No recall for glass found in vaccines made in Monroe County
Sanofi Pasteur, the vaccines division of Sanofi, has its U.S. headquarters in Swiftwater, Monroe County, where it employs about 2,500 people. A batch of vaccines made at the plant several years ago contained glass particulates. (AMY HERZOG/THE MORNING CALL)
Sam Kennedy Contact Reporter Of The Morning Call
Sanofi Pasteur, one the world's leading vaccine makers, had a potentially serious and costly problem on its hands: Its Monroe County plant discovered tiny pieces of glass in batches of a vaccine intended for babies.
The glass was first detected in April 2013 in samples of a vaccine that had already been distributed to customers and which would not expire until September 2014.
Sanofi sent the samples to an outside laboratory for analysis. The lab found evidence of delamination — which occurs when vaccine vials shed flakes of glass called lamellae.
The health risks posed to any individual by vaccine vial delamination are widely believed to be minuscule. None has been documented.
Nonetheless, the U.S. Food and Drug Administration has warned that lamellae could cause serious health problems such as an adverse immune system reaction. When confronted with glass contamination, medical manufacturers have erred on the side of caution, alerting the public and issuing sweeping product recalls.
Related: How the vaccine court protects the pharmaceutical industry from risk
In at least one case, a manufacturer in 2013 recalled a vaccine with a glass contamination rate that was much lower than the rate Sanofi found in its Haemophilus b conjugate vaccine, or ActHIB.
Sanofi, on the other hand, allowed doctors and nurses throughout the country to continue injecting babies with the potentially problematic ActHIB for another year and a half.
The FDA did not push back, either. After the regulatory agency found out about the issue, it accepted the company's assurances that the vaccine was safe.
Word of the delamination at Sanofi — the vaccine division of the French pharmaceutical behemoth Sanofi S.A. — would not reach the public until now. The Morning Call has pieced together what happened, including Sanofi's behind-the-scenes interactions with the FDA, using government documents acquired through the Freedom of Information Act.
Related: Vaccine Delamination Timeline
In response to questions, Sanofi spokesman Sean Clements said in an email, "A root cause for the delamination issue was identified and corrective measures have been implemented."
Asked why the company did not notify the public or issue a recall for the vaccines, which are used to inoculate children against a bacterial infection that can cause meningitis, he said, "The products that were shipped from our facilities met the applicable requirements and specifications for safety and efficacy. There were no additional actions required by FDA."
Some industry experts and watchdogs, however, say the company's and the FDA's handling of the matter raises important questions and concerns.
"If you think your product has a defect, recall the damn thing," said John G. Culhane, an expert in health policy law at the Delaware Law School of Widener University in Chester, Delaware County. "Why wouldn't a company want to? ... A lot of times, it's a matter of economics."
FDA spokeswoman Tara Goodin said a recall was not necessary.
"The firm performed a medical assessment as part of their investigation and concluded that the delaminated glass particulates … would not impact the safety or efficacy of the vaccines," she said. "The agency found no evidence to suggest that the conclusions of the firm's medical assessment were not appropriate."
Dr. Michael Carome, director of the health research group at Public Citizen, an advocacy group in Washington, found this explanation unconvincing. He said it reveals the deference the agency affords the pharmaceutical companies it is charged with regulating and the extent to which it relies on the companies to monitor themselves.
The FDA's lax oversight is an unintended consequence of the Prescription Drug User Fee Act of 1992, which required pharmaceutical companies to subsidize the FDA's work, according to Carome. The act effectively turned companies into "customers" of the agency, he said, and the agency has since been inclined to treat them accordingly.
"Too often the FDA is not an effective regulator. They are often too slow to act when there are serious problems," he said. "The [pharmaceutical] industry is more like a client or customer of the agency, and less like a regulated entity."
Sanofi Pasteur ranks No. 2 among vaccine makers, with global sales of $6 billion. It says on its website that annually it makes more than 1 billion vaccine doses, of which the ActHIB made at its Swiftwater, Monroe County, plant is but one kind. The company is also a top producer of flu vaccines in the United States.
Its ActHIB vaccine is given to babies and children through age 5 to prevent Haemophilus influenzae type B, a potentially deadly bacterial infection that can cause meningitis, pneumonia and other serious illnesses in children. Each dose uses freeze-dried vaccine that must be mixed with a saline "diluent" before injection.
Sanofi's rush to understand the scope of its delamination problem began April 2, 2013, according to the electronic "Biological Product Deviation Report" the company submitted to the FDA in accordance with regulations. The report, sent to the FDA in June, said two vials of the ActHIB vaccine were "observed to contain clear, colorless particulates," and that those vials were associated with two distributed vaccine lots due to expire Sept. 5 and 6, 2014.
Delamination is caused by the separation of the various components that go into the making of glass, explained Arun Varshneya, a retired Alfred University professor of glass engineering science who is president of Saxon Glass Technologies in Alfred, N.Y. The high alkalinity of vaccines and other injectable drugs can cause some of the components to peel away from each other. Because this takes place over time, it might not be detected until after products are packaged and shipped.
