The US Food and Drug Administration announced plans to revise CGMP regulations.

By: Angie Drakulich. This story is courtesy of ePT–the Electronic Newsletter of Pharmaceutical Technology.

The US Food and Drug Administration announced plans to revise the current good manufacturing practice (GMP) regulations at a conference held jointly by the agency and Xavier University in Cincinati, Ohio, June 13-16. Brian Hasselbalch, representing the Office of Compliance’s Division for Manufacturing and Drug Product Quality within FDA’s Center for Drug Evaluation and Research, was speaking as part of the first joint annual Global Outsourcing Conference at the school.

According to Haselbalch’s presentation, which is available on the Xavier website, a draft of new CGMP regulations focusing on component controls is expected before the year’s end. Potential revisions include requiring pharmaceutical manufacturers to physically audit their suppliers (i.e., no more paper audits), test containers in each shipment received, implement tamper-evident packaging and security features, notify FDA of contaminated shipments and lots, and to use only those components recognized as safe for their intended use or listed in an already approved application.

In addition to increased enforcement and information-sharing, FDA also plans to play a stronger “guiding role” in corporate responsibility. Hasselbalch offered some recent guidance documents as examples of FDA’s role in encouraging corporate responsibility: process validation, pharmaceutical quality systems, and testing of glycerin for diethylene glycol. It seems the agency will go even further by issuing a second phase of revised CGMP regulations that focus specifically on corporate responsibility. These revisions might include requirements that management assures compliance, performs self-inspections, evaluates and investigates problems, implements change control, and documents training and effectiveness, according to the presentation.

What’s behind the proposed changes? Hasselbalch’s presentation noted growing gaps in quality control caused by factors such as globalization, new technologies and processes, distribution challenges, and increased outsourcing of production. Between 2001 and 2007, he pointed out, the number of products manufactured outside the United States and the number of manufacturing sites abroad doubled. Some of the new products being imported into the US come from countries with “less developed regulatory systems,” according to the presentation. Along with these more complex supply chains, there has been an increase in pharmaceutical cargo thefts and in drug counterfeiting. More preventative measures are therefore needed.

Industry will have a chance to comment on the proposed revisions once they are issued.

Note: On June 24, 2010, an FDA press officer clarified that the agency is “considering requiring finished pharmaceutical manufacturers to conduct on-site audits of the original manufacturers for components (i.e., ingredients) that they use in manufacturing.”

The End.

Digest Break – Quotes To Make You Think.

“When everything seems to be going against you, remember that the airplane takes off against the wind, not with it.” — Henry Ford

“Make crime pay. Become a Lawyer.” — Will Rogers

“Few things are more satisfying than seeing your own children have teenagers of their own.” — Doug Larson

Today’s Topics – FDA Q&A. Counterfeit Prescription Drugs.
In the fight against counterfeited prescription medicines, don’t bury your head in the sand. Expect the unexpected. Listen for evil, look for evil, and blow the whistle when you encounter evil.

FDA Questions And Answers. Q. What is the definition of a counterfeit drug? A. U.S. law defines counterfeit drugs as those sold under a product name without proper authorization. Counterfeiting can apply to both brand name and generic products, where the identity of the source is mislabeled in a way that suggests that it is the authentic approved product. Counterfeit products may include products without the active ingredient, with an insufficient or excessive quantity of the active ingredient, with the wrong active ingredient, or with fake packaging.

Donfucius Note: As they dilute or divert legitimate products, counterfeiters also make false and wild claims. In the illustration below, would you rather go camping at a three star campground, five star campground, or fourteen-star campground? There is an old phrase that says: “Let the buyer beware”. In most cases, you will get what you pay for: “The bitter taste of poor quality lingers long after the sweet taste of price has evaporated” (Donfucius).

Q. What risks are involved with taking counterfeit drugs?
A. An individual who receives a counterfeit drug may be at risk for a number of dangerous health consequences. Patients may experience unexpected side effects, allergic reactions, or a worsening of their medical condition. A number of counterfeit products do not contain any active ingredients, and instead contain inert substances, which do not provide the patient any treatment benefit. Counterfeit drugs may also contain incorrect ingredients, improper dosages of the correct ingredients, or they may contain hazardous ingredients.

