Big 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 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 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 little time for employees to absorb those changes, he explains.
“With all the data and information available, really understanding it is critical. So many competing regulations are creating complexity in the normal business process; they become distracting,” according to Pat Horstman, senior consultant at TayganPoint Consulting Group.
Market pressures also contribute to the rise in cGMP issues. In addition to the rush to commercialize a product, there is significant pressure from customers to reduce products’ sales prices. “Coupled with the increasing costs of raw materials, solvents, and energy, this can result in internal pressure to reduce manufacturing costs,” says Catherine Dick, Ph.D., site manufacturing manager at Aesica Pharmaceuticals Ltd. “In this situation, the quality systems need to be robust enough to withstand that pressure and to ensure that compliance standards are maintained.” She advises insisting upon realistic pricing. “Don’t undercut prices just to win business.” She also advocates ensuring that there is full understanding of the need for quality, giving realistic timings, and explaining why that extra week or month is necessary and not just a luxury.
Systematic Vetting is Needed
The areas of greatest regulatory risks often are the areas outside the developer’s immediate control — suppliers or contract service providers, according to Ian Markwell, VP of quality and “qualified person” (his real title) at Almac Pharma Services Business Unit. “It’s not the use of the contract service providers, per se, which has fuelled this increase in GMP issues, but rather variation in the application of GMP standards at the contract service providers, which are then identified as significant GMP issues during regulatory inspections and result in warning letters or critical deficiencies being raised.” To combat those variations, Markwell says, companies need to develop a systematic approach to select contract service providers. This should include assessing the provider’s regulatory history and quality standards as well as contractual and financial considerations.
Additionally, Dick says, “Companies should have a well-structured process for identifying, documenting, and assessing quality risks associated with manufacturing activities, facilities, and systems, and have an achievable plan to mitigate those risks.” This points to the need for risk-based analyses that factor experience with the compound into the product’s risk profile.
Dick also points to the rise in aseptic and parenteral therapeutics as an area of potential cGMP concern. “Because they have limited manufacturing options, there is concern those facilities are being overloaded.” Aging facilities and equipment pose another potential risk.
Assessments should go beyond manufacturing to include a comprehensive supply chain risk assessment that fully documents the shipping route and handoffs to identify and prioritize potential risks. Because materials typically pass through several locations and multiple parties before reaching their destination, there is ample opportunity for contamination.
API identity testing typically is performed with chemical tests. To that, Stumpff adds, “Consider additional tests, such as checking the specific packaging format used for the API and the use of numbered security seals on drums, which help confirm the API has not been tampered with prior to receipt.”
“Regulators don’t spend much time evaluating clinical batches,” Stumpff continues. “Clinical batches tend to fly under the radar. Therefore, process issues may slip through to manufacturing. Humidity control is an example. A company may make a product for clinical trials without realizing they need humidity controls until they are making commercial batches, and the validation batch fails for lack of potency.”
Attitude Changes Needed
According to Dick, manufacturers need to accept that investing in both people and facilities will have long term benefits for all stakeholders. Shah expressed that sentiment in the CPhI report, writing, “The growing trend toward zero tolerance will necessitate changes in attitude and culture across an organization.” In an interview for this article, he added, “What is needed is not more controls. Regulators can no longer be just inspectors or forensic auditors.”
Instead, he advocates expanding regulators’ advisory roles, using them as guides to train managers, who then train workers who are “engaged, directly or indirectly, in manufacturing and testing products for export to the U.S. The industry puts more emphasis on process and hardware compliance than on explaining the issues to employees and ensuring they understand their rationale.”
Unless employees understand the rationale for specific procedures, asking them to follow those procedures may not produce the best results in compliance. Horstman advises writing clear standard operating procedures that are heavy on visuals — for local as well as international facilities. Often regulatory specialists write the SOPs from a technical perspective, making them hard for workers to understand. To compound the matter, the SOPs may not address the rationale for the procedures. Explaining the reasons for certain procedures provides context and allows employees to think critically. “Think from the user’s perspective,” Horstman says. “The best solutions often are the simplest.”
Many Big Pharma companies are outsourcing manufacturing, regulatory compliance, and other functions as they downsize. That means there are fewer people in-house to focus on any given area, Flynn points out. “The most successful companies face the challenges head on,” she says. “They bring their knowledge and experience as a large company to bear, partnering with their CMOs, working as a team.”