FDA’s Joe Famulare to a Risk-Averse Industry: There’s No Regulatory Impediment to Continuous Improvement and Modernization

For the cover story, we also interviewed FDA's Deputy Director of Enforcement, Mr. Joseph Famulare.  He says the Agency has seen a lot of improvement within the industry, and more adoption of modern manufacturing principles, although more improvement is needed.  In response to what we often hear from people in the industry---that concerns about revalidation prevent them from trying new technologies or concepts, he says that there is nothing in existing regulations to impede change and that GMPs are flexible enough to allow drug makers to try different approaches (for example, continuous manufacturing, process intensification).  In addition, Agency reviewers and inspectors have changed the way they approach validation, so the old concerns should no longer apply. 


Interview with Joseph Famulare, Deputy Director, Enforcement

PM “ Has the industry made progress so far in applying the advanced concepts behind 21st century GMPs---i.e., risk management and process understanding? Do you see a lot of room for improvement.  

JF - This is a continuum.  Youre not going to see an immediate switchover from conventional to more advanced ways of doing business, but weve been impressed by the application of some of our Quality Systems guidelines. Weve had some companies come to us and explain how theyve done it. Theyve already seen savings in the costs of manufacturing and more efficiencies, and can even show trends in areas such as less deviation follow up. Were encouraged by what were seeing so far.

PM “ What will be the key to changing the industrys motivation for improvement, so that patients are seen as the key driver rather than fear of regulatory agencies? 

JF “ Were trying to get industry to take, in its own hands, the control over quality, advancement of technology, science and continual improvement, so that it moves from a reactive to a proactive mode. Were hoping that, as firms invest more up front and learn about their quality systems over the life cycle of the product, that theyll be able to take this information, use it for themselves and improve themselves from a business perspective, to put them in a place where they can really help the patient, as Dr. Woodcock has said. 

PM “ Is there still a trust gap between industry and FDA?  Some companies are somewhat cynical about PAT or QbD being the latest flavor of the month from FDA.  Is that starting to change? 

JF “ I dont know if Id categorize it as cynicism, but it takes time to change, to communicate and establish trust.  And its not only a question of trust between industry and FDA, but trust within their own internal organizations and ways of doing things¦.how they deal with each other, between development, tech transfer, manufacturing and regulatory affairs.  Certain parties may not be communicating with each other, internally, as to what may best help them.  Some may be more conservative about making changes and communicating with FDA. 

¦By using our QS guideline, you should expect to have less interaction with FDA, once youve identified your critical factors and applied risk management principles. When this knowledge is evident during an FDA inspection, it should make that inspection quicker and much more focused.  And if youve done that work, your knowledge of your process or design space will be well known so you should not need to file additional regulatory submissions such as supplements. 

PM “ We sense some confusion about PAT and Quality by Design.  Does QbD imply that it's only for drug development? Isnt manufacturing all about Quality by Redesign, and how can you easily redesign your processes given current validation requirements and batch definition.  

JF “ First of all, cGMPS, in terms of validation and batch definition, are quite flexible.  A batch is defined as a period of time.  There is no impediment whatsoever to continuous manufacturing or real time release based on existing cGMP regulations parts 210 and 211


Regarding process validation, we have already changed our internal guideline for compliance policy, instructions to field staff, investigators and compliance officers, and its all available on the Web.  We need to get out of this three batch thinking for validation, because modern development, risk management and QS will put in place continuous quality verification methods.  Weve already unshackled that thinking in that guide that wed issued in 2003. Were further revising the guidance documents to reflect what were already saying.

PM “ Please recap progress and goals for risk-based Site selection program progress? 

JF The risk-based site selection program has run, in its current model, two or three complete years.  We have shared those risk factors that were looking at.  Of course, how we score things individually is internal to FDA, but what we see is a way to accomplish those inspections at those sites that really represent the most important risk factors to us in any given year.

