When Do We Get to Bmps? (And Which Bmps Do We Have in Mind?)

COMMENTARY

When Do We Get to BMPs? (and Which BMPs Do We Have in Mind?)

Michael H. Anisfeld

Current good manufacturing practices (GMPs) have synergies, lean manufacturing (and all the other corpo- been around for a long time. Their origins can be traced rate buzz-words that ultimately mean “do more with less to the Canadian QUAD requirements of 1959, the US resources”), we have as an industry seemingly, wittingly GMPs of 1963 (updated to their current form in 1976), or unwittingly, been going along the BMP road all along. the British Orange Guide of 1971, and the Pharma- But instead of heading in the direction of better manu- ceutical Inspection Convention GMPs of 1972, which facturing practices or best manufacturing practices, morphed into the European Union GMPs in 1989. We we actually have, over the past 10 years, been heading have thus been living with “good” manufacturing prac- backwards towards “bad” manufacturing practices. tices for approximately 40 years. During the past ten years GlaxoSmithKline (GSK) The early 2000s have had a major impact on GMP has been fined US$750 million (October 2010) (2), implementation worldwide with the adoption of Inter- Schering-Plough was fined US$500 million (in 2001) national Conference on Harmonisation (ICH) Q8, Q9, (3), Abbott was fined US$100 million (in 2000) (4)– all and Q10 bringing pharmaceutical development, risk for GMP non-compliance. Alza (another J&J division) management, and quality management concepts into has been found guilty by juries in several civil actions the GMP orbit. With half a century of daily working ex- (5) in different US courts for product defects resulting perience with GMPs, and the expansion of GMPs with from GMP non-compliance issues in the manufacture the ICH quality vision, is it not time for the pharmaceu- and testing of Duragesic patches that leaked their con- tical industry to set its sights on doing better? Aiming tents of fentanyl contributing to the deaths of patients. our sights higher? Should we not be asking, “When do I could go on and on with many other similar ex- we get to BMPs”—“better” manufacturing practices, or amples on GMP non-compliance by a plethora of other even “best” manufacturing practices? US companies, but you get the theme—the quality of pharmaceuticals seems to be dropping. And worse yet, GMP COMPLIANCE—HOW ARE WE DOING? no one individual is ever held personally accountable. The year 2010 brought another series of GMP non-com- Not one individual is ever publicly reprimanded, fined, pliance headlines. Among the most publicized, McNeil or jailed. And before any smug European readers say Pharmaceuticals (division of Johnson and Johnson) “only in America,” I should point out that not a single recalled all the liquid infant’s and children’s formula- European company’s “Qualified Person” (the QP being tions of Tylenol, Motrin, and other products made at its the individual who by EU law is legally accountable Fort Washington, PA, manufacturing facility (1). This to ensure GMPs have been followed at the company) debacle has played out with seemingly daily revelations in any of the EU’s 27 member states has ever been of wrongdoing, and this question of “heading to BMPs” fined or jailed for the litany of pharmaceutical product has lately been on my mind. defects and resultant deaths and injuries that have What is of particular concern is that in these days occurred in Europe in the almost 30 years since the EU of seemingly incessant corporate mergers, acquisitions, GMPs were first published.

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The Wall Street Journal (6), in covering recent Con- facility for a two-week period, and includes 20 observa- gressional Oversight hearings on drug safety stated that tions. These are as follows: last year, Johnson & Johnson’s (J&J) consumer business, • The responsibilities and procedures applicable to which includes the McNeil unit and other companies, the quality control unit are not fully followed had $15.8 billion in sales and $2.48 billion in profit. • There are no written procedures for production and Surely getting to BMPs could not cost Johnson & John- process controls designed to assure that the drug son remotely close to US$2 billion, or less than the profit products have the identity, strength, quality, and gained in a single year? purity they purport or represent to possess McNeil announced a recall on April 30, 2010 involv- • Control procedures fail to include adequacy ing more than 136 million bottles of Benadryl, Motrin, of mixing to assure uniformity and homogeneity Tylenol, and Zyrtec for children and infants (7). Accord- • Control procedures are not established that monitor ing to the recall announcement, some of the recalled the output and validate the performance of those products might have had more active ingredient than manufacturing processes that may be responsible approved, while others might have had metallic particles for causing variability in the characteristics of in- in them. FDA investigators had also found bacteria in process material and the drug product some raw materials, and since April 30, 2010 McNeil • Written production and process control procedures shut down its Fort Washington facility. are not followed in the execution of production and Anyone who has worked in pharmaceutical produc- process control functions tion management or quality assurance (QA) has to ask • There is a failure to thoroughly review any unex- how, when metals detectors and automated inspection plained discrepancy whether or not the batch has devices exist, metal particles can get into marketed prod- been already distributed uct? How, when process validation is the norm, and • GMP training is not conducted with sufficient fre- two trained staff are supposed to be involved with the quency to assure that employees remain familiar weighing of chemicals and their addition to the formula- with CGMP requirements applicable to them tion (one person performing the task and the second • Procedures describing the handling of all written person checking the task), and with quality control and oral complaints regarding a drug product are (QC) checking product samples that are supposed to be not followed representative of the bulk batch, can drug over-dosages • Each container of component dispensed to manu- occur? How can raw materials with out-of-specification facturing is not examined by a second person to microbial contamination be approved for use? Surely assure that the weight or measure is correct as when the product is destined for use by the most vulner- stated in the batch record able members of society, infants and children, would • Strict control is not exercised over labeling issued this not impose an extra ethical or moral standard for for drug product labeling operations management responsible for the manufacture of pediat- • There is no written testing program to assess the ric pharmaceuticals, to say nothing of GMP compliance? stability characteristics of drug products • Laboratory controls do not include the establish- THE MCNEIL FDA-483 ment of scientifically sound and appropriate test In an unusual move, the US Food and Drug Administra- procedures designed to assure that components and tion released for public viewing in its electronic reading drug products conform to appropriate standards of room (8) the FDA-483 “Inspectional Observations” cov- identity, strength, quality, and purity ering their April 19–30, 2010 inspection of McNeil’s Fort • Adequate lab facilities for testing and approval or Washington facility where the errant liquid formulations rejection of components and drug products are not were manufactured during 2008, 2009, and 2010. This available to the quality control unit FDA-483, a 17-page list of GMP-compliance deficiencies, • Laboratory records do not include complete records was generated by four FDA investigators present in the of the periodic calibration of laboratory instru-

