Market Place
This week, PharmaCompass brings you a compilation of the Drug Master Files (DMFs) updates at the US Food and Drug Administration (FDA) over the past two quarters. These applications provide an overview of the products active pharmaceutical ingredient (API) manufacturers are investing in. And, they also give a sneak preview into the next possible first-to-file (FTF) generic challenges to patented drugs.
Here are some key findings from our compilation of the FDA’s DMF updates over the second and third quarter of 2016, details of which were provided in July and October:
India leads
the pack, as the number of filings remain the same
Over the period, there were a total of 379 updates of DMFs at the FDA. This number
indicates a pace in filings that is nearly the same as the previous quarters.
We had seen 180 DMFs updates in the last quarter (Q4) of 2015 and 190 in the first quarter (Q1) of 2016.
During the last
two quarters, the DMF updates were led by Indian companies, such as Macleods Pharmaceuticals (14 DMFs), MSN Labs (13 DMFs), Hetero
(12 DMFs), Lupin (9 DMFs), Cipla and Biophore. The other prominent companies were Mylan and Teva.
Companies
with compliance issues stay away
Unlike previous
quarters, where
companies with compliance problems continued to submit DMFs, the last two
quarters were slightly different, since companies like Zhejiang Hisun and Ipca
Laboratories did not submit DMFs.
However,
Emcure Pharmaceuticals — whose Pune facility was inspected by
the FDA last year and a warning letter was issued to the company for violations of current good manufacturing practices (cGMPs) in March this year — submitted one DMF (for Phytonadione)
While
China shut down antibiotic manufacturing in the Shijiazhuang
city, raising concerns about the global supply chain’s dependence on China, Sinopharm Weiqida Datong
Pharmaceutical, located about 300 kilometers away from Shijiazhuang, filed DMFs for the key building blocks of antibiotic manufacturing — 6-APA and 7-ACA.
Once
again, this filing reinforces the dependence of global
antibiotic manufacturing on China.
Click here to view all the updates of the second and third quarter of 2016 (Excel version available) for FREE!
Imminent FTF challenges
The
FTF challenges to Alvimopan Dihydrate (Merck’s Entereg), Apremilast (Celgene’s Otezla), Bosutinib (Pfizer’s Bosulib), Daclatasvir
Dihydrochloride (Bristol-Myer
Squibb’s Daklinza), Elvitegravir (an ingredient in Gilead’s Vitekta,
Stribild, Genvoya), Ibrutinib (AbbVie’s
Imbruvica), Ospemifene (Shionogi’s Osphena), Perampanel (Eisai’s Fycompa), Pomalidomide (Celgene’s Pomalyst), Regorafenib (Bayer’s Stivarga), Tofacitinib (Pfizer’s Xeljanz) and
Vortioxetine
Hydrobromide (Takeda’s Trintellix) seem to be imminent in
view of the recent filings of DMFs.
Roche’s 2014 acquisition of
InterMune for US $ 8.3 billion to gain rights to Esbriet (pirfenidone)
is likely to come under attack as three more DMFs were submitted during the
period under review.
The ink wasn’t dry on the deal papers of Pfizer’s US $1 4 billion acquisition of Medivation in August this year, when two more companies — Watson Pharma (now Allergan) and Scinopharm — submitted filings for Enzalutamide, the product for
which Pfizer paid all that money. This takes the total number of US submissions
for this product to seven.
Apixaban and Canagliflozin are most actively filed products
The most actively updated DMFs in the past six months were for the APIs of Bristol-Myer Squibb’s new-age anticoagulant Eliquis (Apixaban)
and Johnson & Johnson’s diabetes treatment Invokana (Canagliflozin). Sixteen DMFs were submitted for Apixaban along with nine for
Canagliflozin.
Products
like Dimethyl Fumarate and Teriflunomide — which were the
most frequently filed DMFs in our previous reports — continued to see vigorous filing activity.
Synbias Pharma made a submission
for Nelarabine, the only
submission for a Novartis product that was approved in 2005
and for which the only listed patent is expiring in June 2017. Similarly DSM’s submission of Dexpanthenol is the only DMF
listed for a product used in a variety of injectable and intravenous solution
products.
Established
pharmaceutical companies like Quimica Sintetica and Piramal Healthcare made submissions for products — Benznidazole and Norprostol — which are currently not approved in the United States, indicating the possibility of development projects being underway.
Our view
With drug filings ranging from multiple FTFs to cannabis derivatives,
updates over the two quarters have shown that regardless of the compliance
news, activity in the API industry is extremely robust.
You can view the PharmaCompass compilation of
the new DMF filings by clicking here or simply by sending us an email to get
your own Excel version of the new submissions.
Click here to view all the updates of the second and third quarter of 2016 (Excel version available) for FREE!
