GMP Failures: Ignorance or Arrogance?
Transcription
GMP Failures: Ignorance or Arrogance?
A U D I T O R TA L E S . E XPERIENCES FROM THE PHARMA FIELD GMP Failures: Ignorance or Arrogance? BACKGROUND: MARTIN POOLE/GETTY IMAGES Michael H. Anisfeld “Auditor Tales” provides a forum for readers to share their auditing experiences–good or bad–and discuss how to address deficiencies. It is our hope that these discussions serve as learning tools for others in the field. We welcome any thoughts, concepts, ideas, and experiences. Please e-mail your input to managing editor Susan Haigney at [email protected]. INTRODUCTION The litany of major multi-national pharmaceutical companies failing to follow US Food and Drug Administration regulations for good manufacturing practice (GMP) keeps going on and on. In 1999, Abbott Laboratories was fined US$100 million. In 2002, Wyeth-Ayerst was fined US$30 million, and Schering-Plough was fined US$ 500 million. And in October of 2010, GlaxoSmithKline (GSK) was fined US$750 million for failing to manufacture drugs in accordance with GMPs at its Cidra, Puerto Rico facility. GMP problems are not limited to the US pharmaceutical industry. During 1999-2010, serious GMP failings occurred at Chiron in the UK and Pan Pharmaceuticals in Australia, to say nothing of the legion of other companies in other countries with GMP problems that never hit the headlines. It would be easy to assume that because GMP regulations have been around for approximately 50 years, the pharmaceutical industry would know what is expected. The situation that led to GSK losing a US$750-million lawsuit was multi-layered and involved personnel in all levels of the company. In taking a look at GSK’s story and their relationship with FDA, what can the rest of us learn from their experiences? THE GSK STORY In March 2005, FDA seized shipments of Paxil CR and Avandamet tablets from distribution and manufacturing facilities operated by SB Pharmco, a subsidiary of GSK located in Cidra, Puerto Rico and Knoxville, Tennessee (1-5). “In a response to ongoing concerns about manufacturing quality, FDA and the Department of Justice initiated seizures of Paxil CR and Avandamet tablets manufactured by GlaxoSmithKline, Inc. (GSK). Manufacturing practices for the two drugs, approved to treat depression and panic disorder 24 Journal of GXP Compliance Michael H. Anisfeld (Paxil CR) and Type II Diabetes (Avandamet), failed to meet the standards laid out by FDA that ensure product safety, strength, quality, and purity,” FDA stated (1). FDA had found that Paxil CR tablets could be split apart, potentially leading to the absence of the active ingredient or controlled-release factor, while some Avandamet tablets had the incorrect dose of one active ingredient. As a result of inspections in 2003 and 2004, GSK agreed to recall certain batches of these products. FDA wanted to extend the recall to other batches of Paxil CR and Avandamet. GSK did not agree to do so, which led to the March 2005 publicly announced seizures by the Federal Marshal Service at FDA’s request. GSK signed a consent decree with FDA in May 2005 (2), posting a US$650-million bond to guarantee destruction or rework of existing defective product, and leaving the company open to fines in addition to the estimated US$300 million lost in interrupted sales. In October 2010, the US Justice Department stated in a press release (3) “British pharmaceutical giant GlaxoSmithKline has agreed to plead guilty in a tainted drug scandal and to pay a 750-million-dollar US fine. Pharmco Puerto Rico, a subsidiary of GSK, admitted it was guilty of the charges relating to the manufacture and distribution of certain adulterated drugs made at a now-closed Puerto Rico facility, the department said. The resolution includes a criminal fine of 150 million dollars and a civil settlement of 600 million dollars to the federal government and states.” What Happened? A deeper probe reveals a story behind the story, and one that becomes a salutary lesson to the entire pharmaceutical industry. GSK’s problems occurred at its SB Pharmco Puerto Rico Inc. facility (to use the facility’s proper legal name, referring back to the facility’s company name in ‘pre-merger with SmithKline’ days). An inspection performed by FDA between February and April 2002 revealed significant shortcomings that ended in a July 2002 warning letter (6) over issues including bacterial contamination of ointments; failure to have validated processes for