After Sanofi became aware of the delamination, the Swiftwater plant examined vials that hadn't been distributed.
"The glass shards looked almost invisible," an employee told The Morning Call, adding that shaking a vile helped to reveal them. "It would give a little flash, or a little rainbow."
Not everyone would be able to catch that, the worker said.
It is unclear how many ActHIB vaccines potentially affected by delamination were distributed. Sanofi declined to provide numbers.
One delamination expert, who requested anonymity because he is a consultant to pharmaceutical companies, said he was impressed by how Sanofi dealt with the delamination issue.
"In my opinion, I don't think the public was ever at any great risk," he told The Morning Call.
The greater risk, he continued, would have been any delay or reduction in Haemophilus influenzae type B vaccinations because of an unnecessary recall.
"I think [Sanofi] actually did a very, very good job," he said. "It would make a good case study on how to handle that situation."
Public Citizen's Carome, however, believes a recall would have been "prudent." At the very least, he said, Sanofi could have notified the public so parents could have made an informed choice between Sanofi's ActHIB vaccine and one of the other vaccines available for Haemophilus influenzae type B.
"I think most parents would say I'd want the vaccine that doesn't have the glass fragments. … So withholding that information, I think, is unacceptable," said Carome, a physician who had worked as senior leader at the Office for Human Research Protections in the U.S. Department of Health and Human Services.
The lack of transparency, he said, "leads to distrust in the heath care system and the companies that make these products."
Two months passed before Sanofi reported the delamination to the FDA. Another 11 months went by before a team from the agency's Division of Medical Products and Tobacco Program Operations arrived at the Swiftwater plant for an inspection, according to the agency's records.
The visit did not go well. In a 44-page report completed in May 2014, the team described a range of alleged failures. A chief concern in the report was that Sanofi did not inform the agency about all the distributed lots that were potentially affected by delamination, including two associated with customer complaints.
"Finding of delamination of vials used to fill ActHIB did not lead to an examination of other products that used vials from the same vendor," the inspection report reads.
In the written response Sanofi sent to the FDA three weeks later, the company said it had examined the glass particles in the vials that prompted the customer complaints and determined they weren't lamellae but simply glass chips from damaged vials.
Sanofi also countered the inspectors' assertion that the company was remiss for not examining all potentially affected vials:
"The initial phase of the [internal] investigation determined where the issue is observed and where it is not," the company said. "The glass delamination defect was only observed in ActHIB diluent. … This conclusion was based on extensive product testing data and process knowledge."
In all, the FDA inspectors noted 15 shortcomings in Sanofi's handling of the delamination issue or in day-to-day processes such as adherence to standard operating procedures.
"Since detecting the glass delamination in April 2013," Sanofi responded to the FDA, it had "acted responsibly" to identify the scope of the problem and implement corrective action.
A task force that the company formed placed blame on an unnamed third-party contractor — a vial manufacturer — which, Sanofi said, had changed its manufacturing process without informing the company.
"Significantly, we have changed the manufacturer of the vials," Sanofi spokesman Clements told The Morning Call. "While we don't disclose specifics of our operation or details on our investment, as part of continuous improvements to strengthen our manufacturing operations and quality systems, we worked closely with the FDA in our remediation plans.
"Above all else, we want the public to understand and have faith that we are dedicated to providing them vaccines that are safe and effective in protecting them against vaccine-preventable disease," Clements said.
In November 2014, the FDA sent Sanofi a brief letter and a copy of the inspection team's full report, indicating that the agency accepted the company's response and was no longer investigating the matter.
FDA spokeswoman Andrea Fischer told The Morning Call, "In this instance, where delamination was found in certain vials containing vaccine diluent, the agency's medical assessment concluded that the purity of the vaccine was not compromised. As such, there was no reason to believe that there was a safety concern, so a recall was not recommended."
Lawrence Muscarella, a medical safety expert and president of LFM Healthcare Solutions in Montgomeryville, said by relying on the results of Sanofi's internal investigation, the FDA appeared to be allowing the proverbial fox to guard the henhouse.
"If the FDA took the manufacturer's word for it, that's self-regulation," he said.
Fischer defended the agency's independence, saying its decisions are based on its medical and manufacturing experts.
"If the risk to public health due to the reported event outweighs the benefits of the product, FDA encourages the licensed manufacturer to initiate a recall and is poised to take action if the firm refuses," she said.
In recent years, delamination and other glass defects have led to recalls of injectable products from some of the biggest pharmaceutical companies — Amgen in 2010, American Regent in 2011, Merck in 2013.
According to a 2012 article in Contract Pharma, an industry publication, in the previous five years, more than 100 million units of drugs packaged in vials or syringes were withdrawn from the market because of "glass issues," including contamination from delamination and breakage.
"Once delamination is discovered in a commercial drug product, it is already too late and there is nothing to do but recall the product," reads a 2013 Contract article.
In 2011, the FDA issued an advisory to pharmaceutical companies about the potential for delamination to cause problems. It did not, however, specify what manufacturers should do if delamination is discovered in their products.
