FDA Plans to Issue Several GMP Guidances in 2011

The FDA has released its annual list of planned guidances, which includes an anticipated guidance on GMPs for components that may instruct drugmakers to audit raw material suppliers.

Other expected GMP guidances for this year will cover contract manufacturing, importation of active pharmaceutical ingredients (API), nonpenicillin beta-lactam contamination, prevention and con-trol of viral contamination and component quality control, according to the agency’s annual guidance agenda.

Last November, a former FDA official said the agency is working on a revision to GMP regulations that would require pharmaceutical companies to audit raw material suppliers (DGR, December 2010).

2010 Saw GMP Challenges For Industry, Particularly J&J

In 2010, the drug industry faced numerous challenges to GMP compliance, including supplier issues, viral contaminations and unusual smelling drugs. But some companies, particularly Johnson & Johnson (J&J), grabbed more than their share of headlines.

J&J’s manufacturing troubles actually kicked off in late 2009 with a recall of Children’s Tylenol, followed quickly by an unas-sociated, limited recall of Tylenol Arthritis Pain caplets due to an “uncharacteristic smell or taste” with certain lots of the product.

The company first received complaints of the musty and moldy smell in certain drug products in September 2008 but did not notify the FDA until a year later, prompting an FDA warning letter to start off the year (DGR, February 2010).

Pfizer also recalled drugs last year for the same odor issue, thought to be caused by trace amounts of 2,4,6- tribromoanisole

Issue No. 222January 2011

Gar cited for lack of quality unit authority ...........Page 2

McNeil’s Fort Washington plant gets second Form 483 in a year ...................Page 3

Anthera lupus trial back on after investigation ....Page 5

Indian company denies ac-cess to FDA inspector, gets warning ....................Page 5

Pfizer cites odor concerns in Lipitor recall ............Page 6

Form 483 Insider ....Page 7

FDA recommends manu-facturers hire process-drift watchdogs ................Page 8

FDA wants more efforts to guard against viruses in bio-logics ........................Page 9

Warning to Macco cites fly-ing insects in bag ...Page 10

FDA cracks down on sup-plements with hidden ingre-dients ......................Page 11

J&J recalls Rolaids for par-ticles, House questions FDA oversight .................Page 12

INsIde thIs Issue

(See Challenges, Page 4)

(See Guidances, Page 2)

drug gmp report January 2011Page 2

The guidances on API importation and viral contamination are also timely because of recent industry issues with supply chain control and con-tamination (DGR, December 2010).

Guidance on Development Process

Many of the planned guidances will also help drugmakers during the development process. The FDA plans to issue draft or final guidance docu-ments on:

● Qualification of drug development tools; ● Development of extended-release

formulations; ● Adaptive trial designs; ● Multiple endpoints; ● Noninferiority trials; ● Drug and diagnostic co-development; and ● Chemistry, manufacturing and controls

for early clinical trials with live biothera-peutic products.

The FDA also will give industry advice on advertising, with guidances on comparative claims in prescription drug promotion, DTC tele-vision advertisements and promotion of prescrip-tion drug products using social media.

Additional guidances include topics such as chemistry, manufacturing and control changes reportable in annual reports, “Dear Healthcare Professional” letters, types of sub-missions for postapproval changes to combi-nation products, and naming and packaging practices.

The agency is seeking comment on the agenda and on possible topics for future guidances.

It notes that it is not bound by the guidance agenda to produce every topic on the list.

The guidance agenda is available at www.fdanews.com/ext/files/2010-30623_PI.pdf.— April Hollis

Guidances, from Page 1

Lack of Quality Unit Authority Cited in Warning to Gar

An FDA inspection of Gar Laboratories found its quality unit is not exercising sufficient authority in rejecting components.

The company did not comply with rec-ommendations from its quality control unit to destroy drug products used to treat acne because of failing assay results in three separate instances, according to a Dec. 6, 2010, warning letter posted online last month.

Instead, Gar reworked the affected lots to pass testing, without a documented justification, at the direction of the plant manager.

