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Industry: FDA Policies are Raising Threat of Drug Shortages

September 15, 2011 By Leave a Comment

Michael Causey, Editor & Publisher, eDataIntegrityReport.com

A sobering report from the American Society of Health-System Pharmacists (ASHP), the American Society of Anesthesiologists (ASA), the American Society of Clinical Oncology (ASCO), and the Institute for Safe Medication Practices (ISMP) highlights a serious and growing drug shortage problem in this country – and the FDA is one of the big problems, according to many in the drug industry.

“This is a national security and health risk conundrum,” says former FDA reviewer and now industry consultant (and fellow Assurx blogger) Patrick Stone.

“If the pill well runs dry on our seniors or high risk folks they may expire or degrade further in health,” Patrick worries. The FDA’s “GMP controls and tightly held batch quotas are a mess. QbD will add fuel to this fire by doubling the number of drugs that don’t make it to the shelves.”

A distressing article from Marginal Revolution raises further questions about why this is happening and FDA’s role in it. “Currently there are about 246 drugs that are in short supply, a record high. These shortages are not just a result of accident, error or unusual circumstance, the number of drugs in short supply has risen steadily since 2006. The shortages arise from a combination of systematic factors, among them the policies of the FDA.”

Stone’s take: “The FDA simply doesn’t understand how many drugs are impacted by its regulations.” He challenges the agency to track that, just as it tracks 483 violations and other issues.

Editor’s Note: Watch for a new Patrick Stone blog on this topic next week.

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Filed Under: FDA Regulated, Michael Causey, Pharma/Biotech Tagged With: , , , ,

Quality by Design (QbD) Pilot Presents Industry With New Challenges

September 7, 2011 By 2 Comments

Patrick Stone, President, TradeStone QA

What products will be affected by QbD? It will apply to new Marketing Authorization Applications (MAAs)/New Drug Applications (NDAs), Type II Variations/Prior-approval supplements (sNDA) and Scientific Advice requests/CMC formal meeting request that include QbD/PAT elements and are submitted to FDA & EU new applications, for MAAs/NDAs where the sponsor/applicant has agreed to a parallel evaluation by both agencies.

Upon request from the sponsor/applicant, and where procedural time-lines will allow, Type II Variations/NDAs may also be considered on a case by case basis. Right now this is a voluntary pilot with some pharma companies being tapped or nudged by FDA & EMA to join in.

Our geographically diverse health product market involves more contracting and outsourcing for many product components. Finished product real time testing and design space requirements will be crucial for implementing QbD.  ICH third party QA mandates will result from this pilot program.

QbD products will be as unique as the individuals who receive them (personalized medicine). This new model may impact two-thirds of the new health care products in the pipeline (cell therapies, gene therapies, and molecular entity therapy).   There will be many approaches to high order characterization and some are not cost effective at present.  Many of the details will take years to sort out. Collaborations between the FDA, Japan Ministry of Health, and  European Medicines agency will require funding along with mutual scientific trust.

Emerging technologies and laboratory techniques will be required to accomplish the QbD paradigm shift. FDA can’t continue using the chemistry approval model for biotechnology products.  This paradigm shift may increase development times and cost structures.  The ICH model will also bring mandatory third party QA review so prepare your models for this as well.

Here are the essential points to focus on for QbD products:

  1. Target the product profile,
  2. Determine CQAs (Critical Quality Attributes),
  3. Link raw material attributes and process parameters to CQAs,
  4. Risk assessment,
  5. Develop a design space,
  6. Design and implement a control strategy.

Generic Drug TabletThe biotechnology sector QbD product development focus will be on design space and real time release testing. The pilot discussion focus for both regulatory agencies will be on ensuring consistent implementation of ICH Q8, Q9, and Q10 guidelines in the assessment process and to facilitate sharing of regulatory discretion & new regulatory concepts manufacturers of small-molecule generic drugs have concerns the initial lag-time in course correcting for the QbD initiative may exponentially delay the application file time for their products.

It appears some generic-drug manufacturers are not willing to implement any QbD concepts until closer to final harmonization and discussion time frames.

