2014 Drug Recalls: Contamination Surge Enters Fifth Year

Microbial and particulate contamination drove drug recalls to historic levels for a fifth year in 2014, FDA recall data shows. But the data still falters in identifying the weakest links in global pharmaceutical supply chain quality.

Drug recalls continued at historic rates in 2014 as a surge in contamination issues persisted for a fifth straight year.

FDA reported 1,335 drug recalls last year, edging out 2012 for third place after 2009 and 2011.

Details of all the recalls, including the companies and products involved, the designated class and the reason given appear in this issue's online-only table (Also see "Drug Product Recalls in 2014 Categorized by Problem Area" - Pink Sheet, 28 May, 2015.).

Also in this issue is an interactive graphic of 2004-2014 drug recall data (Also see "Drug Recalls: 2004-2014" - Pink Sheet, 28 May, 2015.).

Compared to the annual average over the prior decade, there were half again as many drug recalls last year, largely because of three factors:

• Sterility assurance failures in pharmacy compounding, along with particulate, chemical, microbial and foreign product contamination in pharmaceutical manufacturing;
• A label mix-up at one repackager; and
• A surge in cases where FDA found active pharmaceutical ingredients in dietary supplements.

In a first, there were more Class I than Class III recalls last year. Typically, there are only one-third as many. As usual, however, FDA categorized the bulk of last year’s recalls as Class II.

Class I recalls are the most serious – the ones that FDA believes pose a “reasonable probability” of serious health consequences or death.

Most of last year’s 155 Class I drug recalls fell into one of two camps:

• Particulate contamination in injectables from drug manufacturers and microbial contamination in injectables from pharmacy compounders.
• Undeclared active pharmaceutical ingredients in dietary supplements sold over the counter.

Recalls due to potency, dissolution and other out-of-specification issues remained close to historical norms.

One bright spot in 2013 was even brighter in 2014: A reduction in recalls due to shortcomings in adherence to good manufacturing practices. Last year, recalls due to manufacturing issues fell to less than one third of the average over the prior decade.

Injectables recalls again rivaled oral solids recalls last year. Together, these dosage forms accounted for 80% of last year’s drug recalls. There were nearly as many injectables as oral solid recalls last year; there had been slightly more in 2012 and more than twice as many in 2013.

FDA’s recent focus on compounding pharmacies, a key factor in boosting injectables recalls well above historical levels, also significantly increased recalls of some less common dosage forms last year, most notably ophthalmics and inhalables. Although topicals recalls weren’t out of trend, many of last year’s resulted from sterility assurance issues in pharmacy compounding.

There was an unusual number of recalls last year of drug products that act locally in the mouth or that are absorbed systemically in the mouth. The reasons for these 22 recalls varied widely, but the most significant factor was a 10-product recall by GlaxoSmithKline Consumer Healthcare due to potency issues with nicotine polacrilex lozenges.

This category was renamed this year from “oral health products” to “buccal/sublingual” products to reflect the inclusion of systemic products like nicotine lozenges.

At 21, active pharmaceutical ingredient recalls were significantly out of trend last year, considering the average over the prior decade was just three.

The reasons for API recalls varied last year, but one case stood out: a nine-recall incident on March 24, 2014, that resulted when Apotex Inc. of Toronto, Canada, learned some API from GlaxoSmithKline PLC that Apotex used in manufacturing various paroxetine HCl products was contaminated with residual materials and solvents.

Residual solvents also played a key role in an Aug. 28, 2014, recall by Fougera Pharmaceuticals Inc., Melville, N.Y., of more than 100,000 tubes of fluocinonide gel USP. Fougera said the recalled lots may fail to meet the requirements of the U.S. Pharmacopeia’s <467> general chapter on residual solvents.

There were also a surprising number of recalls last year due to issues with pharmaceutical excipients, particularly incorrect or undeclared excipients. There could be new problems with excipients; more likely FDA is placing a new emphasis on them.

Five years of contamination

Contamination arrived as a major recall issue when it drove a threefold increase in recalls in 2010. The main issue that year was delamination of glass vials of injectable drug products. There were also instances of injectables contaminated with steel, polyester and other particulates, as well as fungus and other microbial organisms. Also that year were recalls of McNeil Consumer Healthcare drug products due to absorption of pallet wood preservative breakdown products into plastic bottles (Also see "Another Busy Year of Drug Recalls Led to Shortages of Injectables" - Pink Sheet, 1 May, 2011.).

Since then, contamination has played a big role in drug recalls, but the mix of contamination issues has varied from year to year.

In 2011, it was all about penicillin cross-contamination and microbial contamination of alcohol and iodine surgical and first aid prep pads as well as a smattering of issues with glass quality and malodorous plastic bottles (Also see "Contamination Issues Drove Drug Recalls to Record Levels in 2011" - Pink Sheet, 28 Mar, 2012.).