It also failed to establish written procedures for annual product reviews and as of the FDA’s July 13 to 29 inspection, it had not conducted any annual product reviews for its drug products. In its Form 483 response, Gar told the FDA it was in the process of conducting an annual review, but it did not provide any documentation as evidence.

The company also was cited for investiga-tion failures. It did not perform and document investigations into conflicting out-of-specification microbiological results obtained from in-house testing and testing performed by a third-party contract laboratory, the letter says.

Further, it failed to investigate the cause of at least 25 out-of-limit results for its deionized water system.

Stability Data

The company also does not have stability data for any of its drug products to demonstrate they will meet the intended finished product specifica-tions for the shelf life.

Some bulk lots were found to be out of speci-fication after seven to nine months in storage.

Gar did not respond to a request for comment by press time. The warning letter is available at www.fdanews.com/ext/files/UCM237026.pdf.— April Hollis

drug gmp reportJanuary 2011 Page 3

McNeil’s Fort Washington Plant Gets Second Form 483 in a Year

Johnson & Johnson (J&J) subsidiary McNeil Consumer Healthcare has received its second Form 483 in 12 months for its troubled and temporarily closed Fort Washington, Pa., manufacturing plant.

A recent inspection found observations related to complaint handling, standard operating procedures (SOPs), process validation and labora-tory investigations, according to the Dec. 9 form posted online last month.

For example, McNeil did not follow its stan-dard operating procedure for Benadryl Allergy Fastmelt tablets, which were the subject of a recent recall (DGR, December 2010).

During process validation for the tablets, mate-rials that did not meet predetermined specifications were used in process validation batches, the form says. Certain materials did not meet the specifica-tion requirements of white to off-white granules because dark specks were found in the materials.

Comprehensive Action Plan Criticized

Additionally, the company continued to manu-facture and release the batches to market before and after obtaining out-of-specification and out-of-trend results, without conducting complete investigations, from August 2008 through March 2010.

Another observation notes McNeil did not fol-low its complaint procedures correctly, and it did not initiate corrective and preventive action in a timely manner to evaluate complaints related to the tablets and how complaints were reviewed and evaluated.

The Fort Washington plant already received a Form 483 in April and McNeil has suspended operations there, leading to a $600 million sales reduction in 2010 (DGR, August 2010).

The form also took issue with part of a com-prehensive action plan the company announced over the summer. For example, according to the data thresholds section in the plan, McNeil indi-cates that products with a certain minimum batch rejection rate will be further analyzed.

However, for St. Joseph enteric-coated 81-mg aspirin tablets, a review of rejection rate data found that partial rejects were excluded from the calculation of rejection rates.

A discussion in the plan’s process valida-tion quality indicator assessment report for the tablets was incomplete, the form adds. It did not thoroughly explain if there were similar trends identified across the review periods concerning the partial and full-batch rejections. Addition-ally, there was no discussion on the rationale for excluding the partial rejected batches from the calculated rejection rates.

The review also did not reveal that investi-gations should have been conducted for certain out-of-trend results.

Further, the company’s laboratory investiga-tions into out-of-specification or atypical results for Sudafed PE non-drying sinus caplets were not always complete or accurate, according to the form.

Possible Consent Decree

Because the company received a Form 483 in November at its Las Piedras, Puerto Rico, facility, there could be between a 25 and 50 percent chance of a shutdown of that facility as well, Larry Biegelsen, an analyst with Wells Fargo, writes in a Dec. 9 note.

J&J’s consumer products business has already seen several regulatory actions as McNeil has had multiple recalls of OTC products and has come under FDA and congressional scrutiny (DGR, October 2010).

Biegelsen added that although McNeil has had a long history of manufacturing issues with-out a consent decree or injunction, ongoing prob-lems provide a basis for the FDA to take addi-tional regulatory action at any time.

The FDA is reviewing the 483 observations but cannot yet make conclusions on their signifi-cance, agency spokesman Christopher Kelly told DGR last month.

(See McNeil, Page 8)

drug gmp report January 2011Page 4

(TBA), which can result from the breakdown of a chemical that is sometimes applied to wood used in pallets for transporting and storing product packaging materials.

