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: 7174
A few months ago, PharmaCompass covered
the Health Canada request to quarantine drugs linked to leading Chinese drug maker, Zhejiang Hisun Pharma (Hisun) due to data integrity concerns.The “interim precautionary measure” was taken “in light of recent findings from a trusted regulatory partner that raised concerns about the reliability of the laboratory data generated at this site”.Last week, the trusted regulatory partner – i.e. the United States Food and Drug Administration (FDA) – announced it had placed Zhejiang Hisun Pharma on its import alert list.
Regulators unite against data
integrity violations International regulatory agencies are collaborating with each other at an unprecedented pace. Health Canada’s decision to quarantine drugs from Hisun almost three months before FDA’s official action indicates an extremely low level of tolerance for companies that fail to maintain data integrity. Health Canada has also taken similar action against companies who have recently failed European inspections (e.g. India’s Polydrug Laboratories and China’s Jinan Jinda Pharmaceutical Chemistry). Polydrug Laboratories was also included
in the most recent FDA Import Alert list indicating a growing impatience in
international regulatory agencies against non-compliant firms. Last week, Brazilian Health Surveillance Agency (ANVISA) announced suspending import of all APIs from India’s Parabolic Drugs. ANVISA’s resolution was driven by Parabolic’s failure of a European Good Manufacturing Practices (GMP) inspection in July this year Hisun’s importance in the pharmaceutical supply chainThe FDA decision to ban almost all products coming from the Hisun facilities into the United States is going to create significant disruption in the pharmaceutical supply chain, given the colossal scale of Hisun Pharma’s operations.Zhejiang Hisun Pharma qualifies as one of
the most prominent active pharmaceutical ingredients (API) manufacturers in the
business, with more than 93 Drug Master Files submitted with the FDA, four
approved finished products listed in the FDA Orange Book and 35 Certificates of
Suitability issued by the European Directorate of Quality Medicine,.Hisun’s core operations in Taizhou city cover a very large area and are divided into three parts (the
Yantou campus; Waisha Campus; and East Factory) which are separated by public
roads. The Taizhou site employs approximately 4,000 people and focuses on fermentation-based anti-infectives, cardiovascular
products (e.g. statins) along with synthetic anti-cancer products. Hisun’s branded generic player ambitions Two years ago, Hisun’s ambitions to transform itself from an API maker to a branded generic
company were announced through the launch of Hisun-Pfizer
Pharmaceutical Co., a joint venture with Pfizer where Hisun has a controlling stake of 51 percent while
Pfizer has the balance 49 percent.With a vision to become “a widely respected international pharmaceutical company,” Hisun exports more than “80 percent of its API products” to more than 30 nations and regions. Hisun will not disappear post
the import banHowever, Hisun’s importance in the supply chain is demonstrated by the number of exemptions which the FDA had to make in order to ensure that there are no drug shortages created as an outcome of the import alert. Fourteen products have been excluded from
the import alert. Bleomycin, Capreomycin, Daunorubicin Citrate Liposomal, Doxorubicin Hydrochloride, Mitomycin, Tazobactam, Granisetron, Cladribine, Cyclophosphamide finished form and API, Cytarabine, Floxuridine, Fludarabine, Ivermectin and Adenosine will still be allowed entry into the United
States from the Hisun plant. Our viewLast month we analyzed if “speedy action by European agencies suggest revival of API production in the West” and suggested that the
era where companies were securing their supply of APIs by looking for low-cost
players in Asia appears to be waning away.With a major Chinese player like Hisun now
running into severe compliance problems and the number of alternatives
available being quite limited, we foresee a significant shift in the
pharmaceutical supply chain.
Impressions: 9877