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.

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?

#FDA Inspection Readiness: Inspect the Inspector @fdazilla

So get this.  That FDA 483 Store has this uber-awesome feature for inspection readiness:

You can inspect the inspector.

FDAzilla has a page for each of the 772 FDA inspectors involved in their 1,000 Form 483 Reports and cross-referenced two key pieces of information about them:

1. Which cGMP site they audited
2. Who else was with them when they conducted the audit

Which means if an FDA investigator shows up in your lobby, you can search their name on the FDAzilla 483 Store and see:

• See who else they've inspected
• See who they've worked with
• Buy and research their 483 observations to see their core expertise

FDA inspectors have core areas of expertise.  Some focus their work in key geographic areas.  The more you know about your inspector, the better you are able to pass the inspection with minimal 483 observations.

This FDAzilla 483 Store is the only tool I know of that lets you inspect the inspector.  

Anyone know of anything better?

1,000 #FDA 483s!?! @fdazilla

Check this out:

http://store.fdazilla.com




It's basically a place where you can search and buy one-thousand FDA 483s reports.

 Here's what a search for Amgen's 483s look like:



Click into the 483 report and see the details:

• Number of observations
• Inspection Time Range
• Investigators

...everything:

Add To Cart and checkout with PayPal.
It's strange because when you're running cell culture production in GMP environments, QA sort of gets these communications and plan their inspection readiness strategy around these 483 reports.

Next thing you know, you're at a change management meeting and you're trying to address all these new requests and can't figure out the drivers for them...

Well, here they are: 483 observations that FDA inspectors make of other plants will also apply to you.

p.s. -  This is, of course, in addition to their FREE 483 offering I wrote about a while back.

Commercial Cell Culture, cGMP and 483s

So when I was at Cornell studying to be a biological engineer and then switching over to chemical engineering, I figured that my career in life would be a biochemical engineer. That was the hot new thing and even the School of Chemical Engineering within the College of Engineering at Cornell changed their name to the The School of Chemical and Biomolecular Engineering.

You learned about fermentation, cell culture, bioreactors and weird hosts like plant-cell culture and insect baculovirus. But what they never got to was cGMP... they had classes on it, but it was very much an outsider's perspective.

GMP Regulations in the real-world

When you get to the real world, drug firms manufacturer under the reign of terror known as cGMPs. The way it works is this:

• By law, drug manufacturers whose products make it into the US markets must register with the FDA.
• FDA issues a Form 482 and presents credentials when they inspect your plant
• Should there be inspectional observations, the FDA inspectors issue a Form 483 detailing your manufacturing risks
• If these observations are not addressed and the problems sufficiently serious, the FDA issues a warning letter.
• If the issues remain unaddressed, the FDA gets a consent-decree to seize product or shutdown your plant.

If you run cell culture processes to make food or drug products sold in the US... and you are conscientious about getting your product to market, you have no choice but to maintain a high degree of compliance with the GMP regulations as well as be aware of the FDA's emphasis.

Where to put your resources?

The key is to focus on items as far upstream of the consent decree as possible. So between addressing the warning-letters vs. the non-binding 483 observations, the vast majority of QA Pharma professionals focus on the dreaded 483.

The deal with the 483s is that the FDA issues a lot of them and cannot release unredacted versions of the inspectional observations. Requesting 483s from the FDA can take months.

FDAzilla offers FREE 483s!!

This is where FDAzilla steps in; FDAzilla is a website that provides FDA intelligence and is coming up with a 483 store and service. They've already organized all the free 483s from www.fda.gov into a Dropbox folder.

I checked it out over the weekend on my iPad. You can read Novartis 483s as fast as you read emails:


Here's the Genzyme's infamous 2009 Form 483. The free ones are the most-requested or deemed a public interest by the FDA.


Here's another view of a (Gilead) 483:


There are over 500 documents in this Dropbox folder and access is free (well, you need to leave an email address to whom they grant the access).

Sign up for FREE FDA Form 483s

by Oliver Yu

From the QA professional that needs these resources to the kept-in-the-dark cell culture engineer, if you work in the cGMP field, you really ought to look into access to this FDAzilla resource.

p.s. - Tony, CEO of FDAzilla, tells me there's a surprise in store, so stay tuned.

All FDA.gov 483s for Free

As discussed in a previous post on cGMP, FDA issues Form 483s to companies for inspection observations. These Form 483s turn into warning letters; warning letters turn into consent decrees and your plant might get shutdown.

So the game is to nip this in the bud at at the 483 level. Well, the guys over at FDAzilla have done it again, offering all the freely posted FDA 483s in a Dropbox folder.

You just put in your email, and they'll invite you to share their Dropbox folder.

Genius.

FDA on pace for record year issuing 483s

Zymergi serves companies that run cell culture and fermentation processes. Nearly all our customers produce biologics... molecules that are synthesized by biological organisms - and all of them get their GMP plants inspected by the FDA.

Yesterday, FDAzilla published the rate the FDA hands out inspection observations called 483 for 2011. It's eye-popping; on average, they hand out 1 (Form) 483 every 50 minutes.

If you need more information on avoiding headache with the inspectional liability side of running cell culture/fermentation processes, go ahead and visit:

• 10 Resources for Avoiding FDA Form 483
• Only online resource listing all 483s issued by the FDA
• FDA 483s Resource Center