Babcock, we did some of this via video, and professionally edited video, not the "You Tube"-ish things that editors like me have thrown together in the past.

Thanks to Robert Zutkis and IFPAC for allowing access, and to everyone, especially FDA's Janet Woodcock, for being so gracious about doing impromptu interviews, and for not running away at the sight of a video camera, and to Emil Ciurczak and colleague Jack Carroll for being open to experimenting with new media. They are both developing an online video course on Quality by Design, PAT and Analytics that will soon be up on our web site.

You'll find the official report on IFPAC our web site. But here is a brief, unsanctioned one. Let's call it the PAT Gossip report. Please don't be offended, anyone, and remember. This is only a blog.

• Insiders say working conditions at FDA are much better, but budgets for travel to training conferences aren't expanding. "Travel is just for the big wigs, " said one.
• Ajaz Hussain is now working on transgenics at Philip Morris International, which is developing tobacco plant strains for cell culture for vaccine production.
• Martin Warman reports that there is life after Pfizer. He's now consulting and, given data management challenges facing most companies embarking on PAT, his work now takes him into the IT realm more often than instrumentation. Who knows? Perhaps he will return to Big Pharma
• Ron Miller reports that life after BMS is good. He is consulting and working on another book.
• Merck is looking for some PAT leaders, at the PhD, MS and BS levels. We hear that Wyeth is, too.
• Move over Tata Consultancy Services. Puerto Rico is considering a new export: PAT team leaders available on a contract basis. The island's universities are strong, and so are their training programs, one of which is taking an accredited PAT training course online to a Web format this year. Now for some extremely random thoughts, comments and questions, in no particular order.

  Why were some pharma PAT presentations this year almost completely identical to last year's?

  IFPAC offers access to some of the greatest minds in the industry. And some of the smaller ones, too. Like the person, who will remain nameless, who turned Scott and me away, literally at the door, at the opening night dinner.

  Thus, Scott had to lug very heavy, awkward video and lighting equipment all over the hotel and store it while grabbing a bite to eat. We didn’t have the electric power or Internet access we needed to cover the program at our booth either

  More revelations from this year’s conference?

  Don’t roll your eyes when your aunt complains that the generic version “just doesn’t feel the same” as old and expensive Brand Name X. She’s onto something. Don’t call her a hypochondriac. The fact is that the excipients used in formulation can show tremendous between-batch variability, even when they meet USP and other specs. At IFPAC, we heard no less an authority than Deputy FDA Commissioner Janet Woodcock suggest that there may be a connection between these complaints and measurable manufacturing issues" We just don’t know yet,” she said.

  One batch of excipient can meet basic USP specifications and yet perform completely differently, within the formulation, than another batch of the same material that meets specs.This is all part of the challenge of relating clinical outcomes to manufacturing issues, and a fundamental reason why pharma needs to use PAT.

  Want to Take Revenge on FDA Inspectors? Teach Them
  Instructors must have had fun designing the hands-on solid dosage training course for FDA’s Inspectorate last year.Using a lab featuring Emerson process control equipment and Optimal’s SynTQ, FDA students performed simple blending operations using lactose, but material from three different batches of lactose. If the blend was made with lactose from one batch, the reaction would be completed much faster than materials using the other batches. Huh? Isn’t lactose lactose? Not exactly. That’s just what prompted GSK’s Ray Scherzer to suggest that...

  Pharma needs more physicists and materials scientists (or, at least, industrial pharmacists with training in those areas----people who understand the mechanical and other physical properties of materials used in drug formulations

  Bored and want to see some intrigue unfold among PAT types? Start a conversation about dissolution test calibration or microbiological testing of pharma-grade water and watch otherwise reasonable people become unreasonable.Anti-USP sentiment appears to be on the rise in some quarters, with insiders of one camp accusing the organization of rank commercialism, conflicts of interest and impeding the interest of science.(But wait a minute: Does ASTM give its standards away for free

  Peter Rost is a favorite read among some folks we met.Said one insider, “He understands what pharma management is all about, because he worked alongside the guys who are so glued to Bloomberg and the stock results that they forget about what’s going on inside their plants. Too bad he doesn’t get into this side of the business. Consider that an open invitation, Peter… somehow, though, I think the subject matter might be a bit dry.

