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DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO
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Zydus receives approval from USFDA to initiate Phase II clinical studies of Saroglitazar Magnesium in patients with Primary Biliary Cholangitis (PBC)
Zydus receives approval from USFDA to initiate Phase II clinical studies of Saroglitazar Magnesium in patients with Primary Biliary Cholangitis (PBC) Read more: https://goo.gl/eugRnZ #ZydusAnnouncement
Ahmedabad, India, February 23, 2017
Zydus Cadila, a research-driven, global healthcare provider, today announced that the USFDA has approved the group’s plans to initiate a Phase 2 clinical trial of Saroglitazar Magnesium (Mg) in patients with Primary Biliary Cholangitis (PBC) of the liver. This randomized, double-blind Phase 2 trial will evaluate Saroglitazar Magnesium 2mg and 4 mg Vs. Placebo.
Speaking on the development, Mr. Pankaj R. Patel, Chairman and Managing Director, Zydus Cadila said, “We are very thankful to the USFDA for their timely and useful feedback on the clinical trial designs of Saroglitazar Mg in patients with Primary Biliary Cholangitis (PBC). This development underlines our commitment to bridging unmet healthcare needs with innovative therapies.”
Primary Biliary Cholangitis (PBC) is a liver disease, caused due to progressive destruction of the bile ducts in the liver which leads to reduction of bile flow – a condition referred to as cholestasis. PBC is often discovered incidentally due to abnormal results on routine liver blood tests. Progression of PBC leads to symptoms of cirrhosis like yellowing of the skin, swelling of legs and feet (edema), ascites, internal bleeding (varices) and thinning of the bones (osteoporosis). The buildup of toxic bile in the liver leads to liver inflammation and fibrosis which can progress to cirrhosis. People with cirrhosis are at increased risk of hepatocellular carcinoma or liver cancer, which is a leading cause of liver transplants or death.
With an increasing number of people being affected by PBC which can lead to progressive cholestasis and even turn fatal, there is a pressing need to develop therapies which help to achieve an adequate reduction in alkaline phosphotase (ALP) or bilirubin and bring in better tolerance and efficacy.
About Lipaglyn™ Lipaglyn™ is a prescription drug authorized for sale in India only. Lipaglyn™ was launched in India during Sept 2013 for the treatment of Hypertriglyceridemia and Diabetic Dyslipidemia in Patients with Type 2 Diabetes not controlled by statins. Saroglitazar Mg is an investigational new drug with the USFDA, and is currently under clinical investigation for three significant unmet medical needs in the United States – Primary Biliary Cholangitis (PBC), Non-alcoholic Steatohepatitis (NASH) and Severe Hypertriglyceridemia (TG>500).
About Zydus Zydus Cadila is an innovative, global healthcare provider that discovers, develops, manufactures and markets a broad range of healthcare therapies, including small molecule drugs, biologic therapeutics and vaccines. The group employs over 19,500 people worldwide, including 1200 scientists engaged in R & D, and is dedicated to creating healthier communities globally. For more information, please visit http://www.zyduscadila.com
http://zyduscadila.com/wp-content/uploads/2017/02/USFDA-approval-for-clinical-trial-of-Saro-Mg.pdf
Saroglitazar magnesium
CAS: 1639792-20-3
Molecular Formula, 2C25-H28-N-O4-S.Mg,
Molecular Weight, 901.4354
Magnesium, bis((alphaS)-alpha-(ethoxy-kappaO)-4-(2-(2-methyl-5-(4-(methylthio)phenyl)-1H-pyrrol-1-yl)ethoxy)benzenepropanoato-kappaO)-, (T-4)-
(2S)-2-Ethoxy-3-(4-(2-(2-methyl-5-(4-(methylsulfanyl)phenyl)-1H-pyrrol-1-yl(ethoxy)phenyl)propanoic acid, magnesium salt (2:1)
DR RANJIT DESAI
ZYDUS
//////////Zydus, USFDA, Phase II, clinical studies, Saroglitazar Magnesium, Primary Biliary Cholangitis, (PBC)
[Mg+2].CCO[C@@H](Cc1ccc(OCCn2c(C)ccc2c3ccc(SC)cc3)cc1)C(=O)[O-].CCO[C@@H](Cc4ccc(OCCn5c(C)ccc5c6ccc(SC)cc6)cc4)C(=O)[O-]
USFDA approves Indoco’s Allopurinol ANDA
Indoco Remedies Limited (India) | Facebook
https://www.facebook.com/Indoco-Remedies-Limited-India-317944458228011/
USFDA approves Indoco’s Allopurinol ANDA… Indoco Remedies Limited (India)’s … Indoco Remedies Limited (India) added a new photo
Allopurinol, sold under the brand name Zyloprim and generics, is a medication used primarily to treat excess uric acid in the bloodand its complications, including chronic gout. It is a xanthine oxidase inhibitor and is administered orally.
