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By Daniel R. Matlis

For years I have been joking about some company marketing a sugar pill based on clinical trial data supporting the “placebo effect”.

I never thought I would see the day when this prediction would come true.

Well, today is the day. Efficacy Brands LLC has begun selling Obecalp “…the First Standardized Branded and Pharmaceutical Grade Placebo…”

Jennifer Buettner, the brains behind Obecalp, offers this rational for the product. “Children, adults and seniors shouldn’t be given any type of drug when one is not needed. Until I invented Obecalp there weren’t any options. Now, with Obecalp, the medical authority figure, whether it be a doctor, nurse, or mommy can decide if medicine is needed. If not, Obecalp might just be the answer.” (Why can’t dad be the medical authority figure?)

I could not believe my eyes when she added, “Manufacturing Obecalp with the cGMP process assures our consumers that they are purchasing the finest pharmaceutical grade placebo.”

Wow, where do I start… This is wrong is so many ways.

Asserting to follow cGMPs to manufacture a sugar pill designed to do nothing?  Nice marketing!!!

I agree that we should not give children or adults medicines they don’t need.  So instead, we should lie to them and tell them that a sugar pill will make them better?

What’s the message we are conveying to the next generation?  A pill can solve all your problems? (I know, we have not made pills in a long time, we now make tablets, caplets, gel-caps, etc.)

When one of my children gets a boo-boo, I have found that “kissing the boo-boo better” works in the vast majority of cases.  When that doesn’t, I escalate the treatment to hugs and kisses.

And if I have to resort to sugar to make them feel better, I provide it in the form of a “non cGMP manufactured” lollypop or USDA regulated ice-cream.

The sad part of the story is that, at a reported $5.95 for 50 tablets, Efficacy Brands will probably make lots of money selling Pharmaceutical Grade Placebo tablets.

XOXO anyone?

By Daniel R. Matlis

For this installment of our “2008 Learning from Success” series, I had the privilege of speaking with Mark Wagner, Vice President Worldwide Clinical Supply Operations and Sarah K. Doshna, Associate Director Parenteral Manufacturing Pharmaceutical Research Institute.  They represented Bristol-Myers Squibb (BMS), the winner of the 2008 Facility of the Year Award for Equipment Innovation.

BMS’s Clinical Supplies Manufacturing and Drug Product Technology Center is located in New Brunswick, New Jersey and supports trials in 60 countries around the world.

This innovative facility was designed to accelerate time to market by bringing together formulation as well as early and late phase clinical manufacturing and development scale-up resources into a single site.  This created the BMS Pharmaceutical Development Center of excellence.

To save time and cost, as well as minimize environmental impact, BMS chose to gut and rebuild an existing structure on the New Brunswick Campus.   The team utilized a phased approach enabling them to leverage lessons learned in the integration of containment and process automation technology into existing operation. 

Phase one included a state-of-the-art Clinical Supply Operations expansion facility-comprised of full containment for expanded Oral Solid Dose (OSD) operations.  The site utilizes some of the most flexible clinical-scale continuous barrier line in the United States for Sterile products.  The facility was designed to support manufacturing of OSD batches up to 400Kg and parenteral liquid fill batches up to 250L.

The goal was to create a flexible facility capable of performing multi-product clinical scale manufacturing and processing solvent-based and potent compound operations.

Key business drivers for the project included:

• Versatility- Capable of supporting Small Molecules and Biologics
• Flexibility - Movable equipment for easy re-configuration
• Multi-use – capable of running up t 5 products concurrently

Phase Two built upon the technologies in Phase One and added additional processing space and scale to the Oral Solid Dose clinical operation and a new stand-alone Product Technology Center for development scale-up activities.  The addition of Oral Solid Dose Operations allows the manufacture of Long Term Stability batches within the Clinical Supply Operations facility in at least one-tenth commercial scale.

In my opinion, the most worthwhile lesson of the project was the use “sweat equity”.  The phrase is used to describe the value added to houses by owners who make improvements by their own toil. The more homeowner labor applied to the home, the more sweat equity that has been used.

BMS appointed the facility’s owners Sarah Doshna and Neil Martin as the project’s leaders.  Their teams were brought on board before the roof was up.

