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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Medical Device Import Entry Review Process

Hello!

The device industry in the US continues to wonder what will become of the 510(k) process.  Senator John Kerry of Massachusetts has written a letter to FDA Commissioner Dr. Margaret Hamburg raising concerns that the medical device industry has over potential changes to the 510(k) process.  You can read more about his letter here: http://tinurl.com/3wyoqsw

FDA raised more concerns and sowed seeds of confusion in the medical device industry by publishing a letter about the import entry review process. (see http://tinyurl.com/4rqlg3r)  I too was confused and so contacted the Center for Device and Radiologic Health (CDRH) for clarification.  Turns out there is nothing new about the process and all that CDRH wanted to say is that imported devices can clear FDA’s border inspections faster if the paperwork includes the A of C code for the medical device being imported.

When importing a medical device into the US, the accompanying entry information should identify the product and include appropriate information to demonstrate that the product is in compliance with FDA regulations. When importing devices you must provide the following information:

1. Foreign manufacturer number (obtained from FDA when the manufacturer registers with FDA)
2. Listing information (Listing of the devices the company manufactures—this is done in conjunction with the registration process.)
3. Identity of the initial importer
4. The 510(k) or PMA number for the device

All of this information is communicated by the A of C codes and FDA’s March letter was simply trying to convey that the AofC codes are very helpful to the agency—so what is an AofC code?

AofC stands for ‘Affirmation of Compliance’.  Use of the code conveys the information listed in 1-4 above but goes further—the importer is pledging, affirming, swearing, that the product meets all FDA requirements specific to each code. So the good news is that you may be able to expedite entry of your devices into the US.  The bad news is that there are some devices that do not have AofC codes.  The codes can be found at the end of FDA’s letter.

My associates and I hope that your product is successful whether you are importing your device or manufacturing it in the US.  Contact us with your regulatory needs be it registration, listing or 510(k) or PMA submissions.

Learn more about the services we offer at www.BioTransApp.com.

Regards,

Evelyn

FDA Delays Publication of Menu Labeling Rules

Well, March 23, 2011, the statutory deadline for FDA to publish proposed rules on how to implement the nutrition labeling provisions of the Health Care Reform Act, has come and gone with no rules.  Nation’s Restaurant News reports that in a statement FDA said, ““We expect only a short delay in getting these documents out, and it is a reflection of the complexity of this issue, but most important an indication that the FDA is willing to work with all interested parties to ensure the best policy is presented,” the FDA said. “We are committed to helping the public get clear and simple information about the food they buy and using a common sense approach to implement this law."

Read the entire article at Restaurant News. 

It will be important for the restaurant industry to review the eventual rule and provide comments to try to shape the final rule.  Contact us if you need help submitting comments or for information on how to tackle providing nutrition information on your menus. (You can reach each us by commenting on this blog or by visiting the Bioscience website)

It will be some time before we know whether nutrition information on menus and vending machines will help with America’s obesity problem.  Chances are slim that it will—food and diet are very personal topics and American’s eating habits are also affected by our busy lifestyles.  We expect our bodies to function on whatever we give them without the type of ‘preventive maintenance’ that we do on our cars. Of course, we get information about how to prevent breakdowns of our cars but most information about how to prevent ‘breakdown’ of our bodies with food is considered to be making prohibited claims.  What is the food industry to do?  My answer is: Watch the nutritional genomics literature and lobby congress to work with FDA on ways to discuss the findings with consumers.  Learn more about nutritional genomics here: Nutrigenomics.

Warning Letters: Gelatin and Water as Dietary Ingredients

FDA warning letters continue to provide information that give insight into the level of detail of FDA inspection, which are relatively new to the dietary supplement industry and may help your company avoid problems when your inspection comes up.

In a February 9, 2011 letter to Ancient Formulas of Wichita, Kansas, FDA declared some products misbranded because they did not include a complete list of ingredients.  Specifically the agency noted that the ingredients that make up the capsules were not listed.  Regulations covering ingredient declaration include 21 CFR 101.4, 101.36 and 101.100.  While there are many details in these listings the highlights are as follows:

Ingredients that must be declared:

101.4 (a)(1) Ingredients required to be declared on the label or labeling of a food…shall be listed by common or usual name in descending order of predominance by weight …

101.4 (g) …Ingredients in dietary supplements that are not dietary ingredients or that do not contain dietary ingredients, such as excipients, fillers, artificial colors, artificial sweeteners, flavors, or binders, shall be included in the ingredient list.

Section 101.100 lists ingredients which do not have to be listed: “Incidental additives that are present in a food at insignificant levels and do not have any technical or functional effect in that food.”

In the letter to Ancient Formulas, FDA listed ‘gelatin’ as an example of an undeclared capsule ingredient but depending upon what the capsule supplier lists, there may be need to declare other ingredients.  Softgels often contain colorants and other excipients and most capsules also list water as an ingredient, which should be declared on the label.  

Speaking of water, another dietary supplement manufacturer, Abba Pharmaceuticals of Tampa, Florida, also received a warning letter with the unique citation that they failed to a) establish specifications for water as an ingredient in the liquid dietary supplement product and b) they failed to determine and keep records demonstrating that water used as a dietary supplement ingredient conformed with local, State and Federal regulations and would not contaminate the dietary supplement. (21 CFR 111.15 & 111.23).

Many of you have heard me say that a product label is really a table of contents of how the product was manufactured.  They way ingredients are declared describes how those ingredients were added and mixed. When reviewing your labels, the team at Bioscience Translation & Application looks beyond the label itself to alert you to the regulatory implications for your manufacturing process.  The warning letters discussed above provide examples of why this is important.  Let us help you ensure that your labels are correct and that your processes are FDA compliant.

To read the warning letters in their entirety, visit http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/default.htm#browse and search on the company names.  To read the regulations cited above, search using the section numbers cited at  http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm .

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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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