James Neal-Kababick Director, Flora Research Laboratories Adjunct Faculty, Bastyr University Botanical Medicine Dept Fellow AOAC International 1©2012 Flora

James Neal-KababickDirector, Flora Research Laboratories

Adjunct Faculty, Bastyr University Botanical Medicine Dept

Fellow AOAC International

1©2012 Flora Research Laboratories

Warning: The Speaker Comes from a State that Allows Dogs to Drive

©2012 Flora Research Laboratories 2

You should

keep this in mind when

considering his advice.

DISCLAIMERThis presentation is not a substitute for qualified

legal advice from competent, expert counselInformation provided is based on a variety of

resources including speakers experience, FDA guidance documents, cGMP’s and regulatory actions- due to the dynamic nature of the industry, changes may occur rendering some of this information inaccurate

Names of companies or case histories are for educational use only and are neither an endorsement nor a condemnation of said entities


Changes and More ChangesThe industry many of us grew up with has

changed dramatically in the last twenty yearsChanges continue to accelerate at a greater pace

as the industry continues to matureBasing decisions on the “good old days” is likely

to result in arrest, inventory seizure, class action suits, and large fines not to mention negative media attention to your company

To address the dynamic market, FRL developed & utilizes Phytoforensic Science to help protect clients


Phytoforensic ScienceThe application of various techniques from

microscopy to mass spectroscopy to protect the global food supply chain

A special emphasis on dietary supplementsApplication of novel and “outside the box”

approaches to problem solvingBringing together data from various

instruments to see the “big picture” and solve the problem at hand

Resolution of confusion through sound science


Private Label-Risk Free?Utilizing a CMO to manufacture your products does

not relieve you of any compliance requirements under 21CFR part 111

FDA warning letters make this point painfully clearEvery CMO, contract testing lab, regulatory affairs

consultant, distributor, packer, fulfillment service and shipper is considered an extension of your company

You are liable for all of their actions under the cGMP’s as if they were parts of your internal organization

That means that…©2012 Flora Research Laboratories 6

Private Label – High Risk!If ANYTHING is out of compliance with 21CFR

part 111 with ANY aspect of your CMO’s manufacturing chain in respect to your products that you are responsible under the cGMP’s!

If ANY product manufactured by your CMO for ANY company is declared misbranded and or adulterated, the FDA can declare all products made by the CMO misbranded/adulterated and subject to recall REGARDLESS of whether or not your product was manufactured in compliance with 21CFR part 111!


Private Label-CMO Issues


So now you have to worry about what your CMO is doing with other companies in the same facility that your product is made in. ANDWorry about your products, about your CMO and about everyone else's products made by your CMO!SO MAYBE IT’STime for some chamomile tea (or maybe a chamomile IV )

This isn’t my beautiful industry. What happened

here?

Is There Hope?Should we just drink the Kool-Aid now or is there

hope to survive in such a highly regulated industry?Consider this- The State of Utah’s largest industry is

now the dietary supplements industry over all others topping $7 billion USD annually.

Now about 60% of MD’s are using and recommending supplements to their patients up from <10% in 1997

The idea of a highly regulated industry, an agency with teeth and strong science & research add to consumer and practitioner confidence = more sales


Why?Why would this be so?The “pass the buck” parachute loop was

closed by these regulations The FDA went through all of this with the

pharma OTC industry – they know all the tricksStudy the Barr Labs decision for a blow by

blow of what is comingYou ain’t seen nothing’ yet as they are just

warming upDon’t think it can’t happen to you


You Don’t Want This


I selected this

warning letter for a reason which we

will examine

more closely

Relevant Section“As an own-label distributor that contracts

with other manufacturers to manufacture dietary supplements that your firm releases for distribution under your firm’s name, FDA considers you to be a manufacturer of such dietary supplements. You have ultimate responsibility for the dietary supplements that you introduce or deliver for introduction into interstate commerce.”