Microbial issues dominated contamination recalls in 2012, the year of the fungal meningitis outbreak that resulted from widespread sterility failures at the New England Compounding Center in Framingham, Mass., and at a related company, Ameridose, in nearby Westborough, Mass. (Also see "What FDA Saw at Compounder Behind Fungal Meningitis Outbreak" - Pink Sheet, 29 Nov, 2012.).

Earlier that year, multiple cases of fungal endophthalmitis led to recalls at another compounding pharmacy, Franck’s Compounding Lab in Ocala, Fla.

Also in 2012 were massive foreign-tablet recalls due to line clearance problems at Novartis Consumer Health Inc.’s plant in Lincoln, Neb. (Also see "Contamination, Mix-Ups Drive Up Drug Recall Totals for 2012" - Pink Sheet, 30 May, 2013.).

FDA cracked down on sterility assurance failures at compounding pharmacies in the wake of the 2012 fungal meningitis outbreak. This drove contamination-related recalls to new heights in 2013. Of that year’s 873 contamination-related recalls, 776 involved microbial contamination, including 709 at compounding pharmacies (Also see "Drug Recalls Soared Again in 2013, Driven by Contamination" - Pink Sheet, 30 May, 2014.).

This trend continued in 2014, with compounding pharmacies accounting for 441 of last year’s 633 contamination-related recalls. Although FDA reported these recalls in 2014, 125 of them occurred in 2013, some as early as April of that year.

FDA crackdown intensified

Usually, contamination recalls are reactive rather than preventive – except when it comes to microbial contamination.

Because microbial contamination is so serious and hard to spot, manufacturers often recall drug product because of a failure to assure sterility rather than in response to actual observed contamination.

Normally, these sterility-assurance recalls result from FDA raising concerns during inspections rather than from companies reconsidering their sterility assurance practices.

For this reason, examining the ratio of sterility assurance to actual contamination recalls provides a ready gauge of where FDA enforcement activity is focused.

Last year’s 82 particulates recalls, 19 cross-contamination recalls and chemical contamination recalls were nearly all in reaction to evidence of actual contamination.

However, the tendency for microbial recalls to be preventive was even more pronounced last year.

In 2013, there were 776 microbial contamination recalls, of which 448, or 57%, were for sterility assurance failures rather than actual contamination.

Sterility assurance failures accounted for even more, 453, or 87%, of last year’s micro recalls.

The sterility assurance component of last year’s microbial recalls was particularly high for compounding pharmacies.

Such FDA-inspection-driven recalls accounted for 95% of microbial recalls at compounding pharmacies last year, compared to just 45% at pharmaceutical manufacturers.

The sheer predominance of sterility assurance recalls at compounding pharmacies last year reflects a concerted effort by the agency to pressure a recalcitrant industry sector into compliance.

2014 drug recalls for microbial contamination
Facility type	Microbial contamination recalls	Sterility assurance share
Compounding pharmacies	441	95%
Pharmaceutical manufacturers	78	45%

Particulate particulars

Of last year’s 82 particulates contamination recalls, 43 were rated Class I.

B. Braun Medical Inc., Irvine, Calif., had 13, all due to particulates found in reserve sample units, all rated Class I.

Baxter Healthcare Corp., Deerfield, Ill., had 15, of which 11 were Class I. Baxter gave relatively specific descriptions of some of the particulates involved: nylon fibers; subvisible agglomerating iron oxide particles; a mixture of the amino acid leucine and inorganic material that contained iron, silicone and chlorine; plastic/rubber; silicone rubber and EPDM rubber from the vial stopper; wood, sodium citrate and dextrose; and blue polyisoprene shavings.

Hospira Inc., Lake Forest, Ill., had 10 particulates recalls last year, all of them rated Class I. Two concerned human hair found in injectables containers – first in August 2013 and then again in September 2014. One was due to glass chips. Many involved metal particles embedded in vials and rust-discolored solutions. Hospira had 16 additional recalls for a total of 36 for the year.

Other notable particulate cases:

• Traxx International Corp., Pine Brook, N.J., recalled guaifenesin API powder that may have contained polyethylene fibers from a screen used to sift the API.
• Golden State Medical Supply Inc., Camarillo, Calif., recalled bottles of losartan potassium tablets made by Arrow Pharm (Malta) Ltd., Bizebbugia, Malta, because some bottles may have contained debris that was swept up during cleaning.

Quality implications still unclear

Many view recalls as a key quality indicator. But recall data in FDA’s enforcement reports last year continued to show limitations as a measure of pharmaceutical manufacturing quality.

