Market Place
In June this year, PharmaCompass
was the first to report that Teva’s newly-built
sterile manufacturing facility in Hungary had been placed on FDA’s import alert list. The FDA warning
letter to Teva, released this week, shares details of what
went wrong.
As has been seen with other sterile manufacturing facilities – such as that of Hospira
(now Pfizer), Agila
Speciaties (now Mylan) and Sun
Pharma – Teva’s facility failed to “adequately investigate media fill and sterility test failures”.
According to the FDA, “media fill is the performance of an aseptic manufacturing procedure using a sterile microbiological growth medium, in place of the drug solution, to test whether the aseptic procedures are adequate to prevent contamination during actual drug production.”
“These failures indicate that there is a lack of adequate sterility assurance in your manufacturing facility,” the warning letter to Teva said.
Data
integrity concerns not limited to Asia
The warning letter makes it amply clear that data integrity
concerns are not limited to India and China. While data integrity concerns at
Asian companies have been hogging the news headlines, similar problems exist in
Europe too.
In the case of Teva’s Hungary plant, FDA’s investigators found “quality-related documents in a waste bin”. Investigators also found Teva’s “stand-alone computer systems” to have lacked controls (such as routine audit trail review and full data retention) to prevent analysts from deleting data.
In addition, the warning letter said that the “colony counts for environmental and personnel monitoring” did not match the plant’s official records.
“After an error was observed on the original data sheet, the record was torn and discarded with no written explanation,” the warning letter said.
All drugs produced at Teva’s finished dosage forms facility in Hungary (barring antibiotics Amikacin and Bleomycin) were
placed on the import alert list.
Data manipulation at Otsuka’s Czech subsidiary
While Teva’s facility was placed on an import alert, a Czech-based subsidiary of Otsuka
Pharmaceuticals – Interpharma
Praha, a.s. – also received a warning letter.
Interpharma, which became a wholly-owned subsidiary of
Otsuka in 2008, manufactures active pharmaceutical ingredients (APIs) and
finished products.
FDA inspectors found that while testing APIs, analysts “used to generate and analyze chromatographic data that allowed them to eliminate failing, atypical and satisfactory results with no notification; alter peak areas; and add or eliminate samples from sequences without authorization.”
During inspection, the FDA reviewed an audit trail from its “Empower-2 system that stored 8,906 entries. Of these, well over half indicated some form of data deletion or manipulation, including at least 1,441 instances of deleted results,” the FDA said.
Interpharma’s personnel confirmed “that these actions are common during chromatographic data processing.”
While reviewing the finished products at Interpharma, FDA investigators uncovered “many deleted results” which made them question whether the quality unit was “presented with incomplete and inaccurate information”.
Our three vital observations in the two cases
PharmaCompass has
made the following three observations pertaining to the inspections at Teva and
Interpharma, and their outcomes:
Both these inspections took place in Europe, as
against Asia.
Interpharma was not placed on FDA’s import alert, even though the FDA reached the same conclusion here, as it did in the case of Teva’s Hungarian plant – that the quality system did not adequately ensure the “adequacy and integrity of data to support the safety, effectiveness, and quality of drugs” it manufactures.
The most interesting observation made by PharmaCompass is that while Teva’s products were banned from entering the United States within four months of the inspection – that occurred between January 21 and 29, 2016, nothing of the kind happened in the case of Interpharma. The inspection at Interpharma took place from October 12 to 16, 2015. And in July 2016, Interpharma’s new oral contrast
reagent for abdominal scans got approved.
Does
data integrity have a relationship with product quality?
This brings us to the statement made by Peter Werth some
months back in our Speak Pharma series, which had raised the hackles amongst some in the pharma industry – that ‘Data integrity has no relationships with product quality’.
Was Werth right in saying so?
With
a large chunk of drugs and drug ingredients being manufactured outside the US,
the American regulator has had to increase its international oversight and ban
products manufactured in plants that do not meet regulatory standards. However,
these bans have led to drug shortages.