"To date," the advisory read, "no adverse events have been reported nor can any be directly attributed to this phenomenon."
However, the advisory continued, there is potential for blood clots to form as a result of contaminated vaccines that are administered intravenously, meaning directly into a vein.
For vaccines such as ActHIB that are administered under the skin and into muscle, delamination isn't as threatening. The advisory noted it could cause swelling, redness or a lump at the injection site, or provoke an immune system response such as the suppression or over-activation of the immune system.
Of course, the parents or pediatrician of a child affected in such a way would be unlikely to suspect a connection to delamination if the contamination had never been made public.
Dr. Kimberly Legg Corba, a second-generation family practitioner in Fogelsville, said she would like to have known about the problem. Because Sanofi has not disclosed where it shipped the ActHIB in question, Corba has no idea if any went to her office.
"I wouldn't inject my own kids with a vaccine that may have had delamination, and I wouldn't treat my patients differently," she said. "How am I supposed to be open and honest about the safety of vaccines when I cannot rely on the drug companies to do the right thing?"
Every year, thousands of adverse reactions to vaccines, including ActHIB, are reported to the CDC. Such reports, however, are not proof of a causal relationship — only that a reaction occurred after vaccination.
A lack of research means much of what scientists believe about the physiological impacts of delamination is based on speculation, according to a number of experts who said any experiment involving the intentional injection of glass fragments into people, and babies in particular, would raise obvious ethical questions. Varshneya, who taught glass engineering, said he knew of no study on the effects of lamellae on the human body.
In recent years, a number of pharmaceutical companies have executed costly recalls specifically of subcutaneous (under the skin) and intramuscular injections that might contain glass particulates. In 2013, for example, Merck recalled a lot of Gardasil vaccine, injected intramuscularly to protect against human papillomavirus, which can cause cervical cancer.
Merck said it believed about 10 vials in a single lot containing 743,360 vials might have contained glass particles due to breakage during the manufacturing process. That's a contamination rate of .0013 percent.
By comparison, Sanofi found glass particulate at a much higher rate of 0.4 percent — or 1 in every 250 vials — during its initial inspection of an ActHIB diluent lot in April 2013. Yet the documents provided by the FDA do not indicate that either Sanofi or the agency ever discussed following Merck's example.
Merck spokeswoman Pam Eisele said Merck conducted a medical assessment that concluded a vaccine containing glass particle posed "a remote risk of an injection site reaction."
"Our actions were a reflection of our conviction that nothing is more important to Merck than the safety of our medicines and vaccines," she said.
Asked why Sanofi chose not to issue a recall as Merck did, Sanofi spokesman Clements responded, "Patient safety is always of paramount concern," to Sanofi as well. The company, however, does not believe it compromised safety by not recalling the vaccine.
"We worked very closely with the FDA throughout the process and based on the information we had gleaned from our investigations, no recall was warranted," he said.
On Jan. 23, 2015, Sanofi informed the FDA it had found particulates in a new batch of ActHIB — this time in the retention sample of a distributed lot that expired the previous March. An analysis determined some but not all of the particulates were lamellae. Some were mysterious bits of glass not caused by delamination, and one was a piece of stainless steel.
Sanofi did not respond to The Morning Call's questions about its additional discoveries last year. But at the time, the company reported to the FDA that "a definitive root cause of the glass particulates not caused by delamination and the stainless steel particulate has not been determined."
The scope of the problem continued to grow. A retention sample of yet more ActHIB was found to contain lamellae, Sanofi told the FDA on March 30, 2015.
"To date, no customer complaints have been received," and no "adverse events" had been recorded, the company assured the agency.
But by then even if Sanofi had wanted to recall the lot, there would have been little point in doing so. The lot expired Aug. 5, 2014.
The clock had run out.
GLASS PARTICULATE RECALLS
Some recent recalls of subcutaneous and intramuscular injections for glass particulates:
• 2010: Baxter recalled an estimated 3,500 vials of Hylenex recombinant, injected subcutaneously to treat dehydration or to facilitate the absorption of other injectable medications.
• 2010: Amgen recalled Epogen and Procrit, an anemia treatment that may be injected intravenously or subcutaneously.
• 2013: Fresenius Kabi USA recalled benztropine mesylate, a treatment for Parkinson's disease, typically injected intramuscularly.
• 2013: Merck recalled a lot of Gardasil vaccine, injected intramuscularly to protect against human papillomavirus, which can cause cervical cancer.
Sources: Company press releases and the Centers for Disease Control and Prevention
ABOUT SANOFI PASTEUR
• Parent company: Sanofi S.A., of France, which earned $43 billion in 2014, making it the fifth largest pharmaceutical company in the world*
• Ranking among vaccine makers: No. 2, with global sales of $6 billion*
• Output: More than 1 billion vaccine doses against 21 infectious diseases**
• US. Headquarters: Swiftwater, Monroe County**
• U.S. Employees: 3,000**
* Source: FiercePharma, a website covering the pharmaceutical industry
** Source: Sanofi website
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