These events prompted the agency to give guid-ance recommending that manufacturers and dis-tributors work to prevent the use of wood products treated with the preservative (DGR, December 2010).

Congressional Scrutiny

But J&J’s troubles did not end with TBA. After several recalls of drugs manufactured at its Fort Washington, Pa., plant, the facility was shut down last year and is expected to reopen by midyear (DGR, September 2010). J&J subsidiary McNeil Consumer Healthcare is undertaking a comprehensive action plan to address manufac-turing issues after recalls of many of its popular OTC drugs, as well as a controversial “phantom recall” of Motrin that drew the attention of Con-gress (DGR, October 2010).

That issue, along with GMP problems at several other companies, led a House committee to ques-tion the FDA’s ability to oversee drugmakers’ Puerto Rico facilities and request information on the agen-cy’s oversight capability (DGR, December 2010).

Reps. Edolphus Towns (D-N.Y.) and Darrell Issa (R-Calif.), chairman and ranking member, respectively, of the House Oversight and Govern-ment Reform Committee at the time, requested information on the FDA’s Puerto Rico district office and an update on the agency’s investigation into McNeil’s so-called “silent” Motrin recall and the actions of FDA employees.

Issa also raised concerns last year with the FDA’s relationship with and regulation of con-tract drug manufacturers, noting in a Decem-ber letter to FDA Commissioner Margaret Ham-burg that a J&J recall of Rolaids identified the potential source of metal and wood particles in the product to be a third-party manufacturer. Issa requested information by Jan. 5 on the FDA’s regulation of contract manufacturing.

Although FDA inspections of foreign plants have increased in recent years, they still pale in comparison to the level of inspections made on U.S.-based manufacturing facilities, the Gov-ernment Accountability Office found in October (DGR, November 2010).

The FDA is also working on a revision to GMP regulations that would require pharmaceu-tical companies to audit raw material suppliers (DGR, December 2010).

In the meantime, the FDA has suggested that drug manufacturers warn each other about suppli-ers that may be adulterating materials for financial gain, and legal experts say it is best to share this type of information through a trade association to protect against liability or antitrust issues.

J&J Not Alone

Although J&J experienced problems with sev-eral of these issues, they weren’t the only company to have troubles in 2010. Genzyme, for example, continued to see ramifications from viral contami-nation at its Allston, Mass., manufacturing plant.

The company signed a consent decree last year requiring it to complete a remediation plan, followed by five years of oversight and annual reports by a third-party consultant (DGR, June 2010). Genzyme expects the plan — which would include milestones for bringing the plant into compliance — to be com-pleted in two to three years. The decree also includes a disgorgement of $175 million from past profits.

GlaxoSmithKline (GSK) and Merck also faced viral contamination issues, as DNA fragments from porcine circovirus-1 (PCV-1) were found in GSK’s Rotarix and Merck’s RotaTeq — both rota-virus vaccines — and fragments from PCV-2 were also found in RotaTeq (DGR, May 2010).

The FDA is now assessing its regulatory rec-ommendations for testing other vaccines for adven-titious agents. In August, it sent written inquiries to manufacturers asking for additional information on plans they may have to implement more testing methods as part of their manufacturing process as they become available. — April Hollis

Challenges, from Page 1

drug gmp reportJanuary 2011 Page 5

Anthera Lupus Trial Back On Following Investigation

Anthera plans to reinitiate enrollment in its suspended Phase IIb lupus drug trial this month after an investigation determined cracks found in vials of the drug, A-623, were likely caused by extreme cold during transport.

The company still expects top-line data on A-623 in the first half of 2012, with interim results expected in the first half of this year, Anthera CEO Paul Truex said during a conference call last month.

“The vial fracture patterns appeared consis-tent with those reported as stress or strain issues … at extreme cold temperatures,” Truex said. The company has had no reports of patient-related side effects or problems with drug administration that can be attributed to the vial problem.

Quality Analysis

Anthera conducted a full quality analysis and investigation, focusing primarily on temperature of the product during transport, after the cracked vials led to a temporary enrollment suspension in the PEARL-SC trial last November.

