Inside This Issue

Issue No. 225 FDA Counting on Global Strategy April 2011 To Better Secure Supply Chain The FDA’s work toward tighter supply chain control through INside this issue international regulatory cooperation is falling short, but a new global strategy may speed up the agency’s progress, a top FDA Sterility issues lead to an- official says. other J&J recall...... Page 2 The next several years are critical in the agency’s transformation FDA zeroes in on compli- to a “global agency,” John Taylor, the FDA’s acting principal deputy ance history to make in- commissioner, said March 14 at a Pew Charitable Trusts conference spection decisions.....Page 3 in Washington, D.C., on drug supply safety. To achieve adequate supply chain control, Taylor said, the FDA 483 Insider...... Page 5 needs novel and updated enforcement tools, a global alliance of regulators, new authorities to create proactive tools for product safety, APP recalls oncologic irinotecan over fungal contami- (See Global, Page 2) nation...... Page 6 McNeil Gets Consent Decree After Pharma manufacturing in Period of Manufacturing Woes Japan largely spared by The FDA has said enough is enough to McNeil Consumer Health- quake...... Page 8 care over its repeated manufacturing problems, issuing a consent decree that indefinitely closes one plant and places oversight over two others. Bill would increase penalties for prescription drug The agency said the Johnson & Johnson subsidiary, which has thefts...... Page 10 been plagued with recalls of its OTC drugs relating to cGMP violations, will not be able to reopen its troubled Fort Washington, Pa., Dakota labs gets warning plant until a litany of changes have been made. for GMP, labeling viola- The March 10 decree, filed in a Pennsylvania federal court, sets tions...... Page 11 strict timeframes McNeil must meet or face fines, further recalls and additional shutdowns. Its also names as defendants McNeil’s vice GAO says FDA oversight is president of quality, Veronica Cruz, and Hakan Erdemir, the compa- at ‘high risk’ for misman- ny’s vice president of operations, for violating federal law by distrib- agement...... Page 12 uting adulterated drugs. Pfizer recalls pain drug Em- Within 30 days of the decree, McNeil needs to outline its beda, prostate drug, antide- plans to destroy all lots of drugs in its possession or recalled since pressant...... Page 14 (See McNeil, Page 4) Page 2 drug gmp report April 2011

Global, from Page 1 The agency must establish a review and audit infrastructure to verify that information and to adequate funding for inspections, examinations ensure that it can quickly take follow-up enforce- and sample collections and analysis, and updated ment action. systems, including IT support, to assist with increased workload. So far, the FDA’s adoption of new oversight strategies and its work with foreign partners has Moving forward, the agency will follow an not substantially increased coverage of its safety action plan with four primary components: activities, Taylor said. ●● Partnering with foreign counterparts to Some programs are facilitating the shift create a global coalition of regulators; toward common safety standards, but the FDA ●● Working to build a global data-information has only used these alternatives to its own stan- system and network, and proactively shar- dards in limited circumstances, he said. ing data with partners; ●● Building additional intelligence-gathering “At the current rate of progress, and through the capabilities with an increased focus on current mechanisms, it would take decades to reach a risk analytics and a transformed IT capa- comprehensive set of common standards.” that would bility; and allow the FDA to leverage the work of third parties, ●● Leveraging the efforts of public and pri- domestically and abroad, according to Taylor. vate sector third parties and industry to But working alone to ensure U.S. product safety, allocate FDA resources based on risk. the FDA’s efforts have sometimes fallen short, and foreign inspections still lag behind domestic inspec- Some of this work is already underway, but tions (DGR, November 2010). — April Hollis needs to be “taken to the next level,” Taylor said, including greater coordination and enforcement of regulatory standards across nations, even if Sterility Issues Lead to those standards are not identical. J&J Product Recall Regulatory authorities with greater experi- Another Johnson & Johnson (J&J) product ence and resources must work together to help is being recalled — the fifth recall in less than a build regulatory systems in countries with devel- month — amid sterility concerns. oping systems or fewer resources, he added. The latest recall follows the UK’s Medicines and The FDA will also enhance its intelligence- Healthcare Products Regulatory Agency (MHRA) gathering capabilities, with an increased focus issuance of a notice March 2, alerting British health- on risk analytics and IT capability. The agency care providers of the possible defect. The MHRA will create tools to quickly assess regulatory data says the packages may not have been completely across various information resources. sealed and the contents may not be sterile. “We must also create a modern means to The action involves 585,000 strands or 104 share data globally, and we must use those data batches of sutures sold under various names — and advanced analytics to proactively prevent Ethilon, Ethibond, Mersilene and Mersilk — by and identify problems,” Taylor said. J&J subsidiary Ethicon. The FDA will also develop programs in each The UK action follows an Ethicon recall last product type it regulates and in inspection pro- month of 700,000 vials of a liquid wound- grams within those categories, for approved pub- sealing product, Dermabond, amid reports of dis- lic and private third parties to conduct inspec- coloration and concerns it may take longer than tions and other oversight activities. expected to set (DGR, March). — David Pittman April 2011 drug gmp report Page 3