In
order to prevent drug shortages, the FDA has (sometimes) had to exempt products
and allow imports from plants that it believes have a poor record. According to
the FDA import alert records, since 2013 the FDA has
allowed eight plants whose products are otherwise banned from the US to go
ahead and import some drugs or ingredients to avoid drug shortages. Amikacin manufactured at Teva’s Hungary plant is once such drug.
However, the FDA’s exemption to prevent a drug shortage suffered a setback when Teva announced a voluntary recall of seven lots of Amikacin Sulfate injection due to the potential for the presence of
glass particulate matter. This announcement follows a similar announcement by Teva when one lot of Amikacin was
recalled in March this year. ”
Our view
With all the compliance alerts that make headlines, if
products still reach the market after regulators uncover concerns related to
data integrity, it is worth investigating the link between data integrity
violations and patient/product safety?
Impressions: 5895
https://www.pharmacompass.com/radio-compass-blog/data-integrity-concerns-in-europe-at-teva-interpharma-raise-the-drug-shortage-versus-quality-debate
#PharmaFlow by PHARMACOMPASS
27 Oct 2016
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It has been an
unprecedented week where compliance glitches have emerged from almost all parts
of the globe. This week, PharmaCompass
brings you a compilation of such troubles to give you an idea about the nature
of such compliance issues. And, the problems regulators are facing walking the
tightrope between drug safety and drug availability. Pfizer halts production in India after joint
inspection by four regulatorsPfizer recently halted production at a plant
near Chennai in India, after a PIC/S (short for Pharmaceutical Inspection
Convention and Pharmaceutical Inspection Co-operation Scheme) joint inspection
with regulators from four international agencies, MHRA (Medicines and
Healthcare products Regulatory Agency of the UK), USFDA (United States Food and
Drug Administration), TGA (Therapeutic Goods Administration of Australia) and
Health Canada, found various quality control problems. A Pfizer spokesperson told
The Economic Times: “A holistic plan is being developed to address specific inspection observations and to implement enhancements to site operations.” The plant was
acquired by Pfizer through its US $ 17 billion acquisition of Hospira, which had run into a fair share of manufacturing compliance problems with the FDA. Over the last few years, numerous Hospira plants — including those in the United States, Europe, Asia, and Australia — received warning letters and had to subsequently issue product recalls. The same
facility in Chennai received an FDA warning letter in 2013. Pfizer’s own operations in Asia ran into problems when US FDA investigator Peter Baker uncovered data integrity malpractices at a
finished dosage manufacturing facility in Dalian (China). Teva recalls product exempted from
import alert on Hungarian facilityA little over
two months ago, Teva’s largest sterile medicines plant in Hungary was placed on FDA’s import alert list. When the alert was announced, all drugs produced at the finished dosage forms facility – barring antibiotics Amikacin and Bleomycin – were placed on the import alert list. With a large chunk of drugs and drug ingredients being manufactured outside the US, the American regulator has had to increase its international oversight and ban products manufactured in plants that do not meet the regulatory standards. However, these bans have led to drug shortages. As a result, the FDA has had to (sometimes) exempt products and allow imports from plants that it believes have a poor record. According to the FDA Import Alert records, since 2013 the FDA has allowed eight plants whose products are otherwise banned from the US to go ahead and import some drugs or ingredients in order to avoid drug shortages. Amikacin manufactured at Teva’s Hungary plant was once such drug.However, the FDA’s exemption to prevent a drug shortage suffered a setback when Teva announced
a voluntary recall of seven lots of Amikacin Sulfate Injection due to the potential for the
presence of glass particulate matter. This announcement follows a similar announcement by Teva when one lot of Amikacin was
recalled in March this year. Wockhardt back on FDA’s import alert listJust when it
seemed Wockhardt was getting its compliance act together and putting its problems behind it, its
bulk drug facility got placed on the FDA’s Red List. The bulk drug division in Ankleshwar (Gujarat) is the latest to join FDA’s import alert list, with Wockhardt’s Waluj and Chikalthana (Maharashtra) units already on the list. While