Q. What can consumers do to protect themselves from counterfeit drugs?
A. Consumers can protect themselves from the risks associated with counterfeit drugs by purchasing prescription medications from state-licensed pharmacies in the U.S. Consumers must be vigilant when examining their personal medications, paying attention to the presence of altered or unsealed containers or changes in the packaging of the product. Differences in the physical appearance of the product, taste, and unexpected side effects experienced should alert the patient to contact their physician, pharmacist, or other healthcare professional who is providing treatment.

Donfucius Note: Ortho Biotech Products issued a warning to health care professionals about the existence of counterfeit vials of its anti-anemia drug Procrit. The concentration of the active ingredient was 20 times lower than what was listed on the label. The two photos (below) show the boxes of the authentic (top) and counterfeit (bottom) product. The counterfeit boxes could be identified by the text running off of the right side of the box. The average consumer would probably not notice this. ATL Pharma Security Label Systems is cGMP compliant. We operate under the strict regulations of 21 CFR 210 and 211. This means we must hold tight registration for both commercial pharmaceutical labels and clinical trials. It is our suggestion that you always buy your brands from reputable companies with anti-counterfeiting protection.

Q. How does FDA work with domestic and foreign government agencies to combat counterfeits?
A. FDA is currently working with various U.S. government agencies, such as the Department of Homeland Security (Customs and Border Protection) and the Department of Justice, to combat counterfeit drugs. FDA is also very active in WHO’s International Medical Products Anti-counterfeiting Task Force (IMPACT) which is a public/private effort to develop regulatory, legislative, enforcement, communication, and technological tools to combat counterfeit drugs around the world. FDA also works bilaterally and multilaterally with individual countries and regions.

Q. Are there any promising technologies that have the capability of preventing counterfeiting?
A. There are several technologies that may prove helpful, including radio frequency identification (RFID) chips and taggants. For example, radio waves are used to automatically read RFID tags that are contained on items, such as pharmaceutical products. These tags could have individual serial numbers on each product, thus allowing the product to be tracked and traced through the supply chain. Appropriate implementation and use of this technology can help decrease the opportunities for diversion and counterfeiting by allowing wholesale distributors and pharmacies to authenticate that the product was handled by legitimate, licensed entities in the drug supply chain.

The fight against counterfeited drugs. Below are two photographs of counterfeited drugs. The average consumer will have a very difficult time telling apart the real from the fakes.

You (as a brand owner or as a consumer) must be able to rely on the labeling/ packaging integrity to identify (thus stop) counterfeiting. ATL has nine trademarked products that provide a mix and rotate (M&R) approach (during sequential production runs) for anti-counterfeiting protection. These include: SecurLock: Tamper-Evident breakaway closure; SecurDetek: Invisible, Hidden Page Marker; SecurMark: Anti-Counterfeiting holograms; SecurStretch: Tamper-Evident Unit Closure; SecurPly: Booklets for soft squeeze tubes; PharmaVoid: Security Closure/ Destructible Tapes; Triple-Ply: Three-Tier overt and / or covert levels of anti-counterfeiting; D2 WAO: Wrap-Around style (up to 35 panels) that fit most cylinders – (U.S. Patent Applied For). Below is an example of ATL’s SecueDetek. This label features an invisible, non-degradable (to 3,000 degrees centigrade) digital forensic code. With this system you can authenticate (anywhere in the world) in one second.

Thus far, the counterfeiting targets discovered in the United States have been largely the popular and expensive “high-value pharmaceuticals”-cancer drugs, performance-enhancing growth hormones, drugs used to treat AIDS, and Viagra. In other parts of the world, however, anti-malaria drugs, antibiotics, and even common analgesics have become counterfeiting targets.
According to the international police agency Interpol, at least 5% of the world pharmaceutical trade involves counterfeit drugs, and up to 60% of medicines in the developing world may be counterfeit. Not only has this cost the drug industry more than $12 billion annually, but it has also resulted in an untold number of deaths. This vulnerability was illustrated when 109 Nigerian children died after taking counterfeit paracetamol (acetaminophen) syrup.

Although many-if not most-counterfeit drugs are manufactured and distributed in India, China, Brazil, South Africa, and Russia, they are poised to make their way to the U.S. market. That is because they are increasingly turning up at pharmacies in Mexico and other intermediary countries and through difficult-to-trace online pharmacies. As a growing number of Americans attempt to save money by purchasing their medication in Canada, Mexico, and other foreign countries or through the Internet, the number of counterfeit or adulterated drugs making their way into the U.S. market is potentially staggering.

