By Edward R. Arling, Senior Director, Biopharma Quality Assurance, Pharmacia Corp.; Ralph L. Dillon, Director of Quality Engineering, Biopharma Quality Assurance, Pharmacia Corp.; Joseph F. Noferi, Director, Quality Assurance, Compliance and Validation, Biopharma, Pharmacia Corp.
This past October, the pharmaceutical industry marked an important anniversary. Twenty years ago in Chicago, seven innocents, ranging in age from 12 to 31 years, lost their lives to tampering. Someone (there has been no conviction to date) had laced Tylenol capsules with potassium cyanide and left packages containing those tampered capsules on retail shelves for consumers to purchase. Tragically, three victims were from one family and had reached for the same poisoned bottle of analgesic after the first family member died.
Today, pharmaceutical products are still in danger. This despite Congress's 1983 Federal Anti-Tampering Act, which provides felony penalties for tampering with or threatening to tamper with any product covered by the Food, Drug and Cosmetic Act, and despite FDA's tamper-evident packaging regulations. First, these regulations only affect consumer products, leaving some prescription drugs without any visible evidence of tampering. Second, with some of today's biopharmaceutical products costing in excess of $2000-$3000 per gram (300 times the price of gold) to produce, some criminals (and even pharmacists, in last year's case of the Kansas City pharmacist found guilty of diluting and distributing cancer drugs) are tampering for profit. Finally, since pharmaceuticals are critical to the social, economic, and political stability of the United States, they are vulnerable targets for terrorism.
The pharmaceutical industry must therefore secure the supply chain using modern technology to protect all stakeholders--patients and manufacturers alike.
The U.S. government recognizes the threat of tampering and counterfeiting. Through nationally commissioned working groups and the Homeland Defense Initiative, proposals are being made for the design and implementation of technologies that can combat and detect tampering.
As a result of the Bioterrorism bill, FDA has been authorized by Congress to hire an additional 4000 employees in the Office of Regulatory Affairs, more than 880 of whom will be investigators trained to respond to bioterrorism and counterfeiting, and to protect food, drug, and medical device supplies. New enforcement powers have been granted to FDA by Congress that allow immediate seizure and embargo of any regulated item suspected of adulteration, tampering, or counterfeiting. New alliances are being forged with state and local municipalities for enforcement and increasing the size of mobilization forces. Foreign inspections of food will be increased, and routine pharmaceutical plant inspections are being increased.
But no government can detect every instance of tampering and protect every consumer. The laws and regulations have been in place for the past 20 years, yet evidence of counterfeiting is increasing. In a perfect world, the control of counterfeiting would be through the application of due process of law. But to do so, pharmacists, wholesalers, government agencies, and pharmaceutical companies must all cooperate to ensure that suspected counterfeits are thoroughly investigated and counterfeiters prosecuted.
Also, there is no unified world authority to promulgate investigations, nor a world tribunal for enforcement. Consequently, pharmaceutical firms themselves must augment legal approaches with alternative ones to protect industry, stakeholders, and consumers. Industry must go beyond the tamper-evident regulations to ensure package integrity.
The first step is to institute higher security and controls. Solutions must be crossfunctional, affirmative, and proactive. Company personnel from packaging, intellectual property, marketing and sales, regulatory affairs, quality, operations, and corporate security must be involved. Manufacturers must make it easy to recognize product authenticity and tampering. A specific "fingerprint" is needed for each vial, drum, shipping container, and label. Unique identifiers, like bar codes, for each and every SKU coming out of the plant shipping dock should be in place, revealing site of manufacture, packaging, storage, distribution, repackaging, handling, testing, etc.
Products also should include multiple layers of tamper evidence. These may include seals that need to be removed, features that must be broken, or permanent measures such as color, taste, and fragrance that are part of the product itself. All these measures need to be integrated together to provide protection at each of three levels: overt, covert, and reserved.
Overt tamper-evidence features are those that a consumer or stock clerk would notice, like the foil/plastic seal on a blister package of tablets. If the features are compromised, typically a stock person will set the product aside, and if consumers see it on the shelf, they will not buy it. Covert tamper-evidence features are those that are not published or are typically unknown beyond select groups of employees. For instance, lot numbers could show that a product does not fit the appropriate pattern for legitimately distributed product. Other tools include codes whose color spectrum is only visible under UV light, or special-coded label words/symbols visible only with special viewing devices. Finally, reserved features are those that are unveiled only on a need-to-know basis. Typically they are not discussed beyond a small, select group of people and are not written into product specifications in an obvious way. A reserved feature may be something as simple as a process-inherent trace compound that would normally not be present should another pharmaceutical ingredient supplier be used. The important concept to understand is that there should be multiple defensive layers in each of the three areas of tamper evidence. A bottle with a breakaway tamper-evident cap might also have a glue-sealed carton and contents with a unique, difficult-to-duplicate fragrance.
Tamper evidence needs to be applied at every level of packaging or containment because every level offers an introduction point for tampered product. The levels for tamper evidence start with the largest unit (the warehouse building) and need to be applied at each package configuration level down to the dosage itself.