Quality Agreements with your Contract Manufacturer

It has been a while since we have sent any updates for our dietary supplement clients.  The FDA has remained busy inspecting supplement companies and writing many, many warning letters. The regulations for dietary supplement Good Manufacturing Practices (GMPs) include a section on quality control requirements (21 CFR 111.103 – 111.40).  Many dietary supplement distributors mistakenly think that quality control is the responsibility of their contract manufacturers.  There have been a number of warning letters to companies who failed to have sufficient oversight or documentation of the system in place to ensure that their contract manufacturer was producing the product specified.  A recent letter to Body Systems, Inc. of Winter Springs, FL delineates this responsibility and in addition states that failure to fulfill this responsibility can result I criminal liability:

“Although your firm may contract out certain dietary supplement manufacturing operations, it cannot, by the same token, contract out its ultimate responsibility to ensure that the dietary supplement it places into commerce (or causes to be placed into commerce) is not adulterated for failure to comply with dietary supplement CGMP requirements (see United States v. Dotterweich, 320 U.S. 277, 284 (1943) (explaining that an offense can be committed under the Act by anyone who has “a responsible share in the furtherance of the transaction which the statute outlaws”); United States v. Park, 421 U.S. 658, 672 (1975) (holding that criminal liability under the Act does not turn on awareness of wrongdoing, and that “agents vested with the responsibility, and power commensurate with that responsibility, to devise whatever measures are necessary to ensure compliance with the Act” can be held accountable for violations of the Act). In particular, the Act prohibits a person from introducing or delivering for introduction, or causing the delivery or introduction, into interstate commerce a dietary supplement that is adulterated under section 402(g) for failure to comply with dietary supplement CGMP requirements (see 21 U.S.C. §§ 342(g) and 331(a)). Thus, a firm that contracts with other firms to conduct certain dietary supplement manufacturing, packaging, and labeling operations for it is responsible for ensuring that the product is not adulterated for failure to comply with dietary supplement CGMP requirements, regardless of who actually performs the dietary supplement CGMP operations.”

An initial step for dietary supplement companies to take in order to address their responsibilities is to carefully write the contracts and agreements they have with their contract manufacturers. This week FDA issued a draft guidance document on quality agreements for the drug industry. While reading through it, I thought that many of the suggestions are relevant to the dietary supplement industry.  The draft guidance discusses how both the ‘Owner’ of the product and the contract manufacturing facility are responsible for quality control and compliance with GMP regulations.  The same is true in dietary supplement manufacturing.  In the following excerpt from the draft guidance on quality agreements, think “dietary supplement” when you read “drug.” (Note that I have separated theses sentences for emphasis but they appear in a single paragraph in FDA’s document.)

“In all cases, the Owner is responsible for assuring that drugs introduced for interstate commerce are neither adulterated nor misbranded as a result of the actions of their selected Contracted Facilities.

All Contracted Facilities must assure compliance with applicable Current Good Manufacturing Practices for all manufacturing, testing or other support operations performed to make a drug(s) for the Owner.”

The second sentence states that the contract manufacturer must assure compliance with GMPs. While first sentence states that the company that will introduce the product into commerce, the “Owner” must take steps to ensure that the product has been properly manufactured.  This requires auditing of the manufacturing process by the Owner to ensure that the manufacturer is fulfilling the contract.  It may be helpful to read the full guidance here.  At the very least, it can provide things to think about as you work with your contract manufacturer.

My associates and I hope you find these occasional updates helpful. If you would like to subscribe to our newsletter updates on foods, cosmetics, dietary supplements or over the counter drugs, simply reply to this post and let us know.

Contact us if you have questions or need help ensuring that your company is in compliance with FDA regulations.

Sincerely,

Evelyn & Associates

Wrinkles and FDA Cosmetic Update

It has been many months since we’ve posted anything on cosmetic regulations. This edition is to make you aware of recent FDA enforcement actions and some proposed legislation that you should be aware of.

We have had discussions with many of our clients about ‘wrinkle claims’.  Typically we note that cosmetic regulations allow claims regarding how a product cleanses, beautifies, promotes attractiveness, or alters appearance or fragrance and that claims about wrinkle reduction are therapeutic or drug claims.  Many of you have responded with questions similar to ‘what about all the big guys and the stuff they say in their commercials?’  Well, a few of the big guys received warning letters from FDA regarding their claims.

In October FDA sent Avon a warning letter regarding claims made on their website about their Anew line of products. The letter lists a number of claims including

“Rebuild collagen to help plump out lines and wrinkles.

Stimulate elastin to help improve elasticity and resilience.

