Lowest Number of FDA Inspections Since 2008

FDAzilla has reported that the FDA conducted 39,774 inspections for the year ending 2013.

I guess on any given day, there are at least 109 auditing teams running around the world inspecting our GMP-regulated existence.

But it turns out that 39,774 inspections is a 5-year low for the FDA.  As FDAzilla puts it, this is the first time since 2008 that the FDA has dipped under 40,000 inspections per year.

Was it the government shutdown?  Was it the sequester?  Who knows?

As we ramp into prime inspection season (Q1/Q2 are known times when there's a lot of FDA activity), how are you guarding against getting dinged by the FDA?

• Inspect the (FDA) Inspector
• FDAzilla offer for Zymergi blog readers
• Buy 483 documents

FDA Is Conducting Fewer Inspections (Yayyy!)

by Oliver Yu

Zymergi's customers include large-scale biologics manufacturers: biotech companies that use cell culture or fermentation to make medicines. In the United States, biologics manufacturers are subject to regulations under Title 21 of the code of federal regulations, which authorizes the U.S. Food and Drug Administration (FDA) to inspect facilities.

Few take FDA inspections more seriously that biotech/pharma companies. Inspections are the path to facility shutdowns. Inspections lead to 483s. 483s lead to warning letters. Warning letters lead to consent decrees.

See FDA Inspections Funnel.

There appears to be relief for those in the regulated markets.  Data collected by FDAzilla (a Zymergi software licensee) shows that the FDA is conducting fewer inspections.  The number of inspections started declining in Q3 2012 and bottomed out in Q2ish 2013.
In fact, the FDA has conducted fewer inspections in 2013 than in any period in the 4-years prior.

It's not clear if biologics manufacturers have benefitted.  Just because the FDA is conducting fewer inspections does not mean that this decrease is impacting all areas (e.g. Food, Cosmetics, Tobacco, Drugs, Biologics, Devices...etc.) evenly.

Also, this decline in inspections appears to have little to do with the recent federal government shutdown:


That last bar (circled in red) is the shutdown.

Non-Essential FDA Inspections to Resume!

News reports indicate that the government shutdown is over.  "Non-essential" federal employees that were furloughed included FDA inspectors (euphemistically called, "Consumer Safety Officers").

Apparently, even the government admits that FDA inspections are... non-essential.

Regardless, I'm quite certain that the effect on the GMP operations around the world was that of pure joy. Inspection Readiness Teams could relax a bit.  Regulatory Affairs and QA managers didn't have to be on high alert (especially ones that hadn't been inspected in a while).

FDAzilla reports a significant drop in sales of 483 documents as RegA and Quality managers had no reason for last-minute research on the inspector that didn't show up (but will still collect backpay).

But now that paid vacation the furlough for FDA inspectors is over, it's time for the GMP community to get back on their toes and maintain inspection readiness.

Good luck.

Pareto Principle at work in Biotech

In the latest FDAzilla post, guest blogger and regulatory professional - Greg Hattoy - talks about 5 ways to prepare for a regulatory audit.

The first idea is that small things can build into big things and that management needs to have a pulse on what's going on. It isn't so much that there's something small out there that's wrong with your plant (like rust on the bottom of the fermentor) that that it becomes big (like your fermentor gets a hole in the bottom of it from the rust).

I've seen this in action where immediate- and short-term fixes are executed in a way that causes long-term maintenance chores. For example:

• The intended design of post-inoculation additions was among the suspect causes of bioreactor contamination.
• In the name of mitigating this potential risk via process of elimination, post-inoc additions were changed away from the intended design.
• True cause of microbial contamination was later deemed to be something else.
• Due to "don't fix what ain't broke" and heavy workload, the modified additions were never changed back.

You get enough of these decisions and a well-engineered plant encumbers itself and slips farther away from good engineering practices.

His second idea is that there are "Big Wins." This is absolutely consistent with the Pareto Principle where 80% of the effects can be explained by 20% of the causes, and though Greg states that it my fly in the face of the "small things add up" thesis, it actually doesn't. Here's why:

Every biotech professional from worker bee on up to the top of management has their list of 100 to-do's. Everybody is loaded down and their email inbox just looks like a constant scroll.

There actually aren't 100 different problems that need to be solved. It's actually something like 12 real problems. The majority of the effect/response (80%) is caused by a minority of the causes/factors (20%).

There are people who tackle this list according to priority: #1...done. #2...done. #3....done. And by the end of the day, the top 10 items get subtracted off the list (and another 10 get added).

Then, there are people who look at the list and go, "Gosh, #3, #7, #13, #49, #62, #85 are all related. If I spend time tackling the true root cause, I can hit six birds with one stone!" And when you go about solving problems in this manner, you can use the Pareto principle in your favor:

You can solve 80% of your problems by fixing 20% of what's wrong.

Obviously, there are times when you need to tackle the list sequentially. But this ought to be a minority of the time compared to tackling your to-do list strategically.

Critics of the sensible approach say that walking away from regulatory inspections has more to do with the personality of the inspector.  For that, there are ways of gathering regulatory intelligence.   But for the rest of us, following defensible plan is the most sensible approach for preparing for a regulatory audit.