FDA Zeroes in on Compliance The agency recently joined the 37-member History for Inspection Decisions Pharmaceutical Inspection Convention and Pharmaceutical Inspection Cooperation Scheme, ATHENS, Ga. — Companies that have a and now has confidentiality agreements with 20 track record of non-compliance with GMPs countries. should come under greater FDA scrutiny and be more likely to get inspected, the FDA’s asso- The FDA also has foreign offices in China, ciate commissioner for regulatory affairs has India, Latin America and Europe, but Corrigan suggested. admitted there still needs more work in the area. Speaking March 15 at the International Good A GAO report last year also suggested Manufacturing Practices Conference, Dara Cor- improved coordination between the FDA’s overseas rigan said the FDA must “be able to shift our offices as well as long-term strategic planning. resources to the high-risk areas, which means the Overseas Inspections high-risks firms.” “There is a very current debate in FDA to fig- “We should be looking at those companies ure out whether we should actually place more with a history of non-compliance. They deserve people overseas versus having to fly them out,” more scrutiny, and they will have more scrutiny,” she said. she added. “And we are looking at ways to better track a company’s history over time.” A 2010 GAO report found that while on the rise, the number of inspections of foreign plants Warning Letter Increase pales in comparison to those done on domestic Corrigan didn’t elaborate on how the FDA facilities (DGR, November 2010). would handle or examine a company’s history, Corrigan, who began her government career but said there should be rewards for those compa- as a trial lawyer for the Justice Department in nies who meet or exceed standards. 1990, also addressed other pressing issues regard- “We need to have a way of looking at those ing her office. [companies] and really assessing where the risk About 40 percent of her department’s work is,” said Corrigan, who took office in Septem- force is comprised of new investigators hired in ber and oversees a field staff of roughly 4,000 the last three years. inspectors. “Good companies deserve FDA’s respect.” “A lot of these investigations and inspections are complicated, especially in drug manufactur- Corrigan noted a 42 percent increase in the ing,” she said. “It takes a while to get people up number of warning letters issued between fiscal to speed.” 2009 and 2010. She also said 68 percent of warning letters from 2010 were issued within a four- In February, Deborah Autor, director of the month period. FDA’s Office of Compliance, said that a lack of resources to conduct foreign inspections is part However, Corrigan said warning letters aren’t of the reason why the agency has a huge backlog always a good metric for the amount or quality of of ANDA applications. compliance enforcement the FDA does. The FDA also needs people devoted to high- Corrigan acknowledged FDA Commissioner level drug inspections. Margaret Hamburg’s work to cooperate with foreign governments and inspectors to better “We’re creating a cadre of specially-trained ensure the quality of products made overseas and professional inspectors,” Corrigan said. shipped to the U.S. — David Pittman Page 4 drug gmp report April 2011

McNeil, from Page 1 As one recent example, the company in Janu- ary recalled nearly 43 million bottles of Tyle- December 2009, that were made at its Fort Wash- nol 8 Hour, Tylenol Arthritis Pain, Tylenol upper ington, Lancaster, Pa. and Las Piedras, Puerto respiratory products, Benadryl, Sudafed PE and Rico, facilities. Sinutab that were made at the Fort Washington, plant before it closed (DGR, February 11). The FDA also ordered McNeil to cease production at Fort Washington until it completes a The FDA issued McNeil a warning letter lengthy 10-step remediation process. The reme- Jan. 15 for being too slow to alert the FDA and diation plan spans seven of the order’s 26 pages. consumers to trace amounts of a wood-treating The company previously said it hoped to reopen chemical in some of its products, including its the plant mid-year after it closed in April 2010, a OTC drug Tylenol. timetable that now looks all but impossible. At least one analyst predicted the consent Remediation Plan decree. Wells Fargo analyst Larry Biegelsen said McNeil said that it expects the consent decree in January he continues to “see some uncertainty to govern the company’s operation of the three regarding Ft. Washington’s targeted mid-year plants for at least five years following the comple- reopen after a mid-Dec. Form 483.” tion of the remediation plan. To view a copy of the consent decree, visit In July, the company said it was developing www.fdanews.com/ext/files/Certified_Filed_Cons its own plan, which included making significant ent_Decree_USA_v._McNeil_PPC.pdf. investment in manufacturing facilities, reorga- — David Pittman nizing operations and developing a comprehensive program to ensure sustainable compliance GMP Issues Behind FDA Hold with regulatory and its own quality requirements On RegeneRX Drug Trial (DGR, August 2010). The FDA has put a clinical hold on a Phase II The decree’s remediation plan includes hiring trial for RegeneRX Biopharmaceuticals’ investiga- an independent cGMP consultant for each facil- tional drug RGN-352, a formulation of Thymosin ity. The consultant must certify the plant’s equip- beta 4 (TB4) to treat acute myocardial infarction, ment and manufacturing processes are compliant after discovering deviations from cGMP regula- before the FDA inspects the facility. tions at the contract manufacturer for the drug. McNeil must also outline a quality control plan and employee training programs to ensure RegeneRX has not disclosed the name of the GMP knowledge and processes. manufacturer or the nature of the issue that led to the hold, but the company March 16 said the Although facilities in Lancaster and Puerto FDA’s action is not directed at the safety of RGN- Rico can remain open, they must complete the 352 or its clinical development plan, and other steps or face closure. trials will not be affected. If McNeil violates the decree, the FDA may The FDA did not return requests for comment order the company to cease production in Lan- on the nature of the hold. caster and Las Piedras and recall products. RegeneRX is developing TB4, a novel thera- The agency could also levy fines of $15,000 a peutic peptide, in a number of different formu- day and an additional $15,000 for each violation lations for various treatments. RGN-352 is an of the law up to $10 million a year. injectable formulation of the drug for treatment Recalls have hammered McNeil’s facilities in of cardiovascular and central nervous system the past year. conditions. — Wilson Peden April 2011 drug gmp report Page 5

