IV. THE PRODUCT AND ITS CONTROL
All industrial democracies have established regulatory regimes to control the testing, manufacture, and marketing of pharmaceutical, biological, and medical device products. The harmful side effects of products such as thalidomide demonstrated that consumers and health care professionals cannot fully evaluate the safety of products that they use on a daily basis, and that liability law may not always provide sufficient additional incentives for manufacturers to test for and maintain the highest standards of quality control.[15] Government regulation attempts to fill that gap for therapeutics by requiring extensive premarket research and testing concerning the safety, quality, and efficacy of new pharmaceutical and biological products, as well as controls on sanitary conditions and quality assurance during manufacture.
Governments impose special regulations on the manufacture and approval of biologics because, compared with pharmaceuticals, they are chemically less stable, more heat-and shear-sensitive, difficult to assay, and more subject to contamination. Contaminated intravenous medicines can rapidly spread disease and even cause death. In the early 1980s, many French patients became infected with the AIDS virus from contaminated blood banks. As recently as 1995, 350 people worldwide contracted hepatitis from a biological drug treatment for immune deficiency.[16] Thus, in the United States, the regulation of biologics manufacture is more stringent than for pharmaceuticals; special attention is paid to the cleanliness of the production area, the operation of the equipment, and the control of the manufacturing process.
Genetically engineered blood products, employing recombinant DNA (rDNA), are less reliant on provisions of donor blood and provide a solution to the problem of viral contamination. The novel techniques, however, raise new questions. Do rDNA-derived products deviate from or contain contaminants not normally present in their conventional equivalents? In response, many countries have imposed special regulatory procedures for genetically engineered biologics and drugs. In 1985 the FDA issued Points to Consider in the Production and Testing of New Drugs and Biologicals Produced by Recombinant DNA Technology, which described the information needed to evaluate the expression system, host cells, and manufacturing procedures for products prepared by rDNA techniques.[17] In 1987 the EU established a new mandatory evaluation procedure for all high-technology medicinal
Development of a new chemical entity (NCE) or biological agent, including approval by the regulatory authorities, takes on average seven to ten years and entails a cost of $100 to $250 million. The regulatory process includes initial preclinical studies in animals, three phases of clinical studies in humans, and the submission of the license application to the regulatory authorities. While carrying out its clinical studies, the company operates a pilot manufacturing plant to provide material for the trials. Regulatory authorities closely monitor the company's methodology and test results, demanding proven results in each phase before allowing the company to move on to the next level of investigation. The regulators also request proof of proper operation of the pilot manufacturing plant.
A. Company Y's Recombinant Coagulation Factor
The product is a new antihemophilic factor, administered to hemophiliacs as an important cofactor for the coagulation of human blood. Until recently, the antihemophilic factor was produced from human plasma. Millions of liters of freshly donated blood plasma had to be obtained and processed every year. The new genetically engineered product, however, relies primarily on a constant supply of the cell culture from the manufacturer's cell bank and an ongoing fermentation process.
Manufacture entails three main steps—fermentation, purification, and finishing—each of which requires extremely high levels of purity and process control. The fermenter is operated, under sterile conditions, for up to six months, during which the culture fluid containing the recombinant coagulation factor is removed and fresh culture fluid is added. To assure the exact reproducibility of the recombinant protein, a variety of culture parameters are monitored and controlled.[19]Purification entails a number of steps that increase the concentration of the coagulation factor, eliminate impurities, and remove or inactivate any viruses that may have been inadvertently introduced into the manufacturing process.[20] The highly purified coagulation factor is then stabilized for longer shelf life by adding (plasmaderived) albumin. Regulatory authorities are interested in the capacity of the purification process to achieve the desired “clearance” (level of impurities), the manufacturer's justification for that level of clearance, and the consistency with which that level can be maintained in long-term production. All control tests, as well as the data from all preclinical and clinical
B. Why Regulation?
Manufacturers of biologics are part of an industry that has strong incentives for strict quality control. Biologics are easily contaminated, with serious consequences for the patient. No company can afford a widely publicized injury to a patient; the adverse reputational effects of putting an unsafe product on the market may hurt all of a company's products and create shortages for patients. In addition, the industry operates under strict liability law and is susceptible to multiple million dollar lawsuits. The industry competes not only on the basis of price but also on the basis of quality, as the products are paid for primarily by a vast array of health insurance arrangements. Finally, any scandal in the new biotechnology industry will affect the entire industry. In that sense, manufacturers of biological and particularly genetically engineered products are hostages of each other; a public health disaster or panic caused by quality control weakness in one company could conceivably destroy trust in the product and ruin the market for all producers.[21] Hence, even aside from product regulation, corporate quality assurance officials in the manufacturing companies are granted powers to prevent shipment and to demand further testing or process changes.
Nevertheless, government and company officials alike believe that government regulation and product license applications are not redundant. Even if most firms are very conscientious, companies with unreliable safety controls may end up hurting a consumer, and thus the reputation of the entire industry. In addition, company officials point out that regulatory agencies review many applications and are in a position to compare, recommend, or require the most effective quality assurance procedures, pushing the industry toward higher standards. Similarly, cGMP (current Good Manufacturing Practices) compliance inspectors provide an extra set of eyes that help prevent and identify deficiencies in company manufacturing controls. This is particularly important when introducing new technologies with yet unknown risks. Finally, company officials claim that regulation increases consumer confidence and legitimizes the end product.[22]