It's True: FDA Inspectors Judge Books by Covers

It's 483 month over at FDAzilla.com and strategy #5 for avoiding dreaded inspectional observations is:

Don't Neglect Your Physical Plant

While it seems like a no-brainer to maintain the physical plant (i.e. perform work orders and change orders to keep the facility performing), judging the physical plant by appearance is a bit superficial.

FDAzilla writes:

One former compliance official used a simple test to get a sense of how seriously companies took having a clean operation: he’d walk into the men’s room and check it out. “If it isn’t clean in there, how can you be making a good product?” the official says.

Does a dirty men's room mean that an entire facility - whose validated environmental monitoring, bioburden levels do not exceed alert or action limits - is also not clean?  It's one thing to conclude that the factory is out of control by looking at the data within validated systems; it's quite another to be judging from the bathrooms.

Sadly our experience comports with FDAzilla's reporting: that FDA inspectors judge books by their covers.

As the saying goes, "neatness counts," and neatness in the GMP world can help sweep a lot of real GMP problems under the rug.

I know of a plant that would go and paint the handrails in the stairwells every time a contingent of regulatory inspectors arrive.  Handrails that get scratched by the button on the gowns operators wear are scratched up all year long, but as soon as an FDA inspector arrives, you have people out there painting it.

This isn't new to me.  Cornell University would have all kinds of construction: orange nets, backhoes, jackhammer noises all year long, but as soon as it was commencement week and the alumni and parents showed up, all the equipment would get packed up and it'd look just like their college brochure.

Biologics manufacturer knows that neatness counts; and they attend to superficial details because neatness can help them avoid 483 inspectional observations.

FDA's Metadata is Public. FOIA through 3rd-Parties.

A month ago, former-NSA-employee turned whistleblower: Ed Snowden, revealed far-reaching surveillance capabilities of the National Security Agency, specifically: metadata collection.

What is Metadata?

Metadata refers to data about the data.

Sort of weird to refer to something that way, but here's a simple example:


In fact, our OSI PI historian search engine: ZOOMS stands for Zymergi Object-Oriented Metadata Search.

• The data itself is time-series data.  
• The metadata is all the information that describes it:
  "V7410 pH" is metadata that our search engine archives.

What the US federal courts are saying is that the data (content of phone calls, content of emails) is protected by the 4th Amendment; but that the metadata (sender, receiver, time of call, duration of call, etc.) is not and therefore available for archival by the NSA for "fighting terrorists."

What does this have to do with biotech manufacturing?

Well, our market is regulated by a federal agency called the FDA, and when you contact them up to request information (called an FOIA request "Freedom of Information Act"), they don't just serve up the documents, charge you and be on your respective ways:

Your FOIA request is logged in a database and your FOIA request can be requested like any other FDA document.

This means:

Your business dealings as they pertain to the FDA are as public as your personal life is to the NSA.

• If you think Amgen wants to buy Onyx but you don't have access to insider information?  Send an FOIA to the FDA asking for all recent documents requested by Amgen.  If Amgen is doing due diligence on the deal, they may leave a trail there.
• If you thought Allergan was going to buy MAP Pharmaceuticals and wanted to test your hypothesis, send an FOIA to request the Allergan metadata.

If you're requesting actual documents, the data will be redacted; however, the log of the requests (the metadata) is public and available in sans redaction.

This is why our customer, FDAzilla, built the world's largest 483 store.  When you buy 483s from FDAzilla, you get the product without having to give up who you are and therefore business information you'd rather not have shared.

And if you're interested in more than just 483s, they have a compliance monitoring service that's built to suit your needs.

by Oliver Yu

Once you purchase through FDAzilla, it is true that they now have a record of your information; but the difference is that they are not compelled by law to share it to the public as the FDA is through the Freedom of Information Act.

On top of anonymously getting information, you also get it instantly...(which we all know from FDA FOIA experience, isn't necessarily on your timeline).

Public Service Announcement: FDAzilla rolls out InspectorRank

What's the first thing that happens when an FDA inspector shows up in your lobby?

by Oliver Yu

Personally, I don't know since I'm not usually hanging out in the lobby...

But when I was a cGMP citizen and I had to carry around a pager (smart phone these days)... everyone's pager goes off saying that "the FDA has arrived."

The element of surprise evaporates within 5-minutes of an FDA inspector showing up at your doorstep.

A conference room gets prepped to host the inspectors... A "war room" gets prepped as a proving ground for QA to review presenter talking points.

Good RegA departments will have intelligence on the inspectors already. Smaller outfits will do their research right then and there.

And a good website to go to is FDAzilla's InspectorRank pages. For example, when researching the FDA investigator for the Rhode Island bioreactor contamination, Megan Haggerty came up in the 483.

The InspectorRank page has her email, phone number and tells me right off the bat that she's based in Massachusetts, has audited 105 facilities since 2008 and inspects with a diverse group of peers.



Her historical 483 issue rate is 77%, so if Megan shows up at your door... you're probably going to get a 483 (yes, I know, this isn't a univariate problem).