It is on the World Health Organization’s List of Essential Medicines, a list of the most important medication needed in a basic health system.
Allopurinol has been marketed in the United States since August 19, 1966, when it was first approved by FDA under the trade name Zyloprim. Allopurinol was marketed at the time by Burroughs-Wellcome. Allopurinol is now a generic drug sold under a variety of brand names, including Allohexal, Allosig, Milurit, Alloril, Progout, Ürikoliz, Zyloprim, Zyloric, Zyrik, and Aluron
Aditi Kare Panandikar, Managing Director, Indoco Remedies
click above
///////////Indoco Remedies Ltd, USFDA, approves, Indoco’s, Allopurinol, ANDA, Aditi Kare Panandikar, Managing Director,
WCK 5222, Wockhardt receives QIDP status for its new drug WCK 5222 from USFDA
WCK 5222
Watch this post as I get to the structure…………..
DEC2015
Wockhardt has received Qualified Infectious Disease Product (QIDP) status for its new drug WCK 5222, a product from its breakthrough New Drug Discovery program in Anti Infectives from the US Food and Drug Administration (FDA).
This is the fourth product from the company to receive this coveted status. During last year, the company has received approval for WCK 771 & WCK 2349 and in early this year approval was received for WCK 4873. The only company globally to receive QIDP status for 4 drugs from US FDA.
Wockhardt is one of the few companies with end to end integrated capabilities for its products, starting with the manufacture of the oral and sterile API’s, the dose forms and marketing through wholly owned subsidiary in the US, enabling the company to capture maximum value.
Ten compounds generally represented by a general Formula (I) were used and are as follows:
(a) Sodium salt of ir ns-7-oxo-6-sulphooxy-l ,6-diazabicyclo[3.2.1]-octane-2-carbonitrile (Compound A);
(b) trans-sulphuric acid mono-[2-(5-carboxamido)-[l ,3,4]-oxadiazol-2-yl)-7-oxo-l,6-diazabicyclo[3.2.1]-octan-6-yl] ester (Compound B);
(c) trans-sulphuric acid mono-[2-(5-(piperidin-4-yl)-[l ,3,4]-oxadiazol-2-yl)-7-oxo-l,6-diazabicyclo[3.2.1]-octan-6-yl] ester (Compound C);
(d) trans-sulphuric acid mono-[2-(5-azetidin-3-ylmethyl-[l ,3,4]-oxadiazol-2-yl)-7-oxo-l,6-diazabicyclo[3.2.1]-octan-6-yl] ester (Compound D);
(e) (25,5i?)-7-Oxo-6-sulphooxy-2-[N’-((i?)-piperidine-3-carbonyl)-hydrazinocarbonyl] -1,6-diaza-bicyclo[3.2.1]octane (Compound E);
(f) (25, 5i?)-7-Oxo-N-[(25)-pyrrolidin-2-ylmethoxy]-6-(sulfooxy)-l,6-diaza bicyclo [3.2.1] octane-2-carboxamide (Compound F);
(g) (25,5i?)-7-Oxo-6-sulphooxy-2-[N’-((i?)-pyrrolidine-3-carbonyl)-hydrazinocarbonyl]-l ,6-diaza -bicyclo[3.2.1]octane (Compound G);
(h) (25,5i?)-7-Oxo-N-[(25)-piperidine-2-ylmethyloxy]-6-(sulfooxy)-l ,6-diazabicyclo
octane-2-carboxamide (Compound H);
(i) trans-sulphuric acid mono-[2-(5-((5)-l-amino-ethyl)-[l ,3,4]-oxadiazol-2-yl)-7-oxo-l,6-diazabicyclo[3.2.1]-octan-6-yl] ester (Compound I); and
j) trans-sulphuric acid mono-[2-(5-((5)-pyrrolidin-2-yl)-[l,3,4]-oxadiazol-2-yl)-7-oxo-l,6-diazabicyclo[3.2.1]-octan-6-yl] ester (Compound J).