80 Journal of GXP Compliance Michael H. Anisfeld

ments, gauges, and recording devices Neill issued a recall of 88,104 packages of Motrin in July • Written specifications for laboratory controls do not 2009, but, rather than formally recall the product, the include a description of the sampling procedures company hired a contractor to send representatives into used pharmacies to purchase all the stock they could find, • Samples taken of in-process materials for deter- thus taking it off the market–as the Oversight Commit- mination of conformance to specifications are not tee calls it “a phantom recall.” The first week of June representative revealed that this recalled stock was then recycled and • Each lot of components was not appropriately iden- made available for sale at gas stations and other outlets tified as to status in terms of being quarantined, without pharmacist supervision. This being the United approved, or rejected States of America, the lawyers are already circling, and • Components are not microscopically examined whatever the committee does not uncover into how the when appropriate GMP non-compliances arose will almost certainly be • Records are not kept for the maintenance and uncovered when the company is eventually taken to inspection of equipment court for real or imagined damages or injury. • The persons double-checking the cleaning and In an inspection report released at the beginning maintenance are not dating and signing or initialing of December 2010, FDA said a recent visit uncovered the equipment cleaning and use log. multiple quality control problems, including a failure to properly handle customer complaints. Inspectors also As of December 2010, the company’s response to the found “a failure to thoroughly review any unexplained FDA-483 has yet to be made available in FDA’s Electron- discrepancy” in batches of products and a lack of proper ic Reading Room. We, therefore, can only see one side record keeping according to report of the inspection that of the picture; but as responses to the FDA-483 typically ran from October 27 to December 9. only relate to corrective actions, we will not officially get In November 2010, J&J recalled about four mil- to understand the background to how the GMP deficien- lion packages of cherry- and grape-flavored Children’s cies came to be. But all the observations really point Benadryl allergy tablets and about 800,000 bottles of to one question–where was management, both general junior-strength Motrin caplets. The recall was necessary management and especially QA management? Where because, quoting Bonnie Jacobs, a company spokes- was management both at the Fort Washington facility woman, “of insufficiencies in the development of the and where was management at the corporate J&J level manufacturing process.” Also recalled were 71,000 that allowed the situation to happen? Surely internal caplets of Extra Strength Rolaids soft-chews, which were audits by McNeil QA and by J&J corporate QA would manufactured by another firm for McNeil, Jacobs said have revealed all, or even more, GMP compliance issues (10). According to the Rolaids website, “The recall was that FDA observed, allowing for their timely and effec- initiated as a precaution following consumer complaints tive remediation. And if these basic non-compliance of an uncharacteristic consistency or texture, traced issues had been identified, then why had they not been to crystallized sugar in the product, and following effectively fixed? consumer reports of foreign materials in the product, including metal and wood particles” (11). Again the same US CONGRESS OVERSIGHT questions need to be asked: “who’s in charge? where’s Among other matters, how the deterioration in drug senior management? and what’s their role?” manufacturing quality and compliance to GMPs came FDA has criticized McNeil and J&J for a series of about is now the subject of an investigation by the Over- quality-related problems at other manufacturing sites. sight Committee of the US Congress (9) with seemingly J&J has been criticized for waiting a year to notify FDA daily revelations of malfeasance—it is beginning to seem of complaints of musty odor problems with adult Tylenol like a pharmaceutical soap opera. In late May 2010, the tablets made at a Puerto Rico plant. This problem was Committee revealed that under pressure from FDA, Mc- later traced to a pesticide used on the wooden pallets