During shipping, the vials are packed in dry ice, exposing them to temperatures well below -20 degrees Celsius. An Anthera labora-tory experiment and additional tests support the theory that these temperatures led to the cracked vials, he said.

Anthera now has a good understanding of the conditions under which cracking is likely and has modified its distribution process to avoid those temperatures.

Truex noted the FDA has responded to Anthera’s initial response, with no action indicated.

Although the PEARL-SC trial is a Phase IIb study, Anthera has said it hopes to use it as one of two pivotal trials for the drug. The trial is mod-eled on the BLISS studies Human Genome Sci-ences and GlaxoSmithKline used for their lupus drug Benlysta (belimumab), which received over-whelming support from an advisory committee.

Anthera has been developing a reinitiation plan for the trial, including a strategy for patients who already received at least one dose of the drug. For those 12 patients, an open-label exten-sion study plan should be submitted to the FDA to capture long-term safety data.

The company also has identified additional clinical sites and hopes to add new patients, but it is comfortable the study remains powered to detect a meaningful clinical effect, Truex said. Anthera has previously stated PEARL-SC will enroll up to 600 patients.

Anthera will study A-623, administered weekly or monthly, using weight-based dosing of approximately 2.5 mg per kg per month, up to 11 mg per kg per month.

In the meantime, all inventory has been returned to a new distributor for full inspection, repackaging and relabeling. Anthera said it would work with Merck BioManufacturing Network, which will manufacture large-scale clinical and pre-commercial supplies of A-623 at a UK site. — April Hollis

Indian Company Denies Access to FDA Inspector, Gets Warning

Synbiotics, an India-based active pharma-ceutical ingredient (API) manufacturer, denied the FDA access to its facility and requested the investigator remain in an office at another loca-tion, a recent warning letter says.

Between Aug. 23 and 27, 2010, the company provided information and limited documents to the investigator, revealing significant devia-tions from GMPs, according to the Dec. 16 letter posted online last month.

For example, the company shipped a product lot to the U.S. last January even though no procedures were in place for change control, out-of-specification investigations, process deviation investigations, lab-oratory incidents, consumer complaint handling or annual product reviews.

(See Synbiotics, Page 6)

drug gmp report January 2011Page 6

Pfizer Cites Odor Concerns In Another Lipitor Recall

Pfizer is recalling an additional lot of Lipi-tor — its fourth recall since last August — over another report of an uncharacteristic smell ema-nating from the product’s bottle.

Last month’s recall of 19,000 bottles follows three other recalls made in August, October and November of 2010 that have totaled more than 350,000 bottles. As in those instances, the odor related to the latest recall was found to be consis-tent with 2,4,6 tribromoanisole (TBA), a preser-vative often applied to the wood in pallets used to ship and store products.

Pfizer said the bottles were made by a third-party manufacturer and the lot was shipped prior to changes in quality control made at the manu-facturer’s plant. However, the company reiter-ated that because bottles from before the changes were made may still be on the market, additional recalls may be forthcoming.

The world’s largest drugmaker added that the health risk to consumers from the odor “appears to be minimal.”

“The company has taken quick action to ensure its product continues to meet the compa-ny’s high quality and patient safety standards,” Pfizer says. “We have identified the source of the odor, and we are enacting rigorous measures to prevent odor-related issues going forward.”

Some of those measures include increasing the speed of bottle delivery, requiring plastic pallets for the transport of empty bottles and relocating bottle production from Puerto Rico (DGR, December 2010).

Despite the four recalls, Pfizer said it does not anticipate any Lipitor (atorvastatin) shortages.

Pfizer is not alone in recalling a drug due to an odor. In October, Johnson & Johnson recalled one lot of Tylenol caplets after reports of an odor — also thought to be caused by TBA — com-ing from the product’s bottles (DGR, November 2010). — Jonathan Block

“Without these and other basic GMP pro-cedures in place, there is minimal assurance of appropriate systems to assure product quality,” the letter says.

The company’s Form 483 response includes standard operating procedures requested dur-ing the inspection attempt and it is the compa-ny’s responsibility to ensure these and other criti-cal procedures and quality assurance functions are in place before manufacturing, the FDA says, adding that Synbiotics’ quality system will be reviewed during the next inspection.