Even More Relevant“The inspection revealed serious violations of the

Current Good Manufacturing Practice (CGMP) regulation for Manufacturing, Packaging, Labeling, or Holding Operations for Dietary Supplements, Title 21, Code of Federal Regulations, Part 111 (21 CFR Part 111). These violations cause your dietary supplement products to be adulterated within the meaning of section 402(g)(1) of the Federal Food, Drug, and Cosmetic Act (the Act) [21 U.S.C. § 342(g)(1)], in that the dietary supplement products have been prepared, packed, or held under conditions that do not meet CGMP regulations for dietary supplements.”


Look Again“These violations cause your dietary

supplement products to be adulterated within the meaning of section 402(g)(1) of the Federal Food, Drug, and Cosmetic Act (the Act) [21 U.S.C. § 342(g)(1)],

in that the dietary supplement products have been prepared, packed, or held under conditions that do not meet CGMP regulations for dietary supplements.”


That MeansUnlike ANY other food category of

regulations, dietary supplements can be declared ADULTERATED because of cGMP violations

We think of that word meaning some contamination such as fibers, hairs, wrong ingredient, rodent excreta and so on but

It can be a violation of protocolWhat do you think consumers think

ADULTERATED means?


What FDA Said-Private Label CMO“As an own-label dietary supplement distributor

that contracts with a manufacturer to manufacture a dietary supplement that you distribute under your own label, you have an obligation to know what and how manufacturing activities are performed so that your firm can make decisions related to whether your packaged and labeled dietary supplement products conform to established specifications and whether to approve and release the products for distribution [See 72 Fed. Reg. 34752, 34790 (Jun. 25, 2007)]. “


Your Firm’s QAU“Your firm's quality control personnel must

ensure that your manufacturing, packaging, labeling, and holding operations ensure the quality of your dietary supplements and that your dietary supplements are packaged and labeled in accordance with established specifications, as required by 21 CFR 111.105 and 21 CFR 111.120(b).”

Not ‘their firm’s QAU” but “your firm’s QAU”


Important FDA Statement“Your firm failed to make and keep written procedures for

the responsibility of quality control operations, as required by 21 CFR 111.103 and 21 CFR 111.140(b)(1). As an own-label dietary supplement distributor that contracts with a manufacturer to manufacture a dietary supplement that you distribute under your own label, you have an obligation to know what and how manufacturing activities are performed so that your firm can make decisions related to whether your packaged and labeled dietary supplement products conform to established specifications and whether to approve and release the products for distribution [See 72 Fed. Reg. 34752, 34790 (Jun. 25, 2007)]. Your firm's quality control personnel must ensure that your manufacturing, packaging, labeling, and holding operations ensure the quality of your dietary supplements and that your dietary supplements are packaged and labeled in accordance with established specifications, as required by 21 CFR 111.105 and 21 CFR 111.120(b).”


And This“Your firm failed to establish a

specification for any point, step, or stage in the manufacturing process where control is necessary to ensure the quality of the dietary supplement and that the dietary supplement is packaged and labeled as specified in the master manufacturing record, as required by 21 CFR 111.70(a).”


Oh, And This Too“Your firm failed to establish specifications for each component that you use in the manufacture of your dietary supplement products, as required by 21 CFR 111.70(b).”


Another one“Your firm failed to prepare and follow a written master manufacturing record for each unique formulation of dietary supplement that you manufacture, and for each batch size, to ensure uniformity in the finished batch from batch to batch, as required by 21 CFR 111.205(a).”


Standard Closing Paragraph“You should respond in writing within fifteen

(15) working days from your receipt of this letter. Your response should outline the specific things you are doing to correct the violations noted above. You should include in your response, documentation and any other useful information that would assist us in evaluating your corrections. If you cannot complete all corrections before you respond, you should explain the reason for your delay and state when you will correct any remaining violations.”


And Finally (this is not from FDA)Sincerely,

Your local FDA Office who will be watching you from now on very closely and will bring federal Marshalls in next time to seize your inventory, arrest your management and shut down your company if you fail to adequately respond to our warning letter.

Oh, any by the way, we might just do that while you are responding to the letter because we can.