Regenerate hydroproteins to help visibly minimize creasing.”

The letter also notes claims comparing Avon products to botox and goes on to say, “Your products are not generally recognized among qualified experts as safe and effective for the above referenced uses and, therefore, the products are new drugs as defined in section 201(p) of the [Food Drug and Cosmetic] Act.”

In September Lancôme also received a warning letter noting numerous drug claims on their Genefique line of products.  While one claim cited in the letter did discuss wrinkles, “See significant deep wrinkle reduction in UV damaged skin, clinically proven,” the Lancôme website claimed that their products stimulate stem cells.  It may be that it was the stem cell claims that prompted FDA to act but the fact that wrinkle claims were also cited is noteworthy.

Cosmetics may be promoted to reduce the appearance of wrinkles but not to repair, correct, plump or make them go away.

Now for the future: Last April US Congressman Leonard Lance of New Jersey introduced a Bill in the US House of Representatives.  The Cosmetic Safety Amendments Act of 2012 proposes “to establish new procedures and requirements for the registration of the cosmetic product manufacturing establishments, the submission of cosmetic product and ingredient statements, and the reporting of serious and unexpected cosmetic product adverse events, and for other purposes.” 

For a number of years FDA has had the Voluntary Cosmetic Registration Program (VCRP) in place.  This program is ‘regulations light’ but mirrors the drug listing and registration program.  I have heard rumors that cosmetic good manufacturing practice regulations have been written but have not seen them published this year; which is not surprising since much in government was on hold in 2012 due to the Presidential election and remains on hold awaiting the outcome of Congressional efforts to address looming budget cuts and tax changes. Nevertheless, it is important for cosmetic companies to be aware that they will be affected by future increased regulation.

To learn more about the VCRP, visit http://www.fda.gov/Cosmetics/GuidanceComplianceRegulatoryInformation/VoluntaryCosmeticsRegistrationProgramVCRP/default.htm.

To read the proposed legislation visit http://www.gpo.gov/fdsys/pkg/BILLS-112hr4395ih/pdf/BILLS-112hr4395ih.pdfhttp://www.gpo.gov/fdsys/pkg/BILLS-112hr4395ih/pdf/BILLS-112hr4395ih.pdf .

To read an intelligent and information article about the legislation, visit FDALawBlog at http://www.fdalawblog.net/fda_law_blog_hyman_phelps/2012/04/representative-leonard-lance-r-nj-introduces-industry-supported-bill-to-modernize-cosmetics-regulation.htmlhttp://www.fdalawblog.net/fda_law_blog_hyman_phelps/2012/04/representative-leonard-lance-r-nj-introduces-industry-supported-bill-to-modernize-cosmetics-regulation.html

To read the Avon warning letter visit http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/2012/ucm323738.htm

To read the Lancôme warning letter visit http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/2012/ucm318809.htmhttp://www.fda.gov/ICECI/EnforcementActions/WarningLetters/2012/ucm318809.htm

I hope you find these periodic posts informative and interesting.  If you  would like to be added to our newsletter distribution list, please reply to this post. 

Contact us with any questions you have regarding cosmetic, food or dietary supplement regulations.

FDA Warning Letters to Cosmetic Companies

FDA Warning Letters to Cosmetic Companies

The US Food and Drug Administration has responsibility to ensure the safety of consumer products through enforcement of regulations on many consumer products, including cosmetics.  Cosmetics are subject to fewer regulations than are foods and drugs and it is not common to see FDA issue warning letters; however, in the past few months FDA has sent warning letters to two cosmetic companies.

In a June letter to Set-N-Me-Free Aloe Vera Company  FDA objected to therapeutic claims on the cosmetic products.  Cosmetics may be marketed to cleanse, beautify, promote attractiveness and alter appearance but not to affect the structure or function of the skin.  While in this warning letter FDA objected to some outrageous claims about cancer, it also included the following claim, which is a lot like many seen in the market today:

“Natural B-vitamins in the safflower and avocado oils [ingredients in this product] help in cell formation and build skin-immune functions. These oils renew skin flexibility by permeating natural vitamins A and E into skin cells, making regeneration of these cells occur faster.”

The claims about immune function and regeneration are problematic, going well beyond cleansing, beautifying, promoting attractiveness and altering appearance.

Last week FDA published a letter sent to Vienna Beauty Products.This was the most disturbing warning letter I have ever read about a cosmetic company. According to the letter Vienna Beauty Products were producing cosmetics under insanitary conditions that included:

“Apparent filth and dust build up on manufacturing equipment in the production area” 

“A layer of sediment and encrusted material was observed on the exterior and tops of production kettles.”

