Mfg News: GSK, Merck KGaA & More

A roundup of manufacturing news from GSK, Sanofi, Pfizer, Merck KGaA, Emergent BioSolutions, and the US government. Highlights below.

* GSK, Sanofi & Pfizer Issue Statements over Ranitidine Litigation
* US Gov’t Ups Delivery Schedule of Monkeypox Vaccine
* Merck KGaA Reports Supply Disruptions of IVF Drug Cetrotide
FDA Issues Warning Letter to Emergent BioSolutions Subsidiary
* GSK, UNICEF in $170-M Malaria Vaccine Supply Pact

GSK, Sanofi & Pfizer Issue Statements over Ranitidine Litigation
Sanofi, GlaxoSmithKline (GSK), and Pfizer issued separate statements earlier this month (August 11, 2022) to clarify media speculation regarding product liability litigation over ranitidine, a prescription and over-the-counter (OTC) drug used to decrease the amount of acid created by the stomach. The litigation, which began in 2019/2020, involves claims surrounding nitrosamine impurities as potential cancer-causing agents in ranitidine, which is no longer marketed. The companies issued statements following market reactions to upcoming pending litigation and to emphasize that there have not been additional material developments to those previously disclosed.   

The issue of nitrosamine impurities in ranitidine began in September 2019 when the US Food and Drug Administration (FDA) reported that some ranitidine medicines, including the OTC product, Zantac, contained a nitrosamine impurity called N-nitrosodimethylamine (NDMA) at low levels. NDMA is a known environmental contaminant found in drinking water, soil, and common foods, including meats, dairy products, and vegetables, but at higher levels may be a potential carcinogen. The finding was part of larger investigation by the FDA and the European Medicines Agency into nitrosamine impurities in certain active pharmaceutical ingredients (APIs) that was first initiated in 2018 of “sartan”-containing APIs, used in anti-hypertensive and cardiovascular drugs, such as valsartan candesartan, irbesartan, losartan, and olmesartan. The investigation was later broadened to include ranitidine and metformin extended-release products, a drug used to treat Type II diabetes. As part of their investigations, the regulatory agencies issued guidelines for testing of products to detect nitrosamine impurities, acceptable daily intake levels, and risk evaluation and risk assessment.

Following FDA’s report in 2019, the companies voluntarily recalled ranitidine products, and in September 2020, the FDA requested that all manufacturers withdraw all prescription and OTC ranitidine products. Sanofi and GSK reported that litigation was filed against them beginning in 2019/2020, but that there has not been additional material developments to what the companies had previously disclosed. Since February 2020, Pfizer said a number of lawsuits have been filed against many defendants, including Pfizer, involving Zantac. Pfizer sold Zantac only between 1998 and 2006, and the withdrawal of Zantac products from the market in 2019 and 2020 did not involve any Pfizer products. “We believe at this time that the outcome of the litigation is not likely to be material to Pfizer,” said Pfizer in its statement.

For Sanofi, the first trial that may involve Sanofi as a defendant is currently scheduled for February 2023 as a part of a California state court proceedings. As of August 1, 2022, Sanofi said it was aware of approximately 2,850 personal injury plaintiffs across both state and federal jurisdictions with filed cases naming Sanofi in addition to other defendants. When factoring in additional Zantac cases that do not involve Sanofi, Sanofi is aware of approximately 3,450 total personal injury plaintiffs across all jurisdictions. There are other potential personal injury claimants who, in lieu of filing a court case, have instead joined a registry of unfiled claims established by a federal multidistrict litigation (MDL) court.

GSK has been named as a defendant in approximately 3,000 filed personal injury cases in federal and state court and in numerous unfiled claims in a Zantac MDL proceeding. Class actions alleging economic injury and a third-party payer class action also have been filed in federal court. In the US, among the state court cases naming GSK, a trial in California is currently scheduled to begin February 13, 2023, and a trial in Madison County, Illinois is set to proceed in February 2023. GSK reported this week (August 16, 2022) that the plaintiff in the first trial, which had been scheduled for later this month (August 2022), informed the court that he will file a notice of voluntary dismissal. GSK said it did not settle the claim and has not paid anything in exchange for the voluntary dismissal.

With respect to the claims of the link between ranitidine and cancer, GSK said: “GSK, independent cancer researchers, the Food & Drug Administration (FDA), and the European Medicines Agency (EMA), have all undertaken extensive reviews of available data and conducted numerous investigations into this issue since 2019,” said the company in its August 11, 2022 statement. “Based on these investigations and experiments, GSK, the FDA, and the EMA have all independently concluded that there is no evidence of a causal association between ranitidine therapy and the development of cancer in patients.”