ATL strongly suggests that you protect your brands. In so doing you will be protecting the public. Coach Pat Riley said it best: “There’s no such thing as coulda, shoulda, or woulda. If you shoulda and coulda, you woulda done it.”

Question. Do I have to notify FDA before I start to use covert markings or materials in my labels?

Answer. The current labeling requirements for pharmaceuticals are part of 21 CFR Parts 210 and 211 – Current Good Manufacturing Practice In Manufacturing, Processing, Packing or Holding of Drugs; General and Current Good Manufacturing Practice For Finished Pharmaceuticals. These are the cGMP’s (Current Good Manufacturing Practices).

The cGMP’s deal mainly with overt labeling features. These include, but are not limited to:
Written procedures designed to assure that correct labels, labeling, and packaging materials are used for drug products. These written procedures must be followed. These procedures incorporate the following features:
(a) Prevention of mixups and cross-contamination by physical or spatial separation from operations on other drug products.
(b) Identification and handling of filled drug product containers that are set aside and held in unlabeled condition for future labeling operations to preclude mislabeling of individual containers, lots, or portions of lots. Identification need not be applied to each individual container but shall be sufficient to determine name, strength, quantity of contents, and lot or control number of each container.
(c) Identification of the drug product with a lot or control number that permits determination of the history of the manufacture and control of the batch.
(d) Examination of packaging and labeling materials for suitability and correctness before packaging operations, and documentation of such examination in the batch production record.
(e) Inspection of the packaging and labeling facilities immediately before use to assure that all drug products have been removed from previous operations. Inspection shall also be made to assure that packaging and labeling materials not suitable for subsequent operations have been removed. Results of inspection shall be documented in the batch production records.

As for pharmaceuticals and tamper-evident packaging: Each manufacturer who packages an OTC drug product (except a dermatological, dentifrice, insulin, or lozenge product) for retail sale must package the product in a tamper-evident package, if this product is accessible to the public while held for sale. A tamper-evident package is one having one or more indicators or barriers to entry which, if breached or missing, can reasonably be expected to provide visible evidence to consumers that tampering has occurred. To reduce the likelihood of successful tampering and to increase the likelihood that consumers will discover if a product has been tampered with, the package is required to be distinctive by design or by the use of one or more indicators or barriers to entry that employ an identifying characteristic (e.g., a pattern, name, registered trademark, logo, or picture).

The term “distinctive by design” means the packaging cannot be duplicated with commonly available materials or through commonly available processes.

Photos Below: “Distinctive By Design” examples from August 13, 1776. This New York ten dollar bill had a distinctive pattern on the back. Please note the penalty that was printed on the bill: “Tis Death To Counterfeit”.

A tamper-evident package may involve an immediate-container and closure system or secondary-container or carton system or any combination of systems intended to provide a visual indication of package integrity. The tamper-evident feature must be designed to and must remain intact when handled in a reasonable manner during manufacture, distribution, and retail display.

Covert features lack the standardization that you would find in cGMP’s. To my knowledge, the FDA supports covert features, but there are no standards that are mandated. This is why “The International Organization of Standardization” (ISO) has approved the creation of a new Technical Committee (TC) on fraud countermeasures and controls to help address development of standards related to combating fraud. The TC, proposed by the American National Standards Institute (ANSI) in conjunction with the North American Security Products Organization (NASPO), focuses on the development of standards in the areas of brand and intellectual property protection, identity management, and financial fraud.

The proposal, identified as ISO/TS/P 206, hopes to bring together fraud experts, law enforcement, government agencies, criminologists, brand owners, and solution providers to develop relevant security standards for the use of private industries and governments worldwide. ISO recognition and support from other international standards organizations will help to counter the rising financial and social cost of worldwide fraud activity.
The new committee provides a framework to engage international fraud experts with existing ISO technical committees to create solutions to complex issues. Standards will affect parties concerned with brand protection, intellectual property, drug counterfeiting, supply chains for products of value, authentication of goods, food supply chains, identity credentials, identity management, identity theft, customs and immigration enforcement, and financial fraud. Although the scope may appear broad, it effectively addresses the wide variety of fraud throughout industry segments.

So, for now, the FDA is concerned with 21 CFR 210 and 211. These standards do not encompass covert features.

Notable & Quotable: “Your true value depends entirely on what you are compared with.” — Bob Wells