The agency requests a timeline by which the facility will be ready for reinspection, accounting for process validation, essential procedures being put in place, critical quality functions being established and employee training.

Another citation notes that at the time of lot shipment, the company also had not performed

validation on one of its manufacturing processes, nor had it established a process design, a valida-tion plan or qualification protocols. Process vali-dation is essential and is expected before com-mercial distribution begins, the letter says.

The company’s 483 response states that the lot met U.S. Pharmacopeia (USP) requirements at its release and again during retain retesting and that because it meets those requirements, the batch is completely safe and there are no quality issues.

But the FDA disagrees, as the company already acknowledged that process validation had not yet been completed at the time of the lot’s manufacture, that its quality system was inad-equate and that critical quality assurance func-tions were missing.

Synbiotics did not respond to a request for comment by press time. The warning let-ter is available at www.fdanews.com/ext/files/UCM237767.pdf. — April Hollis

Synbiotics, from Page 5

drug gmp reportJanuary 2011 Page 7

Novartis Gets 483 for Use of Down Bottle Bin

Novartis Pharmaceuticals has received a Form 483 noting a failure of its changeover inspection to ensure products from previous packaging operations are removed.

A customer complaint for the blood pressure medication Diovan HCT (valsartan/hydrochloro-thiazide) reported finding tablets with the wrong dose of the drug in a sealed bottle, according to the Sept. 16, 2010, form.

The Suffern, N.Y., facility’s investigation con-cluded that inappropriate clearance of a down bottle bin from the previous run was one of the most likely root causes. The bin is used to hold filled bottles that had not been positioned cor-rectly on the conveyer for labeling.

Packaging operators were allowed to return unlabeled bottles back to the packaging line without breaking the foil to examine the bottle’s contents.

Novartis has implemented corrective actions and believes its responses and the actions fully address the observations, the company told DGR.

The Form 483 is available at www.fdanews.com/ext/files/NovartisPharmaSept10_483.pdf.

Mylan Form 483 Notes Documentation Failures

Mylan Pharmaceuticals was handed a Form 483 after it failed to follow its own written proce-dures to document certain items on its qualifica-tion discrepancy reporting form and file them as part of the qualification protocol.

The Morgantown, W.Va., facility also did not completely fill out training development forms. Some forms did not list the name of the trainer and lacked the signature of the supervisor, according to the Feb. 17, 2010, form.

Additionally, the FDA inspection found vali-dation batch records that did not include the

name of the employees who performed or com-municated the end-point moisture percentages recorded for sub-parts II-VII of the batches to the manufacturing department.

Mylan did not respond to a request for com-ment by press time. The Form 483 is available at www.fdanews.com/ext/files/Mylan010311.pdf.

Hill Dermaceuticals Gets 483 For Several GMP Issues

The FDA has given Hill Dermaceuticals a Form 483 after an inspection revealed several GMP deviations, such as failure to perform ade-quate and thorough investigations and to propose adequate corrective actions.

The Sanford, Fla.-based company did not always complete documentation for deviation investigations, according to a Sept. 10, 2010, form. Hill’s quality assurance department further failed to evaluate and challenge or approve all out-of-specification (OOS) investigation reports, the form says. In addition, there is no documen-tation or signature to support that the analyst or personnel involved in the event is included as part of the OOS or deviation report.

Other observations note:

● Failure to record deviations from written specifications;

● Lack of manufacturing equipment qualification;

● Failure to have a stability indicating meth-od for certain products; and

● Failure of quality assurance or quality control to assure that analytical testing results for finished drug products are accurate.

The company is on schedule to have its prod-ucts fully remediated by April and its equip-ment was validated last year, Neil Di Spirito, legal counsel for Hill, told DGR. The Form 483 is available at www.fdanews.com/ext/files/HillDer-maceuticals.pdf.

form 483 INsIder

drug gmp report January 2011Page 8

FDA Recommends Manufacturers Hire Process-Drift Watchdogs

Manufacturers need to get in-house experts in statistical tools to monitor unwanted variability in their processes if they don’t already have them, according to an FDA official.