This is not an idle threatThe FDA has become very aggressive in

enforcing the cGMP regulations and rightly soThe fact that the industry had over a decade

of warning about what would be expected means FDA is not very empathetic to those that just decided to start working on compliance now

FDA and FTC work closely together and that means everything from trade show literature to import of raw materials used in your product are subject to review


The 6 Stages of cGMP Acceptance1. The cGMP’s will never get issued2. The cGMP’s will never be enforced3. Only the big guys will get hit now and then4. Only the bad players with major deficits

will be hit5. Only those making the products (CMO’s or

in-house manufacturing facilities will be hit6. Oh my god, I’ve been hit! I need to

comply.


Steps to take with your CMO and factors to consider when you engage a CMO to make any product in 427,000 easy steps…

(Just kidding, there are only 18,000 critical steps)


ConsiderationsA flashy website is nice and so are glossy

brochures, pictures of lab equipment and people in lab coats

So what? Really, so what? Does this actually reflect the real CMO’s focus or is their marketing department?

As you scratch the surface, it can be like pulling the thread on a sweater that suddenly unravels

Better to come apart in front of your audit team than the FDA CO!


Gaps? Me? Not Prestigious Me?Nobody knows everything- we all have

knowledge gapsYou may not know what you don’t know until

you have the counsel of qualified expertsRapidly assessing the gaps in your expertise

and determining the best way to fill them is essential to success (hire in our outsource)

Take advantage of those in the know to help make your product line rock solid & regulatory compliant by conducting a gap audit & evaluation


Get Boots on the Ground!There are many very good CMO’s out thereHowever, nobody is perfect & issues ariseDon’t be the retailer that has never seen the CMO’s

facility that makes your private label productsDon’t go it alone unless you are an auditor and

analytical chemist and microbiologist and regulatory affairs specialist and have x-ray vision and read minds (if you do, I have a job opening for you at the tables tonight in that poker competition)

Hire some qualified help to fill in the gaps you have


What am I saying?You do what you do best but if that is not

qualifying a CMO, get someone that can or a teamSaying “But I did not know that…” falls on deaf

ears at FDA because by law it is your responsibility to know

You did read the 900+ page preamble to the cGMP final rule right? If not you should as it spells out the FDA’s thinking on each point

This is a common problem– CMO’s making products for private label and the client never audits them until its too late


CMO EvaluationAuditing by a third party auditor with expertise

in 21CFR part 111Evaluation of the overall facility and logisticsKnowing everything from how the ingredients

arrive and are evaluated to how the final product is boxed and shipped out is your requirement so know it solid

Make sure all aspects are compliant including documents

There are common warning letter themes that we see repeatedly in situations like this


CMO PartnershipsYour liability exposure is significant so you

need to have a CMO that operates transparently and cooperates with your team

That means being an open book of sortsA spirit of cooperation towards a more

compliant product, company and industry should be the philosophy

If you get the runaround then run away to another CMO

They work for you & need to comply too©2012 Flora Research Laboratories 32

MMR/Product/Ingredient SpecsYOU need to work with your CMO to

establish a written master manufacturing record for each and every product you sell

YOU need to work with your CMO to establish written specifications for each ingredient used and for each product made

YOU need to work with your CMO to make certain that ALL of these specifications are properly implemented and AUDIT them to the specifications


Common Issues- IDENTITYFDA’s biggest fear is based on historical

disasters involving the mix-up of botanicals which resulted in consumer injury or death- hence IDENTITY

YOU must establish and test incoming dietary ingredients to ensure proper identity and that the product is free from reasonably anticipated contaminants (RAC’s)

You must use one or more scientifically valid examinations to meet this identity requirement


Common Issues-IDENTITYWe all know an onion from an apple but do

we know if that yellow powder is goldenseal root extract standardized to 5% alkaloids?

If you are a veteran in this industry, you can probably differentiate goldenseal from closely related adulterants based on taste, smell and appearance (organoleptic) but…


Common Issues-IDENTITYIf your product specification is GS extract

standardized to 5% alkaloids you MUST ensure that the product meets this IDENTITY specification

That will include making sure it is not adulterated with other botanicals or synthetic berberine (RAC’s)

And that it contains the right amount of alkaloid content (assay)

So you just have it tested in a lab right?