////
WCK 2349 in phase II trials by Wockhardt
. CH3SO3H
WCK 2349: A novel fluoroquinolone (FQ) prodrug-13 week oral (PO) safety profile in cynomolgus monkeys
47th Intersci Conf Antimicrob Agents Chemother (ICAAC) (September 17-20, Chicago) 2007, Abst F1-2133a
8-{4-[2(S)-Amino-propionyloxy] piperidine-l-yl}-9-fluoro-5 (S)-methyl-ό, 7-dihydro-l- oxo-lH, 5H-benzo[i,j]quinolizine-2-carboxylic acid of structural Formula I can be used to treat bacterial Gram-positive, Gram-negative and anaerobic infections; especially infections caused by resistant Gram-positive organism and Gram-negative organism, mycobacterial infections and emerging nosocomial pathogen infections.
Formula I
U.S. Patent Nos. 6,750,224 and 7,247,642 describes optically pure S-(-)-benzoquinolizine carboxylic acids, their derivatives, salts, pseudopolymorphs, polymorphs and hydrates thereof, their processes of preparation and their pharmaceutical compositions.
PATENT
WO 2007102061
http://www.google.co.in/patents/WO2007102061A2?cl=en
Scheme 1
Experimental:
(S)-9-Fluoro-6,7-dihydro-8-(4-hydroxypiperidin-l-yl)-5-methyl-l-oxo-lH,5H-benzo[ij] quinolizine-2-carboxylic acid was prepared as per procedure described in Chem. Pharm. Bull. 1996, 44(4), 642-645.
Example-l
Preparation of (2’S,5S)-9-fluoro-6,7-dihydro-8-(4-(N-tert-butoxycarbonyI-L-aIaninyl- oxy)-piperidin-l-yl)-5-methyl-l-oxo-lH,5H-benzo[i,j]quinolizine-2-carboxylic acid:
Method-1 : To a mixture of N-tert-butoxycarbonyl-L-alanine (473 g) in dichloromethane (2 L), dicyclohexylcarbodiimide (515 g) dissolved in dichloromethane (2 L) was charged at -10 to 0 0C to provide a turbid suspension. To the turbid suspension, 300 g of (S)-9-fluoro-6,7- dihydro-8-(4-hydroxy-piperidin- 1 -yl)-5-methyl- 1-oxo- lH,5H-benzo[i,j]quinolizine-2- carboxylic acid was added followed by 4-N,N-dimethylamino pyridine (58 g) and the reaction mixture was stirred at -10 to 5 °C temperature over a period of 2 h. Suspension was filtered and solid was washed with 500 ml of dichloromethane. The filtrate was washed with water. Filtrate was dried over anhydrous sodium sulfate. Dried organic layer was then concentrated to its half volume where upon solid was precipitated. The solid was filtered and washed with 300 ml of dichloromethane. Clear organic filtrate was concentrated to dryness to provided an oily mass. Oily mass was triturated with diethyl ether (4 L) to provide white solid. The solid was filtered under suction and washed with diethyl ether (1 L) to provide title compound in 415 g (94%) quantity.
Method-2: To a mixture of triethylamine (98.0 ml) and N-tert-butoxycarbonyl-L-alanine (110 g) in tetrahydrofuran (1050 ml) and N,N-dimethyl formamide (350 ml) mixture, was added 2,4,6-trichlorobenzoyl chloride (100 ml). The resultant mixture was stirred at a temperature -5 to 0 °C for 5 h. To the > reaction mixture 4-N,N-dimethylamino pyridine (24g) and (S)-9-fluoro-6,7-dihydro-8-(4-hydroxy-piperidin-l-yl)-5-methyl-l-oxo-lH,5H- benzo[i,j]quinolizine-2-carboxylic acid (70 g) was added. The reaction mixture was stirred for additional 7 h at -5 to 0 0C temperature. The suspension was filtered at room temperature and the filtrate was extracted with ethyl acetate after addition of water. The evaporation of organic layer under reduced pressure provided a sticky solid, which upon triturating with diethyl ether provided a white solid in 85 g quantity.