“If you don’t have in-house, you need to hire it and bring it in,” Grace McNally, a consumer safety officer in CDER’s Office of Compliance, Division of Manufacturing & Product Quality, told attendees of the PQRI-FDA Workshop on Process Drift last month in Bethesda, Md.

Such experts can help drugmakers choose the best tools to monitor products and processes to avoid “process drift,” or undesired process variability.

In order to detect process drift, normal vari-ability for a process must first be understood and measured where possible, McNally said.

She noted that the process design stage might not predict the full range of variability a company will see in commercial production. Manufacturers need to collect data from actual commercial-scale manufacturing to determine the true inherent vari-ability in the process.

These data can be used as a basis to estab-lish levels and frequency of routine sampling and monitoring for a particular product or process or could be used to justify reducing your oversight, McNally said. “You have to have a basis for mon-itoring frequency and it has to come from data.”

When a product is first launched, a manufac-turer will likely do enhanced sampling, with the length of this heightened sampling period deter-mined by factors such as production size, com-plexity of processes and previous experience with similar products.

“It should be a step-down approach, particu-larly where there’s not a lot of previous experi-ence,” McNally said. — April Hollis

On the other hand, if McNeil resolves the pro-duction issues and returns to full operations, cou-pled with potential Xarelto (rivaroxaban), tela-previr, and abiraterone launches, 2012 could be a turnaround year for the company, Biegelsen adds.

McNeil will quickly provide a detailed response to the FDA and work to address these most recent observations, company spokesman Marc Boston told DGR. McNeil has made prog-ress toward ensuring manufacturing operations meet expectations and will invest all necessary resources in that commitment.

In a separate development, J&J announced last month that it appointed Sheri McCoy, currently worldwide chairman, pharmaceuticals, as vice chairman of the company’s executive committee. In her additional role, she will assume expanded responsibilities, including in the consumer group.

Last September, J&J announced that Colleen Goggins, head of the company’s consumer prod-ucts division, would retire in March.

The Form 483 is available at www.fdanews.com/ext/files/UCM237043.pdf. — April Hollis

McNeil, from Page 3

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FDA Wants More Efforts to Guard Against Viruses in Biologics

The FDA is expecting biologics manufac-turers to work harder to reduce the possibility of adventitious virus contamination at contract manufacturers, as well as their own sites, after recent significant and preventable contamina-tions, an FDA official says.

For example, using multiple methods for viral clearance could have prevented some contami-nation issues seen at companies, Rick Friedman, director of CDER’s Division of Manufacturing and Product Quality, told DGR last month.

The agency is also finding “too many signif-icant issues” between manufacturers and their contractors, such as quality assurance ethics that are not compatible with each other, Friedman said at the PDA/FDA Adventitious Viruses in Biologics workshop in Bethesda, Md. He noted the FDA has issued warning letters to both spon-sors and contract manufacturers.

Audits

Friedman recommended meaningful audits and proper change notification provisions in qual-ity agreements as important steps toward mini-mizing the risk of contamination.

Contamination prevention and control are “particularly tough when there’s so much bio-logical sourced material and biological systems involved,” he added.

Areas manufacturers should scrutinize include cell banks, raw materials (particularly animal-derived), processes, facilities, material segregation and containment, and controls over storage and handling.

“Raw material choices are big,” Friedman emphasized. “It’s something we’re going to be looking at in [good manufacturing practice] inspections a lot.” The FDA will be assessing companies’ treatment of incoming raw materials, and disinfection of supplies brought into the pro-cessing area is critical, he said.

Inspectors will also determine how well a manufacturer or contractor can close systems off to personnel and the environment, as well as cleaning and sterilization of equipment.

Biologics manufacturers also should assess their production processes’ ability to inactivate and remove infectious viruses. Friedman recom-mended using different methods of virus inacti-vation or removal in the same production process to achieve maximum viral clearance. However, some legacy processes do not include multiple viral clearance techniques, he told DGR.

But companies’ evaluation of their processes should not stop with one-time studies, he warned, adding manufacturers must monitor their processes every day and look for signals of process drift, or opportunities for improving production processes.