  One anonymous contrarian then posed a few interesting philosophical questions:

Is standards development by consensus, as with E-55, really a good thing for FDA to be promoting? Ditto for the idea of real time/parametric release of product. "Doesn’t this approach allow industry to write its own rules," this person asked. "I mean, it would be one thing if all of pharma’s senior management were universally on board and always put the public health first and foremost in their minds, but many of them are too busy watching Bloomberg.”

Is mechanical dissolution test calibration truly science based, since it eliminates the only baseline measurement now available? Would the FAA send planes out without mandating crash tests, using uniform testing methods, rather than tests developed by each vendor? One camp has argued convincingly that USP calibrating tablet quality can vary, leading to flawed results. The insider begs to differ. Using mechanical calibration does not provide any way to judge how the given drug will behave in the human bodyFurthermore, insider says, it forces each company or facility to develop its own internal standards, and FDA inspectors to master different internal standards at each facility. Isn’t that a waste of resources and money for an already cash-strapped Agency, and even for the companies themselves I don’t think anyone should worry too much about this. I hope that all drug companies the world over move to real-time product release, but I suspect they’ll still the USP tester tablets as a final check for a very long time to come. Will generics companies, in particular, suddenly throw out all their SOPs and go modern for the sake of trend setting

Please note: We are firm believers and supporters of PAT, Quality by Design, parametric release and continuous quality improvement.We have drunk deeply of the Kool-Aid and support E-55, USP and science-based standards, and we know that FDA has never mandated mechanical calibration. But it’s important to remember that PAT and all this is still fairly new to pharma and that certain scientific basics remain unknown. As this insider says, PAT is a great thing and critical to the future of pharma, but some of the underlying science isn’t there yet, and until it is, any radical changes in industry regulation may be premature, with the industry risking “slapping lipstick on a pig

Long story short, IFPAC is well worth a visit.

FDA issued a press release today (see below), noting that the Agency is calling for safety-related labeling changes for three biopharmaceuticals used to treat certain types of anemia. The release suggests that erythropoiesis-stimulating agents (ESAs) may pose serious health risks and have questionable efficacy in alleviating symptoms of anemia and fatigue in cancer patients.

In addition to being a blow to Amgen, which manufactures the ESAs Aranesp, Epogen and Procrit (the latter of which is marketed by Johnson & Johnson's Ortho Biotech unit), this news likely dismayed Sandoz and other biopharma companies that earlier this year urged members of the Senate Committee on Health, Education, Labor and Pensions to accelerate approval of "biosimilars."

Wouldn't you love to be a fly on the wall in strategic planning meetings at Amgen, J&J, Sandoz and other biopharma companies during the next several weeks?

-HP
FDA Strengthens Boxed Warnings, Approves Other Safety Labeling Changes for Erythropoiesis-Stimulating Agents (ESAs) Nov. 9, 2007 -- The U.S. Food and Drug Administration today approved revised boxed warnings and other safety-related product labeling changes for erythropoiesis-stimulating agents (ESAs), which treat certain types of anemia. These new statements address the risks that the drugs Aranesp, Epogen and Procrit pose to patients with cancer and patients with chronic kidney failure.

The labeling changes, which incorporate advice from FDA advisory committees and expand upon labeling changes made in March 2007, also include a statement that symptoms of anemia, fatigue and quality of life have not been shown to improve in patients with cancer who are treated with ESAs.

Epogen, Procrit and Aranesp are approved to treat anemia in patients with chronic kidney failure and anemia caused by chemotherapy in certain patients with cancer.  Epogen and Procrit are also approved for use in certain patients with anemia who are scheduled to undergo major surgery to reduce blood transfusions during or shortly after surgery and for the treatment of anemia caused by zidovudine (AZT) therapy in HIV patients.

