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Drugs

FDA Issues Warning Letter due to Celebrity Endorsement

The U.S. Food and Drug Administration (FDA) issued a warning letter to Duchesnay, Inc after a social media endorsement posted by U.S. celebrity Kim Kardashian was reported through FDA’s Bad Ad program.  Kardashian published a lengthy post on her Instagram describing her successful experience with Duchesnay Inc’s product DICLEGIS, a prescription morning sickness medicine. “It’s been studied and there was no increased risk to the baby,” Kardashian said in her post.

FDA has strict regulations regarding the promotion of prescription drugs.  Advertisements of drug products may only include information supported by strong evidence and must provide risk information in equal proportion to any benefit information.  A referral to risk and safety information in another location, such as a website, does not fulfill this requirement.

“The social media post is false or misleading in that it presents efficacy claims for DICLEGIS, but fails to communicate any risk information associated with its use and it omits material facts,” FDA said in the warning letter. FDA said Kardashian’s post “suggest[s] that DICLEGIS is safer than has been demonstrated” and therefore misbrands the drug product. FDA requested that Duchesnay Inc either cease misbranding DICLEGIS (remove Kardashian’s endorsements) or stop distributing DICLEGIS in the United States, as distributing misbranded drugs in the U.S. is a prohibited act.

Registrar Corp is a U.S. FDA consulting firm that helps drug establishments navigate FDA regulations.  Registrar Corp offers website and advertisement reviews through which Regulatory Specialists review the text of a drug establishment’s website and advertisements line by line and alert drug establishments of any non-compliance.

For questions or assistance with FDA regulations for advertising drug products or other FDA requirements for drug establishments, contact Registrar Corp at +1-757-224-0177.  Live help is available 24-hours a day at https://regstaging.wpengine.com/livehelp.

U.S. FDA Drug Manufacturer Inspections: What to Expect

On July 16, 2015, U.S. Food and Drug Administration (FDA) Facility Reviewer Denise DiGuilio presented a seminar titled “What to Expect During a FDA Drug Manufacturing Inspection.”  The seminar was part of a two-day regulatory education event held in Silver Spring, Maryland, USA.  During her presentation, DiGuilio discussed the various types of FDA Current Good Manufacturing Practice (CGMP) inspections, how FDA investigators prepare for an inspection, and finally, what to expect during an inspection.

Types of FDA Drug Manufacturer Inspections

There are four types of FDA CGMP Inspections:

  1. Pre-approval – FDA conducts pre-approval inspections before a New Drug Application (NDA) is approved to ensure the listed establishment is capable of manufacturing the drug and that data submitted in the NDA is accurate. FDA will likely request data to support that the processes listed in the NDA are feasible and will confirm whether the manufacturer has contamination and hazard prevention in place.
  2. Post-approval – FDA usually conducts post-approval inspections between 6 and 24 months after an NDA is approved. Post-approval inspections are used to monitor changes in production and control practices.  The extent of a post-approval inspection is determined by a manufacturer’s pre-approval inspection and compliance history.
  3. Surveillance/Routine – FDA conducts routine establishment inspections to ensure that drug manufacturers maintain compliance with CGMPs throughout their lifetime of operation.
  4. For-Cause/Directed – FDA conducts for-cause inspections to investigate specific problems brought to the agency’s attention.  For-cause inspections are typically the result of compliance issues, such as NDA field alert reports, recalls, a cluster of adverse events, etc.

FDA can choose to conduct a full or an abbreviated inspection.  During a full inspection, FDA will inspect a drug manufacturer’s quality system plus three other systems.  During an abbreviated inspection, FDA will inspect the quality system and only one other system.  FDA will always conduct a full inspection for a manufacturer’s initial inspection.   Other reasons FDA may choose to conduct a full inspection include a history of non-compliance, significant changes to the company (new management, new equipment, etc.), or as a follow up to a warning letter.