Contract Manufacturers

Process drift also needs to be monitored at contract manufacturers, Friedman said last month during the PQRI-FDA workshop on process drift.

A shift in product characteristics may be caused by a new batch of raw materials or a new supplier, and a company’s panel of incoming product testing should be able to detect if a batch is different. Testing also should be conducted during significant manufacturing stages.

These issues can also pose problems for com-panies’ preapproval, Jay Elterman, director of CBER’s division of manufacturing and product quality, said at the workshop.

Adventitious agents have been cited in clini-cal hold letters, and the FDA has noted issues with materials sources, lack of information on viral strain history, or lack of information on the identity and purity of source materials. Companies also have neglected to provide the agency with their descrip-tion and results of their adventitious agent testing.

“Lack of documentation has certainly been raised during the [preapproval reviews] and would certainly lead into the next couple of ques-tions,” Elterman noted. — April Hollis

drug gmp report January 2011Page 10

Warning to Macco Cites Flying Insects in Bag

Macco Organiques, a Canadian active phar-maceutical ingredient (API) manufacturer, was cited in a warning letter after inspectors found live flying insects in a large bag of material next to production equipment.

The inspection also found dust and debris covering products at the company’s Quebec facil-ity, according to the Dec. 12 letter posted online last month. Some of the products were stored in drums but numerous lids were missing.

Macco’s Form 483 response indicated it would improve its practices and has procedures to control insects, housekeeping and raw mate-rials. But the response lacked a specific correc-tive action plan for maintaining and cleaning the warehouse and production areas to prevent contamination.

The company’s quality unit also was cited for failing to adequately review and investigate pro-duction deviations.

For example, the inspection found Macco released and shipped a batch of product to a cus-tomer while it was still under investigation for black particles. The nonconformance investiga-tion found a feed interruption led the product to be in contact with hot areas and become charred or burned.

The FDA requests copies of all letters or other communications with Macco’s distributors on how to address lots with the charring defect, as well as a list of distributors and known drug manufacturers.

The agency notes it appreciates the scope of Macco’s corrective action plan, submitted April 30, and believes it is critical for GMP compli-ance. “Many of the repeat deviations resulted from poor supervision or a failure of quality assurance oversight,” it adds.

Macco also was cited for failure to perform process validation for three U.S. Pharmacopeia

(USP) products, a repeat observation, according to the letter.

In its response, Macco indicated its products will no longer have a USP claim on the label and therefore do not need to comply with USP stan-dards. The FDA disagrees with this response, as the products must either conform to the mono-graphs or state on the label how they differ from the compendia standards.

Macco is neither registered with the FDA nor has it listed every API it commercially distributes in the U.S., the letter says. Although the agency investigator discussed this with the company, its Form 483 response did not address the issue.

Several of the deviations are the same types noted on a previous Form 483 issued from June 2001.

Macco could not be reached for comment by press time. The warning letter is available at www.fdanews.com/ext/files/UCM236832.pdf.— April Hollis

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FDA Cracks Down on Supplements With Hidden Ingredients

FDA Commissioner Margaret Hamburg is warning dietary supplement manufacturers they may face felony charges if undeclared ingredients are found in their products.

The warning was included in a letter Ham-burg sent last month to manufacturers follow-ing an increasing number of supplements found with hidden ingredients that can cause adverse reactions.

Hamburg says company officials can be crim-inally prosecuted under the Federal Food, Drug, and Cosmetic Act, even if they did not participate or were not aware of any violations, a reference to the Park doctrine.

The letter follows a guidance issued by the HHS Office of Inspector General in October that said high-level company officials can be crim-inally charged for misconduct and subject to exclusion, even if the misconduct was committed by someone else or the official was unaware of it, but should have known.

Three Steps

The FDA has taken three steps to keep the public aware of products marketed as dietary supplements but containing the same, or analog versions, of FDA-approved drugs or novel syn-thetic steroids.

The agency has established a rapid pub-lic notification system (RSS feed) on its website alerting consumers when it finds a tainted prod-uct. The feed will include a link to information on how the product is mislabeled, ingredients that may cause adverse reactions and the types of adverse events associated with the product.