For Patients with Cancer

For patients with cancer, the new boxed warnings emphasize that ESAs caused tumor growth and shortened survival in patients with advanced breast, head and neck, lymphoid and non-small cell lung cancer when they received a dose that attempted to achieve a  hemoglobin level of 12 grams per deciliter (g/dL) or greater.The boxed warnings also emphasize that no clinical data are available to determine whether there is a similar risk of shortened survival or increased tumor growth for patients with cancer who receive an ESA dose that attempts to achieve a hemoglobin level of less than 12 g/dL. This is the hemoglobin level commonly achieved in clinical practice.Health care providers determine whether a patient is anemic and decide on ESA dosing by measuring how much of the protein known as hemoglobin is present in a patient’s red blood cells.An earlier boxed warning, approved in March, described the results of six studies demonstrating that survival was shorter and tumors progressed faster when ESAs were used to achieve hemoglobin levels of 12 g/dL or greater in cancer patients.Today’s new boxed warning also clarifies that ESAs should only be used in patients with cancer when treating anemia specifically caused by chemotherapy and not for other causes of anemia. Moreover, it states that ESAs should be discontinued once the patient's chemotherapy course has been completed.

“Health care professionals need to consider the risks of increased tumor progression and decreased survival in patients with cancer when prescribing ESAs,� said Janet Woodcock, M.D., FDA’s deputy commissioner for scientific and medical programs, chief medical officer and acting director of its Center for Drug Evaluation and Research. “ESAs should be used in patients with cancer only when their anemia is due to chemotherapy and only at the lowest dose necessary to avoid the need for blood transfusions.�

The FDA is working with the manufacturer to design and conduct clinical trials of different dosing regimens and tumor types to further characterize potential tumor progression associated with ESAs.

For Patients with Chronic Kidney Failure

For patients with chronic kidney failure, the new boxed warning states that ESAs should be used to maintain a hemoglobin level between 10 g/dL to 12 g/dL. Maintaining higher hemoglobin levels in patients with chronic kidney failure increases the risk for death and for serious cardiovascular reactions such as stroke, heart attack or heart failure, the boxed warning states.

In addition to the boxed warning, the new labeling provides specific instructions for dosage adjustments and hemoglobin monitoring for chronic kidney failure patients who do not respond to ESA treatment with an adequate increase in their hemoglobin levels.

The new labeling also emphasizes that there are no data from controlled trials demonstrating that ESAs improve symptoms of anemia, quality of life, fatigue, or patient well-being for patients with cancer or for patients with HIV undergoing AZT therapy.

In March 2007, the FDA approved labeling changes and issued a public health advisory outlining the new safety information about ESAs. Safety concerns regarding ESAs were discussed during May 2004 and May 2007 meetings of FDA’s Oncologic Drug Advisory Committee and a September 2007 joint meeting of FDA’s Cardiovascular and Renal Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee. ESA product labeling was previously revised in 1997, 2004 and 2005 to reflect new safety information.

The agency is currently reviewing a proposed Medication Guide that will better communicate the safety and effectiveness of ESAs to patients and will replace the existing patient labeling.

ESAs are a bioengineered version of a natural protein made in the kidney that stimulates the bone marrow to produce more red blood cells. These drugs are manufactured by Amgen Inc., Thousand Oaks, Calif.  Procrit is marketed and distributed by Ortho Biotech LP of Bridgewater, N.J, a subsidiary of Johnson & Johnson.

For more information:  http://www.fda.gov/cder/drug/infopage/RHE/default.htm

Installment 5

ISPE management deserve special praise for inviting a high-ranking engineer from a generic pharmaceutical manufacturing company---in this case, the rapidly growing Teva, to speak at this meeting. 