Common Issues-LABORATORYNot all labs are created equalDo they know what they are doing and does the

analyst have the training and qualifications to do what they are doing?

Is the instrument calibrated and is the incoming standard characterized properly?

Is the equipment being utilized correctly and do they have the proper equipment to do the test that they are supposed to be doing for you?

Who is checking the checker?


How Forensic TV Crime Shows Have Made Our Job Harder


How We Wish Analysis WorkedUnfortunately, this is not how it works except

for the Tricorder on Star Trek & On CSI


SAMPLE

RESULT

BLACK BOX SCIENCE

How It Really Works


Plus sweat!

CRO’s & the Big PictureDS products and ingredients are highly

complex (with some exceptions) and thus each test is really a study in itself

A good CRO will step back and get the big picture of what is going on to assure that critical factors are not missed

The Phytoforensic process starts with information gathering at all levels BEFORE analysis

It requires outside-the-box thinking and high skill levels & a passion for excellence


LaboratoriesSome labs are mills that put out data at a low

price and high pace to make profitAll profit is based on high throughput testingHigh throughput testing mandates limited

scope, short time focus on any sample and low operator skill levels (people with jobs not careers)

How much personalized attention is your sample going to get in this environment?

How many problems slip by? More than you think…


A Case Study- Phytoblab 9000Phytoblab 9000 is a fictitious product that I

am going to use for this exercise so that you can better understand the process – let’s say PB9K

Situation, the CMO tests Phytoblab 9000 with the “machine that goes bing” (actually it is FTIR) and it does not go bing

The material appears to be OOSThe material is sent to an outside lab for

evaluation


The Laboratory & PB9KLaboratory sample receiving- the lab must have

protocols in place for the receiving and handling of samples even if it is the laboratory inside the CMO’s facility- PB9K is received into the lab

PB9K is tested by HPTLC using the laboratories compendia reference for the actual botanical in the formulation and it is legit- PASS?

PB9K is tested by FTIR using a Phytoforensic examination and it is different than prior lots-FAIL?


Phytoforensic Science MattersSo you have a pass and a fail and that is

initially inconclusive or confusing but very typical

The lab reaches out to the supplier and they say that PB9K is made using an ancient Chinese process used for thousands of years but it is proprietary and they can only give us the ingredients/excipients used

This is very common and it does not really fly in the face of new regulations- black box specs are not FDA OK!


So What Else Is There?The scientists notice that the solubility

parameters are not the same between the samples

The insoluble part is mostly excipientThat would easily explain the pass on HPTLC

and fail on FTIRIf the excipient ratios changed is it okay?NO- FDA considers that a deviation from the

MMR and it requires a documentation process and OOS report!


Phytoforensic Science MattersThe PB9K sample that failed QC at the CMO’s

facility is compared to older lots and we see differences in the minor compounds by HPTLC which is common for extracts

Does it matter? Maybe. What does the spec say about the compounds in PB9K? That is the answer

FTIR differences appear to be related to declared excipient changes so the material is OOS

Conclusion- Failed Material or Deviation for OOS material use


FDA Warning for an excipient?Would FDA really give a warning letter to a

company because they had an excipient change?Yes they would and they did in a case where a

company changed an excipient involving cellulose

This caused the product to be misbranded and adulterated

FDA takes this very seriouslyYou should too if you want to thrive and you can

thrive by doing the right things


CRO A Partner for YouA Contract Research Organization (contract

laboratory) can be your partner in making sure that the CMO maintains compliance and in investigating issues like PB9K’s OOS incident

Again, all labs are not created equalLook for a CRO that has expertise and the

capability and ability to apply advanced techniques and multiple disciplines to the problem at hand (which may be highly variable over your products life cycle)

Shopping on price alone will bite you eventually


VISIT YOUR CRO!You should pay a visit to the facility and meet the

teamSee the equipment and inspect work performed on

your behalfMake sure that the employees are properly trained

to do what they are doingBe certain that the CRO has the ability to apply many

technologies and techniques to solve your problemsToo often, labs pound square pegs into round holes

and you don’t want that-DS products are complicated


CRO’s ContinuedDon’t use a non-transparent CRO! They should be an

open book for your partnership or their data is not usable for FDA compliance issues

Proprietary means it can’t be evaluated so this old way of the lab world in the industries early days is no good

The lab should be willing to assist you in an FDA inspection and agree to allow FDA to inspect their facility and data for your samples

If they say no then go to another lab that you can useThe CRO works for you!