How FDA Investigators Prepare for an Inspection

Before an inspection, FDA investigators review:

DiGuilio strongly suggested that manufacturers familiarize themselves with these documents when preparing for an inspection, especially the IOM.  She said the documents will help manufacturers understand FDA’s expectations, guide them to relevant regulations, and help them interpret what the regulations mean.

What to Expect

The following steps are indicative of the typical flow of FDA drug manufacturer inspections:

  1.   FDA investigators are required by law to show credentials to the top management official of an establishment being inspected upon arrival.  Management may examine the credentials and record the number and name, but FDA credentials may not be photocopied.  Drug manufacturers located in the U.S. will also receive a Notice of Inspection upon FDA’s arrival.
  2. The lead investigator will state the purpose of the inspection and provide a general overview of the agenda.
  3. FDA investigators will tour the facility. They may ask if anything has changed since the manufacturer’s NDA was approved.
  4. After the tour, FDA investigators will look more critically at the establishment.  They will likely examine incoming raw materials, as well as review equipment logs and other records.  They may even question some employees about their daily work and watch as processes are executed. “Expect your investigators to stand there for an hour watching a sterile process,” DiGuilio said.
  5. DiGuilo suggested that manufacturers ask their investigators to participate in daily wrap up meetings so they can get an idea of how the inspection is going and what else may need to be inspected.  Manufacturers should ask if there is anything they can prepare for the investigator for the next day.
  6. At the end of the inspection, FDA may collect samples, issue an affidavit, or issue an Inspectional Observations Report (FDA Form 483).  At the end of a pre-approval inspection, FDA investigators will inform management of his or her initial recommendations before leaving.  FDA will not provide recommendations at the end of post-approval inspections.  Manufacturers can expect a copy of FDA’s inspection report within a month.

CGMP violations that FDA investigators typically look for include poorly trained employees, poorly maintained or contaminated equipment and facilities, lack of process controls, failure to conduct investigations or resolve CGMP issues and complaints, and more.  FDA will want proof of claims. If a manufacturer claims to be conducting routine maintenance, FDA will want to see documentation.  FDA will want scientific evidence to support conclusions made in various reports.

FDA generally classifies drug manufacturer inspections under one of three outcomes:

  1. Official Action Indicated (OAI) – This means FDA identified significant compliance issues during an inspection that require immediate corrective action.
  2. Voluntary Action Indicated (VAI) – This means FDA identified objectionable conditions or practices, but they do not warrant regulatory significance.
  3. No Action Indicated (NAI) – This means FDA did not identify objectionable conditions or practices.

It’s prudent for drug manufacturers to always be prepared for an FDA inspection.  FDA investigators’ inspection plans are influenced by previous FDA inspection reports and manufacturers’ past responses to 483s and warning letters. The better the outcomes of a manufacturer’s first few FDA inspections, the more likely the manufacturer will endure shorter and more lenient inspections in the future.

Registrar Corp is a consulting firm that helps drug establishments comply with U.S. FDA regulations.  Registrar Corp can help drug manufacturers:

For assistance with U.S. FDA regulations for drug manufacturers, contact Registrar Corp at +1-757-224-0177 or chat with a Regulatory Advisor 24-hours a day at https://regstaging.wpengine.com/livehelp.

U.S. FDA Approval – Common Misconceptions

Registrar Corp is often asked about how to obtain U.S. Food and Drug Administration (FDA) approval for a variety of products.  While FDA has extensive regulations for food, drugs, medical device, and cosmetics marketed in the U.S., many products do not require FDA approval.  In fact, in some cases it’s a prohibited act to claim that FDA has approved a product.  To address common misconceptions, Registrar Corp put together a guide to what products do and do not require FDA approval.

Food

FDA does not approve food, beverages, or dietary supplements.  Food facilities do not have to obtain any type of certification or approval before distributing products in the United States.  Food facilities are required to register with FDA, but being registered with FDA does not indicate approval of the facility or its products.