Method-3: To a solution N-tert-butoxycarbonyl-L-alanine (7.9 g) in tetrahydrofuran (75 ml) and N,N-dimethyl formamide (25 ml) mixture at -10 to 0°C was added methanesulfonyl chloride (2.42 ml) dropwise. To the above solution triethylamine (8.7 ml) was added dropwise over 5 min. the reaction was stirred for 1.5 h maintaining the temperature between at -10 to 0 0C. To the reaction mixture (S)-9-fluoro-6,7-dihydro-8-(4-hydroxy-piperidin-l- yl)-5-methyl-l-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic acid (5.01 g) and 4-N5N- dimethylamino pyridine (1.70 g) was added. The reaction mixture was stirred for additional 1 h at -5 to 0 °C temperature. The suspension was filtered at room temperature and the filtrate was diluted with water (300 ml) and extracted with ethyl acetate (150 ml x 2). The evaporation of organic layer under reduced pressure provided a sticky solid, which upon triturating with diethyl ether provided a white solid in 6.38 g (86%) quantity.
Example-2
Preparation of (2’S, 5S)-9-fluoro-6,7-dihydro-8-(4-L-alaninyl-oxy-piperidin-l-yl)-5-methyl- l-oxo-lH,5H-benzo[i,j]quinolizine-2-carboxylic acid methanesulfonic acid salt:
To a mixture of (2’S, 5S)-9-fluoro-6,7-dihydro-8-(4-N-tert-butoxycarbonyl-L-alaninyloxy- piperidin-l-yl)-5-methyl-l-oxo-lH,5H-benzo[i,j]quinolizine-2-carboxylic acid (415 g) in acetone (4.5 L) was charged methanesulfonic acid (66 ml). Reaction mixture was stirred at 65-67 °C temperature for overnight. The suspension was filtered at 40-45 0C. Solid was washed with acetone (1.5 L) followed by diethyl ether (1.5 L). Off white solid was dried under 40 to 45 mm vacuum at 55-60 °C temperature over the period of 3-4 h. Title compound was obtained as a free flowing off white material 383.0 g (93%).
For MF: C23H30FN3O8S, MS (ES+) m/z 432 (obtained as free base for MF: C22H26FN3O5);
M.P. 278.50 0C by DSC
PATENT
Patent
PATENT
The tablets may optionally be coated with film forming agents and/or pharmaceutically acceptable excipients. Particularly suitable for use are commercially available coating compositions comprising film-forming polymers marketed under various trade names, such as Opadry® and Eudragit®. The coating layers over the tablet may be applied as solution/dispersion of coating ingredients using conventional techniques known in the art.
The present invention is further illustrated by the following examples which are provided merely to be exemplary of the invention and do not limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
Example 1 :
Table 1 provides the composition of batches of the present invention.
Table 1
Procedure: The compound of Formula I or pharmaceutically acceptable salts, esters or products thereof, lactose and croscannellose sodium were sifted and dry mixed in a rapid mixer granulator. The above mass was granulated by spraying aqueous solution of povidone. The granules were dried in a fluidized bed drier, sifted and oversize granules were milled in a Quadra mill. The resultant granules were mixed with talc, croscarmellose sodium, microcrystalline cellulose and sodium stearyl fumarate in a double cone blender. The lubricated granules were compressed into tablets using suitable tooling. Tablets were coated with aqueous dispersion of opadry.