form 483 insider Form 483 Reveals McNeil Plant’s Syringe Batches at Center of 483 Trouble Before Spate of Recalls For Pfizer’s Pearl River Plant Workers at McNeil Consumer Healthcare’s An FDA inspection of Pfizer’s Pearl River, troubled Fort Washington, Pa., facility routinely N.Y., plant resulted in 22 Form 483 observations. ignored abnormal test results for various products During a previous third-party inspection of the that were later recalled, according to a six- plant, Pfizer found hair and fibers adhered to syringe observation Form 483. stoppers, the FDA’s New York District Office notes. FDA inspectors found McNeil workers con- The company identified batches that used tinued to release batches of Benadryl Allergy the stoppers; “however, the investigation did not Fast Melts after obtaining out-of-specification identify five other batches of Prevnar 7v which (OOS) and out-of-trend (OOT) results from used the syringe and stopper batches,” the Oct. 1, August 2008 to March 2010. 2010, form states. The agency’s Philadelphia District Office also Pfizer also failed to investigate a black speck notes no OOS or OOT investigations were con- on the glass of a syringe barrel found during an ducted for Sudafed PE Cold and Cough Caplets inspection of retention samples, the FDA’s Sept. from April 2009, to March 2010, despite results 14, 2010, to Oct. 1, 2010, inspection found. that warranted further view. The company is working to address the Both products were affected by recalls in the observations, Pfizer spokesman Rick Chambers last six months (DGR, February). told DGR. The Form 483 is available at www. McNeil also sought outside advice on the fdanews.com/ext/files/Pfizer-483.pdf. chemical 2,4,6-tribromoanisole (TBA) and Form 483 Notes Several Issues learned analytical testing can detect haloanisole With Genzyme Kidney Drug below people’s sensory threshold. Manufacturing issues with chronic kidney But despite continued problems with the disease drug Hectorol have resulted in a multi- odor at the plant and in products, “such quantita- item Form 483 for Genzyme. tive testing was not preformed,” according to the form, which came after an Oct. 27, 2010, to Dec. The company failed to check that 10 fin- 9, 2010, inspection. ished lots of Hectorol (doxercalciferol) were free of particulates, the FDA’s New Jersey District McNeil also used bottles that may have been Office says. exposed to haloanisole to package Tylenol 8 Hour caplets. “The initial non-conformance report and subsequent CAPA investigation failed to indentify That product was included in the 43 million all potentially impacted lots,” states the Jan. 31 bottles of product recalled by the company in form to the Ridgefield, N.J. plant. January. An automated machine in the plant rejected McNeil, which closed the Fort Washing- more than 6,200 vials of Hectorol. However, ton plant last April, agreed to a consent decree FDA inspectors found no evidence to identify the March 10 that indefinitely closes the facility. source of particulates found in rejected vials. McNeil declined to comment on the form. Genzyme did not return a request for com- The 483 is available at www.fdanews.com/ext/ ment by press time. A copy of the 483 is available files/McNeil-483.pdf. at www.fdanews.com/ext/files/Genzyme-483.pdf. Page 6 drug gmp report April 2011

Law Firm Asks FDA to Disclose lot, as a precautionary measure, APP is recalling Legal Enforcement Actions lots produced before and after the affected lot. A Washington, D.C., law firm is pushing for The recall involves a total of 90,000 vials, the FDA to create a website that will disclose Matthias Link, a spokesman for Fresenius Kabi, more information on legal enforcement actions. APP’s parent company, told DGR. The request, sent by Hyman, Phelps and McNa- The recalled lots involve 100 mg/5mL (20 mara, cites a memorandum to executive depart- mg/mL), 5 mL single-dose vials and 40 mg/2mL ments and agencies that President Barack Obama (20 mg/mL), 2 mL single-dose vials. issued in January as the basis of its request. A chemotherapeutic agent given intrave- The memo requests “agencies with broad reg- nously that is non-sterile has the potential to ulatory compliance and administrative enforce- cause infections, which could be fatal if a patient ment responsibilities develop plans to make is immunocompromised. However, the company public information concerning their regulatory says it is not aware of any adverse events. compliance and enforcement activities accessible, An FDA MedWatch report issued March downloadable, and searchable online” by May 18. 28 recommended that healthcare providers and “There is no reason why the FDA can- patients report any adverse events that may be not place on its website public notice for every related to the product. enforcement action that is publicly filed in court,” Irinotecan is used for the treatment of meta- the law firm says in a letter March 11 to FDA static colorectal cancer and is a generic version of Chief Counsel Ralph Tyler. Pfizer’s Camptosar. — Jonathan Block The firm says it would like to see a new website provide the names and judicial districts of all lawsuits filed by the government with regard to activity regu- FDAnews Guide to International lated by the FDA. They would also like the names Medical Device Regulation and judicial district of all lawsuits filed against the FDA and/or its officials in connection with FDA reg- An Publication ulatory or enforcement activities, as well as all briefs In medical device manufactur- and other pleadings publicly filed in such cases. ing, success means staying abreast of regulatory changes FDA’s Tyler has received the letter and his from Asia to Argentina ... office is in the process of compiling a formal and beyond. response, spokeswoman Karen Mahoney told Impossible? Not at all. Here’s how: FDAnews Guide to DGR March 14. — Virgil Dickson International Medical Device Regulation, 2011 is the one-stop APP Recalls Oncologic Irinotecan authority for quick, accurate Over Fungal Contamination answers to all your questions on: • Application processes for new Price: $377 APP Pharmaceuticals is recalling five lots of device approvals the oncologic irinotecan HCl injection after sev- • Emerging changes in inspection practices • Changes to quality manufacturing requirements eral reports of particulates found in vials. • And dozens more key topics in device regulation worldwide The company says it received three customer complaints of foreign material from one lot, later Order online at: identified as fungal microbial contaminant. www.fdanews.com/30134A Or call toll free: (888) 838-5578 (inside the U.S.) Although a preliminary investigation indi- or +1 (703) 538-7600 cates the particulate was only found in the one April 2011 drug gmp report Page 7