As  ISPE vice chair Bruce Davis affirmed, generics manufacturers are not "the enemy," but an increasingly important part of the global healthcare system.  They also face margin and profit pressures that present a possible future scenario for pharma innovators---pressures that demand that they embrace new ways of doing things. 

So far, Ajaz Hussain has been fairly quiet about development and manufacturing challenges at Sandoz, so it was interesting to hear from Uri Boneh, director of global engineering at Teva Global Generic Resources, about how the company has applied GMP principles and some Toyota-esque principles to the building of a new oral solid dosage manufacturing plant in Jerusalem.

As Mr. Boneh said, "Tomorrow ---and at least half of the next decade---is already here. We have to think about what we'll do after that point.:

The facility has been designed to facilitate expansion, he said.  I wished that he'd focused a bit more on "how" but assume that would have been considered giving away trade secrets. 

Mr. Bonet devoted a great deal of his presentation to affirming the fact that oral solid dosage manufacturing is still fairly low tech and labor-intensive, and has been operated the same way---using mixing, drying, milling, sieving, blending, tablet compression, filling.... for decades. "The market is growing, people are living longer and need more medications...someone has to make OSDs...

"I was sitting last week with leading tablet press manufacturers who showed how equipment had improved….when I asked him how process had changed in last 150 years he had to admit, "not very much," Boneh said.  "I hear that Novartis is working with MIT on long term 10-year project to change the way we make drugs….I am curious….this should be very interesting….maybe in 10 years everything will be different….for the moment, it’s pretty much all the same…."

Mr. Boneh outlined the main functions critical to the process: Warehousing, transport and staging, washing, in process control, tooling and size parts, and noted that conventional production concepts needed detailed planning and control and aimed for high utilization of equipment and other resources.

The result, he said, has been long cycle time and low flexibility. "Like a commander on the battlefield, each department manager would issue work orders but [didn't] know what’s going on in other departments….

To eliminate waste, the new plant was designed with a "pull" focus for production planning and manufacturing. Cycle time is now 1.5 days, where, for some of the company's older plants, it's typically three weeks.

Design for the new plant began late in 2002, by 2005 it was ready for inspection and FDA inspected it in 2006.

"Online quality assurance equipment is there but it is labor intensive," Boneh said, "and results depend on the quality of your staff. You need comprehensive quality systems in place, to prove to yourself and inspectors that you are really in control of what you’re doing.

The new facility uses a newer, crossfunctional approach to operations, he suggested. "We don’t need chief of staff to tell everyone what to do."

Since packaging has to work all the time, it determines requirements for other departments.

Teva has also created virtual production lines or "lean production" lines extending from weighing, granulation, fluid bed drying.  At this point, he says, only packaging is 80-100% utilized.

To use gravity fully, the company needed to build a high facility (several floors), but tall buildings are more expensive, and require more local permitting issues, so Teva eventually decided on a four-floor concept. 

To enhance GMP, a critical part of the facility design was the concept of closed material transfer between process steps, Boneh said. Manufacturing is carried on in production suites, each of which is separated from the others by corridors with airlocks.  Each suite produces one specific product.  Everything is washed inside each suite so that nothing dirty comes out.

Airlocks, meanwhile, enhance separation and ensure that no air is recirculated into the HVAC system. Only cleaned containers, parts and equipment leave the suites.

Production people didn’t like airlocks at first, Boneh said, but they improved overall hygiene.  Once staff pass airlocks they must wear extra protective gear.  Environmental and ergonomic considerations also drove design.  Special focus was given to exhaust air filtration, solvents and thermal oxidation, wastewater treatment and noise reduction.

Teva used simulation extensively to design the facility, which uses a multilevel concept model.  The plant is based in North Jerusalem, where the government offers investment incentives. Teva manufactures globally in 36 plants, Bohen says, and plans to double production by 2012.

It will be interesting to learn more of the specifics of this facility and its design. In the meantime, it was important to see representation from generics at this conference.

AMS