FDA does approve new food additives.  If a manufacturer wishes to use a new food additive in his product, he will need to put the additive through appropriate testing and prove to FDA that the additive is safe.

Drugs

Whether or not a new drug product requires FDA approval depends on whether the new drug conforms to an over-the-counter (OTC) monograph.  OTC monographs establish conditions under which FDA has pre-determined a drug will be safe and effective.   Once an OTC monograph is final, drug establishments can market OTC drugs that conform to the monograph without FDA approval.  FDA also uses enforcement discretion to allow certain drugs to be marketed without approval if they conform to tentative final monographs.

If a new drug does not comply with a monograph, it will require FDA approval.  Drug manufacturers must conduct lab, animal, and human clinical testing and submit their data to FDA.  FDA will then review the data and may approve the drug if the agency determines that the benefits of the drug outweigh the risks for the intended use.  Marketing a new drug that does not conform to an OTC monograph without FDA approval is considered as marketing an unapproved new drug, which is a prohibited act under the Food, Drug, and Cosmetic Act (FD&C Act).

Though FDA approves new drugs, the agency does not approve compounded drugs. Drug establishments must register with FDA and list their products, but neither registration nor listing indicates approval of the establishment or its products.

Medical Devices

FDA places medical devices into one of three risk-based categories: Class I, Class II, and Class III.  Class III devices are the highest-risk devices and the only devices that require FDA premarket approval.  Manufacturers of Class III devices must demonstrate to FDA that the device provides reasonable assurance of safety and effectiveness.

Class I and II devices do not require premarket approval.  These devices, unless exempt under the FD&C Act, must submit premarket notification (510(k)) to FDA instead.  The purpose of a 510(k) is to demonstrate to FDA that the device is substantially equivalent (as safe and effective) to an already legally marketed device.  If FDA determines that the device is indeed substantially equivalent to a legally marketed device, the agency clears the product for marketing rather than approving it.

Device establishments must register with FDA and list their devices, but neither registration nor listing indicates FDA approval of the establishment or its devices.

Cosmetics

FDA does not require approval of cosmetic products and their ingredients (other than color additives) before marketing.  Cosmetic companies are not required to register with FDA, but cosmetics do have to be safe for their intended use.

It’s important to be aware that certain claims made in cosmetic labeling can cause FDA to regulate a cosmetic product as a drug.  In some cases, this could cause the product to require FDA approval.

Color Additives

FDA does approve color additives used in food, drugs, cosmetics, and some medical devices.  Certain high-risk colors also require FDA color batch certification of every individual batch.   Color additives may only be used in compliance with their approved uses, specifications, and restrictions.  Products that contain unapproved color additives are considered to be adulterated under the FD&C Act.

Manufacturers of drugs and devices that do require approval may include the phrase “FDA Approved” on the product’s labeling, as long as the manufacturer has received a letter from FDA confirming its approval.  The FDA logo should not be used on a product’s labeling whether the product is approved or not.  Use of the FDA logo could imply that the product is endorsed by FDA, therefore unauthorized use of the logo may violate federal law.  Manufacturers who use FDA’s logo on their product labeling may be subject to civil or criminal liability.

Whether their products require FDA approval or not, food facilities, drug establishments, device establishments, and cosmetic companies must adhere to FDA’s Current Good Manufacturing Practices (CGMPs) and extensive labeling requirements. For those products that do require approval, such as certain drugs and devices, labeling is approved when the product is approved.  However, labels are not generally subject to FDA approval.

You may be wondering how FDA enforces its requirements when so many products do not require premarket approval.  FDA enforces its requirements through routine facility inspections and randomized shipment inspections at the U.S. border.

Registrar Corp helps food, drug, medical device, and cosmetic companies comply with U.S. FDA regulations.  Registrar Corp can register a company with FDA, list its products with FDA, and review product labels for FDA compliance.  Registrar Corp can also help submit color additives to FDA for color batch certification.  For any questions regarding FDA regulations, or to learn more about how Registrar Corp can assist, contact +1-757-224-0177 or chat with a Regulatory Advisor 24 hours a day at regstaging.wpengine.com/LiveHelp.