FDA May Send Warning Letters to chain if the industry doesn’t take more efforts to Clients of Noncompliant Suppliers ensure the quality of products. ATHENS, Ga. — The FDA may begin issu- The materials in any given drug can change ing warning letters to drugmakers when their con- hands numerous times and can come from sev- tracted suppliers fall out of agency compliance, eral countries, Wolfgang said. Drugmakers’ names signaling further agency efforts to strengthen the are on the labels of their finished products, so they safety of pharmaceutical supply chains. must take more action in ensuring the quality of materials they receive and the manufacturing pro- Too often, FDA inspections find drug compa- cesses used to make those imported products. nies aren’t properly qualifying their suppliers, Ste- ven Wolfgang, a consumer safety officer at CDER’s Steven Niedelman, an industry consultant with Office of Compliance, said last month at the Inter- law firm King & Spalding, toldDGR that supplier national Good Manufacturing Practices Conference. quality issues are a top concern for many companies. The fallout has resulted in patient harm, such as the “If this helps stem the tide of problems and gets the deaths from the 2007 Chinese tainted heparin crisis. attention of industry, they will take a more proactive approach to assure the quality of their suppliers The agency recently issued a warning letter to before they enter into long-term contracts.” a contracted supplier and copied all the companies it had supplied products to. The outside compa- The FDA has taken additional steps to focus nies were not listed on the warning letter, but were attention on the issue as well. Late last year, a notified of the FDA’s action against their supplier. former FDA official said the agency is working on revising GMP regulations that would require Wolfgang said the next logical step is to begin companies to audit raw material suppliers (DGR, handing letters to all companies in the supply November 2010). — David Pittman FDA Border Protection Plan to departments of Justice, Commerce and Home- Cut Down on Counterfeit Drugs land Security. The FDA will soon begin working more The Justice Department and Homeland Secu- closely with other federal agencies — including rity will also continue to work internationally to Customs and Border Protection (CBP) — as it combat counterfeit pharmaceuticals. The agen- hopes to nab more counterfeit drugs entering the cies still intend to work with internet-hosting U.S. drug supply chain. sites such as GoDaddy, Google and Microsoft, to crack down on illegal online pharmacies. The two agencies will develop a plan to catch more illegal drugs at ports by the end of fiscal 2011. “PhRMA supports and commends the Administration for its commitment to protect- “As part of this process, FDA and CBP will ing patient health and safety by safeguarding the examine the flow of imported pharmaceutical closed U.S. drug supply system from the global products through different ports of entry, identify counterfeit medicine epidemic,” PhRMA Presi- all available legal authorities and develop best dent John Castellani said. practices to enhance collaborative enforcement efforts,” states a 17-page report delivered to Con- However, in a media conference call March 11, gress and Vice President Joe Biden in March. PhRMA Assistant General Counsel Kendra Mar- tello stopped short of calling for increased fees to The recommendations came from the Coun- help FDA fund overseas inspections. A GAO report terfeit Pharmaceutical Inter-Agency Work- ing Group, which was comprised of mem- bers of various federal agencies, including the (See Border, Page 8) Page 8 drug gmp report April 2011

Pharma Manufacturing in Japan Although Bausch & Lomb does not conduct Largely Spared by Quake any manufacturing in the country, Mike McDou- gall, the company’s vice president for corporate As Japan continues to deal with the aftermath communications and public affairs said that its of a massive 9.0 earthquake and ensuing tsunami, operations went back March 14. it appears the country’s pharmaceutical industry and U.S. companies with operations there have Abbott has about 2,400 employees in Japan in not suffered extensive damage. offices in Tokyo, Chiba (near Tokyo) and Fukui. Luckily, for most Japanese pharmas, the Japan’s pharmaceutical market is considered earthquake rocked the northeastern part of the the second largest in the world, according to IMS country, 200 miles away from urban centers such Health, which projects it will reach $100 billion in as Tokyo, Osaka and Kobe, where many compa- sales this year. — Jonathan Block, Virgil Dickson nies have offices or facilities. , from Page 7 A preliminary survey conducted by DGR of sev- Border eral U.S.-based pharmaceutical companies that have last year found that agency inspection of foreign operations in Japan has found that at this stage, for plants pales in comparison to domestic ones. the most part, no major damage has been reported. “We support increased appropriations to help Employees Safe FDA carry out its vital mission,” she said. “We “We have received word that our colleagues have not taken a position on that.” at Eisai’s headquarters office in Tokyo are safe,” Eisai U.S. Senior Director for Corporate Com- Martello also said PhRMA supports greater flex- munications Lynn Kenney told DGR, adding the ibility for the FDA in overseas inspections and company’s facilities at the Tsukuba Research stronger criminal penalties for counterfeiters. Laboratories and the Koishikawa Knowledge Center in Tokyo housing Eisai product creation “International harmonization will be an impor- systems headquarters have suffered damage, but tant issue for FDA to focus on as it moves for- all employees there are safe. ward,” she said. However, the company has a large employee Following an infusion of counterfeit heparin base in Sendai, one of the areas hardest hit by the and resulting patient deaths, the safety of the U.S. earthquake, “and we have not been able to reach drug supply chain has garnered a great deal of all of our employees due to communications sys- attention recently. tems being down,” she noted. A group of Republican lawmakers recently “Regarding our facilities, worldwide secu- opened a Congressional investigation into the rity and business continuity teams are work- FDA’s handling of the 2007 tainted heparin crisis ing closely with local management to assess our (DGR, March). facilities thoroughly for any damage,” Johnson & Johnson spokeswoman Carol Goodrich told DGR. In February, approaches to a track and trace The company “is in communication with local system for prescription drugs that would make it relief agencies to determine local needs.” easier to root out counterfeits were discussed at an agency-industry workshop (DGR, March). Covidien Vice President for Public Rela- tions Bruce Farmer told DGR that all of its 1,500 The interagency report is available at www. employees in Japan have been accounted for and whitehouse.gov/sites/default/files/omb/IPEC/ none of its facilities suffered major damage. Pharma_Report_Final.pdf. — David Pittman April 2011 drug gmp report Page 9