Why do you need higher order structure modeling?  Higher order structure product applicants will have to provide protein folding kinetics models with characterization integration into the application and annual report.  Your research models and early development modeling may be progressed for this function. Personalized medicine with batch to batch consistency including stability of 1-90 days is recommended. There are also talking points about including variants and aggregates of your products in the higher order structure models.  Intra and inter chain disulfide bonding, aggregation, and complete polypeptide modeling may be requested application material.

This may prove to be more cost effective while two juggernauts (FDA & EMA) iron out the red tape that will flow from this type of global initiative.  If the funds necessary to make this effort progress are not available on the FDA or EMA, side delays in the process are inevitable.

Molecular and personalized medicine can’t continue to be reviewed with the FDA chemical entity systems approach, approval model.   Effective cancer therapies and molecular medicine may not have the statistical significance necessary when only a handful of patients are treated with the cell or gene therapy.

Warning to Industry: FDA will obviously not let you have your cake and eat it too.  Innovate inevitable change by comments to FDA or accept the QbD change that is inevitable.   Your comments to the FDA will be monitored on the FDA’s Facebook page and current open comment requests. Contact your respective FDA liaison or center contact for discussion points directly related to your product.

Patrick Stone is the author of Bubble Gum Badge – An FDA His-Story. You can also follow him on Twitter.

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Filed Under: FDA Regulated, Patrick Stone, Pharma/Biotech, Quality Management, Regulatory, Risk Management Tagged With: , , , ,

Protect Your Firm as FDA Inspections Spike for CROs, Sponsors

May 24, 2011 By 2 Comments

Patrick Stone, President, TradeStone QA

During the last two years of my time with FDA I noticed the amount of Sponsor and CRO inspections triple in number (for CDER, CDRH, & CBER).  CRO’s with less than adequately trained clinic staff and facilities to conduct human clinical trials are receiving warning letters and other FDA regulatory penalties.  The FDA has not conducted enhanced Sponsor or CRO Inspections in many years.  I have observed study sites get warning letters because monitors did not catch informed consent violations early in the trial or for other regulatory and subject record keeping violations.  Catching serious problems early in the trial can prevent adverse events, save time and assets in the long run.

Clinical Investigators and Sponsors  do not want to throw study data out due to preventable errors and inconsistent data.  Monitors for CRO’s and Sponsors should be proficient at the Quality Assurance (QA) they provide and be given adequate time at the study site to ensure regulatory and protocol compliance.

In my time at the FDA, even up to the end of my tenure this past March, I have observed CRO’s collecting original source site documentation from the clinic site at study close-out. I wonder how CRO’s seem to keep missing the basic reason FDA investigator’s conduct data-validation audits.  FDA wants to validate that source documentation match the case report form (CRF) and the sponsor provided data-listing with efficacy end points & adverse event lists.  CRO’s can easily scan the original documents into their system, but physically removing the source documents has conditions.

If a CRO truly wants the original documents for whatever reason, the CRO may certify each copy as a true duplicate of the original (21 CFR describes this process).  In many cases the Clinical Investigator relocates or there is no available space and money to store the records so the sponsor may step in to take over.  There’s not going to be any problem as  long as the FDA can follow the paper trail and review original documents as needed.   Copies may and have been found to be falsified so Investigators will not review paper copies of paper source records.  Electronic printout (output) is a different way to operate now and is acceptable for review.  Sponsors & CRO’s are using more electronic case report forms CRF’s & electronic records in general.  FDA is now requiring field Investigators to review computer systems for 21 CFR part 11 compliance & legacy system maintenance.

Do a search for your competitors’ recent FDA inspections and you will see the trend I am describing.  Build quality into your system from the ground up and you will get quality product results.  Trying to retroactively validate electronic systems and equipment or implement late stage corrections will leave you vulnerable to 483 observations.

You can follow Patrick on Twitter.