The facilities future technicians, operators and mechanics began by training and working on the legacy process, enabling them to learn what worked in the past, as well as providing opportunities to shape and improve the new process.

In addition to “sweat equity” here are a few more lessons from BMS’s Success:

1. Foster water cooler cooperation
  Bringing team members together can solve and prevent problems

2. Open informal lines of communication
   Tear down silos by leveraging knowledge fostering integration, commingling and shared learning

3. Involve QA early in the design phase.
  Keeping QA engaged throughout the life of the project ensures continuity and minimize holdups

4. Plan and Design for technology integration.
   Don’t wait till the equipment gets to the site

5. Integrate Process Analytical Technology (PAT) into the process
  Is should not be an afterthought

6. Seamlessly Incorporate Electronic Batch Record (eBR)
  Do not implement “Paper-on-Glass”, take full advantage of eBR capabilities

As a result of the “Sweat Equity” approach, the new facility provides BMS with the increased capacity to meet clinical demand and deliver Compliance, Productivity and Technical Innovation for present and future drug development pipeline needs.

An added bonus of this approach was the virtual elimination of the steep learning curve often associated with the startup of a new facility.  After all, It’s easy to navigate through, and hard to point fingers at the decisions made in the facility you helped build.

By Daniel R. Matlis

No, it is not a typo; I mean to spell it C-A-C-A.

Last week, I had the opportunity to present at Camstar’s 2008 “Vision to Value” Manufacturing 360 Customer Conference. One of my sessions was entitled “Shifting from CAPA to PACA”. The takeaway message was simple: Our industry must move from the current Reactive “Corrective and Preventive Action” (CAPA) to a proactive “Preventive and Corrective Action” (PACA) approach of Quality management.

A brief History of CAPA systems in Life-Sciences:
In 1996, the FDA’s Center for Device and Radiological Health issued the Quality System Regulation. 21 CFR § 820.100 (a) requires manufacturers to establish and maintain procedures for implementing CAPA.
In the fall of 1999, FDA conducted a series of industry workshops on its new Quality System Inspection Technique (QSIT). The fourth slide in the presentation showed this chart depicting the “Top Ten FDA 483 Items” for Non-QSIT inspections.

 
It did not take Life-Science companies long to begin implementing some kind of a CAPA or Quality Management System.

The challenge is that Life-Science companies have often focused on the “Corrective” rather that the “Preventive” aspects of CAPA.

In most organizations “Time to Closure” is the Key Performance Indicator used to measure the effectiveness of the CAPA system. Yet, the word “time” is never mentioned in 21 CFR § 820.100 (a).

The regulation does include requirements for:

• Analyzing
• Investigation
• Identifying
• Verifying and Validation
• Implementing and Recording
• Ensuring
• Submitting

Furthermore, the amount of time a CAPA is open has little or no correlation with the successful implementation of a CAPA. Identifying the root cause of the issue and implementing an appropriate plan to address it does.

Root cause analysis can be a time consuming process. This is especially true when critical information resides in desperate disconnected systems or, worse yet, on paper records.

Unfortunately, the emphasis on “Time to Closure” has lead to a significant percentage of closed CAPAs resulting in updated SOPs or operator training. As the closure date draws near, and the pressure to meet the time requirement increases, some fall into the trap of assigning “human error” as the source of the problem.

One of the attendees brought the point home. “We call ours a CACA system” he said, “since we often implement Corrective Action upon Corrective Action (CA, CA…) to address recurring issues.”  This is an example of the industry’s focus on the “Corrective” rather that the “Preventive” aspects of CAPA.

Moving to a proactive approach to quality requires a paradigm shift. It requires driving toward zero Corrective Actions by increasing Preventive Actions. You don’t have to fix it if it didn’t break.

So what does it take for this shift from CACA to CAPA and ultimately PACA?

• Cultural change from “Testing Quality Out” to “Building Quality In”
• Shift in organizational structures from silos to seamless
• Meaningful understanding of people, product and process characteristics
• Control of “critical to quality” product and process parameters
• Mash up of fragmented systems to gain visibility across the enterprise
• Distillation of actionable facts from ineffectual data 
• Root cause analysis based on all available and relevant data
• Intelligence and Pattern Recognition tools to identify trends before they become problems
• Fully integrated platforms to keep pace in the Age of Continuous Innovation