Farther down, you'll see firms inspected in the past year. So for Megan... that's Amgen, AstraZeneca, Biogen, Genzyme, Alexion, Boehringer, Abbot... etc.


These are all the major biologics manufacturers, so if you're a biotech company, chances are... you're not going to be able to snow Megan.

One beef is that this data seems to be refreshed monthly, so it can be a little stale.

And as previously mentioned, you can even go and purchase select 483 documents that the inspector has issued.

If you have armies of Regulatory Affairs and Quality-folk on it, you're probably fine.  If you're a small- to medium- sized outfit, this may be a good resource for you.

Disclosure: FDAzilla licenses Zymergi software

Rising Trends With FDA 483s

by Oliver Yu

Manufacturing Quality Assurance and Regulatory Affairs professionals are no longer the only people spying FDA Form 483s.

In their latest blog post, FDAzilla reveals a rising trend that hedge funds, law firms and reporters are requesting these documents at greater frequency:

http://blog.fdazilla.com/2013/01/4-trends-the-rise-of-the-fda-483/

Other 483 posts:

• Using 483s to Your Advantage
• FDAzilla's 483 Store (Buy docs here)
• LeanBiotech's Biotech Pharma Manufacturing Directory

Use #FDA 483s to Your Advantage

If you have a minute...



One thousand FDA Form 483s are in the FDAzilla 483 Store.

As they say, "A smart man learns from his mistakes.  A wise man learns from others' mistakes."

Disclosure: Zymergi LLC receives nothing from FDAzilla sales.  They are a licensee of our software and we think they add signifcant value to commercial cell culture.

CGMP.CO (without the M)

Anyone that engage(s) in the manufacture, preparation, propagation, compounding, or processing of a drug or drugs shall register and submit a list of every drug in commercial distribution [to the FDA]

The above statement is the text of 21 CFR section 207 and appears to be the way the FDA gets a list of all drug facilities they need to inspect.  Incidentally, the FDA provides a way to search that here.

Search for Lonza Biologics:



and you get this:



Whoop-dee-do.

Now check this out.  Here's the same query over at cGMP.co:

http://cgmp.co/biotechpharma/directory/search?q=lonza+biologics

Click into the Hopkinton, MA result and you see wayyyyy more information:




Quite frankly, you can cross-reference the address with Google Maps to get a picture of where this place is.

You can cross-reference this facility with the list of FDA inspections that happened there.  Perhaps a list of 483s or warning letters that was issued there.

You can see all the other facilities that are owned by Lonza as well as the other cGMP companies located in Hopkinton.

So what's this have to do with Zymergi?

Well, for one, this was built with our software: Zymergi SQL Tool.  We eat what we bake.

For two, I'm interested in finding more leads that I can turn into customers.

For three, I'm interested in owning web-properties that can help connect cell culture/fermentation/cGMP folks.

Let me know how I can improve it.

disclosure: cGMP.co is owned and operated by Zymergi LLC.

Free #FDA 483s Offer Is Over. But @FDAzilla Has Opened A 483 Store

Bad News.  The Free 483s Dropbox Folder Offer has ended.

Earlier this year, I found out that FDA483s.com was offering all of the FDA.gov's free 483s in an organized format in a Dropbox:

http://blog.zymergi.com/2012/03/all-fdagov-483s-for-free_6895.html

My biggest problem using these files was:

• Click through 7 separate pages to see what was free
• When you downloaded the file, it was some gibberish like ucm191924.pdf

So when FDAzilla went through and curated it all and put it in a Dropbox, I was really happy to get access.

Afterall, commercial cell culture that produces API in the US is regulated by the FDA and that means you are subject to FDA inspection... most of which my customers are.

Good News.  FDAzilla has opened a 483 store where you can purchase 483s cheaply, instantaneously and anonymously.

Tony tells me that qualifying purchase will grant you access to the Dropbox.

Dang @Novartis, 9 #FDA 483s Since 2009!? You Should Get With @fdazilla

I was reading this FiercePharmaManufacturing's Article on Novartis' CEO under a Regulatory Cloud.

So I got to thinking... how many FDA 483s are these guys getting?

It turns out, Novartis - across all their businesses has gotten at least nine 483s since 2009.

• 17 observations made at the Liverpool UK site in 2011
• 14 observations at the Emeryville site in 2010
• 8 observations at the Vacaville site in 2011 after 5 observations from 2009
• 5 observations at Suffern NY in 2010 after 4 observations from 2009
• 1 observation at Brea in 2011
• 13 observations issued in 2011 after 2 observations at Lincoln, NE in 2010 

As Eleanor Roosevelt once said, "Learn from the mistakes of others.  You can't live long enough to make them all yourself."

Fierce is doing a good job tracking Novartis' quality problems. I'm just letting you know how to get your hands on their 483s.

#FDA Inspector Just Showed Up... @fdazilla

It’s Friday. 8:30am. You’re looking forward to a long, nice weekend. Then, you get a call from one of your associates. An FDA inspector is waiting in the lobby. She’s unannounced, she’s experienced, she’s eager, and she’s ready to go.

Do you know the feeling?