Market Place
Spanish API manufacturer cited for data-integrity violations; FDA recommends new system to rate quality of drugmakers
This week in Phispers, we bring you news on USFDA’s new report that recommends a new system to measure and rate the quality management maturity of drug manufacturing facilities.
The drug regulator in Spain issued a statement of GMP non-compliance to drugmaker Uquifa’s facility in Barcelona.
The Roche-Spark US$ 4.3 billion deal was delayed yet again due to regulatory concerns.
Allergan said it would pay US$ 750 million to settle a class action suit over its Alzheimer’s drug — Namenda.
EMA said it is outlining a three-step process whereby manufacturers can identify and control nitrosamine impurities, including N-nitrosodimethylamine (NDMA).
And Novartis said it will close its API plant in Cork, Ireland, that employs about 550 people.
FDA
report recommends new system to rate quality management of drugmakers
This week, the US Food and Drug Administration (FDA) published a new report on the root causes and potential solutions for drug shortages. The report recommends a new system to measure and rate the quality management maturity of drug manufacturing facilities.
In its 124-page report, the FDA’s Drug Shortage Task Force has recommended creating such a rating system, along with recommendations on creating an understanding on drug shortages, contracting practices and on promoting sustainable private sector contracts.
As many manufacturing sites have focused on compliance with current good manufacturing practices (cGMP), which FDA says set “a minimum threshold,” companies do not have a need to pursue “more advanced levels of quality management”, nor do they establish a culture that rewards process and system improvements, which is important as drugs in shortage are typically older drugs, with a median time since first approval of almost 35 years.
For generic drugs, the task force notes that the market often does not provide incentives for manufacturers to invest in updated manufacturing technologies and improvements in quality management.
Last week, in a blogpost, Janet Woodcock, director of FDA’s Center for Drug Evaluation and Research, had said the agency’s task force on drug shortages supports the idea of creating a new rating system to help drug purchasers, including consumers, better understand the quality management of drug manufacturing facilities.
The idea of a drug manufacturing ratings program follows the revelation that many drug shortages occur in the US because of quality issues. A team of FDA economists examined a sample of 163 drugs that first went into shortage between 2013 and 2017 and found that 62 percent were associated with manufacturing or product quality problems. FDA had previously highlighted a relative surge in drug shortages in 2018.
Woodcock noted on a call with reporters that the rating system would likely be voluntary and not linked to the agency’s push for quality metrics. The FDA maintains that by creating a rating system, buyers will recognize and reward manufacturing quality maturity.
Spanish
API manufacturer cited for data-integrity violations
The Spanish Agency of Medicines and Medical Devices issued a statement of GMP non-compliance to Union Quimico Farmaceutica, SA’s (Uquifa) facility located at Llica de Vall, Barcelona, Spain, following a September 2019 inspection.
The facility was cited with 11 deficiencies, out of which four were categorized as critical. The non-compliance certificate mentions deficiencies in the firm’s pharmaceutical quality system and highlights inadequate handling of manufacturing deviations and out of specification (OOS) results as well as a lack of batch traceability.
Uquifa is owned by India’s Vivimed Group. In 2011, as part of its growth strategy, Vivimed Group had acquired Uquifa’s operations in Spain and Mexico.
The Spanish agency’s inspectors raised concerns over the lack of proper control and recording of batches which were reprocessed. On some occasions, fractions of batches that met specifications were mixed with batches that had quality defects in order to improve their analytical results.
The inspection also uncovered evidence of falsified and rewritten documents, hidden products, and destroyed documentation and electronic files. In the production area, the integrity of the data was compromised as there was a systematic practice of manipulation and falsification of data related to filling of the manufacturing batch records.
The firm’s production managers were also found “obstructing and blocking the inspector's actions by not giving complete and clear information in response to the questions of the inspectors”.
The Spanish agency has recommended a suspension of the certificates of suitability (CEP) for the active substances manufactured at Uquifa SA’s site in Llica de Vall. Following the inspection, all manufacturing activities of APIs and/or intermediates that are carried out at the facility have been temporarily suspended until all the deficiencies observed in the inspection have been corrected and verified through an inspection, which is scheduled on November 13, 2019.
On September 9, an inspection of another manufacturing site of Uquifa SA at Sant Celoni was performed where there was no evidence of GMP non-compliance.
Uquifa’s customers, which manufacture finished medicinal products, are recommended to carry out a full testing on every container of active substance or intermediate received from the Llica de Vall manufacturing plant and should ensure a representative sampling is used (including sampling at different depths in the drum).
The following APIs manufactured by the firm are covered in this non-compliance statement — carnidazole, cyclopentolate hydrochloride, clindamycin hydrochloride, esomeprazole magnesium trihydrate, esomeprazole sodium, etofenamate, fluoxetine, ketorolac trometamol, lamotrigine, memantine hydrochloride, omeprazole, omeprazole magnesium, omeprazole sodium, pantoprazole sodium sesquihydrate, pethidine hydrochloride, strontium ranelate, ranitidine, ranitidine hydrochloride, risedronate sodium, mirabegron, valaciclovir hydrochloride, minocycline hydrochloride, tapentadol and tapentadol hydrochloride.
EMA
provides more details on nitrosamine testing in chemically synthesized APIs
Earlier this month, European Medicines Agency (EMA) had requested marketing authorization holders (MAHs) for human medicines containing chemically synthesized active substances to review their medicines for the possible presence of nitrosamines and test all products at risk. The review was to include all generics and over-the counter (OTC) products.