Wockhardt recently said it had received establishment inspection reports (EIR) for the facilities with observations, it also mentioned that the “receipt of EIR does not materially change the status of import alert for the concerned manufacturing units for the US market.” The bulk drug facility in Ankleshwar had received a EU Written Confirmation from the Indian Central Drug Authority for the following seven products – dextromethorphan hydrobromide, adenosine, tamsulosin, nicardipine, cefuroxime axetil, fexofenadine and ceftriaxone sodium. FDA’s warning letter to China’s Xiamen reveals horrific details of GMP deficiencies Chinese drug maker Xiamen Origin Biotech (known
as Attix Xiamen Pharmaceutical in North America) was placed on the
FDA Import Alert list in May 2016. However, it was only recently that its warning letter was put up on the FDA
website, bringing to light the magnitude of GMP deficiencies. According to the warning letter, the company “repeatedly falsified and omitted information on the certificate of analysis (CoA)” issued to customers and went to the extent of fabricating the name of an employee, which was used as a false signing authority on the CoA sent to customers.The company also included an ‘expiration date’ which exceeded the manufacturer’s labeled expiration date without any basis for the extension. In addition, the company made deceptive statements
to the investigator, who also found dirty warehousing spaces and a rodent in
the room adjacent to the warehouse.The FDA’s action in China follows an import alert which was placed on the North American operation of the company – Attix Pharmaceuticals – in Canada in February 2015. The warning letter issued to Attix Canada showed the company was packaging highly potent beta-lactam products “in a facility that is not dedicated to manufacturing beta-lactam drugs”. The practices created “an unacceptable risk of beta-lactam cross-contamination in other beta-lactams and in non-beta-lactam APIs”.An outcome of the North American inspection was a
series of API recalls in both the United States and Canada. Japanese camphor producer refuses inspection; lands up on FDA’s Red ListWhile Wockhardt got placed on FDA’s import alert list as an outcome of an inspection, Nippon Fine Chemical in Japan appeared on the dreaded Red List
for refusing to be inspected.Nippon Fine
Chemical produces pharmaceutical grade Camphor, an active ingredient (along with menthol) in vapor-steam products, such as
Vicks VapoRub. Inno Pharma’s Vitamin D drops with 75 times higher content recalled in DenmarkIn Denmark, Vitamin D drops made by Inno Pharma were recalled recently as the content was “75 times too high”. The product is marketed to infants and pregnant women in Denmark, and sold under the brand ‘Vitamin D3-draber’.The hazardous nature of the drops made the Danish Health Authority (Sundhedsstyrelsen) advise anyone who had taken ‘Vitamin D3-draber’ from Inno Pharma for a week or longer to see their doctor for a blood test to assess the risk posed to them of Vitamin D toxicity. Also known as hypervitaminosis D, this is a rare but
potentially serious condition that occurs when you have excessive amounts of
vitamin D in your body. The main consequence of vitamin D toxicity is a buildup
of calcium in your blood
(hypercalcemia), which can cause poor appetite, nausea, vomiting, weakness, frequent
urination and kidney problems.
Impressions: 7173
https://www.pharmacompass.com/radio-compass-blog/compliance-troubles-emerge-at-pfizer-teva-wockhardt-and-xiamen-origin
#PharmaFlow by PHARMACOMPASS
11 Aug 2016
This week, Phispers covers news about David Cameron urging the G7 to fight superbugs, FDA regulatory action against Corden Pharma’s Italian facility and a new implant that fights opioid addiction.Teva’s largest sterile medicines plant in Hungary placed on FDA import alert listTeva Pharmaceutical’s facility in Hungary was placed on the US Food and Drug Administration’s import alert list. The action was taken after an FDA inspection found that the plant was not conforming to the current good manufacturing practices (GMPs). All drugs produced by the finished dosage forms facility – barring antibiotics Amikacin and Bleomycin – have been placed on the import alert list. Teva had commissioned the US $ 110 million plant in Gödöllő, Hungary, in 2012. At the time, Teva had announced that the facility was one of the largest sterile medicines plants in the world. The plant has an annual production capacity of 160 to 200 million units of injectables and the six production lines can produce six different products simultaneously. It supplies medicines to patients in over 70 countries in Europe, North America, and the Far East. The FDA import