 

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Filed Under: FDA Regulated, Medical Devices, Patrick Stone, Pharma/Biotech, Regulatory Tagged With: , , , , ,

Institutional Review Boards Contend with FDA, OHRP

May 9, 2011 By Leave a Comment

Patrick Stone, President, TradeStone QA

I have noticed some concern from many IRBs about the GAO & OHRP difference of opinion regarding some aspects of human subject testing. If accreditation is ever fully pulled from an IRB, the reasons will be stated by FDA or OHRP. Through my review of many types of IRBs large and small (central & institutional) I have noted a few trends.

Central IRBs have two fundamental issues to deal with: quality assurance (QA) at the study site, and having a local representative of the community where studies are being conducted present at IRB meetings.

FDA & OHRP are now expecting IRBs to conduct QA audits as is done with most institutional IRBs. If the central IRBs can do a bit more with the funds they receive for service, they will survive this transition. The IRB’s basic functions are to insure patient safety & rights and assure clinical trials are following the CFR (all applicable sections).

In the end, the most basic function of an IRB is patient advocacy & record retention of patient safety discussions (for verification of review). Institutional IRBs in some cases do not scrutinize the in-house clinical trials adequately. In-house clinical trials do not get monitored as frequently due to lack of funds.

The institutional IRB’s should insure the name of the parent company/institution is tied to CFR compliant clinical trials, or the brand may be effected.

But I have a question for IRBs using electronic records: are you ready for the FDA investigator to challenge your 21 CFR Part 11 electronic record compliance? I have observed many large IRB’s staying in the paper records format. Due to cost & physical space issues, electronic is now the obvious way to go.

IRBs are getting more ICH audits and vendor qualifications which help IRBs stay in compliance with ICH guidance and the FDA regulations. FDA needs IRBs in good standing to review the many studies FDA field Investigators will not be able to Inspect. IRB’s play a major part in regulating clinical trials.

When I was with the FDA I always tried to encourage the IRB’s after a 483 was issued to do more for the patients and to effect real change in the amount of studies audited for QA. The FDA cannot get to every study or even thirty percent of the on-going clinical trials combined (biologics, drugs, & devices).

You, IRBs, do the heavy lifting for domestic clinical trial regulatory compliance. Thanks for the hard work.

You can follow Patrick on Twitter here.

 

 

 

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Filed Under: FDA Regulated, Patrick Stone, Regulatory, Warning Letters/Recalls Tagged With: , , , , ,

FDA’s Electronic Record Review Enforcement Policies Present Challenges

April 26, 2011 By 2 Comments

Patrick Stone, President, TradeStone QA

In 1999 the FDA released guidance for industry on the electronic records requirements for human clinical trials involving drugs, devices & biological entities (including the manufacturing of the approved products previously listed). In 2002 the FDA started training the field investigators how to review electronic records during routine inspections of human bioresearch and manufacturing for drugs, devices & biological entities. The catch was FDA investigators were not able to actually cite violations for 21 CFR Part 11 (code of Federal regulations) until approximately 2006.

The FDA instructed field investigators to only write up 21 CFR Part 11 violations if there were other non-Part 11 violations as well. One of the reasons it took so long to enforce the 21 CFR Part 11 violations was that fact that TurboEIR (FDAs report writing template system) did not have 21 CFR Part 11 483 cites. TurboEIR 483 citations became standardized because of the inconsistencies of 483s issued throughout the nation.

Fast forward to 2009 and the FDA starts to ramp up electronic record review for every firm that uses electronic records.

As an FDA investigator I have conducted many electronic record reviews and discussed many 483 cited observations with the Center for Drug Evaluation & Research and the Center for Devices and Radiological Health.

The most recent inspection I conducted for electronic records was a molecular diagnostic laboratory conducting testing for human clinical trials. This was a very special case in which I observed the clinical trial data did not match the data-listing provided by the sponsor. Long story short, the firm was using a data-stick to transfer original data-output and transferring it to an Excel data-set. Microsoft Excel® is not 21 CFR Part 11 compliant and the Excel® program cut off too many digits after the decimal place. The solution was an easy fix in that I suggested the molecular lab simply print out the original data and use that instead of the data-stick transferred data.

The Center put a short hold on the project until the reems of paper could be submitted in proper fashion.

The moral of the story is that as a sponsor or health care manufacturer you have to ensure that any projects slated for all electronic record submissions must be qualified and verified to comply with the electronic record regulation.