Former KV CEO Gets Hefty Fine, conducted an inspection of KV’s facilities and Jail Time for FDCA Violations found numerous drug-production problems and other potential violations. The Justice Depart- Former KV Pharmaceutical CEO Marc Her- ment then filed a civil suit against KV and Ethex, melin has been fined and will do jail time for the asking the court to have the companies and the distribution of misbranded products, including executive officers take immediate action to rem- oversized morphine tablets. edy the problems. A federal court issued an order requesting that the executive officers fix the pro- Hermelin, who also served as the chairman of duction problems. — Molly Cohen the company’s board, pleaded guilty March 10 to two misdemeanor violations of the Food, Drug, FDA Warns Drugmakers About and Cosmetic Act (FDCA), and admitted KV dis- Fragment Formation in Vials tributed misbranded morphine sulfate tablets in 2007 and 2008. As part of his sentence, Herme- In response to several recalls, the FDA is lin was ordered to pay a $1-million fine, forfeit warning drug manufacturers of the potential for- $900,000 and serve a sentence of 30 days in jail. mation of glass fragments in injectable drugs filled in small-volume glass vials. The government charged that Hermelin, as the responsible corporate officer for KV and its The agency says glass has advantages over subsidiary Ethex, had the authority and responsi- other packaging materials. However, there is bility to prevent and correct FDCA violations at still the potential for glass, under certain condi- both companies. tions, to shed thin, flexible fragments called glass lamellae from the interior surface of the con- Therefore, Hermelin was ordered excluded tainer directly into the drug. from participation in federal healthcare programs under guidance from the HHS Office of Inspec- The agency says the lamellae are difficult to tor General (OIG) and Ethex was dissolved. detect by visual inspection. Misbranded Tablets Last September, Amgen recalled lots of its anemia drug Epogen (epoetin alfa) and Centocor The oversized morphine tablets contained Ortho Biotech’s Procrit (epoetin alfa) due to glass more morphine than was specified in its label, lamellae (DGR, October 2010). deeming it “misbranded” under federal law. In June 2008, KV discovered the oversized tablets The same problem affected Sandoz a month and reported them to the FDA in addition to pub- later, forcing the company to voluntarily recall licly recalling several lots (DGR, December 2008). lots of its methotrexate injections (DGR, Decem- ber 2010). The government alleged although KV knew of other oversized tablets and that one of its Earlier this year, Cumberland Pharmaceuticals machines could randomly produce them, the recalled six lots of overdose drug Acetadote (acetyl- company did not inform the FDA of this. cysteine) because of glass particles (DGR, February). In May 2010, Ethex pleaded guilty to two Most recently, American Regent voluntarily felony offenses as a result of its failure to file recalled potassium phosphate and sodium thio- required reports with the FDA concerning the sulfate injections because of glass lamellae for- oversized tablets. Ethex was then ordered to pay mulation (DGR, February). $28.1 million in fines and was placed on proba- While no adverse events have been reported tion for five years. from glass lamellae, they could cause embolic, In a related federal case in St. Louis, after the oversized drugs were acknowledged, the FDA (See Glass, Page 10) Page 10 drug gmp report April 2011

Bill Would Increase Penalties contingencies to respond when thefts occur For Prescription Drug Thefts (DGR, May 2010). In August, the FDA issued a release after a number of patients suffered ill Citing a dramatic spike in thefts of prescrip- effects related to stolen insulin. — Meg Bryant tion drugs and medical devices, a group of demo- cratic senators March 8 introduced legislation to Glass, from Page 9 crack down on medical product heists at every point in the supply chain. thrombotic and other vascular events when administered intravenously, or when administered subcu- Among other things, the SAFE Doses Act taneously, could lead to the development of foreign (Strengthening and Focusing Enforcement to body granuloma, local injection site reactions and Deter Organized Stealing and Enhance Safety) increased immunogenicity, the FDA warns. would increase federal penalties for pharmacy theft and give authorities additional tools, includ- According to the FDA, several conditions ing wiretaps, by bringing drug thefts under the may lead to a higher incidence of glass lamellae Racketeer-Influenced and Corrupt Organizations formulation: (RICO) Act. ●● Vials manufactured by a tubing process Sens. Amy Klobuchar (Minn.), Charles are less resistant than molded glass vials Schumer (NY), Jay Rockefeller (W.Va.), Sherrod and may shed more easily. However, the Brown (Ohio), Bill Nelson (Fla.) and Bob Casey processing conditions can be designed to (Pa.) are co-sponsoring the bill. mitigate the potential for later delamina- tion; The legislation would: ●● Drug solutions formulated at high pH ●● Increase possible sentences for theft of and with certain buffers like citrate and controlled substances from pharmacies; tartrate; ●● Increase sentences for theft of medical ●● Length of time the drug is exposed to the products and subsequent transportation inner surface of the container; and storage; ●● Room temperature storage requirements; ●● Strengthen penalties for stolen medical and product “fences,” including parties who ●● Terminal sterilization has a significant ef- knowingly obtain stolen products for fect on glass stability. resale; The FDA recommends several actions to help ●● Enhance sentences when ingestion of a prevent lamellae formulation. For “at-risk” prod- stolen substance results in death or when ucts, vial surface alkalinity can be minimized the defendant is a participant in the supply through selection of highly resistant, non-alkaline chain; earth borosilicate glass. ●● Make medical product theft subject to the RICO Act; and Appropriate selection of vendors is also ●● Provide for civil penalties and the forfei- important as well as proper quality control of ture of monetary gains from stolen goods. incoming vials. The FDA issued alerts twice last year about The agency also advises manufacturers to re- the potential dangers to patients from sto- examine their supplier quality management pro- len drugs. In April 2010, the agency warned gram and reminds manufactures current good of several cases involving adverse reactions in manufacturing regulations require drug contain- patients who had taken stolen drugs and sent ers not be reactive or additive so as to alter the a letter to drugmakers urging them to develop safety or quality of the drug. — Molly Cohen April 2011 drug gmp report Page 11