Impressions: 4464
https://www.pharmacompass.com/radio-compass-blog/us-dmf-filings-indicate-a-robust-api-industry-with-multiple-first-to-file-challenges
#PharmaFlow by PHARMACOMPASS
08 Dec 2016
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With Novartis shutting two plants in Germany and one in India by 2016-end, the global reliance on China for bulk drugs has increased even further, raising serious concerns over safety, supplies and national security. Which
plants? Last week, Novartis announced it will be shutting three plants of its generic business – Sandoz – by the end of 2016. The first plant is in India and the other two are located in Germany, in Gerlingen and Frankfurt. Frankfurt,
manufacturer of a key antibiotic intermediateThe Frankfurt plant is where Sandoz manufactures
7-ACA
(7-aminocephalosporanic acid), the core chemical structure (building block)
for producing a whole host of cephalosporin antibiotics. The reason given for closure -- prices of the cephalosporin active pharmaceutical ingredients (APIs) and intermediates have collapsed as Asian competitors have dumped excess capacity on the market. The shutdown of the Frankfurt facility
means that the global reliance on China for APIs, used to produce antibiotics
(such as cephalosporin) and especially
7-ACA, will increase only further. Chinese
APIs are already a security threat for India India produces a third of the world's
medicines, mostly in the form of generic drugs. However, according to an Oct 2014 report
by a Boston Consulting Group (BCG) and Confederation of Indian Industry (CII), more
than 90 percent of the key raw materials (intermediates and APIs) that go into
making at least 15-odd essential drugs come from China.The drugs listed include the most commonly used painkiller such as paracetamol, aspirin; antibiotics such as amoxicillin and ampicillin, cephalexin, cefaclor, ciprofloxacin, ofloxacin, levofloxacin; first line diabetes drug metformin; and antacid ranitidine. There are no domestic producers left for many drugs such as penicillin-G, and its derivative 6-aminopenicillanic acid, or 6-APA.Since India is still receiving a large quantity of 7-ACA from Germany (confirmed by the import statistics available on the PharmaCompass database), 7-ACA and its derivatives were not mentioned in this report.As per news reports, the Indian government
is now worried about over-dependence on imports from China. "Any
deterioration in relationship with China can potentially result in severe
shortages in the supply of essential drugs to the country. Additionally, China
could easily increase prices of some of these drugs where it enjoys virtual
monopoly," said Bart Janssens, partner, BCG, in a news
report published in The Economic Times. Recognizing the national healthcare
security challenge facing India, the Department of Pharmaceuticals (DoP) has
decided to declare the year 2015 as ‘Year of Active Pharmaceutical Ingredients.’ As part of this initiative, the Indian government intends
to build
cluster parks to boost India’s self-reliance on Chinese imports. Quality,
environmental concerns over Chinese AntibioticsChinese supplies of 7-ACA have been plagued
with multiple issues in the past. In 2012, for instance, several Chinese drug
companies were accused of manufacturing 7-ACA using contaminated ‘gutter oil’, instead of more
expensive soybean oil. Gutter oil is reprocessed oil manufactured from waste oil and animal fat collected from restaurants’ fryers, drains, grease traps and slaughterhouses. Chinese restaurants can get through a lot of cooking oil and this waste oil fuels a highly profitable gutter oil black market as there are few other outlets, such as biofuel production, for this by-product.Similarly, antibiotic pollution in the rivers of China is a serious cause of concern for the Chinese. Our previous analysis, “Antibiotic
resistant superbugs: deadlier than cancer and closer to you than you think” provides a detailed overview regarding the challenge being faced. However, with growing focus on antibiotic pollution in China, a shutdown of factories failing pollution norms would be a severe setback for the global antibiotic supply chain. In addition to these challenges, quality concerns have been raised during international regulatory inspections of some of the leading antibiotic producers in China, like Zhuhai
United and North
China Pharmaceutical Company. South
African stock outs of essential drugs a global concernThe outcomes of these challenges are already being felt in countries such as South Africa which are facing an acute shortage of critical drugs. According to a report
published in Groundup, drug shortages in South Africa’s health facilities have become a crisis. The story mentioned the situation in a hospital (Stanger Hospital) in Ilembe District KwaZulu Natal, where 200 products were out of stock. These included various doses of morphine, some antibiotics and antiretrovirals, especially paediatric ones, used to treat HIV. “About a hundred patients per week are going without ranitidine which prevents stomach ulcers. Several Ilembe facilities are even out of stock of paracetamol tablets,” the Groundup report said. There are multiple reasons for the drug stock
outs. However, unprofitability because old, off-patent products are being sold by
manufacturers at prices very close to the cost of production has played a major
role. Firms are abandoning such products and seeking higher return
alternatives. In addition, due to quality failures suppliers are unable to provide lifesaving medications to the South African population. Our
ViewThe problems of stock outs and quality concerns in South Africa can easily expand across the world and can’t be addressed until the global pharmaceutical industry reduces its reliance on China for bulk drugs and intermediates. It remains to be seen if the threat to the global supply chain will make Novartis reconsider its decision or drive a national government to buy the Frankfurt facility.
Impressions: 7491
https://www.pharmacompass.com/radio-compass-blog/novartis-plant-shut-down-creates-urgency-to-find-alternatives-to-chinese-apis
#PharmaFlow by PHARMACOMPASS
30 Jul 2015