I will also give you one more example of a scenario where a project was held up by the agency for electronic record issues. I was inspecting a human clinical drug trial and I observed that source data did not match the sponsor provided data-listing because when the study was closed out and the data-lock was put in place it changed the audit trials and greyed out many data-points.

When choosing an electronic records vendor make sure that the data is never obscured or unreadable when the clinical trial is completed and data-lock is in place. You have to go from cradle to grave with your data and validate every step.

The FDA has made numerous electronic records exemptions for the Department of Defense and other U.S. Government agencies under the following exemption law (device products). A Compilation of Exemptions for Electronic Products Found in 21 CFR Chapter I, Sub-Chapter J — Radiological Health Parts 1000 – 1050.

However, the FDA does not currently abide by the electronic records regulation it enforces, for another case of do what I say, not what I do.

You can follow Patrick on Twitter: http://twitter.com/BIMOQA

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Filed Under: FDA Regulated, Medical Devices, Patrick Stone, Pharma/Biotech, Regulatory, Warning Letters/Recalls Tagged With: , , , , , , ,

What to Expect When the FDA Comes Calling

April 20, 2011 By 1 Comment

Patrick Stone, President, TradeStone QA

Enduring data validation audits and for-cause audits for human clinical trials involving biologicals, devices, or new chemical drugs may at first remind some of going to the dentist to get your wisdom teeth pulled.

But, the FDA has just as much at stake as your company does in the products marketed in the U.S., because if there is a problem or unsafe conditions FDA gets blamed for not doing enough.  That’s top of mind for most inspectors and important for regulated entities to remember.

With that in mind, let’s examine industry trends for these types of inspections.

Lets start by what Consumer Safety Officers (CSOs) look at first.  The regulatory binder is a road map of what happened during the clinical trial.  The IRB approvals, FDA approval documentation, and protocol versions are reviewed and recorded for the report.  The monitor reports and frequency of visits directly corresponds to the amount of observations FDA CSOs finds. So far, so good.

The areas most scrutinized for review are the protocol deviations & violations and adverse event reporting.  If a serious adverse event was not reported or not reported per protocol, you’d better expect a 483.  Failure to follow the IRB approved protocol version is the most cited 483 observation.

How does this keep happening over and over again? Easy: research clinic turn-over, lack of training on updated protocol or study procedures and the lack of monitoring.  The FDA is now requiring 100% consent form review of all subjects.  Failure to obtain informed consent with IRB approved document is the second most cited 483 item.

The third and most documented for clinical research 483 items is lack of complete or inaccurate source documentation.  The FDA is now requesting CSOs to audit the firm electronic systems and record any deficiencies on a 483.  The electronic records evolution started in 1999 and the FDA is now catching up and training CSOs to find your Part 11 computer system shortfalls and deficiencies.  Here, the FDA is turning to the ICH model as a bridge to the European Medicines Agency counterpart inspectorate.

The EMA model requires third party QA for every research trial which has proven to cut down on regulatory deficiencies.  In my opinion having that third set of QA eyes is all the difference between no action indicated (NAI) &  voluntary action indicated (VAI) from official action indicated (OAI) and a project hold.

Editor’s note: This is the the first in a series from our new blogger, Patrick Stone, M.S.  Patrick left the FDA in March 2011 after 12 years as a Biosresearch monitor at the agency’s Austin, TX office. He’s now President of TradeStone QA. While with the FDA, Patrick conducted domestic and international inspections of clinical investigators for pre-approval of pharmaceutical drugs, pharmaceutical drug manufacturing plants and domestic Institutional Review Board investigations.

As Stone recently told us, “I have worked closely with all departments (except foods CFSAN) CDER CBER CDRH and CVM. My work has gone through all of those department heads, too. I have 13 warning letters, one NDA revocation, and countless 483’s. I completed on average of 24 BIMO (clinical trial) audits every year since 2001 when I started conducting audits solo. It is my hope to bring some of that experience to readers of this blog.”