FDA Requires Color Batch Certification for High Risk Color Additives

All color additives must be approved by the U.S. Food and Drug Administration (FDA) before they are used in food, drugs, cosmetics, or medical devices that come in contact with a human or animal body for a significant period of time.  What many people don’t realize is that many of these color additives also require color batch certification, which is obtained by sending a sample of a batch of color to FDA for testing.

Highly synthetic color additives have a higher risk of contamination than other additives.  These additives, for which the U.S. name begins with “FD&C” or “D&C”, are subject to color batch certification.  Color batch certification must be obtained for every individual batch of color by sending a four ounce sample of each batch to FDA.  FDA will then test the sample to ensure any contaminants contained in the batch, such as lead or arsenic, do not exceed the amount allowed.

The fee for color batch certification is based on the weight of the batch.  For straight colors, the fee is $0.35 per pound with a minimum fee of $224. The fee is nonrefundable despite whether the color batch passes or fails the certification testing.

When purchasing a color additive for use in a product that will be sold in the U.S., the purchaser should check to see if the additive requires color batch certification.  If so, the purchaser should request proof of certification before purchasing the additive.  It’s important to use the U.S. name of a color additive when researching whether or not it requires color batch certification.  For example, a commonly used color additive is named “sunset yellow” in Europe.  “Sunset yellow” translates to “FD&C Yellow #6” in the U.S., a color which requires certification.  Similarly, the commonly used additive “Allura Red” is named “FD&C Red 40” and is another that requires certification.

If FDA certifies a color batch, the agency will send the manufacturer a certificate with a lot number.  If a product is shipped to the U.S. and it contains a color additive that requires certification, FDA may contact the owner or his U.S. Agent and ask for the lot number of the color batch.  If the contact cannot provide a valid lot number, the product may be deemed adulterated and may not be allowed into the United States.

FDA has published an import alert for companies with a history of shipping foods that contain illegal color additives, including those that are uncertified.  Any company on the import alert will have its products detained without physical examination at the U.S. border.  It’s important to comply with FDA’s color batch certification requirements to avoid the delays associated with being on an import alert.

For guidance on FDA’s requirements for a specific color additive, or to submit a sample for color batch certification, contact Registrar Corp.

About the Author:  David Lennarz is Vice President of Registrar Corp, an FDA compliance firm located in Hampton, Virginia, USA.  Lennarz served as a Technical Expert for FDA’s Foreign Facility Registration Verification Program and has conducted seminars on U.S. FDA regulations in more than 30 countries around the world.

FDA Label Suggestion for Products Not Made with Latex

On December 2, 2014, the U.S. Food and Drug Administration (FDA) issued a final guidance regarding the labeling of products and packaging that are not made with natural rubber latex.  If a manufacturer wishes to state that his product and its packaging do not contain latex, FDA recommends that he use the following statement when labeling:

“Not made with natural rubber latex.”

The statement is recommended for all FDA regulated medical products (including devices, drugs, biologics, and veterinary products) for which natural rubber latex or any synthetic derivative was not used in the manufacturing of the product, its container, or its packaging.

If only a certain component of a product is not made with natural rubber latex, the manufacturer should adjust the statement to reflect that.  For example, if a syringe was not made with latex, but its packaging was made with latex, the statement should be as follows:

“The syringe is not made with natural rubber latex.”

FDA published the guidance because of the agency’s concern that statements currently being used, such as “latex-free” or “does not contain latex”, are not scientifically supportable and may mislead consumers, which can be dangerous for people who are allergic to latex.  According to FDA, it’s impossible to be sure that a medical product is completely free of the allergens associated with reactions to natural rubber latex.  FDA’s suggested statements inform consumers that a product was not made with natural rubber latex without suggesting that it is completely void of all allergens related to latex reactions.