Table 2 provides the dissolution data for the compound of formula I or pharmaceutically acceptable salts, esters or products thereof tablets prepared as per the formula given in Table 1. For determination of drug release rate, USP Type 2 Apparatus (rpm 50) was used wherein 0.1 N hydrochloric acid (900 ml) was used as a medium. Table 2: Dissolution data
NEW DELHI: Drug maker WockhardtBSE -1.83 % today said that two of its anti-infective drugs
have received Qualified Infectious Disease Product (QIDP) status from the US
health regulator.Two drugs – WCK 771 and WCK 2349 – have received QIDP
status, which allows fast-track review of the drug application by the US Food and Drug Administration (USFDA),
Wockhardt said in a statement.
http://economictimes.indiatimes.com/articleshow/41359481.cms?utm_source=contentofinterest&utm_medium=text&utm_campaign=cppst
RN: 306748-89-0
-
C19-H21-F-N2-O4.C6-H14-N4-O2
- MW: 534.5855
-
L-Arginine, mono((5S)-9-fluoro-6,7-dihydro-8-(4-hydroxy-1-piperidinyl)-5-methyl-1-oxo-1H,5H-benzo(ij)quinolizine-2-carboxylate)
J Med Chem 2005, 48(16): 5232
| WO1991012815A1 * | Feb 25, 1991 | Sep 5, 1991 | Squibb Bristol Myers Co | COMPOSITIONS AND METHODS FOR TREATING INFECTIONS CAUSED BY ORGANISMS SENSITIVE TO β-LACTAM ANTIBIOTICS |
| WO2000068229A2 * | May 8, 2000 | Nov 16, 2000 | S K Agarwal | (s)-benzoquinolizine carboxylic acids and their use as antibacterial agents |
| WO2001085095A2 * | May 3, 2001 | Nov 15, 2001 | Shiv Kumar Agarwal | Chiral fluoroquinolizinone arginine salt forms |
| WO2002009758A2 * | Jul 31, 2001 | Feb 7, 2002 | Satish B Bhawsar | Inhibitors of cellular efflux pumps of microbes |
| EP2062582A1 * | Aug 14, 2007 | May 27, 2009 | Tianjin Hemey Bio-Tech Co., Ltd. | The antibiotics composition comprising beta-lactam antibiotics and buffers |
| US4524073 * | Jul 20, 1983 | Jun 18, 1985 | Beecham Group P.1.C. | β-Lactam compounds |
| US6465428 * | Aug 25, 2000 | Oct 15, 2002 | Aventis Pharma S.A. | Pharmaceutical combinations based on dalfopristine and quinupristine, and on cefepime |
| US20040254381 * | Aug 15, 2003 | Dec 16, 2004 | Day Richard A. | Antibiotic compositions and methods of using the same |
| US20050148571 * | Nov 29, 2002 | Jul 7, 2005 | Nancy Niconovich | Method of treating bacterial infections using gemifloxacin or a salt thereof and a betha-Lactam antibiotic |
| US20090148512 * | Apr 17, 2008 | Jun 11, 2009 | Lannett Co Inc | Novel uses of chloramphenicol and analogous thereof |
| US20090232744 * | Feb 26, 2009 | Sep 17, 2009 | Pari Pharma Gmbh | Macrolide compositions having improved taste and stability |
| WO2002009758A2 * | 31 Jul 2001 | 7 Feb 2002 | Satish B Bhawsar | Inhibitors of cellular efflux pumps of microbes |
| US6750224 | 17 Aug 2000 | 15 Jun 2004 | Wockhardt Limited | Antibacterial optically pure benzoquinolizine carboxylic acids, processes, compositions and methods of treatment |
Mr Habil Khorakiwala, Chairman, Wockhardt Ltd.
///////////keywords USFDA, Qualified Infectious Disease Product status, Wockhardt, drugs, WCK 2349, QIDP
ORGANIC SPECTROSCOPY
US priority review for Eisai cancer drug lenvatinib
US priority review for Eisai cancer drug lenvatinib
Eisai has been boosted by news that regulators in the USA have agreed to a quicker review of its anticancer agent lenvatinib.
The US Food and Drug Administration has granted a priority review to Eisai’s New Drug Application for lenvatinib as a treatment for progressive radioiodine-refractory differentiated thyroid cancer. This means that the agency has assigned a Prescription Drug User Fee Act action date of April 14 next year, eight months after the NDA was submitted.