CRO PartnershipYour CRO should be able to advise you on

this from a long history of working in the industry and on products

The CRO may not know a particular material but they certainly, as scientists, should be able to rapidly figure out what the issues might be and what should be evaluated

This goes back again to choosing the right CRO partner


Common Issues- State of ScienceIn cases where the state of science does not

allow for the testing of a given ingredient in a finished product the cGMP’s allow for exemptions

For instance, if your final product contains 1 mg of PS, it is not possible to test that with current science (without a tremendous multi-million dollar multi-year research project)

However…


Common Issues-State of ScienceIn the last five years, technology jumps have made

possible what was impossible only a short time agoYour CMO and CRO must be on top of the science

because FDA is and if you are making decisions on old data you are at risk

We can now see compounds at about 100-1000 times lower levels than before due to technology jumps

That means that the 25ug of selenium methionate in your finished product can be tested for the Se level and the raw material can be tested for identity


Common Issues-State of ScienceFDA does not consider the cost of technology

required to comply with the cGMP’s in evaluating this issue

If you need a million dollar instrument to do the test then you either buy it or find a lab that has it and knows how to use it for your testing needs

This is especially true for situations where the tests are for RAC’s that are a safety concern

Put up or get out is the FDA stance on this matter and it shows in warning letters


Common Issues RAC’sRAC’s are contaminants that are “reasonably

anticipated” and you MUST assure that your ingredients and products are free from them

While the law does allow you to use the suppliers C of A for all but identity, you must validate that information with your own testing

Typical protocol is to test 6 lots and it all pass then do skip lot testing – for ingredients not finished product

Some RAC’s should ALWAYS be tested for anyways


Common Issues RAC’sHow do you know what the RAC’s are for a

given product?Utilize historical incidents to set precedence-

i.e. melamine in protein, pesticides in ginseng, selenium super potency etc.

Consider what would be used on or for a product- pesticides for botanicals, dyes in bilberry, lead in calcium, carageenan in chondroitin

What if you don’t know the RAC history or potential RAC’s to test for?


RAC’s- API SpikingClandestine API adulteration has become epidemic

in the industrySome products are more at risk than others but NO

PRODUCT is immuneTesting a sample for known compounds is not

enoughNon-targeted screening is essential in high risk

productsDon’t risk it. This is the stuff that you can go to jail

forBe sure your CRO is a leading expert in clandestine

adulteration testing and that you are covered


How Bad is Spiking?Samples sent for clandestine adulteration testing

at FRL are adulterated more often than notIt is not unusual for a 90% failure rate to occur in

pre-lost shipments or offshore encapsulated/tableted products

Raw material suppliers often add API’s to make the product appear high quality for repeat business

The people doing this are very sophisticated and new compounds are continuously being discovered


Systematic Phytoforensic ApproachIt is not uncommon for FRL to detect major

pharmaceutical adulteration at active levels in products that were passed by labs in the US and Europe!

Labs performing targeted screening miss novel analogues and pro-drugs

SPA takes hours or days of expert time per sample in some cases-hence production labs miss many API’s

This is a top concern of FDA


Economic AdulterationLess than 1% of all products entering the US

are inspected.Global trade is greater than ever before in

the history of the USThere are continuous cases of product

contamination due to ingredient substitutionEconomic adulteration is at minimum a

financial loss but is more often catastrophicMaking sure the whole shipment is authentic

is a challenge©2012 Flora Research Laboratories 61

Representative Sample?


Biggus contanerous

Someus drumus

Stratificus bagus

Micro sizeus test

LOT REPRESENTATI

VE TEST RESULT???