“The last cleaning [of the production room floor] was performed November 2010.”

“The 250 and 500 gallon kettles were last cleaned 15 years ago.” 

“The last cleaning of the 400 gallon shower gel kettle could not be determined.” 

“Additionally, the finished product storage tank and storage totes were said to have last been cleaned over 20 years ago.” 

Not surprisingly, these conditions led to production of products with high bacterial counts.  The scary thing is that Vienna Beauty Products manufactures several private label lines of product for major retailers.

Since registration of cosmetic manufacturing facilities is voluntary, I wondered how the FDA ever discovered all the problems at Vienna Beauty Products.  I noticed that the warning letter was signed by Paul Tietell, District Director of FDA’s Cincinnati District Office.  Mr. Tietell used to be in the Denver District Office and I had the pleasure of serving with him on the board of the Rocky Mountain Regulatory Affairs Society, so I wrote to ask him how cosmetic companies come to FDA’s attention.  Here’s his reply,

“Cosmetic establishments may find their way to FDA's OEI (Official Establishment Inventory) in a variety of ways.  

In addition to the firm registering with FDA through the VCRP, the firm may also be a manufacturer required to register under one of many existing regulations.

The firm may have been involved in a complaint (Consumer, Med-Watch other agency referral) and have been entered into our OEI in conjunction with our receiving and recording of that complaint.

The firm may have come to the attention of a FDA through general surveillance of retail sales, by observation during and employee's day to day operations, or perhaps through observation of an advertisement.”

This means that if you advertise or sell cosmetics, you could be subject to FDA inspection.  It also means that you should review your manufacturing methods against FDA's Inspection Checklist  and be sure to have your labels reviewed for regulatory compliance.

Cosmetic companies provide products to help make the world beautiful and attractive.  The folks at FDALabels.com and Bioscience Translation & Application would like to help you keep your business beautiful.  Contact us if you have questions or need help ensuring that your company is in compliance with FDA regulations.

We hope you find these occasional posts interesting and informative.  You can subscribe to our mailing list by replying to this post.

The Cosmetic Team

FDALabels.com

Bioscience Translation & Application

Dietary Supplement Educational Opportunities

Hello!

Many of our dietary supplement clients have come to us for proactive assistance with proper labeling and other FDA regulatory issues.  Unfortunately, some companies only found us after they had problems and were subject to enforcement action by FDA.  It is expensive and time consuming to have to respond to FDA warning letters or have products held at the border.  Further, some violations raise the possibility of product recalls or even complete removal of the product from the US market.  My team and I do our best to alert our clients and help them understand the FDA’s Good Manufacturing Practices (GMP) regulations and I want to be sure you have heard about two opportunities to learn more about them.

August 22^nd from 1:00 pm to 3:00 pm Eastern Time (Webinar)

The Natural Products Association is Sponsoring a webinar on the GMPs the effect companies that distribute but do not manufacture their own products. FDA calls such companies ‘Own Label Distributors’. I believe this information is crucial for dietary supplements that want to grow and stay out of trouble with FDA. Here is a link to registration for this webinar and a brief description follows:

http://www.npainfo.org/NPA/EducationCertification/NPAGMPWebinar.aspx

FDA says that if your name is on the product, you are responsible for it. The agency has issued numerous warning letters to own-label distributors for GMP violations—Ensure your product is in compliance with GMPs by registering for this webinar. Hear directly from FDA about their expectations are for specific for own-label distributors, re-packagers, and re-labelers, and hear from our industry speaker about how to achieve compliance.

September 13^th and 14^th In person conference in Boulder, CO

Sponsored by The Rocky Mountain Dietary Supplement Forum: What Does FDA Really Expect from Us?

At this day and a half seminar you will learn directly from industry experts.

    Learn how to dramatically change the outcome of your inspection with the Agency

    Hear from FDA Denver District representatives on what they expect during an inspection plus the top 483 items trended by FDA 

    Receive step-by-step instructions and a template on how to respond to 483s and Warning Letters

    Interact with other industry professionals who are facing the same challenges you are

http://www.regonline.com/builder/site/Default.aspx?EventID=1055067http://www.regonline.com/builder/site/Default.aspx?EventID=1055067

We at FDALabels.com and Bioscience Translation & Application hope that you find this information helpful.  If however, you wish to receive these occasional posts as newsletters, please post a reply to this entry.

Meanwhile, we would be pleased to help you with your questions about FDA regulations. 

All the best to you and yours!

Evelyn

Does your Contract Manufacturer Comply with cGMPS?

Hello!