Fabrazyme, Thyrogen Supplies facility in Framingham, Mass., comes online Run Into Manufacturing Snag later this year (DGR, February). Supplies of Genzyme’s Fabry disease drug Genzyme is also warning healthcare profes- Fabrazyme have hit another snag as the company sionals that global supplies of Thyrogen will be announced further manufacturing problems for a limited through July, possibly causing temporary drug already in short supply. shortages in some countries. The company halted production of a lot of Thyrogen Shortage Fabrazyme (agalsidase beta) when the finished While Genzyme transferred fill/finish activi- batch was rejected for not meeting release crite- ties of some of its products to Hospira last year, ria, Genzyme announced March 23. the move led to a low inventory of Thyrogen “Our current plans are to fill and finish all (thyrotropin alfa for injection), spokeswoman future lots of Fabrazyme at a contract manufac- Erin Emlock told DGR. turing facility that is already handling a large On top of that, “we had a batch recently portion of Fabrazyme fill/finish,” Genzyme said. that was supposed to go to Europe that was not The company previously moved the fill/finish released,” Emlock added. activities to a contract manufacturer site in Ire- The European Medicines Agency said it was land after a consent decree forced the closure of informed by the company that a manufacturing Genzyme’s troubled Allston, Mass., plant (DGR, issue will result in a supply shortage and the com- December 2010). pany will meet about 45 percent of EU demand Genzyme said in January Fabrazyme supplies through July. aren’t likely to be on track until a new production — David Pittman, Molly Cohen

Dakota Labs Gets Warning for adequate system for monitoring environmental GMP, Labeling Violations conditions,” the letter states. Because of the severity of Dakota’s cGMP Dakota Laboratories has received a warning violations, the FDA suggests Dakota, “engage letter for significant violations of cGMP regula- a third party consultant having the appropri- tions and for mislabeling two drugs. ate cGMP expertise,” to assist the company in The FDA’s Minneapolis District Office dis- assessing its practices. covered a number of cGMP and product sterility The FDA also takes issue with the label- issues during a June 22 to 23, 2010, inspection of ing of two of Dakota’s products, Ring Relief ear Dakota’s Mitchell, S.D., facility. drops and Iwise pink eye drops. Both products are Dakota failed to establish written proce- labeled homeopathic, but “these products are pre- dures “to prevent microbiological contamination scription drugs … because they are intended to of drug products purporting to be sterile,” the treat diseases that require diagnosis and treatment FDA says. Dakota released several batches of eye by a physician,” according to the letter. drops without validating their sterility, and did Dakota has been working with a number of not assure that filters were adequately suitable. cGMP consultants to address the violations noted in the warning letter, company President Charles Dakota also did not investigate environ- Voellinger told DGR. mental data that failed to meet company limits, neglecting to test water used in the production The Dakota warning letter can be found at of its Ortho-K Eye Drops and its Women’s Eye www.fdanews.com/ext/files/11.pdf. Drops. Moreover, the company “does not have an — Kevin O’Rourke Page 12 drug gmp report April 2011

GAO Says FDA Oversight Is at criteria for withdrawing drugs that fail to con- ‘High-Risk’ for Mismanagement firm clinical benefit under the program. The FDA’s oversight of medical products remains The report acknowledges some progress in a “high-risk” area for mismanagement, according this area though, pointing to FDA initiatives to to a recent update to the GAO’s High-Risk Series, improve reporting of adverse events and make which points to ongoing issues with the agency’s tracking more efficient. inspection of overseas facilities and postmarket Despite these improvements, the FDA has a safety monitoring. long way to go, GAO says. Before the high-risk designation can be removed, the agency must: The series highlights federal government operations GAO determines to be at risk for ●● Strengthen its resource management and “fraud, waste, abuse, and mismanagement” or strategic planning; that require “transformation to address economy, ●● Develop results-oriented performance efficiency, or effectiveness challenges.” measures; ●● Create a workforce plan for new overseas The FDA was first added to GAO’s High- offices; and Risk List in 2009, after the office determined ●● Implement a rigorous postmarket safety the agency “needs to enhance its oversight program. — Wilson Peden of medical products to better protect public health.” That update criticized the FDA’s inspec- FDA Cross-Contamination Guidance tions of foreign facilities as well as the agency’s Addresses Beta-Lactam Antibiotics monitoring of clinical trials and review of pro- motional materials. The FDA has issued new guidance to help manufacturers decide when separate buildings are neces- Since then, the FDA has continued to strug- sary to prevent non-penicillin beta-lactam antibiotics gle with foreign inspections (DGR, November from cross-contaminating other pharmaceuticals. 2010). While the agency has opened new offices overseas, it still lacks performance goals and a If the products are made in the same facility, plan to address potential staffing challenges. the area dedicated to manufacturing a non- penicillin beta-lactam must be structurally iso- The FDA’s approach to choosing facilities for lated from areas where other products are manu- inspection is also inconsistent with the GAO’s factured, the March draft guidance states. recommendation that the agency inspect facilities with the highest public health risk potential at a Beta-Lactam compounds’ chemical structure is comparable rate, regardless of whether they are believed to initiate allergic reactions in some patients. in the U.S. or overseas. Beta-lactam antibiotic manufacturers should also In addition, the agency continues to struggle establish stringent controls to prevent cross contami- with postmarket safety monitoring, another weak- nation, the guidance says. For example, manufactur- ness noted in the 2009 report. The 2011 update ers must use separate air-handling systems for sensi- Customer Service: Kim Williams Editorial: April Hollis Ad Sales: Matt Salt Content Sales: Alka Desai expresses concern that some FDA staffers con- tizing non-penicillin beta-lactams and other products. (888) 838-5578 • +1 (703) 538-7600 (703) 538-7650 (703) 538-7642 (703) 538-7669 sider premarket responsibilities a higher priority, The FDA has handed out warning letters for [email protected] [email protected] [email protected] [email protected] and that staffing and technological issues limit the cross-contamination risks, including one to Venezue- agency’s capacity to conduct safety studies. lan-based Laboratories L.O. Oftalmi last May related to beta-lactam antibiotics (DGR, October 2010). GAO is also concerned that the FDA is not routinely monitoring postmarket studies for The new draft guidance is available at www. drugs expedited under the accelerated approval fdanews.com/ext/files/UCM246958.pdf. program, and notes the agency has not developed — David Pittman April 2011 drug gmp report Page 13