We have enhanced the data were using to determine risk.  We use our adverse drug experience, drug quality reporting experience. This year, were also using our recall database.  There are other factors, too.   Facility size and type, whether its a manufacturer or a repackager, the last three district decisions, field alert reports, recalls and time since last inspection.


PM - Are you using a new IT platform to mine the data and help with all this?


 JF “ Its always a challenge to have all databases where you want them to be.  We used our existing databases, but added another program to bring them all together.  But data systems are never perfect and resources are limited.  So we did expert elicitation, interviewed expters to enhance the information that we get straight out of the databases.


PM “ What are you most proud of re: Inspectorate program?

JF “ Weve already seen the benefit of their knowledge and understanding in the inspection work that weve seen done, their participation in the office of new drug quality pilot,  some of the advanced things that weve seen there, their insights and input of investigators have been helpful, e.g., we forged ahead internationally in getting their input on ICH Q10  document.  A lot of interactions where pharma inspectorate folks have been helpful.


PM “ Is FDA part of the Global inspectorate program?

JF “ We've applied to join PICs.  To use their terminology we have applied for a session were in the process of explaining our system.   


PM “ Are all inspectors at FDA doing both food and pharma inspections? Or have you segregated the two different functions to any level?


JF -  If you refer back to the MOU, 85% of the PI groups program work will be pharmaceutical related.  Other folks will still do some mix of work.  I think that people are becoming more specialized, and pharma inspectorate is one example, team biologics is another, Level III ceritified trained inspectors in devices or food is another.  Theres a trend to more specialization among field force, overall, but theres still a need for some degree of flexibility, and some of the principles involved in food and pharma are the same. 


PM “ Some inspectors are now doing both preapproval and GMPs? What special education and background needed?


JF The group is a diverse group of people with scientific training with different degree levels and different scientific disciplines.  That has traditionally constituted the investigator background---the basic sciences.  Youll probably see more folks with engineering backgrounds now. 

Then a great deal of the training comes from the basic training that we already have.  We work with colleagues in ORA through the dvision of HR development¦.we have a series of pharma schools that have always been part and parcel of getting people certified to Level II. Our basic drug school, industrial sterilization, API¦.we have intensive internal training. 

Layered on top of that is the PI training, highly specialized technical training that we arrange in house through ORA-U.  That coupled with peoples basic scientific background and experience constitutes a very well trained workforce.


PM “ How will the Agency handle the backlog of inspections outside the U.S.?


JF -  In the short term, we use risk management principles to drive limited number of inspections that we can do oversees.  Were focused on pre-approval inspections. Long term, the ability to share info with other inspectorates will be helpful to enhance inspections that we can do.  Were hoping that will be one of the expected benefits of our involvement with PICS.


PM “ If PAT and more advanced process control were fully implemented by the drug industry, could remote plant inspections be possible in the future, via computer connections?  The very beginnings of such connections already exist for companies that outsource manufacturing or development to contract partners overseas and need to keep close tabs on what they're doing.   Do you envision a day when FDA inspectors could inspect some facilities remotely?


JF “ Its blue sky.  I could certainly see where some type of information exchange like that could take place in a number of different ways, in some cases, in the future.


PM  Are there any new ground rules for investigators when they are evaluating facilities with new technologies?

JF “ Principles are no different from those that are used for regular inspections.  We give them instructions through compliance programs, and training. And for more novel types of facilities or equipment or processes, the CDER Office of Compliance and ORA field inspection people who are part of OND QA pilot are getting involved in the beginning so that we look at it on the front end.


PM - How is the Agency's Dispute Resolution program shaping up?  When we'd last heard, only two companies had taken advantage of it.


JF “There haven't been many disputes, but there are many means to resolve any issues that come up. We're open to discussion, to opening lines of discussion¦.in terms of tech support, if company is at odds, local district management folks are very open to hearing out that issue.


This is only, let's say, an inclination rather than a full-blown trend, but we are noticing that, at some companies, there is more of a willingness to call up and find out and discuss through the issues, get the Center on the phone and work through things. 

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