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storing empty bottles and prompting a recall (12). 2. US Department of Justice, GlaxosmithKline to Plead Guilty In 1982, a still yet to be identified person in Chicago & Pay $750 Million to Resolve Criminal and Civil Liability purchased Tylenol capsules in supermarkets, took Regarding Manufacturing Deficiences at Puerto Rico Plant, Press them home, adulterated some packages with cyanide, Release, October 26, 2010. and then returned the tainted capsules to supermarket 3. FDA News, Food and Drug Letter, issue 653, June 2002. shelves resulting in five deaths. McNeil (J&J) performed 4. http://articles.latimes.com/1999/nov/03/business/fi-29195. such a tremendous job in handling the recall that the 5. Examples of civil actions against J&J can be found at http://www. mechanics of how they did the task is today taught in morelaw.com/verdicts/case.asp?n=05-081116&s=FL&d=33338; business schools as a benchmark in corporate ethics and and http://www.hop-law.com/index.php/news/51-jury-awards- responsibility and as a paragon of corporate reaction to nearly-166m-in-ill-skin-patch-case. accessed 12/30/2010. crisis. The McNeil “recall” of today is not the McNeil 6. “FDA Widens Probe of J&J’s McNeil Unit,” The Wall Street Journal, “recall” reaction of 30 years ago. May 18, 2010; downloadable at http://online.wsj.com/article/SB It seems probable that one outcome of this current 10001424052748704314904575250751056239816.html (ac- case is that Congress will give FDA the authority to cessed 12/28/2010. require a company to perform a product recall. Cur- 7. “Mcneil Consumer Healthcare Announces Voluntary Recall Of rent US law requires FDA, if they cannot persuade a Certain Over-The-Counter (Otc) Products In The United States, company to voluntarily recall its products, to obtain a Fiji, Guatemala, Dominican Republic, Puerto Rico, Trinidad & court order to either enforce a recall or have the product Tobago, And Jamaica,” Press Release, Tylenol.com, July 8, 2010. declared adulterated and seized by the US Marshall’s http://www.tylenol.com/page2.jhtml?id=tylenol/news/subp_tyle- Service. Almost always, companies perform voluntary nol_recall_3.inc recalls, but this new McNeil entity “the phantom recall” 8. The April 30, 2010 FD-A483 can be downloaded at: http://www. (seemingly created so as not to generate adverse com- fda.gov/downloads/AboutFDA/CentersOffices/ORA/ORAElec- pany or product publicity) might cause a change in the tronicReadingRoom/UCM210772.pdf. law and in GMP regulations. It is of historic interest that 9. Jack, Andrew, “Report into J&J product recalls looms,” Financial the only major change to US GMPs since they were first Times, September 5, 2010, http://www.ft.com/cms/s/0/e4a- published in 1976 was also prompted by McNeil. After fa9d2-b909-11df-99be-00144feabdc0.html the 1982 Chicago cyanide incident, the requirement for 10. Philadelphia Inquirer, “J&J Recalls More Drugs From Troubled tamper-evident packaging as a requirement for all over- Plant,” Quality News Today, ASQ, November 24, 2010. http:// the-counter drugs entered the GMP lexicon. asq.org/qualitynews/qnt/execute/displaySetup?newsID=10093 11. “McNeil Consumer Healthcare Announces Voluntary Recall WHEN DO WE GET TO BMPS AND WHICH BMPS DO WE Of All Lots Of Rolaids Extra Strength Softchews, Rolaids Extra HAVE IN MIND? Strength Plus Gas Softchews, And Rolaids Multi-Symptom Plus A sad sidebar to the story is that A. J. McNeil, the Anti-Gas Softchews Sold In The United States,” Rolaids.com, De- founder of McNeil Laboratories, passed away in April cember 9, 2010. http://www.rolaids.com/page.jhtml?id=rolaids/ 2010 at the age of 94 in the middle of this crisis. He include/recall_dec.inc. had long ceased to have any connection to the company. 12. FDA, http://fda.gov/ICECI/EnforcementActions/WarningLetters/ One wonders what he must have been thinking of the ucm197811.htm. GXP mission of the company he founded. Which BMPs are we headed toward—BMPs, the “better” kind or BMPs, ABOUT THE AUTHOR the “bad” kind? Michael H. Anisfeld is a senior consultant for Globepharm Consulting specializing in GMP/quality activities for the healthcare manufacturing industries. His clients include United Nations agencies (WHO, REFERENCES UNFPA, UNIDO), national regulatory agencies, and over 260 phar- 1. Layton, Lyndsey, “Johnson & Johnson division recalls 43 OTC maceutical, medical device, biotechnology and bulk pharmaceutical medicines for infants and children,” Washington Post, May 2, companies in the Americas, Africa, Europe, and Asia. Mr. Anisfeld 2010. can be reached by e-mail at [email protected].

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