The agency has talked about using recall rates as a quality metric for deciding when or whether to inspect manufacturing facilities (Also see "FDA, Industry Metrics Initiatives Confront Challenge of Tracking Quality Culture" - Pink Sheet, 20 Nov, 2014.).

However, FDA’s enforcement reports fall short in identifying which facilities are responsible for recalls.

FDA officials often say that about 40% of drug products marketed in the U.S. are manufactured abroad. But recallers identified only 167, or just 13% of last year’s recalls, as originating outside of the U.S.

If true, this would mean drug products made domestically were three times more likely to be recalled than products made in India, China, or other countries.

A more likely explanation is that recallers often fail to identify the facilities where recall-generating problems occur.

Similarly, recallers said only 247 of last year’s recalls, or 19%, were for products manufactured at a separate location, either of their company, a related company or of another company such as a contract manufacturer.

Given the complex nature of today’s global supply chain and the prevalence of contract manufacturing in the pharmaceutical industry, this figure would likely be higher with more complete reporting.

2014 drug recalls by country of origin as indicated in FDA enforcement reports
USA	1,168	Switzerland	3
India	56	Ireland	2
Germany	24	Poland	2
Dominican Republic	15	Singapore	2
China	12	Australia	1
Israel	10	Austria	1
Canada	9	France	1
Guyana	7	Malta	1
Japan	7	Philippines	1
Italy	5	Puerto Rico	1
Mexico	5	Taiwan	1

Solvent-tainted API

A March 18, 2014, FDA warning letter to GSK led Apotex to launch nine recalls of paroxetine the following week due to the agency’s concerns about contaminated API from GSK’s plant in the town of Currabinny in Ireland’s County Cork.

That recall stood out in last year’s record showing of 21 API recalls.

FDA determined during an Oct. 18-23, 2013, inspection of the Currabinny plant that something used to manufacture some batches of two products, presumably the immediate and continuous release forms of paroxetine, “was contaminated with material from your pharmaceutical waste tank, which contained APIs, intermediates and solvents,” according to the partially redacted copy of the warning letter posted on FDA’s website.

GSK had identified the issue in January 2012, but didn’t complete a risk assessment until April 19, 2013, the day after FDA inspectors arrived onsite, according to the warning letter.

The plant distributed the API without alerting the receiving site to the issue because there was no way it would impact the quality of affected drug products, plant personnel told FDA investigators.

“We are concerned that your firm does not consider the entry of pharmaceutical waste streams into your manufacturing process a significant deviation with a potential quality impact,” FDA said in the warning letter.

Joe Power, site director, GSK Cork, told RTÉ News in an interview that “we’ve done medical and toxicological tests and we believe there’s no increased risk to patient safety in relation to this.” The Irish television network Raidió Teilifís Éireann broadcast the interview in an April 2, 2014 news report on the incident.

Apotex recalled several strengths of controlled-release paroxetine and controlled-release, immediate-release and oral liquid dosage forms of authorized-generic Paxil (paroxetine) that it had manufactured with the API batches in question. GSK told RTÉ News it recalled the antidepressant from the Irish market.

The wrong excipients

Eighteen of last year’s recalls resulted from the use of incorrect or undeclared excipients, including one that FDA rated Class I.

Recalls due to incorrect or undeclared excipients appear to be a relatively new phenomenon. A search of FDA’s current and archived enforcement reports show the first occurred in April 2009, when Ivax Pharmaceuticals Inc., Weston, Fla., recalled sennosides laxative tablets made by Time-Cap Laboratories Inc., Farmingdale, N.Y., because they may have contained undeclared anhydrous lactose and tartaric acid.

The next wasn’t until August 2013, when Procter & Gamble Co., Mason, Ohio, recalled NyQuil Liquid Original cough syrup overwrapped with NyQuil Liquid Cherry information that gave the wrong color additives.

Last year’s bolus of wrong-excipient recalls could be a fluke, it could be an artifact of the surge in compounding pharmacy recalls, or it could be a sign of a new focus in FDA inspections.

One compounding pharmacy, Brookfield Prescription Center doing business as Custom Rx in Brookfield, Wis., was responsible for six of these recalls last year, due to use of an incorrect solvent.

Another four of these recalls resulted when Teva Pharmaceuticals USA Inc., Horsham, Pa., used the wrong gelatin excipient for ethambutol HCl tablets.

The Class I recall followed an April 2-8, 2014, FDA inspection of Pharmakon Pharmaceuticals, a sterile compounding pharmacy in Noblesville, Ind.

The founders of Pharmakon Long Term Care Pharmacy Inc., a unit-dose repackager that dates back to 2003, launched Pharmakon Pharmaceuticals in 2008 to provide sterile admixtures. That company registered as a Section 503B outsourcing compounder shortly after enactment of the FDA Drug Quality and Security Act.