Source: Pfizer, GlaxoSmithKline (August 11, 2022 statement), GlaxoSmithKline (August 16, 2022 statement) and Sanofi

US Gov’t Ups Delivery Schedule of Monkeypox Vaccine
Under a revised delivery schedule, the US government is making up to 442,000 doses of Bavarian Nordic’s monkeypox vaccine, Jynneos, available to US states and jurisdictions in an effort to accelerate supply of the vaccine.

The US government, through the US Department of Health and Human Services, is accelerating Phase 3 of its National Vaccine Strategy for monkeypox. Under the original timeline for Phase 3, doses were to be made available for ordering in three segments to be released on July 29, August 15, and later in August (August 2022). The HHS says in light of the recent emergency use authorization (EUA) by the US Food and Drug Administration (FDA) to allow for intradermal administration of the vaccine as part of a dose-sparing strategy and the subsequent revised  dosing guidelines from the US Centers for Disease Control and Prevention), HHS is now able to make doses under both Segment Two (originally available August 15, 2022) and Segment Three (originally to be available later in August), available for ordering, which doubles the number of originally anticipated doses. 

Under the FDA EUA for Jynneos, the vaccine may be injected intradermally (in the upper skin layer) for individuals 18 years of age and older who are determined to be at high risk for monkeypox infection, a change that increases doses by up to five-fold, over subcutaneous administration (underneath the skin), for which the vaccine was originally approved. US states and jurisdictions can now access additional doses from the federal government earlier than projected and expand use of vaccine they have already received.

Earlier this month (August 2022), the US government declared monkeypox a public health emergency.

In addition to accelerating access to doses under Phase 3, the US government will be launching Phase 4 of its National Vaccine Strategy later this month (August 2022), also faster than anticipated. HHS is working with all jurisdictions to determine how many Jynneos vials deployed to date (as reported on August 15, 2022) are still available for use that potentially may yield up to five doses each. This will inform specifics of Phase 4 based on the increased number of doses in each unused vial.

Source: US Department of Health and Human Services

Merck KGaA Reports Supply Disruptions of IVF Drug Cetrotide
The European Medicines Agency and Merck KGaA report that technical problems at the main product manufacturing site for Merck’s Cetrotide (cetrorelix), a drug to prevent premature ovulation in women undergoing fertility treatments, have led to a reduced and delayed supply of the drug (as reported on August 10, 2022). 

A technical issue at the main manufacturing site for Cetrotide resulted in closure of the site between December 2021 and March 2022. This has led to reductions and delays in the supply of the medicine, which may affect supply to certain European Union member states until the end of 2022. The quality of the manufactured and released product batches is not affected by the technical problems.

The supply disruptions affect EU member states and countries of the European Economic Area where Cetrotide is marketed: Belgium, Bulgaria, Cyprus, Greece, Hungary, Ireland, Latvia, Lithuania, Estonia, Luxembourg, Malta, Netherlands, Poland, Portugal, and Romania.

Source: European Medicines Agency (Direct Healthcare Professional Communication) and European Medicines Agency (Supply Notification)

FDA Issues Warning Letter to Emergent BioSolutions Subsidiary
The US Food and Drug Administration (FDA) has issued a Warning Letter to Cangene BioPharma, a subsidiary of Emergent BioSolutions, for cGMP violations at its drug-product manufacturing facility in Baltimore, Maryland, following an inspection of the facility from February 7 to 11, 2022, and from February 14 to 18, 2022.

The FDA cited the company for various quality-control issues relating to documentation and standard operating procedures in aseptic manufacturing. Specifically, the agency cited the company for not using suitable equipment for aseptic manufacturing, which led to particulate contamination of the company’s sterile drug products. The agency cited incidences of contamination due to metal and silicone particulates in tray units, but said the company did not have adequate procedures and documentation in place for inspecting the tray units as part of routine maintenance.

Additionally, the FDA cited that the company failed to establish and follow appropriate written procedures that are designed to prevent microbiological contamination of drug products purporting to be sterile, and that include validation of all aseptic and sterilization processes. Specifically, it cited poor aseptic technique by operators on the aseptic manufacturing line during production runs that led to potential contamination of drug product.

In addition, the FDA noted similar violations at the facility from an inspection conducted from April 12 to 16, 2021 and that were discussed during a regulatory meeting held on October 6, 2021. Overall, the agency said that findings from this Warning Letter demonstrate that the company does not operate an effective quality system in accordance with cGMP and that is quality unit was not fully exercising its authority or responsibilities.

The FDA listed a series of actions to be taken by the company to address these violations.

Source: FDA

GSK, UNICEF in $170-M Malaria Vaccine Supply Pact
GlaxoSmithKline (GSK) has entered into an agreement with the United Nations Children’s Fund (UNICEF) to supply 18 million doses of its malaria vaccine, RTS,S, over three years, in a deal worth up to $170 million.

The vaccine acts against Plasmodium falciparum, a malaria parasite and the most prevalent one in Africa.

Source: UNICEF