I hope that your business is doing well enough to allow you to relax a bit as summer starts.  Knowing that your contract manufacturer complies with FDA’s current Good Manufacturing Practices (cGMPs) can reduce stress a bit. But how do you know that their cGMPs are up to snuff?  Many of you will recall conversations we’ve had about ingredient specifications and certificates of analysis. Well, today I saw a well-written article on this topic in Natural Products Insider by Kevin Cloud, senior method development chemist in the Capsugel Licaps® laboratory.  You may read the article below or link to it here: http://www.naturalproductsinsider.com/articles/2011/06/inquire-about-incoming-ingredient-inspection.aspx

FDA continues to inspect dietary supplement manufacturers and to write warning letters detailing a wide variety of GMP violations. Responding to such letters and correcting the violations can mean that your manufacturer may not be able to fulfill your next order on time or worse, that your product will have to be recalled and possibly destroyed if not produced under cGMPs.  Something like that would certainly ruin your summer.

Avoid future problems by thoroughly investigating your manufacturer and suppliers and be aware of the GMPs that you as the distributor must have in place.  The team at Bioscience Translation & Application wants to help you succeed.  Contact us for help with labels, GMPs or your questions about FDA regulations and processes.

Happy Summer!

Evelyn & Associates

Bioscience Translation & Application

Inquire About Incoming Ingredient Inspection

By Kevin Cloud

Natural Products Insider

June 17, 2011

 Dietary supplement cGMPs (current good manufacturing practices) establish minimum practices necessary for activities related to manufacturing, packaging, labeling and holding dietary supplements to ensure product quality. The final product owner is ultimately responsible for the dietary supplement that is released to the market, and each company in the supply chain contracted by the final product owner is responsible for ensuring its activities comply with cGMPs. Final product owners should make sure contract manufacturers have the resources, processes and commitment to comply with the cGMPs.

One important part of the equation for manufacturers is to ensure the integrity and quality of the raw materials purchased for production of finished goods. Federal regulations require manufacturers establish raw material specifications covering identity, purity, strength, composition and limits on contamination before placing an order.

How can the final product owner ensure these specifications are met? By asking three simple questions related to ingredient identification, and getting the answers related to testing, equipment and results in writing.

Question 1: Can I see the raw material specifications for raw material X that will be included in my product?

The contract manufacturer should provide a copy of a specification with all of the testing that is expected to be performed plus the criteria for passing or failing the raw material. Following are examples of mandatory specification parameters and what information they provide:

• Identity: What is the substance? Is it the ingredient as desired, to ensure the integrity of the product as labeled? Or is it a mixture or even perhaps an entirely different substance altogether?
• Assay: Determines the strength or potency of a substance.

Contamination: Determines unwanted substances in the raw material, such as heavy metals, pesticides and residual solvents, and any allowable limits.

Question 2: What instruments does your facility use to identify the incoming raw material X and can I see the qualification package for at least one of these instruments?

The manufacturer should have the ability to provide copies of the qualifications for each instrument listed. A qualification is made up of three distinct parts: Installation Qualification (IQ), Operational Qualification (OQ) and Performance Qualification (PQ). The qualification package is usually purchased at the time the instrument is installed or moved. The qualification is performed by a certified technician from the manufacturer of the equipment.

Typical laboratory instruments used for testing include high performance liquid chromatography (HPLC); gas chromatography (GC); ultraviolet visible spectroscopy (UV/Vis); fourier transform infrared spectroscopy (FTIR); high performance thin layer chromatography (HPTLC); melting point (MP); microscope; and near infrared spectroscopy (NearIR).

Question 3: What types of methods are you using to assay incoming raw material X and can I see a validation/verification summary and standard operating procedure (SOP) for that raw material?

From the list of instruments above, HPLC is the workhorse of the nutrition industry for analyzing potency or strength of a substance. But HPLC is only a piece of equipment. A method, or set of directions, is also essential to assay a sample; it is like a road map for the HPLC.

Whatever method or direction is used—and there are many from a wide variety of sources—it should be scientifically valid. Some recognized scientific compilations of methods are the U.S. Pharmacopeia (USP), American Oil Chemist Society (AOCS), Japanese Pharmacopeia (JP) and British Pharmacopeia (BP). Methods are often put into a company’s particular format, such as a SOP, a standard operating instruction (SOI) or a work instruction (WI).

Remember the final product owner is ultimately responsible for the dietary supplement released to the market, and that responsibility includes ensuring the product is manufactured, packaged, labeled and held according to dietary supplement cGMPs. Asking some basic questions related to ingredient qualification can provide helpful information, realizing a manufacturer that is missing any of the three major components—raw material specs, qualified instruments or written procedures—is not compliant with cGMPs.