tablet manufacture and failure to assure batch uniformity and integrity of drug products; failure to conduct out-of-specification (OOS) and deviation investigations in a timely manner and to take corrective actions to prevent recurrence; and media fill vials not being incubated for the required time that would assure bacterial growth for both slow and fast-growth microorganisms. In an FDA inspection performed between October and December 2003, a nine-page FDA-483 list of observations was given to the company. This FDA-483 (7) begins: “Your firm’s quality assurance unit lacks sufficient responsibility and authority to exercise the controls necessary to assure that consistent and reproducible manufacturing processes and laboratory controls are established and followed and that scientifically sound and appropriate actions are taken when process deviations or failures of product to meet established specifications occur for drug products manufactured at your firm. The quality control unit also failed to assure that adequate and complete records are maintained and that accurate and complete reports and information are submitted to the FDA when appropriate.” The report delves into 18 areas of failures to meet GMP observations, each illustrated with examples of the observation, elaborating on the above introduction. The key issue addressed, and the focus of about three quarters of the list of observations, involves process controls. The section on failures in process controls states: “Your firm fails to have appropriate procedures and controls in place to prevent mix-ups and/or adverse effects to product from occurring during manufacturing/packaging process. Furthermore, batches are released by your quality unit for distribution although you are aware of findings of mix-ups prior to these batches being released to the market…” The section ends with the statement: “…Note: Product mix-up incidents have been repeatedly occurred (sic.) since year 2001 through 2003. Products mentioned in the above examples were approved and released for distribution. Furthermore, complaints related Spring 2011 Volume 15 Number 2 25 A U D I T O R TA L E S to the mix-ups have been received from FARs [Field Alert Reports; a company’s notification to FDA that there might be problems with product already in the marketplace] and previous and the current inspection (sic) that all incidents are isolated and not related to your manufacturing operation.” The section cites the company for various failings including the following: •Observation two—“the current manufacturing process for Avandamet tablets is different and inconsistent to the manufacturing process that was validated during year 2002.” •Observation three—“investigations related to OOS (assay/content uniformity and/or dissolution) obtained for Avandamet have not been questioned in terms of the adequacy of the process validation for Avandamet.” •Observation four—“failure to take appropriate actions against all lots that may be affected by a conclusion as the assignable cause of the failing result although your conclusion assigns the most probable cause of the use of a common Roglitazone concentrate, not all lots using this same granulation concentration were rejected … furthermore no action has been taken against any batch that may have been released to the market for distribution.” •Observation five—“your 2003 OOS manufacturing investigations related to assay, content uniformity, and/or dissolution OOS, obtained for batches of Avandamet 2/500 and 1/500 are inadequate in that none of these investigations have questioned the adequacy of the process validation used to determine that your manufacturing process is robust and reproducible.” •Observation six—“investigations [have been performed] with the wrong raw data.” •Observation seven—“written records of investigations into the failure of a batch or any of its components to meet any of its specifications do not include conclusions or follow-up. Specifically your firm failed to implement effectively preventive and/or corrective actions to reduce 26 Journal of GXP Compliance the number of investigations attributed to analyst error.” The FDA-483 goes on, page after page, covering inadequate standard operating procedures (SOPs), inadequate sampling, inadequate analyst training, and not extending OOS investigations to other potentially impacted batches of product. The report digresses to criticize failures in the validated water system and poor complaint