The FDA also set up an email address, TaintedProducts@fda.hhs.gov, so consum-ers can contact the agency regarding possibly tainted products. If consumers prefer to report anonymously, they can do so using a “Report Suspected Criminal Activity” form.

Since December 2007, the FDA has identified and warned consumers of nearly 300 tainted sup-plements, most of which are in the weight loss, sexual enhancement and bodybuilding categories, according to Principal Deputy Commissioner Joshua Sharfstein. The FDA recalled close to 200 of those products.

The FDA has also issued warning letters and conducted seizures and criminal prosecutions in response.

As an example of the agency’s crackdown on mislabeled dietary supplements, the agency recently issued a warning letter to the manu-facturer of Man Up Now, an erectile dysfunc-tion product, whose main ingredient is simi-lar to the active ingredient in Pfizer’s Viagra (sildenafil).

Adverse Events

During a conference call last month, Sharfs-tein listed stroke, acute liver injury, kidney fail-ure, pulmonary embolism and death as examples of adverse events reported with supplements, but could not offer details on the instances of each type of event.

He explained the FDA gets reports about adverse events from a product and then obtains and tests it. The agency often finds ingredients that could be linked to adverse events, but not all events are reported. Therefore, the agency can-not know exactly how many people have been affected and in what ways.

“We want consumers to be aware that there are products masquerading as dietary supple-ments that could pose dangers,” Sharfstein said. He advised consumers to be aware of products claiming to be alternatives to FDA-approved drugs or legal alternatives to steroids.

In addition, consumers should be wary of products that are marketed primarily in a foreign language or through mass emails, promise rapid sexual enhancement effects or warn about testing positive in performance enhancement drug tests. — Molly Cohen

drug gmp report January 2011Page 12

J&J Recalls Rolaids for Particles, House Questions FDA Oversight

Johnson & Johnson (J&J) is adding to its string of consumer product recalls, this time recalling 118 lots of various Rolaids products after consumer complaints of foreign materials, including metal and wood particles.

The company’s investigation found a third-party manufacturer, Best Sweet, might have introduced the materials during manufacturing processes, J&J said last month.

While the investigation is ongoing, the company has suspended production of the products — Rolaids Extra Strength Softchews, Rolaids Extra Strength Plus Gas Relief Soft- chews and Rolaids Multi-Symptom Plus Anti-Gas Softchews — until corrective actions have been implemented.

New Questions

The recall has caused issues for the FDA as well. The length, breadth and depth of J&J sub-sidiary McNeil Consumer Healthcare’s latest GMP violations raise new questions about the company’s relationship with the agency, Rep. Darrell Issa (R-Calif.), ranking member of the House Committee on Oversight and Government Reform at the time, said in a letter last month to FDA Commissioner Margaret Hamburg.

The letter includes questions on the FDA’s relationship with and regulation of contract drug manufacturing.

Issa raises concerns about the FDA’s knowl-edge of Best Sweet’s contractual relationship with J&J and whether the agency is acting appro-priately to determine if there are other safety concerns with products manufactured by Best Sweet.

The issues J&J has seen as a result of con-tract manufacturing raise fresh questions about the practice, as well as the FDA’s knowledge and awareness of the issue, Issa says.

Issa requests that by Jan. 5, the FDA tell the committee:

● Whether J&J identified Best Sweet to the FDA as the third-party manufacturer of Rolaids;

● Whether the identification was provided in documents produced to the FDA during the course of GMP compliance for Ro-laids; and

● Whether the Rolaids recall raises con-cerns for the agency about the safety of other products manufactured by Best Sweet.

The committee also requests a copy of any document identifying Best Sweet as the third-party manufacturer, dates and reasons for any inspections of Best Sweet, and copies of any inspection reports or warning letters issued by the FDA.

The agency will respond directly to Issa and will not comment outside of that, FDA spokes-woman Crystal Rice told DGR. — April Hollis

Reporters: David Belian, Virgil Dickson, Wilson Peden, Molly Cohen

President: Cynthia Carter; Editorial Director: Pamela Taulbee; Executive Editor: Jonathan Block

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