A Form 483 report FDA issued at the end of the inspection focused on a failure to prevent release of midazolam with inconsistent labeling, and a subsequent failure to follow standard operating procedures “to issue recalls when appropriate.”

A clinical quality manager had changed labeling to indicate each syringe contained 0.2mg/2ml and 0.4mg/2ml of midazolam.

FDA can’t require drug recalls but it can enforce SOPs that require them.

Pharmakon began a Class I recall of 80 superpotent, mislabeled midazolam syringes on March 26, 2014, a week before the FDA inspection.

Then on April 21, Pharmakon also recalled some vials and IV bags of midazolam and syringes of atropine sulfate and glycopyrrolate because they contained an incorrect/undeclared excipient, benzyl alcohol. FDA also rated this as a Class I recall.

‘Study drug’ recalled

A “study drug” was caught up in one of the major compounding pharmacy sterility assurance recalls that FDA reported last year.

When staff at the Henry Ford Hospital in Detroit noticed something floating in vials of dextrose 50% injectable, later identified as mold, they reported the incident to FDA in October 2013.

Two days later, Specialty Medicine Compounding Pharmacy in South Lyon, Mich., which had manufactured the dextrose, recalled 1,000 vials of dextrose and all unexpired lots of the 51 other purportedly sterile products it had distributed since that July.

Among the products: Injectable and topical dosage forms of tranexamic acid intended for use as a “study drug.” Left unclear is whether it was for clinical, non-clinical or in-vitro studies.

Four days after FDA was contacted, two agency investigators arrived and conducted an inspection that resulted in a six-observation Form 483 report that highlighted various sterility assurance and other failures.

At the time, at least two manufacturers were seeking FDA approval for generic injectable versions of tranexamic acid.

The following month, an industry expert and University of Tennessee pharmacy professor, Laura Thoma, warned attendees of the American Association of Pharmaceutical Scientists to be careful when relying on pharmacies to compound drugs for clinical trials. An industry consortium found by surveying research manufacturers that this is an increasingly common practice, a Merck official told the meeting (Also see "Risk and Reward: Pharmacy Compounding of Clinical Materials" - Pink Sheet, 27 Feb, 2014.).

A big label mix-up

Aidapak Services LLC on July 2, 2013, recalled 274 drug products as a result of labeling mix-ups at its Vancouver, Wash., unit-dose repackaging facility, including 171 oral solid prescription drugs, 98 oral solid over-the-counter drugs and five OTC buccal/sublingual drug products.

These were unit-dose repackaged products sent to 25 hospital inpatient pharmacies in four states. Aidapak notified the hospitals and all but one responded that all potentially affected drugs in inventory were properly labeled. Aidapak had packaged the affected strip packs between May 1 and July 1, 2013. The company did not say how many had been used prior to the recall.

Aidapak is no stranger to repackaging snafus. In 2011, a 1,024-recall penicillin cross-contamination incident at Aidapak’s Vancouver, Wash., facility pushed that year’s drug recall total to 2,329 – well above any year before or since (Also see "Contamination Issues Drove Drug Recalls to Record Levels in 2011" - Pink Sheet, 28 Mar, 2012.).

Because these recalls are of unit doses, the numbers they generate are out of proportion to their significance.

Undeclared active ingredients cases

There were 125 recalls last year due to new and abbreviated drug application issues, up from 55 the year before and 64 per year on average over the prior decade.

FDA designated 77 of last year’s recalls in this category as Class I.

For the most part, these recalls involved dietary supplements sold over the counter – typically over the Internet – that FDA found through testing to contain undeclared active pharmaceutical ingredients.

It remains possible that the extent of these recalls is limited more by the extent of FDA testing than by the extent of the fraudulent activity.

2014 Drug Recall Analysis by Dosage Form
		Market Type		Problem Area							Recall Class
Dosage Form	Total	Rx	OTC	Contamination	Labeling	NDA	Other Spec	Manufacturing	Potency	Dissolution	I	II	III
Oral solid	551	345	206	38	303	85	59	23	16	27	82	401	68
Injectable	524	518	6	464	14	21	9	12	4		70	444	10
Topical	65	29	36	23	4	17	8	1	12			47	18
Oral liquid	62	20	42	29	1	1	22	3	6		2	42	18
Ophthalmic	62	57	5	54	1	1	2	4				57	5
Buccal/ sublingual	22	5	17		5		3	3	10	1		10	12
API	21	18	3	11	1			9			1	19	1
Inhalable	16	15	1	9			4	3				13	3
Suppository	4		4	4								4
Otic	3	3							3				3
Transdermal	3	3					3					3
Nasal	2	2		1				1				1	1
Grand Total	1335	1015	320	633	329	125	110	59	51	28	155	1041	139