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Pfizer’s US facility receives a warning letter, as Baxter’s cGMP deficiencies result in multi-million dollar legal settlement

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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Zydus Cadila & Sun Pharmaceuticals: FDA Warning Letters find problems aplenty

Two weeks before the end of 2015, PharmaCompass compiled a list of all the non-compliances issued in 2015 by major global regulatory agencies. Little did we know that, while the world was wrapping up for the holidays, the U.S. Food and Drug Administration (FDA) would be busy issuing warning letters to Sun Pharmaceuticals (Sun) and Cadila Healthcare Ltd (Cadila / Zydus Cadila). The facilities cited in the warning letters, for both Indian generic majors, are primary contributors to their revenues in the United States. While Sun’s Halol facility was cited in the warning letter, in Cadila’s case, the warning letter was issued for violating manufacturing standards at two of their production facilities, Zyfine and Moraiya. Data integrity issues at ZyfineThe data integrity violations mentioned in the warning letter related to Zyfine, which produces active pharmaceutical ingredients (APIs), did not come as a complete surprise.PharmaCompass had covered most of the data integrity concerns mentioned in the warning letter in May 2015 (read: Serious GMP concerns uncovered at Lupin (ANVISA) and Zydus Cadila (USFDA)) Zyfine had glaring data-integrity observations which ranged from: Records were not made readily available during the inspection; the Vice President, Corporate QA stated that the requested document was located at an employee’s home. During the FDA walk through the inspectors found five original and rewritten records, which were falsified. Inspectors found rough notebooks in the scrap yard as well as the engineering and QA offices. Documents were signed and dated by individuals who were not present at the site. Reprocessing was performed without review and approval of the quality unit. Batch records were not reviewed by production and QA personnel before release. Washing and toilet facilities lacked soap. Cadila’s response stating that papers found were “personal notebooks intended only for meeting and other discussion notes” failed to sway the FDA. A turnaround challenge at MoraiyaThe Moraiya facility accounts for 60 percent of Cadila’s revenues in the United States, its largest market, had no data integrity issues mentioned in the warning letter. However, the task ahead for Cadila is formidable since PharmaCompass reviewed the Form 483 issued to the Moraiya facility by obtaining it from FDAZilla.com. The September 2014 inspection 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).At the time of the inspection, Cadila had already taken the decision to recall products like Warfarin 2mg (due to oversized tablets), Promethazine 25mg (due to mixed tablets in the same bottle) and Atenolol 25mg (due to “thicker appearance”). However, 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 your site”.Eleven responses later, the FDA still remained unconvinced and mentioned, in the warning letter, that “persistent failures indicate that your manufacturing process is not in a state of control.” “Bottles containing Zydus (Cadila) products mixed with other Zydus (Cadila) products”At Moraiya, Cadila’s use of the same packaging line to bottle different products created problems as nine customer complaints were received “of bottles containing Zydus (Cadila) products mixed with other Zydus (Cadila) products”.The view at the time of the inspection was that the “mix-up might have taken place possibly at the pharmacy” which did not convince the FDA inspectors since the “two mixed products contained within the complaint bottle, were packaged on the same line at the same facility”. As a result of the FDA’s inspection, Cadila re-opened investigations related to the nine consumer complaints about product mix-ups and found manufacturing deficiencies that could have led to the mix-ups. While Cadila initiated a product recall of several lots, the FDA still believes that the scope of Cadila’s activities are insufficient. Facility problems at Sun Pharmaceuticals In the case of Sun Pharmaceuticals, the warning letter wasn’t a complete surprise for us. PharmaCompass had asked the question almost 6 months ago, “Sun has a new quality head, why?” and subsequent news indicated that Sun’s problems were more than just their integration challenges with the acquisition of Ranbaxy. However, on reviewing the warning letter issued by the FDA, the alarming concern about Sun’s sterile manufacturing operations is that the FDA found their “aseptic processing equipment is not properly designed”. Smoke studies or unidirectional airflow studies are performed to determine how the movement of air and personnel during aseptic operations could pose risks to product sterility. Almost every warning letter issued to sterile manufacturing operations is related to an organization’s inability to conduct smoke studies to the level of FDA’s expectations. In Sun’s case, the concerns related to the adequacy of the facility were to be addressed by conducting smoke studies, by November 15, 2014. However, their three responses dated December 12, 2014; February 10, 2015; and May 5, 2015 did neither submit a revised smoke test nor a satisfactory new smoke study. Sun’s case was definitely not helped by the fact that during the inspection, the inspector documented the “presence of leaks in the form of water stains and ceiling damage in the parenteral manufacturing area personnel corridor. The FDA investigator observed buckets with water collected from ceiling leaks and other leaks in this manufacturing area.” The FDA in their warning letter has asked Sun to describe any major equipment and facility upgrades that are planned. It seems that without changes in the physical infrastructure at Sun’s Halol facility, a key anchor to their business in the United States, it will not meet the FDA’s expectations. Our View Manufacturing non-compliances dominated pharmaceutical news headlines last year. As we’re still at the early stage of 2016, where people are making New Year resolutions, the big resolution manufacturers should make is what the FDA clearly says in their warning letter to Sun Pharmaceuticals. “It is essential that executive management systematically improve their oversight of manufacturing quality to ensure sustainable quality assurance”. View our UPDATED non-compliances compilation In case you missed some of the compliance news, PharmaCompass has compiled all the FDA Warning Letters, Import Alerts and EDQM (European Directorate for the Quality of Medicines) Non-Compliance Reports issued in 2015 for easy access. A special word of thanks to FDAZilla.com –makes actionable FDA information accessible.

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Pfizer’s US facility receives a warning letter, as Baxter’s cGMP deficiencies result in multi-million dollar legal settlement

Zydus Cadila & Sun Pharmaceuticals: FDA Warning Letters find problems aplenty

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