Within two
months of 2017, we have already seen several pharmaceutical companies come
under the regulatory lens and face action.
This week, PharmaCompass
does a compliance recap, wherein companies like Pfizer saw lapses in their current good
manufacturing practices (cGMPs) and companies in India, like Dr. Reddy’s and Cadila Healthcare, who received warning letters in the
past, were busy with regulatory re-inspections at the erring sites.
Pfizer’s US facility receives a warning letter from the FDA
Pfizer’s fill/finish manufacturing facility in the United States recently received a warning letter from the US Food and Drug Administration (USFDA). This information was revealed in a press release
issued by Momenta Pharmaceuticals a
biotechnology company developing a generic version of Teva’s long-acting Copaxone® 40mg/mL (glatiramer acetate injection).
Momenta’s Glatopa 20 mg/mL product is already
available in the US market and is promoted by Sandoz, which in turn has contracted the fill/finish manufacturing operation to Pfizer’s facility in McPherson, Kansas.
In February 2015, Pfizer
acquired the McPherson site through its US $17 billion acquisition
of Hospira. Pfizer was aware of Hospira's manufacturing record when it struck
the deal to buy the drugmaker as the company was issued FDA warning letters on four of the seven continents
Europe, North America, Asia and Australia.
While previous FDA inspections
at the McPherson facility had raised concerns over the assurance of product
sterility, no warning letter had ever been issued to this site.
This has been the first
positive news for Teva this year, after a series of setbacks. Copaxone
had generated US $ 4.22 billion in sales
last year.
And as per Momenta’s press statement, “Glatopa 40 mg ANDA (abbreviated new drug application) remains under regulatory review.” While Momenta says it is working with Sandoz to resolve the matter, it is of the view that “an approval in the first quarter of 2017 is unlikely.”
“Pfizer has indicated that the warning letter does not restrict the production or shipment of the Glatopa 20 mg (glatiramer acetate injection) product,” Momenta stated in its press release.
The Pfizer warning letter
will also be welcome news for Mylan as it had recently won a court ruling where four Orange Book-listed patents relating to Copaxone® 40 mg/mL were invalidated based on obviousness. Mylan has “filed a substantially complete ANDA” for a three times per week Glatiramer Acetate Injection 40 mg/mL.
Baxter’s cGMP deficiencies result in US$ 18 million settlement
Last
month, Baxter International and Baxter Healthcare Corporation settled a type of civil lawsuit that
whistleblowers are known to bring. It was settled under the False Claims Act
(FCA) case with the Department of Justice (DOJ) for US$ 18 million.
The
settlement in which there was
neither an admission of liability by Baxter nor a concession by the United States that its claims are not well founded was an outcome of the government alleging that Baxter submitted false claims for a drug sold to the Department of Veterans Affairs and Department of Defense, as well as reimbursed by the Medicare and Medicaid programs, because the drug was “adulterated.”
A detailed blog written by Stephanie Trunk and Emily M. Leongini
highlights that the issue emanated from the “presence of visible mold on HEPA filters installed above the clean rooms” where Baxter manufactured sterile intravenous (IV) solutions. The managers at Baxter prevented the relator and others from removing the moldy filters and from cleaning or sanitizing other associated contaminated surfaces, says the complaint.
This
handling of the moldy filters by Baxter allegedly violated numerous cGMP
requirements set forth in the FDA regulations. This includes the requirement
that a manufacturer establish, and also follow, its own internal standard
operating procedures.
While the government acknowledged that there was no evidence to suggest that Baxter’s IV solutions had been impacted by the moldy filters, it alleged that the IV solutions violated the FCA because of “Baxter’s failure to comply with cGMP requirements.”
In
the past, cGMP violations have had the DOJ collect US$ 750 million from a GSK subsidiary in 2010 and US$ 500
million from Ranbaxy in India in 2013. With an increasing trend of warning letters being issued by the FDA to pharmaceutical manufacturers, it remains to be seen if DOJ will further “highlight the materiality of cGMP compliance to product purchases in support of FCA claims”.
Zydus turns around compliance problems with a zero 483 inspection
Zydus’ Moraiya (Gujarat, India) facility accounted for 60 percent of Cadila’s revenues
in the US, its largest market. In an inspection performed by the FDA in
September 2014, the investigators found that in 2013, Cadila had failed to
adequately review 106 consumer complaints (out of 106 complaints received) and
in 2014, up to the date of the inspection, they failed to adequately review
another 132 consumer complaints (out of 132 complaints received).
While at the time of the
inspection, Cadila had already taken the decision to recall products like Warfarin 2 mg (due to oversized tablets), Promethazine 25 mg (due to mixed tablets in the
same bottle) and Atenolol 25 mg (due to “thicker appearance”), the inspectors got “no assurance” that the quality system at Cadila was under control and stated that the “deficiency appears to be a pattern of problem” at the Cadila site.
Zydus
received a warning letter from the FDA in December 2015. Last week, Zydus announced
that it did not receive any observations from the USFDA for its formulation facility at Moraiya,
which indicates a successful resolution of the compliance at the plant.
The
company said that the USFDA inspected the plant from February 6 to 15.
What’s next at Dr. Reddy’s and Marksans in India?
Marksans Pharma, a company with a questionable compliance track record, saw its manufacturing facility in Goa (India) fail an inspection by the UK drug regulator last year. The inspectors noted critical data integrity violations which included “evidence of destruction of multiple parts of records of prime data”.
In
a filing with the Bombay Stock Exchange (BSE), the company announced that its plant in Goa had an inspection by the UK’s Medicines and Healthcare products Regulatory Agency (MHRA) from February 14-17, 2017. The inspection was completed without any critical observations, the company informed. It is now awaiting further instruction from the agency in this regard.
In a similar announcement, Dr. Reddy’s informed the bourses that its Miryalaguda facility has been issued a Form 483 by the USFDA with three observations, which the company is addressing. The audit of the company’s API manufacturing plant at Miryalaguda by the USFDA was completed on February 21, 2017.
Back
in November 2015, the same facility had received
a warning letter after FDA inspectors found partially-filled documents in the garbage.
Our view
Over
the past years, we have seen compliance concerns being raised time and again at
pharmaceutical manufacturing operations. Last week, Sato Pharmaceutical, a
company established in 1939 in Japan, received a warning letter from the FDA as it
failed to establish an adequate system for monitoring the conditions of its
cleanroom environments.
Prior to that, FDA’s April 2016 inspection of ACS Dobfar’s operations in Brazil Antibioticos do Brasil (ABL)
led to the issuance of a warning letter after
the FDA investigators found that the filling zone for sterile injectable
product was not sufficiently robust.
While
data integrity concerns dominated news headlines last year, it seems that
aseptic fill/finish may become a leading cause of concern with regulators.
It’s clear that manufacturing can no longer be taken for granted as companies of all sizes are suffering economically from their inability to comply with good manufacturing practices.
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