Read more at: http://www.pharmatimes.com/Article/14-10-15/US_priority_review_for_Eisai_cancer_drug_lenvatinib.aspx#ixzz3GH3iXiDU
SEE SYNTHESIS
USFDA grants Qualified Infectious Disease Product status to two Wockhardt drugs WCK 771, WCK 2349.
NEW DELHI: Drug maker WockhardtBSE -1.83 % today said that two of its anti-infective drugs
have received Qualified Infectious Disease Product (QIDP) status from the US
health regulator.Two drugs – WCK 771 and WCK 2349 – have received QIDP
status, which allows fast-track review of the drug application by the US Food and Drug Administration (USFDA),
Wockhardt said in a statement.
http://economictimes.indiatimes.com/articleshow/41359481.cms?utm_source=contentofinterest&utm_medium=text&utm_campaign=cppst
RN: 306748-89-0
-
C19-H21-F-N2-O4.C6-H14-N4-O2
- MW: 534.5855
-
L-Arginine, mono((5S)-9-fluoro-6,7-dihydro-8-(4-hydroxy-1-piperidinyl)-5-methyl-1-oxo-1H,5H-benzo(ij)quinolizine-2-carboxylate)
J Med Chem 2005, 48(16): 5232
WCK 2349: A novel fluoroquinolone (FQ) prodrug-13 week oral (PO) safety profile in cynomolgus monkeys
47th Intersci Conf Antimicrob Agents Chemother (ICAAC) (September 17-20, Chicago) 2007, Abst F1-2133a
ORGANIC SPECTROSCOPY
Glenmark Generics receives final ANDA approval for Telmisartan Tablets
Glenmark Generics receives final ANDA approval for Telmisartan Tablets
Mumbai, India, July 8, 2014
Glenmark Generics Inc., USA a subsidiary of Glenmark Generics Limited has been granted final abbreviated new drug approval (ANDA) from the United States Food and Drug Administration (US FDA) for Telmisartan Tablets. Glenmark will commence distribution of the product immediately.
Telmisartan Tablets are Glenmark’s generic version of Boehringer Ingelheim’s Micardis®. Telmisartan is indicated for the treatment of hypertension.
The approval is for the 20mg, 40mg and 80mg tablets. For the 12 month period ending March 2014, Telmisartan garnered annual sales of USD 250 Million according to IMS Health.
Glenmark receives USFDA approval for telmisartan tablets
Telmisartan, which is the generic version of Boehringer Ingelheim’s Micardis, garnered annual sales of $ 250 million for the 12 month period ending March 2014
Stability Data for ANDAs in the USA: a new Q&A Document of the FDA provides further Clarity
Stability Data for ANDAs in the USA: a new Q&A Document of the FDA provides further Clarity
The applicant for an ANDA in the USA has to submit data of several stability tests. The FDA guidance on this topic coming into force last year left open some issues, however, that now are clarified with a questions and answers document published lately.
Read more.
Stability Data for ANDAs in the USA: a new Q&A Document of the FDA provides further Clarity
The FDA Guidance for Industry with the title “ANDAs: Stability Testing of Drug Substances and Drug Products” was published in the Federal Register on 20 June 2013 (also see our News dated 1 August 2013) and is addressed to applicants for ANDAs in the USA. This guidance describes the stability data the FDA expects in the documents submitted for an ANDA and is rather short having only five pages. As expected, the FDA received vast amounts of questions concerning certain problems that were not answered clearly in the guidance. Therefore, the Agency was prompted to address these questions in a questions and answers document. This document has the title “ANDAs: Stability Testing of Drug Substances and Drug Products – Question and Answers” and was published on the FDA “Guidance”-Website in May 2014.
The questions and answers are addressed in the following five chapters:
- A. General
- B. Drug Master File
- C. Drug Product Manufacturing and Packaging
- D. Amendments to Pending ANDA Application
- E. Stability Studies
Some of the case studies discussed in these chapters are rather complex and therefore are answered in detail. In the following some questions and answers are listed for each chapter by way of example.
A. General
Question: Can an ANDA be submitted with 6 months of accelerated stability and 6 months of long-term stability data?