handling. Inadequate Response FDA told the company in 2002, 2003, and again in 2004 that it had significant problems. It would have made sense if the company had sent a task group down to the site, reviewed every system top to bottom, and systematically fixed all the issues. But when FDA performed another inspection from September–November 2004, they issued another FDA-483 (7) citing the following: •“Procedures for the cleaning and maintenance of equipment are deficient regarding the inspection of the equipment for cleanliness immediately before use. Specifically, line clearance procedures and controls are not appropriate to prevent mix-ups during the manufacturing/packaging process.” •“There is a failure to thoroughly review any unexplained discrepancy and the failure of a batch or any of its components to meet any of its specifications whether or not the batch had been thoroughly distributed. Specifically, your firm failed to take adequate corrective and preventive action to prevent the split tablet defect, classified by your firm as a critical defect, in distributed Paxil CR product. Although your process controls include an inspection after the coating process to detect the defect, the defect has been found during the packaging operation of Paxil CR 12.5 tablets and Paxil CR 36.5mg tablets, in approximately 2% and 25% of the batches manufactured/packaged during 2004.” •“ Your firm failed to adequately investigate and take corrective actions to address the root Michael H. Anisfeld cause of burnt induction seals in Avandamet bottles reported in complaints.” •“Control procedures are not established which monitor those manufacturing processes that may be responsible for causing variability in the characteristics of in-process material and drug products.” •“Employees are not given training in the particular operations they perform as part of their function and written procedures required by current good manufacturing practices regulations.” •“Investigations of an unexplained discrepancy and a failure of a batch or any of its components to meet any of its specifications did not extend to other batches of the same drug product.” The 2004 FDA-483 often repeated comments of previous inspections and brought into the discussion examples of GMP deficient operations impacting other creams, tablets, and oral suspensions manufactured by the company at the Cidra facility. LESSONS TO BE LEARNED There are obvious lessons to be learned from SB Pharmco, and from all the worldwide companies failing GMP inspections over the years. The lessons learned at a minimum are as follows: •Design your manufacturing and laboratory system well, and keep in mind that our products are taken on trust and that our potent products will be ingested by our grandparents and by our children–the most vulnerable in society. •The regulatory authorities do not want to be a company’s quality assurance (QA) group. Design your system well, train your staff to follow the system, and frequently repeat the training. Make sure you have an effective QA audit program to ensure that you catch the issues before they become “issues.” •If the authorities do find problems with your systems, immediately adopt a global approach to the corrective actions. Do not just address the symptoms discovered by the inspectors, but get to the root cause and tackle the issue system-wide and company-wide. •Hire QA staff with the intestinal fortitude to refuse to release batches of product that are not manufactured according to GMPs. •Speed is of the essence–make the fix, make sure it is fixed, and do it quickly. Woe betide your company if the issues are still outstanding when the authorities come again; and ‘woe betides’ get exceedingly expensive in money and corporate reputation. IGNORANCE OR ARROGANCE? John Scharmann, an ex-FDA Denver District Director, asked if such egregious GMP failures are due to company ignorance or company arrogance in an article in Dickinson’s FDA Review (8). Obviously with two to three years’ worth of FDA-483s at hand and four warning letters issued by registered mail to the GSK CEO prior to the seizure, ignorance cannot be claimed a factor in this case. Can it be company arrogance? As Scharmann states, “as long as company CEOs and company presidents see these fines as a cost of doing business, arrogance will continue. Make it personal and it will stop.” Which leaves the question–when will FDA and the European Medicines Agency start holding senior management personally