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Issue link: https://lifescienceleadermag.epubxp.com/i/233442
Pharma Manufacturing cGMP Issues Are Increasing B By Gail Dutton, contributing editor ig Pharma and small companies alike are failing when it comes to cGMP violations. The increasing number and complexity of global regulations, outsourcing, price pressures, and compressed time to market all contribute to these failures. Consequently, the number of compliance issues is expected to rise. Between January 2010 and June 2013, the FDA issued 67 warning letters about cGMP compliance, affecting some of the world's largest and most reputable companies, including Bausch & Lomb, Bayer, Genentech, GSK, J&J;, Sandoz, and others. During that time, API concerns decreased while finished product issues increased, according to the recent CPhI Annual Industry report. After looking at drug recalls, withdrawals, and safety alerts, CPhI reported 178 incidents involving 120 companies. According to that data, 27 percent of the warning letters concerned undeclared ingredients, while 21 percent involved visible particulates, and another 21 percent were triggered by contamination. LETTERS QUESTION DATA INTEGRITY The increase in warning letters may be part of the normal political climate, notes Jim Stumpff, principal consultant at PAREXEL, a large CRO. "The FDA regulatory pendulum swings from very aggressive to less aggressive stances," he adds. Others attribute the increase to the new scrutiny of compounding laboratories after last spring's meningitis outbreak. Before the outbreak, compounders were regulated only by state boards of 42 LifeScienceLeader.com pharmacy. Because they are new to FDA regulations, they are experiencing a high number of cGMP discrepancies. However, the increase began before the outbreak. Many of the FDA warning letters cite a procedural lapse or a lack of data integrity. "There are many instances in which there's no known problem, but the FDA is concerned that procedural lapses will lead to future problems," notes Jonathan Berman, partner at the law firm Jones Day. Berman, who analyzed FDA warning letters last spring, found that most of the adulterated products worked properly and conformed to release specifications. His analysis determined the FDA cited procedural flaws more frequently than actual product failures. "Four of the seven most common violations relate to failure to establish written procedures," Berman says. Other common issues include a failure to develop written responsibilities for quality control units, failure to investigate out-of-specification batches, and the use of laboratory controls that have not been validated. "Data issues range from being unable to produce the raw data to support information analysis certifications and submissions, to outright falsification of batch records, bioequivalency testing, or other data," Stumpff says. "This is an across-theboard issue. The EMA is talking about it, too. The problem could be as simple as January 2014 a single employee who falsifies data." He recommends performing a robust data integrity evaluation. For example, "When a batch is released, quality assurance often sees only the test results. It trusts that the data provided by their lab showing sterility, pH, compound identity, etc. are accurate and that the tests were performed correctly. But, unless you examine the raw data, you don't know whether you have issues." REGULATORY COMPLEXITY INCREASES RISK The growing number of regulators, globally, who have slight variations in their requirements contributes to the complexity of cGMP issues even within major markets. "As companies go after business in newer markets that are developing their own health authorities and regulations, they must serve many masters," points out Amy Flynn, senior consultant at TayganPoint Consulting Group. That makes it easy for details to be overlooked. The increase in global regulatory noise makes it imperative for regulators to express their requirements clearly. "Inadequate dissemination of the regulatory requirement by the regulator and frequent changes in the requirements contribute to the increase in FDA warning letters," says Dilip Shah, CEO at Vision Consulting Group. Frequent regulatory changes leave