Guidance: Manufacturers Need Lastly, the FDA recommends compa- Contingency Plans at Plants nies maintain records that support decisions to changes approved during the plan for manufac- In the wake of a devastating earthquake in Japan, turing and release of MNPs. the FDA is urging drugmakers to develop contingency plans to use during emergencies that result in The guidance, planning for the Effects of many workers absent from manufacturing plants. High Absenteeism to Ensure Availability of Med- ically Necessary Drug Products, is available at The agency’s guidance, finalized last month, pro- www.fda.gov/downloads/Drugs/Guidanc vides suggestions for the development and imple- eComplianceRegulatoryInformation/Guidances/ mentation of a plan to continue producing medically UCM196497.pdf. — Molly Cohen necessary drug products (MNPs) during a crisis to avoid shortages that could impact public health. FDA, USP and Industry Working to Improve Drug Quality Standards As part of the guidance, the FDA recommends manufacturers discuss with suppliers actions to In an effort to bolster the safety and reliability avoid or mitigate disruptions in the supply chain. of widely used drugs, the U.S. Pharmacopeia (USP) The agency suggests a plan should address is partnering with FDA and the Consumer Health- each location’s specifications as part of a broader care Products Association (CHPA) to update quality plan to address multiple sites within a company. standards for more than three dozen products. MNP Priorities The initial effort is focused on a priority list of drugs and ingredients identified by the FDA The FDA recommends companies identify as being susceptible to counterfeiting or raising the percentage of resources routinely dedicated other concerns. to the manufacture of MNPs and conduct quality risk assessments to help identify activities that The list — which includes 30 acetaminophen can be reduced, delayed or substituted. monographs, seven diphenhydramine monographs and monographs for inactive ingredients People or positions within the company should be copovidone, crospovidone, povidone and talc — identified who have the authority to activate or deac- is part of a larger USP standards modernization tivate the plan and any other necessary decisions. initiative targeting about 700 small molecule and Companies should also prioritize their MNPs, 96 excipient monographs. with special attention given to products for which the company is the sole provider or supplies a In addition to the initial list, the FDA will significant share of the U.S. market, and products recommend other drug and ingredient standards vulnerable to shortage. for updating as it sees fit. The agency points out MNPs may include prod- FDA Commissioner Margaret Hamburg has ucts for maintenance of dependent populations, as endorsed the USP project. But the CHPA has well as products related to the particular emergency. expressed concern that not enough attention has been given to product degradants. The FDA acknowledges that during an emergency, CDER is prepared to exercise enforcement The CHPA proposed working with the USP discretion on statutory and regulatory requirements, and FDA to ensure industry input in the process provided the product remains safe and effective and and has established working groups to study and has adequate identity, strength, quality and purity. propose degradant standards for acetaminophen and diphenhydramine. The FDA also encourages manufacturers to notify CDER when an emergency plan is acti- USP CEO Roger Williams said he welcomes vated and deactivated. CHPA’s involvement. — Meg Bryant Page 14 drug gmp report April 2011

Pfizer Recalls Pain Drug Embeda, The Peapack, N.J.-based generic-drug maker Prostate Drug, Antidepressant said March 26 it was recalling the antidepressant citalopram as well as finasteride, which is indi- Pfizer has recalled all lots of its chronic pain cated for benign prostatic hyperplasia. medication Embeda due to a defect found during testing, a move that could keep the drug out of Bottles labeled citalopram may in fact contain pharmacies for months. finasteride and vice versa, the company says. The possible labeling mishap was caused by Indian Roughly 100,000 bottles of Embeda (mor- third-party manufacturer Aurobindo, Pfizer phine sulfate/naltrexone HCl) extended release spokesman Rick Chambers told DGR. capsules are being pulled from the market because of stability issues, Pfizer said March 16. Citalopram 10-mg tablets (100-count bottle) and Finasteride 5-mg tablets (90-count bottle) “We are investigating the cause and will with lot number FI0510058-A on the label should make every effort to return the product to be returned, Greenstone says. Citalopram is the patients as soon as possible,” company spokes- generic equivalent of Forest’s Celexa and finaste- man Rick Chambers told DGR. “We do expect ride is equivalent to Merck’s Proscar. Embeda will be off the market for many months.” Health Warnings Pfizer said it hasn’t received any adverse event reports, and the issue is unlikely to cause them. Greenstone warned of possible ramifications for cessation of treatment. In particular, patients “During routine stability testing of repre- who discontinue use of citalopram abruptly may sentative samples, elevated levels of sequestered experience a worsening of depression or other naltrexone degradants were found,” Chambers discontinuation symptoms. Finasteride should not said. “Naltrexone HCl is contained in the core of be used or handled by pregnant women, as it can Embeda and is sequestered when the medicine is cause birth defects. used as prescribed.” Approximately 2,600 bottles of both drugs Pfizer acquired Embeda as part of its $3.3 bil- were affected, of which 700 were on market, lion purchase of King Pharmaceuticals in October. according to Chambers. Pfizer is conducting The FDA approved Embeda in August 2009 as the an investigation into the cause of the mix-up first abuse-resistant prescription opioid. The nal- and does not expect a shortage of either drug, trexone blocks the morphine’s euphoric effects. Chambers added. No adverse events have been Recalls in March and April last year caused reported. Embeda’s sales to drop an estimated $2.9 million, The FDA in February issued an import alert according to SEC filings. King also voluntarily banning importation of antibiotics made at one recalled two lots of the drug in late 2010 because of Aurobindo’s plants. The company supplies a of post-manufacturing testing unrelated to prod- number of injectable and solid oral-dose products uct safety. to Greenstone. Sales of Embeda nearly reached $34 million Earlier this month, the two companies signed for the first nine months of 2010, according to a licensing agreement that will have Aurobindo SEC filings from King. expanding the number of generic products it Other Recalls manufactures for Greenstone. Pfizer subsidiary Greenstone is also recalling According to reports, Pfizer has recently been two generic drugs — one used to treat depres- considering selling its Greenstone unit, as part of sion, the other used by men with enlarged pros- a possible strategic shift to a smaller, pharma-only tate — due to a labeling snafu. company. — David Pittman, Kevin O’Rourke April 2011 drug gmp report Page 15