accountable for GMP failures within their company? RESPONSIBILITIES OF QUALITY ASSURANCE PERSONNEL In reviewing SB Pharmco’s case, it would be easy to assume that the company’s management at all levels in the organization was only concerned with corporate profits and their own careers, and was not willing to think of the patient when faced with typical corporate bottom line pressures. However, former quality assurance manager Cheryl Eckard took a stand. Cheryl Eckard noticed a number of US GMP violations at GSK’s Cidra facility after she was sent there to lead a team of 100 scientists and quality experts in 2002. She discovered bad practices such as mixed-up products, diabetes drugs that were too weak or too strong, and that an area of the factory used to make injectable drugs was not sterile. Ms. Eckard exSpring 2011 Volume 15 Number 2 27 A U D I T O R TA L E S pressed her concerns to senior management, but she said her concerns were ignored. She was eventually removed from her job during a company merger. In 2004, she filed a lawsuit. According to that lawsuit, she had told her boss that “she would not participate in a cover-up of the quality assurance and compliance problems” at the company (9). In October 2010, GSK pled guilty and agreed to pay US$750 million in fines, penalties, and settlements. Ms. Eckard was awarded US$96 million “for her role in helping the government secure a criminal guilty plea” from GSK (9). It was Ms. Eckard’s willingness to do the right thing that helped ensure patient safety. If only the pharmaceutical industry had more people like Cheryl Eckard and if only more US QA departments or European qualified persons (QPs) did what they were supposed to do, then global patient safety would be dramatically enhanced. According to all GMP regulations, codes, directives, and guidelines in existence worldwide, it is the job and responsibility of the QA department to release product to market when it is manufactured and tested according to GMPs. But equally, directly inferred if not explicitly stated, it is the job and responsibility of QA and QP personnel not to release product to market when it is not manufactured and tested according to GMPs. As an industry, we need QA directors and QPs to have the intestinal fortitude to stand up and do the right thing. 3. US Department of Justice, “GlaxoSmithKline to Plead Guilty & Pay $750 Million to Resolve Manufacturing Deficiencies at Puerto Rico Plant,” Press Release, October 26, 2010. 4. FDA, “GlaxoSmithKline Will Plead Guilty and Pay $750 Million to Resolve Manufacturing Deficiencies at Puerto Rico Plant,” Press Release, October 26, 2010. 5. Connor, Michael, “GSK to Pay $750 Million Fine; Whistleblower to Get $96 Million,” Business Ethics, October 26, 2010. 6. FDA, Warning Letter issued to Smithkline Beecham Pharmaceuticals Co., July 1, 2002, http://www.fda.gov/ICECI/ EnforcementActions/WarningLetters/2002/ucm144993.htm 7. Both FDA-483s referred to in this article can be obtained by making a request under Freedom of Information directly to FDA (they are currently not available on FDA’s website). 8. Scharmann, John, “Ignorance or Arrogance? How Firms Get into Big FDA Trouble,” Dickinson’s FDA Review, March 15, 2005. 9. Loftus, Peter, “Whistleblower’s Long Journey,” Wall Street Journal, October 28, 2010. http://online.wsj.com/article/SB 10001424052702303443904575578713255698500.html. GXP ARTICLE ACRONYM LISTING FDA US Food and Drug Administration GMP Good Manufacturing Practice GSKGlaxoSmithKline OOS Out of Specification QA Quality Assurance QP Qualified Person REFERENCES 1. FDA, “U.S. Marshals Seize Lots of GlaxoSmithKline’s Paxil CR and Avandamet Tablets Because of Continuing Good Manufacturing Practice Violations, FDA News,” FDA.gov, March 4, 2005. 2. FDA, “GlaxoSmithKline Signs Consent Decree with FDA; Agrees to Correct Manufacturing Deficiencies,” FDA News, FDA.gov, April 28, 2005, http://www.fda.gov/NewsEvents/ Newsroom/PressAnnouncements/2005/ucm108432.htm. 28 Journal of GXP Compliance ABOUT THE AUTHOR Michael H. Anisfeld is a senior consultant for Globepharm Consulting specializing in GMP and quality activities for the healthcare manufacturing industries. His clients include United Nations agencies (WHO, UNFPA, UNIDO), national regulatory agencies, and more than 260 pharmaceutical, medical device, biotechnology, and bulk pharmaceutical companies in the Americas, Africa, Europe, and Asia. Mr. Anisfeld can be reached by e-mail at [email protected].