You can follow Patrick on Twitter: http://twitter.com/BIMOQA

 

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Filed Under: FDA Regulated, Patrick Stone, Pharma/Biotech, Warning Letters/Recalls Tagged With: , , ,

Outgoing FDA Inspector Advises Patience with New Faces

March 29, 2011 By 2 Comments

Michael Causey, Editor & Publisher, eDataIntegrityReport.com

After 12 years and some 300 inspections Patrick Stone, outgoing Consumer Safety Officer and Investigator at the FDA’s Austin office, says the large influx of new inspectors is going to take some time to come up to speed. Most inspectors need about five years of training before they have a solid foundation, Stone says.

His advice for medical device companies and others who face FDA inspections from one of the Young Guns? “Patience.”

As we’ve blogged before, the FDA has suffered from something of a brain drain in the past several years, where some of the more experienced personnel left for greener pastures because they were tired of budget cuts, politics and other issues many felt hampered the agency’s ability to do its job of protecting the public while encouraging innovation. Stone, who left the agency March 25, estimated he’d helped hire and train about 200 new employees in his Texas, Oklahoma and Arkansas territory over the past several years.

Stone says it’s not particularly wise to ask your inspector how much experience they have, but it’s basic common sense that “if they are young and fresh-faced, they probably don’t have much yet,” he advises. In those cases, it behooves you to gently educate them without getting condescending about it.

He says these inspectors will focus like laser beams on any changes in your procedures, even ones you genuinely believe are unimportant. “They want to see changes and failures, to see what went wrong and how you investigated it,” Stone says.

“Be proactive with the agency” in this area, he advises, and you’ll earn a lot of street cred. “Account for changes beforehand even if they are seemingly benign.” The new crop of inspectors is particularly focused on “transparency,” and if they feel you are being open with them, you’re chances of having a relatively smooth inspection are a lot better, Stone says.

Stone has specialized in IRB compliance & QA audits and cell & gene therapy development and implementation, and helped many IRB’s and gene therapy labs comply with FDA regulations, 21 CFR, GCP, & ICH compliance. He’s setting up his own independent consulting shop in the coming weeks.

Stone also applauded the FDA’s recent efforts to centralize more of its operations in its White Oak, MD headquarters. It will take some time, but he believes that effort will eventually make the inspection process more uniform nationwide. “It will help them to be on the same page” with inspections, and that will be helpful to regulated companies who have complained of inconsistency in the past.

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Filed Under: FDA Regulated, Michael Causey Tagged With: , , , ,

How Risky is Risk for FDA-Regulated Life Sciences Companies?

January 19, 2011 By 1 Comment

Russ King, Managing Partner, Methodsense

The simple word “Risk” is certainly one of the most frequently used terms in the contemporary Compliance Lexicon. It has become a cliché to say that the FDA advocates a “risk based approach.” Risk Management, Risk Assessment and Risk Mitigation are staples on the menus of virtually every life science conference and exhibition. Life Science publications behave similarly and as a case in point the tag line of the AssurX Blog site is “Compliance, quality and risk: Straight talk for regulated industries” (emphasis mine).

But what the heck is “risk”? Should the very nature of “risk” in and of itself really matter to life science companies on a level beyond scenarios of potential harm, SOP creation and record generation?

First, the (sophomoric) exercise of reviewing alternative definitions of risk to get us started:

  • risk = an unwanted event which may or may not occur.
  • risk = the cause of an unwanted event which may or may not occur.
  • risk = the probability of an unwanted event which may or may not occur.
  • risk = the statistical expectation value of an unwanted event which may or may not occur.
  • risk = the fact that a decision is made under conditions of known probabilities (“decision under risk” as opposed to “decision under uncertainty”)

All of these definitions, as well as others, have a couple of things in common: risk involves unwanted consequences and uncertainty. Obvious, right? (Remember this was a sophomoric exercise). Nevertheless, it is interesting to note that unwanted consequences and uncertainty are something we humans tend to fear and hate. Uncertainty is also generally unpopular with humans.