Dubious datus

Latin binomials from excessive roadrunner

cartoons

Common Issue- SamplingAs we see from the prior slide, what you get

in a shipment and what the laboratory tests may not always be consistent

Tonnage of material can’t be evaluated with a ten gram sample

The way the samples are taken, composited (if that is proper for the given test) and how the lab processes the sample before testing are all vital to getting lot representative data

Why is this important?


Common Issue- SamplingBecause the cGMP’s and FDA say that the

sample under examination by the laboratory must be lot representative

Sampling is a science unto itself and we see most CMO’s do not take lot representative samples and are not in compliance thus the lab data is not in compliance thus the product made from the materials is MISBRANDED AND ADULTERATED!


Representative of the Lot?


Hypothetical Containers of Lot 123 Ice Cream Supplement for Mood Elevation

Scoop sample sent to lab for organoleptic

testing-

Sampling Must be Validated!The cGMP’s require that sampling protocols be

documented and validated to assure that they are lot representative

All too often, samples sent to labs for testing are scoops off the top 6 inches of one container

In a supertote or 20 drum shipment, that is not lot representative

USP Articles of Botanical Origin requires multiple container sampling including core samples from different sections of the drums


Typical Stratified Sample


It takes more time for a laboratory to properly prepare the composite sample from this container than it does to conduct the analysis. What does your lab do? You need to know and it needs to validated!

Laboratory Compositing


The Scientifically Valid Sampling Plan for our Laboratory Sampling of Protein Powder for steroid testing takes about two hours to conduct. Dr. Mason (seen here) is a preeminent expert in statistical sampling plans. He has developed sampling plans used on some of the largest superfund sites. This method is an elaboration of the USP cut and quarter mix method but utilizes 8 stainless bowls to ensure uniform sampling of the large protein container. The final lab sample will be 100 grams. What is your lab doing? Bad sample = bad data.

Take Away PointsThere is more to choosing a CMO than just

getting a quote and checking their flashy websiteEven the nicest facilities I have been inside of had

some raw materials that would never be considered compliant by FDA or methods that were not valid

Many ingredients are very hard to characterize and because you must have specifications you must be certain to assure material identity

How samples are taken for laboratory testing is the first critical control point in the ingredient evaluation process. Bad sample technique = cGMP violations


Take Away PointsCMO’s run the range from scumbags in rat

infested warehouses to sincere and diligent first class facilities with great talent and skill

The more you to do ensure your products are made to compliance with cGMP’s and to your product specifications, the less liability and exposure you have

When you do not know how to do something, you should have trusted partners- a good CMO will work with you to help establish specifications and other necessary documents or bring in an expert to help


Take Away PointsAlways have outside evaluation on a CMO by

qualified experts (independent auditors) because it is your reputation and company that is at risk

It is not about mistrust, it is about due diligence and making good business choices

In the nearly 20 years I have been working with DS products, I have seen plenty of well intentioned CMO’s and retailers with private label products in serious trouble

Work with trusted partners and trust nobody (within reason)


Take Away PointsRemember, FDA considers EVERYONE involved

in the production, packaging, testing, holding and distribution of your product to be an extension of your company

You are ultimately responsible for all of your partners actions so choose partners that will work with you

CMO’s and CRO’s work for you and that means that they should support you in an FDA inspection

Partners not willing to do this are not partners you want to work with


The Good NewsThe DS industry continues to grow even during

the economic downturnMore and more doctors and consumers are

using DS products to maintain healthSoon, most insurance companies will start

covering supplements that are essential to preventing disease (such as a supplement program for metabolic syndrome)

There is more technology and resources than ever before to help you succeed in the industry


FinallyWhile your CMO and CRO work for you, we

all work for one common goal (or at least we should)

That goal is to provide high quality dietary supplements made in compliance with the cGMP’s to the consumers that will buy and use them

If we all do our job right and you make good products that help consumers, the recipe is win-win-win for all involved


THANK YOU!


Milo helps with research

Documents

James Neal-Kababick Director, Flora Research Laboratories Adjunct Faculty, Bastyr University Botanical Medicine Dept Fellow AOAC International 1©2012 Flora