Evelyn Cadman

Principal Consultant

Hand Sanitizers and OTC Drug Regulation

In August of last year we sent our cosmetic and OTC drug clients a link to a Hyman, Phelps and McNamara Law Blog Post about a lawsuit against FDA that sought to force the agency to finalize the tentative final monograph on hand sanitizers that has been “tentative” since 1994. This week FDA issued four warning letters to companies promoting hand sanitizers and other products as effective again MRSA (methicillin-resistant Staphylococcus aureus bacteria).  FDA issued a press announcement about these letters due to the concern that the public could be misled and subsequently harmed by the MRSA claims (http://tinyurl.com/4x6j777).  I find the warning letters interesting because of what we can learn about the regulation of over the counter drug products, particularly those under review by FDA or subject to tentative final monographs.

One of these warning letters went to Oh So Clean, Inc, doing business as CleanWell Company, which markets thymol-based hand sanitizers and sanitizing wipes. (Thymol is a constituent in the herb thyme.)  The warning letter demonstrates how FDA can enforce the stipulations of over the counter drug monographs that remain tentative. The warning letter results from FDA inspection of the company in August of 2010.  At that time CleanWell Company received a 483 letter detailing the violations FDA observed during the inspection. The warning letter issued last week notes that the company’s September response to the 483 letter “lacks sufficient corrective actions” and details FDA’s findings that the products are unapproved new drugs.

Based on the product labels and the company’s website, FDA categorizes the CleanWell products as “OTC topical antimicrobials” and cites the tentative final monographs (TFMs) for OTC healthcare antiseptics and OTC first aid antiseptics as the governing regulations for these products.  Interestingly, the response to an inquiry our company made to FDA in 2009 listed only the healthcare TFM as pertaining to hand sanitizers. Nevertheless, both of these monographs are being evaluated under FDA's OTC Drug Review process and the April 18 warning letter notes that “Pending a final monograph, the agency does not object to the marketing of OTC drugs that meet the formulation and labeling requirements described in the TFM.”  Unfortunately, the CleanWell “products’ formulation and labeling are not consistent with any of these TFMs.”  You can review the TFMs at http://tinyurl.com/3pxx464.

So what were the problems with these products?

First, the drug facts boxes identified Thymus vulgaris oil (thymol 0.05%) as the only active ingredient. The pertinent TFMs do not list this as an approved active ingredient but the First Aid Antiseptic TFM lists thymol in combination with eucalyptus, menthol, methyl salicylate and alcohol as an acceptable active ingredient. In addition, the product claims go beyond what is permitted by the tentative final monographs for antiseptic products. In particular, the claims of effectiveness against MRSA are non-monograph. The only way to make claims outside of those detailed in the monographs is to undertake clinical trials in order to gain FDA approval for new over the counter drug claims.

Even if thymol alone were an acceptable active ingredient for this type of OTC product, the company’s own website and other labeling state that active ingredient used in the products is a blend of essential plant oils.  FDA refers to incorrect labeling such as this as “misbranding”.

The warning letter further cites violations of good manufacturing practices, which render the products “adulterated” and orders the company to “cease manufacturing and distributing all your unapproved new drug products” and to take corrective action and respond to the warning letter within 15 working days. This is undoubtedly a real blow to products that were available in several well-known retail outlets.  

Similar problems were noted in the other warning letters about MRSA claims—simple failure to follow the monographs, which detail how to formulate and label over the counter drug products.  It is our view that timely and competent review of the product labels and claims could have helped these companies identify the issues cited by FDA and remain active in the marketplace.  Is your product compliant with applicable FDA regulations or has a slight tweak of the marketing materials skewed your claims beyond those permitted?  Let the Bioscience Translation & Application team help you ensure compliance so your marketing plans are not disrupted by FDA enforcement activities.

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Johnson & Johnson Consent Decree: A lesson in Drug cGMPs

The folks at Pharmalot have written an article about the Johnson & Johnson consent decree (http://tinyurl.com/4bxxl44).  The article includes a link to the consent itself, which details the cGMP requirements FDA expects to see at the drug manufacturer's facility. 

The consent decree details the systems that need to be set up to ensure that the company's drug products are produced properly and are safe and efficacious. The document makes clear that the plant needs to build a quality system from the ground up and is evidence of the catastrophic QA failure that lead to the recalls and the consent decree itself.  

My purpose in posting this information is not to spread salacious gossip but to provide what I think is useful information.  In my view, the consent decree can be used as a checklist to review the cGMPs at your manufacturing facility.  If you are unable to download the consent decree, please leave a comment with your email address and I will send it to you. (Your email address will not be published.)

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