alert is bad news for Teva and comes at a time when investors believe the US $ 41 billion
it paid for Allergan’s generic business was too high a price. FDA inspection in Corden Pharma’s Italy plant uncovers ‘black grime and filth’ While details about Teva’s GMP shortcomings are awaited, an inspection by the FDA of Corden Pharma Latina’s active pharmaceutical ingredients (API) facility in Italy revealed that “black grime and filth were visible” on tiles and stagnant water was found collecting under aseptic filling machines. Meanwhile, Corden Pharma said it will respond to FDA’s warning letter and stressed that the supplies of APIs and finished dosage forms manufactured at its Italy plant will not be impacted. The FDA also
posted on its website the long-awaited warning letter for Megafine Pharma in India, which had been placed on FDA’s import alert list in October 2015. The warning letter revealed the usual data-integrity concerns. On a positive
note, Granules India shared it has successfully addressed FDA’s observations during a recent inspection. It would be worthwhile to have more companies share such positive news so that the ‘noise’ about non-compliances gets balanced. This comes at
a time when the Indian drug regulator is introducing a risk-based inspection model to address concerns at manufacturing
plants in India. Cameron urges G7
nations to step up fight against superbugsBritain has asked G7 nations to do more to fight
killer superbugs. This was after the United States reported the first case in the country of a patient with bacteria resistant to a last-resort antibiotic – colistin.
The antibiotic is reserved for nightmare bugs. The patient, a 49-year old woman
from Pennsylvania, succumbed to the truly pan-drug resistant bacteria. In Japan, David Cameron, Britain’s Prime Minister, said leading countries need to tackle resistance by reducing the use of antibiotics and rewarding drug companies for developing new medicines. “In too many cases antibiotics have stopped working. That means people are dying of simple infections or conditions like TB (tuberculosis), tetanus, sepsis, infections that should not mean a death sentence,” he said at a conference in Japan. “If we do nothing about this there will be a cumulative hit to the world economy of US $ 100 trillion and it is potentially the end of modern medicine as we know it,” he said. FDA approves implant
that dispenses opioid addiction medicationThe FDA has approved an implant that continuously dispenses
an opioid
addiction medication – buprenorphine – for six months. Branded as Probuphine, the device will cost less than US $ 1,000 per month, said the spokesperson for Braeburn Pharmaceuticals – the company that has the commercial rights to the implant in the United States. That’s a lot more expensive than other forms of buprenorphine existing in the market, such as a daily pill or a dissolvable film. But it’s cheaper than Vivitrol,
another form of opioid medication, priced at around US $1,100 a month. However, doctors have cautioned that the implant, originally
developed by Titan
Pharmaceuticals, needs to be supplemented with counseling and other forms
of support. Sun Pharma subpoenaed
for information on drugs it sells in the USIndia’s largest pharmaceutical company – Sun
Pharmaceutical Industries – was subpoenaed
by the US Department of Justice (DoJ). The DoJ sought more information about
the pricing and marketing of the generic drugs Sun Pharma sells in the US. The DoJ, through its antitrust division, has also asked Sun Pharma’s US unit for details related to communications with competitors, employee and corporate records. The subpoena is part of a wider probe by American regulators into the steep increase in prices of generic drugs in the recent past. The investigation had been prodded by US Senator Bernie
Sanders and Democratic Representative Elijah Cummings. Other generic drug
manufacturers like Dr. Reddy’s Laboratories and Allergan also received subpoenas from regulators
seeking similar information last year. Alibaba tells vendors
to stop online sales of medicines in ChinaAlibaba Group Holding has told vendors on its Tmall website
to stop selling drugs online. The Chinese e-commerce company cited an “urgent” directive issued by a local regulator that halts drug sales through third-party platforms. A Reuters news report mentioned a circular issued by the Hebei province branch of the China Food and Drug Administration (CFDA) on “urgent control measures relating to drug products”. No reasons for such a directive had been cited.
Impressions: 5958
https://www.pharmacompass.com/radio-compass-blog/gmp-problems-at-teva-s-hungary-plant-place-it-on-fda-s-import-alert-list-alibaba-halts-online-sale-of-medicines
#PharmaFlow by PHARMACOMPASS
02 Jun 2016