Now consider this within the context of a medical device, pharmaceutical or biotechnology company. Among the passions driving life science companies is scientific knowledge (humans love knowing) and the practical execution of knowledge on behalf of at least two other passions: improving the length and quality of our lives (something humans generally endorse on a wholesale basis) and economic success (a value that is a tad more controversial, but still generally endorsed by most of us). Not surprisingly, these two values are intimately connected: if a life science company can successfully improve our lives, we tend to be willing to pay for it.

Recall now that element of risk called ‘uncertainty’. Uncertainty seems to be diametrically opposed to knowledge, a core value of a science based endeavor. Uncertainty seems at cross purposes to the other passions of life science companies. There is nothing like the uncertainty about the performance of devices or drugs to keep them out of the market or drive buyers away. (But isn’t that the way things should work?)

How a life science company responds to uncertainty will tell you a lot. We have seen fear, fearlessness, dissembling behavior, aggressive truth seeking….you name it and everything in between.

Uncertainty has the powerful ability to threaten everything built by the driving passions of a life science company from market share to profitability. No wonder the reactions to uncertainty vary so greatly from organization to organization. But there is something special about uncertainty and the advocacy of a risk based approach that should be strongly embraced by life science companies.

Confronting and overcoming uncertainty means that at a level much deeper than SOPs and Quality Records we gain knowledge, the very kind of knowledge that fuels the passions of contributing to our welfare and success. Assessing and understanding risk, managing risk and mitigating risk accomplishes this by delivering a better understanding of a company’s products, their manufacture, new products, better operations, etc. which invariably creates greater opportunities to improve our lives and enhance our wealth.

Yes, peeling back the veil of uncertainty can reveal the possibility or even the probability of unwanted consequences. It is very difficult to keep the ‘bad’ out of everything. But the strength of successful life science companies comes from what they know, when they know it, and what they do with that knowledge. The more skillfully life science companies look for, root out, and drag risks into the appropriate (not just any) well lit forum, the more uncertainty is condemned to understanding. Consequently, the opportunity to forestall the possibility or reduce the probability of unwanted consequences improves dramatically.

In other words, risk is a lot more risky if you take the risk of not facing it.

Russ King is Managing Partner at MethodSense, Inc.

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Filed Under: FDA Regulated, Medical Devices, Pharma/Biotech, Regulatory, Risk Management Tagged With: , , ,

Need for Change Control Never Changes

April 5, 2010 By 2 Comments
Michael Causey, Editor & Publisher, eDataIntegrityReport.com

Michael Causey, Editor & Publisher, eDataIntegrityReport.com

They say that change is about the only constant in life (we’ll leave out death and taxes for the sake of this discussion).

And we all got an excellent reminder of that earlier this month when the FDA smacked Boston Scientific by saying the agency would not speed up the review of manufacturing changes required for Boston Scientific to resume selling its implantable heart defibrillators.

 As first reported by The Wall Street Journal, the medical-device maker recalled all seven brands of its defibrillators in March after having failed to receive FDA approval for the manufacturing changes. The company had earlier told physicians that it expected the review to take less time than the typical 30 days, according to the WSJ.

 Boston Scientific submitted the changes to the FDA for approval on March 15 and 16, according to an email sent by a Boston Scientific sales representative to a physician on March 17 that was reviewed by WSJ.

What’s at the core of Boston Scientifics’ problem here? Well, at least part of it is change control failures. As noted in the Journal report, “The Natick, Mass., company’s failure to report the manufacturing changes to the FDA was the latest in a string of problems in following reporting requirements. The FDA is investigating the company’s failure in this recent case as well as past lapses,” an FDA official said.

But Boston Scientific is by no means the only company out there with a shaky hand on change controls. If you are reading this blog and your gut is starting to churn a little, you know who you are.

It may be time to review your change control program, right?

We thought it might help a little to review exactly what change control is, while we’re at it.

Good old Wikipedia defines change control within Quality management systems (QMS) and Information Technology (IT) systems as “a formal process used to ensure that changes to a product or system are introduced in a controlled and coordinated manner. It reduces the possibility that unnecessary changes will be introduced to a system without forethought, introducing faults into the system or undoing changes made by other users of software. The goals of a change control procedure usually include minimal disruption to services, reduction in back-out activities, and cost-effective utilization of resources involved in implementing change.”