Answer: Yes. An ANDA applicant should submit this data. However, if 6 months of accelerated data show a significant change or failure of any quality attribute, the applicant should also submit 6 months of intermediate data at the time of submission.
Question: In the event of an adverse change of quality attributes at accelerated condition: When do intermediate stability studies need to be initiated?
Answer: An ANDA applicant should start accelerated, intermediate, and long-term stability studies at the same time so the data are available at the time of submission, if needed.
Question: During the review cycle, will the application need to be updated with 12 months of long-term data?
Answer: Yes. FDA will grant a shelf life period to the drug product of two times the available long-term data at the time of approval (up to 24 months). This is on condition, however, that the submitted stability data are satisfactory, and data evaluation and appropriate commitments are provided. With this the authority follows a recommendation of the Guideline ICH Q1E.
B. Drug Master File
Question: How many months of long-term and accelerated data are required when a “Completeness Assessment” is performed on the Drug Master File? Also, what should the stability section contain for a Completeness Assessment?
Answer: To pass the Completeness Assessment, the DMF should include the stability protocol and commitments. It also should contain data demonstrating that stability studies have started. The initial and one additional time point for the accelerated studies and long-term studies are sufficient. If the DMF does not meet the requirements for a successful assessment (see the following question/answer) the DMF holder must hand in updated stability data later.
Question: Are stability data from three current good manufacturing practice (CGMP) batches required to be filed in the DMF to support the active pharmaceutical ingredient retest date? How many months of long-term and accelerated data are required for pilot scale batches?
Answer: Yes. The DMF should contain data from stability studies on at least three primary batches of the API (these batches should be made under cGMP conditions) and the batches should be manufactured to a minimum of pilot scale (also see ICH Q1A(R2)).
The FDA stability guidance recommends 6 months of accelerated data and 6 months of long-term data for the pilot scale batches to be submitted for a full scientific review of the DMF. Additional long-term data for all three batches, as the data becomes available through the proposed retest period, should be submitted as an amendment.
C. Drug Product Manufacturing and Packaging
Question: What is the Agency’s position on using different lots of APIs and/or packaging materials? How many API lots should be used in the manufacture of finished product lots used to support the ANDA?
Answer: It is not necessary to use different lots of packaging material, except in cases where the packaging material could affect drug product performance and/or delivery.
A minimum of two lots of the drug substance should be used to prepare the three primary batches of drug product. For nasal aerosols and nasal sprays, you should use three different lots of drug substance.
Question: Should the small scale batches be packaged with commercial equipment? Is it acceptable to package using research equipment?
Answer: Yes. Small scale batches should be packaged with commercial equipment. Anyway, the packaging equipment should be similar to that proposed for use prior to market distribution.
No, it is not recommended to package small scale batches using research equipment or by hand. …
D. Amendments to Pending ANDA Application
Question: What are the recommendations for amendments and responses filed to pending ANDAs after issuance of the final FDA stability guidance?
Answer: All amendments submitted to pending ANDAs after the effective date of the final FDA stability guidance will be held to the standards in place concerning stability data at the time of the original ANDA submission, unless there is a concern with the submitted stability data.
E. Stability Studies
Question: Can the Agency clarify expectations for the storage positions for products placed into the stability program?
Answer: For primary batches of liquids, solutions, semi-solids, and suspensions, the product should be placed into an inverted (or horizontal) position and an upright position. For routine stability studies, the applicant should pick the worst case orientation for the study.
Question: Can the Agency clarify expectations around the number of batches to support tests such as preservative effectiveness and extractable leachable testing?
Answer: One of the primary batches of the drug product should be tested for antimicrobial preservative effectiveness (in addition to preservative content) at the end of the proposed shelf life. The drug product specification should include a test for preservative content, and this attribute should be tested in all stability studies.
Extraction/leachable studies are generally one-time studies. However, if multiple types of containers/closures are employed for packaging, then additional studies could be recommended.
The FDA tries to clarify the cases described in this Q&A document as clear and as much in detail as possible. In doing so the Agency complements its declarations by numerous indications concerning the provisions in the ICH guidelines Q1A(R2), Q1D, Q1E and in 21 CFR Part 211. Thereby, this very important and updated document covers most situations with regard to stability testing for ANDAs.