Registrar Corp can review medical product labels for FDA compliance.  Our Label and Ingredient Review Specialists will cross-reference a product’s labeling with numerous regulatory documents, from the Code of Federal Regulations to guidance documents and warning letters.  Registrar Corp also offers other services for medical product companies, such as registration, listing, and U.S. Agent services.  For more information about Registrar Corp’s services or FDA’s regulations for medical products, contact +1-757-224-0177 or chat with a regulatory advisor 24/7 at https://regstaging.wpengine.com/LiveHelp.

Less than 3% of Companies on FDA Import Alert Red Lists Petition for Exemption

According to U.S. Food and Drug Administration (FDA) records obtained by Registrar Corp through a Freedom of Information Act request on October 20, 2014, FDA received approximately 368 petitions to be removed from an import alert red list in 2013. This may seem like a substantial amount, but there are approximately 13,000 companies currently on FDA import alert red lists. Along with this, only 165 companies petitioned to be added to an import alert green list in 2013.

What is an Import Alert?

An import alert occurs when FDA determines a pattern of non-compliance from a specific company, country, or a specific type of product. Products that fit the criteria of an import alert are subject to Detention Without Physical Examination (DWPE). Products subject to DWPE will be detained at the U.S. border without being examined by FDA. The importer or exporter of the product must then prove to FDA that the shipment is compliant in order for the product to be released into the United States.

What are red and green lists?

A red list contains all the companies that FDA has specifically identified as having a history of violation and are therefore subject to DWPE under a certain import alert. For example, FDA Import Alert 45-02, “Detention Without Physical Examination and Guidance of Foods Containing Illegal and/or Undeclared Colors,” currently lists approximately 1,750 unique companies with products to be detained when shipped to the United States.

When an entire product type or region has a history of violation, FDA may create an import alert to cover all shipments of that product or from that region. These broad import alerts may have a green list, a list of companies that meet the criteria of an import alert, but have proven they are suitable for exclusion from DWPE. For example, FDA noticed a pattern of adulteration in shrimp coming from India in 1979. In response, FDA created Import Alert 16-35 to cover all shipments of raw and cooked shrimp from all manufacturers in India. An Indian facility can, however, petition FDA to be added to the green list of this import alert if it is able to prove that adulteration will not be a concern with its products.

Petitioning for removal from an Import Alert

When a company finds its products are subject to DWPE due to an import alert, the company can petition to be removed from a red list or added to a green list, whichever is relevant for the particular alert. The petition process typically has three steps:

  1. Acompany must analyze its business to determine whether adequate preventive controls or corrective actions are in place to remove the appearance of violation.
  2. The company will need evidence that its preventive controls or corrective actions are effective over a reasonable period of time. At minimum, FDA will require proof of five to twelve cleared, non-violative shipments of the product on import alert to the United States.
  3. Lastly, the above evidence must be organized into a petition and submitted to FDA’s Division of Import Operations.

So why do such a small percentage of companies on import alert petition FDA? Many companies simply don’t know that petitioning is an option. For those that do, many are intimidated by the petitioning process. Import alert petitions are often extensive and complicated, requiring hundreds of pages of supporting documents. Though it’s a daunting process, petitioning FDA is worth it for most companies. Dealing with detentions can be a huge expense for companies, both directly and indirectly, and can stress the relationship between an exporter and importer. Companies often go through the petition process even if they don’t ship to the United States because they feel that being listed on an FDA import alert may negatively affects their corporate image and brand.

Registrar Corp Regulatory Specialists are highly experienced in obtaining and properly organizing the necessary documentation required for a successful import alert petition, and can assist companies on import alert through the petition process. For assistance with import alerts and detentions, contact Registrar Corp at +1-757-224-0177 or speak with a Regulatory Specialist 24 hours a day at: https://regstaging.wpengine.com/LiveHelp.

This blog was originally published as a press release.