This week, EMA said it is outlining a three-step process whereby manufacturers can identify and control nitrosamine impurities, including N-nitrosodimethylamine (NDMA). Nitrosamine impurities can cause cancer, and have been identified in some blood pressure and heartburn medicines, such as valsartan and ranitidine. The updates from EMA come as recalls of ranitidine and sartan medicines continue in the EU and US.
The EU regulatory agency has released new templates for manufacturers to complete as part of their risk evaluations and confirmatory testing. EMA is calling on companies to conduct a risk evaluation by April 26, 2020 that would identify products at risk of N-nitrosamine formation or (cross-) contamination and report the outcome and fill out either the template indicating “no risk identified” or “risk identified.”
“EMA plans to complete this exercise by September 26, 2022. This timeline should be shortened in case of findings indicating higher risk to public health and that may require further risk minimization measures,” the agency said.
EMA also recently updated its question and answer document on nitrosamines to include the currently identified root causes for the presence of nitrosamines.
Novartis
to close API plant in Ireland as part of its transformation program
Novartis will close a production facility at the Ringaskiddy site (County Cork) in Ireland as it consolidates its active pharmaceutical ingredient operations there by mid-2022, a company spokesman said.
Novartis, which employs more than 1,600 people across Ireland, had earlier called a meeting of workers at its main Ringaskiddy plant. Novartis operates three facilities in Cork — a manufacturing facility and a supply complex in Ringaskiddy and a separate facility on the Model Farm Road. The company also has a shared services operation in Dublin.
Novartis also announced plans to relocate from the site a number of workers in the global services unit to centers in Europe and Asia by 2021. Both units are part of Novartis Technical Operations.
“This is a strategic decision and part of the ongoing evaluation of the Novartis manufacturing network around the world and transformation programs. These changes could impact up to 320 employees at the Novartis Ringaskiddy campus,” the company said.
Novartis has given assurances of good separation packages. It said some business services will continue at Ringaskiddy and the site will continue to manufacture medicines for hypertension, heart failure and acromegaly. But Novartis made clear more cuts are possible at the site where about 550 people currently work.
It is estimated that Novartis’ economic activity in Ireland is worth more than US$ 278 million (€250 million) to the domestic economy — with the firm also delivering around US$ 256 million (€230 million) in direct spending on wages, research and development, service supports and purchasing.
Opened in the early 1990s in Ringaskiddy under the Sandoz brand, the facility now ranks as one of the major pharmaceutical-chemical operations in the Cork harbor area.
Allergan pays US$ 750 million to settle class action suit over its Alzheimer’s drug
Allergan Plc has said it would pay US$ 750 million to settle a class action lawsuit from a group of direct purchasers of its Alzheimer’s disease therapy — Namenda.
The class-action suit accused Allergan of blocking generic competition to Namenda through a forced switch to a newer, more expensive version (known as Namenda XR).
According to a Reuters news report, the settlement makes no admission of wrongdoing on its part and will be recorded as a charge to its third-quarter earnings, the company said.
The lawsuit alleged that Allergan’s Forest units worked to delay generic competition for Namenda, including entering into an illegal agreement with its competitor Mylan NV.
Forest, the original maker of Namenda, discontinued the tablets taken twice daily in February 2014 and replaced it with Namenda XR (to be taken once daily) before the launch of a generic version in July 2015.
Days later, Allergan (which was then known as Actavis Plc) announced its acquisition of Forest. The plaintiff claimed that the plan to drop the older version caused patients to switch to the newer version in advance, forcing them to pay a higher price for Namenda. These patients would have otherwise taken the (cheaper) generic version.
Roche-Spark
deal delayed yet again due to regulatory concerns; Alphabet to buy Fitbit
This week, for the eighth time since it announced a deal to buy the American gene therapy specialist Spark Therapeutics, Roche extended the window on the US$ 4.3 billion acquisition through November 25.
The offer was extended to provide additional time for the US Federal Trade Commission (FTC) and the UK Competition and Markets Authority (CMA) “to complete their previously disclosed reviews of Roche’s pending acquisition of Spark. The parties remain committed to the transaction and are working cooperatively and expeditiously with the FTC and the CMA,” Roche said in a statement.
The FTC staff reviewing the deal reportedly recommended approval last week. The FTC reportedly recommended that the deal be approved without requiring any asset sales.
But a recommendation is not an official approval. The deal must also win approval from the CMA, which said this week that it had a deadline of mid-December for a Phase I decision. If the CMA decides the deal warrants a Phase II, it would initiate a more exhaustive probe.
In a third-quarter results call held last week, Severin Schwan, the CEO of Roche, told investors he was confident the deal would be done before 2020.
There is speculation that the holdup is over anticompetitive concerns around Roche’s hemophilia drug Hemlibra and a hemophilia gene therapy in development at Spark — SPK-8011.
Concerns that Roche may be forced to abandon a hemophilia gene therapy being developed by Spark in order to close the deal erupted after FTC issued a second request for information in June. A second request is rare and typically augurs a divestiture demand.
Back in February, Roche — the biggest maker of cancer drugs — had said it would buy Spark and acquire a portfolio that includes a blindness treatment that has US and European approval and other projects for neurodegenerative disorders like Huntington’s disease.
Alphabet may buy Fitbit: Alphabet Inc, the owner of Google, wants to enter the market for fitness trackers and smartwatches. The company is learnt to have made an offer to acquire San Francisco-headquartered wearable device manufacturer, Fitbit Inc.
According to sources quoted in a Reuters report, there is no certainty that the negotiations between Google and Fitbit will lead to a deal. The report also didn’t have the exact price that Google has offered for Fitbit.
If it materializes, Fitbit won’t be the first deal that Google would be carrying out in the wearables space. Fossil Group Inc said in January it would sell its intellectual property related to smartwatch technology under development to Google for US$ 40 million.
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