Excipients Also Used as Actives These expectations for excipient suppliers May Cause Issues for Industry may increase costs or reduce supply, if excipient makers submit to inspections or cease production As the FDA continues to clamp down on drug of the atypical active. Either option means more supply chains, some companies are concerned hurdles for drugmakers. that an ill-defined sliver of drug ingredients will drive suppliers to increase costs or reduce supply. What Can Be Done? Atypical actives are chemicals listed as active CDER Consumer Safety Officer Steven Wolf- pharmaceutical ingredients (APIs) but used com- gang recommended drug companies audit their mercially as excipients or for other uses. Although materials’ supply chain and ensure the qual- the FDA doesn’t keep count of how many such ity and integrity of the ingredients they use. But chemicals exists, Europe lists more than 100. some drugmakers have found excipient and raw material suppliers unwilling to divulge informa- The atypical actives’ dual use has caused tion or yield to FDA inspections. headaches for industry because if a drug or dietary supplement maker lists a product as an Schoneker suggested creating a new set of API, that maker’s supplier and its plants would be standards for atypical actives to complement subject to a more stringent set of FDA standards. those for excipients and APIs, noting the industry needs better quality standards for suppliers. Supplier Surprise However, Pfizer’s Director of Quality and In some cases, suppliers have been surprised Regulatory Policy Janeen Skutnik-Wilkinson when FDA inspectors arrived because they didn’t pointed out that suppliers have no obligation know their clients used what they believed was to sell to pharmaceutical companies and qual- an excipient as an API, according to attendees at ity standards could limit products. “We have to a Parenteral Drug Association workshop March 9 work with them to fit their systems rather than and 10 in Bethesda, Md. ask them to fit our models,” Skutnik-Wilkinson said. “We were all in shock how often this was happening,” David Schoneker, global regulatory Further regulation of excipient makers could affairs director for Colorcon, an excipient maker cause some suppliers, such as Colorcon, to stop in Harleysville, Pa., said. production altogether. Colorcon, for example, stopped producing Representatives from the FDA and the Euro- a product called Cal-Carb, a calcium carbonate- pean Medicines Agency spoke with less urgency based excipient used primarily as filler in pills. on the topic than industry attendees. While the Some drugmakers used Cal-Carb as an API, FDA has done little to address the issues around which led the FDA to show up at Colorcon’s atypical actives, Wolfgang encouraged drug plants for inspections and issue a multi-item companies to take a proactive stance on the Form 483. issue. “We were trying to make clear that this was “You’re seeing a movement towards develop- an excipient and that it was not suitable as an ing standards,” Wolfgang said. “Now is the time API,” Alexa Smith, global regulatory services to start thinking about those standards.” manager for Colorcon, said. Wolfgang told DGR afterward that the FDA But that didn’t seem to matter to some of the isn’t working toward new atypical active stan- company’s clients. Colorcon concluded there were dards and, that if new standards were to come, too many problems with producing the product as they likely would be developed within industry an API rather than solely as an excipient. and not the FDA. — David Pittman Page 16 drug gmp report April 2011

FDA, EMA to Do Parallel Reviews EMA Signs Agreement With For QbD Application Components International Regulatory Body Under a new pilot program, NDAs submit- The Pharmaceutical Inspection Convention ted to the FDA and European Medicines Agency and Pharmaceutical Inspection Co-operation (EMA) with quality by design (QbD) components Scheme (known jointly as PIC/S) signed a new will undergo parallel review from both regula- cooperation agreement with the European Medi- tory agencies. cines Agency (EMA) to strengthen their cooperation in areas of common interest related to The pilot, which will run from April 1 until good manufacturing and distribution practice March 31, 2014, at which time the agencies will (GMDP). assess and issue a joint outcome of the program, the EMA says. The agreement, signed Dec. 28 and released Feb. 18, will focus on sharing resources and The dual review will neither expedite nor avoiding duplicative activities. lengthen the approval process, FDA spokeswoman Morgan Liscinsky told DGR. PIC/S will work mostly with the EMA’s Com- pliance and Inspection Sector, and the arrange- Reviewers from both agencies will assess, ment runs for two years. separately, the quality/chemistry, manufacturing and control section of submissions. The exchange of information between the two organizations may include legislation and guid- In Europe, the pilot will apply to new MAAs ances prepared by both entities, timings of public and quality-related scientific advice requests. consultation and publication of documents, confidential or restricted information exempt from Meanwhile, in the U.S., the program will public disclosure and confidential information cover NDAs, sNDAs and chemistry manufactur- shared during official meetings. ing control meeting requests. Both organizations will exchange informa- One goal of the pilot program is to ensure tion in regards to auditing schedules to avoid International Conference on Harmonisation guide- duplication. lines are implemented consistently in both regions. The cooperation agreement is available at The agencies request interested applicants www.ema.europa.eu/docs/en_GB/document_ notify both agencies three months in advance of library/Other/2011/02/WC500102054.pdf. submission. — Molly Cohen — Molly Cohen

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