And that’s a great definition — as far as it goes. What it leaves out is what can go wrong when change control isn’t handled properly.

But we already know what the consequences are when change control isn’t properly managed, don’t we?

ADDITIONAL RESOURCES

For more on the FDA’s change control requirements, go here:

Boston Scientific sees it all a little bit differently. In a March 18 release the company notes that the FDA did recommend approval of an expanded indication of its heart medical devices. However, Boston Scientific has thus far declined to address the FDA’s decision not to review it more quickly.

AssurX will host a complimentary webinar on this important topic April 8, 2010 at 10am PDT. Click here to register.

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Filed Under: FDA Regulated, Michael Causey, Quality Management, Regulatory Tagged With: , , , , , ,

FDA Lifts Curtain on Inspection Process, Rationale

March 25, 2010 By 2 Comments
Michael Causey, Editor & Publisher, eDataIntegrityReport.com

Michael Causey, Editor & Publisher, eDataIntegrityReport.com

Gotta give the FDA some credit here. In addition to its transparency initiative we’ve talk about before, the agency is also trying to remove some of the mystery about how it handles inspections and other inner workings at the FDA. From where I sit, it appears to be a sincere effort and I believe it is helping outsiders better understand what the FDA is trying to do – and how it is trying to do it.

For example, at the second in a new series of monthly online webinars, FDA’s Michael C. Rogers, deputy director, Office of Regional Operations, said today (March 25, 2010)  tried to outline how an FDA inspection tends to work, and what drives inspectors before, during and after an inspection.

As an aside, Rogers also said that the agency currently has about 1,800 total inspectors across its full portfolio, though food gets the bulk of the bodies. He also said there will be more foreign inspections this year, and that the number should continue to grow.

Inspections are based on risk, Rogers said. In other words, the riskier the potential drug, device or food item, the more likely they will be inspected.

Most inspections are unannounced, Rogers said. Before they go on-site, the inspector on inspection team will look at previous inspection reports and identify what corrective actions were promised during prior inspections. They also prepare inspection tool kits with sampling equipment, info to drive inspection based on guidance documents and the Investigation Operations Manual. They also carry a camera to document evidence.

They also conduct “for cause” inspections driven by consumer complaints or other outside activity.

Typically, the inspection begins with a discussion with management to explain the purpose of the inspection, and they try to learn about the corporate structure and any changes made since last inspection. They also ask about complaints, positive tests or returns. Answers to those questions help FDA inspectors focus their on-site efforts.

Next, they go to the physical manufacturing area. They try to observe and understand the on-site process. They ask about acceptance criteria and want specifics on failures, especially the reasons.

Inspectors also draw a diagram of the facility showing the manufacturing process from start to finish. They’re looking for problems in the system and looking to identify critical control points in the manufacturing process.

FDA inspectors then identify procedures in place and assess if company is actually following them. They also look for controls in place to mitigate any contaminated products.

They also look at training and cleaning programs. They also watch employees while they are actually making the product.

If they find evidence of an adulterated product, they collect evidence based on inspector observations and collect samples to prepare their case for possible legal action in court.

At conclusion of inspection, the FDA team meets again with management. They then inform the top company official what is in the official Form 483. That form documents observations during the inspection but does not include final recommendations. They also ask for the firms corrective actions planned or in place to get into compliance.

These corrective actions are taken into account as agency formulates official recommendations.

After the inspection at the firm, the inspector develops a report back at the home office. It includes evidence collected and what the firm has already agreed to do about any shortcomings.

In some cases firms can offer voluntary corrections. But sometimes the agency decides it needs enforcement action such as a warning letter, and can also impose civil and/or monetary penalties.

The webinar was extremely popular. In fact, it “sold out” so many who tried to join it could not get in to the live event. There will be a recording available on Monday March 29.

UPDATE: Slides are now available from this event here in PDF format.

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Filed Under: FDA Regulated, Food, Medical Devices, Michael Causey, Pharma/Biotech, Regulatory, Risk Management, Uncategorized, Warning Letters/Recalls Tagged With: , , , , , , , ,
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