Prediction of Drug Degradation Pathways leading to Structural Alerts for Potential Genotoxic Impurities


An in-depth analysis of the web-based CambridgeSoft Pharmaceutical Drug Degradation Database, Pharma D3, was conducted in two phases in an attempt to generate some general rules for the prediction of alerting structures for genotoxicity that may arise as a result of degradation. The first phase involved interrogation of the database to determine the nature and frequency of alerting structures present in the degradants. This analysis revealed five functional groups, which account for approximately 70% of the alerting structures found in the degradants within the database: (1) aldehydes; (2) α,β unsaturated carbonyls; (3) aromatic amines, hydroxylamine and its derived esters; (4) epoxides; and (5) polyaromatic hydrocarbons. The second phase of the analysis involved categorizing the major chemical reactions responsible for the generation of the five most prevalent alerting structures. This two-step approach led, in turn, to a proposal for the prediction of functional groups that may have a propensity to degrade to alerting structures not necessarily present in the parent molecule.

Prediction of Drug Degradation Pathways leading to Structural Alerts for Potential Genotoxic Impurities

Stephen P. Raillard, Joel Bercu, Steven W. Baertschi and Christopher M. Riley
Org. Process Res. Dev., 2010, 14 (4), pp 1015–1020
Publication Date (Web): April 21, 2010 (Article)
DOI: 10.1021/op100007q

Risk Assessment of Genotoxic Impurities in Marketed Compounds Administered over a Short-Term Duration: Applications to Oncology Products and Implications for Impurity Control Limits


Controlling impurities during drug development improves product quality and minimizes safety risks to the patient. Recent regulatory guidance on genotoxic impurities (GTIs) state that identified GTIs are unusually toxic and require lower reporting, identification, and qualification limits than outlined in the International Conference on Harmonization (ICH) guideline “Impurities in New Drug Substances Q3A(R2).” [ ICH Harmonized Tripartite Guideline: Impurities in New Drug Substances (Q3A), (R2); International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH), 2006.] Patient safety is always the underlying focus, but the overall impurity control strategy is also driven by appropriate “as low as reasonably practicable” (ALARP)(2)procedures that include assessment of process capability and associated analytical techniques. In combination with ALARP, safe and appropriate GTI levels are currently identified using chronic toxicology-based limits calculated under the standard assumption of 70-years for exposure duration. This paper proposes a risk assessment approach for developing GTI limits based on shorter-term exposure durations by highlighting marketed anticancer compounds with limited dosing schedules (e.g., 2 years). These limits are generally higher than the defaulted threshold of toxicological concern (TTC of 1.5 μg/day) and can result in more easily developed and less complex analytical methods. The described approach does not compromise safety and can potentially speed life-saving medicines to patients.

Org. Process Res. Dev., 2010, 14 (4), pp 986–992
Publication Date (Web): June 7, 2010 (Concept Article)
DOI: 10.1021/op1000226

Authorisation of Generic Drugs in the USA: Requirements on APIs Stability Data for US Drug Master Files

Authorisation of Generic Drugs in the USA: Requirements on APIs Stability Data for US Drug Master Files
According to the new Generic Drug User Fee Act (GDUFA) for the marketing authorisation of generic drugs in the USA, the Drug Master File (Type II) for APIs must undergo a completeness assessment (see our GMP News from 11 October 2012). The approach is described in the Draft Guidance for Industry entitled “Initial Completeness Assessment for Type II API DMFs under GDUFA” from October 2012.

Which information about the stability of the API contained in a generic drug is required in a Drug Master File submitted for a marketing authorisation application? The answers to this question can be found in a Q&A document published by the FDA on 26 August 2013 entitled “Guidance for Industry; ANDAs: Stability Testing of Drug Substances and Products; Questions and Answers“. This Q&A document refers to the “Guidance for Industry; ANDAs: Stability Testing of Drug Substances and Products” which was released 2 months before and tackles a range of outstanding issues with regard to stability data of APIs and finished products for the marketing authorisation application of generic products.

The statements laid down in the Q&A document regarding the stability data of the API required in a DMF are explicit: in addition to the stability protocol and commitments, data demonstrating the beginning of stability studies have to be provided. The initial and one additional time point for the accelerated studies and long-term studies are sufficient. Yet, the DMF holder should provide amending data to keep the DMF as up-to-date as possible. This is the only way to ensure the successful completeness assessment by the reviewer in the Office of Generic Drugs (OGD) of the FDA. Furthermore, stability data from production scale batches are also accepted. Three production batches are necessary. The data must come from 6 months of accelerated data and long-term data covering the proposed retest period.

The Q&A document contains a range of other interesting clarifications like for example a concrete explanation of the term “small scale” with regard to the various dosage forms.

How to submit an Active Substance Master File?

How to submit an Active Substance Master File?

The Active Substance Master File (ASMF) describes the quality of an API and is an essential document for the marketing authorisation of medicinal products. The procedure to submit an ASMF has been recently updated and described extensively in a new EMA Q&A document. Read more about the newest provisions.

How to submit an Active Substance Master File?
As part of the authorisation procedure for a medicinal product, applicants have to provide detailed information about the quality of the API. Generally, the applicant doesn’t manufacture the API himself but receives it from an API manufacturer and has to submit  the quality-related information regarding the API directly to the authority (see Directive 2001/83/EC, Annex I) in a separate document: the “Active Substance Master File” (ASMF, former name: “European Drug Master file”). An ASMF is always composed of two parts: the “open” part (applicant’s part) which doesn’t contain any confidential information and is known by the applicant – and the “closed” part which is much more detailed and represents the manufacturer’s know-how with regard to the manufacture of the API and its analytics. For the competent authority, this closed part of the ASMF represents the basis for the assessment of the API’s quality and safety in the context of the proceeding of the marketing authorisation application.Although this procedure has been established for several years now, there are time and again uncertainties regarding certain points. In the Question and Answer document entitled “Pre-authorisation Procedural Advice for Users of the Centralised Procedure” (EMA/339324/2007) which has been recently revised and published in December 2013, the EMA covers the topic extensively under Question No 24 “How shall I submit an Active Substance Master File”. The answer to this question is treated in 7 pages which were also revised in December 2013 and are thus up-to-date. There are in total 9 sub-chapters dealing with the following issues:

  • 24.1. What data should be submitted by the ASMF holder?
  • 24.2. What data should be submitted by the applicant or MAH?
  • 24.3. What is the EMEA/ASMF reference number?
  • 24.4. Who should request an EMEA ASMF reference number?
  • 24.5. When and how to request an EMEA ASMF reference number?
  • 24.6. EMEA ASMF or EU ASMF reference number?
  • 24.7. Which format and submission channel should be used for submitting ASMFs?
  • 24.8. How to proceed if the ASMF was previously submitted in paper format?
  • 24.9. How to proceed if there is an existing eCTD life-cycle for the ASMF?

The issues dealt with within the sub-chapters indicate how urgent the update of the Question and Answer document was. Indeed, there are now two numbering systems for ASMFs: EU’s ASMF reference number and EMEA’s ASMF reference number. Whereas EU’s ASMF number is used for centralised, decentrialised as well as national authorisation procedures, an EMEA’s reference number has to be applied for in case of new applications or variation applications which are submitted after the 1st September 2013 (possibly in addition to an already existing EU ASMF number). This is a requirement from the “Guideline on Active Substance Master File Procedure” dated 1st October 2012. The Question and Answer document should now help avoiding confusion with regard to applications, the two numbering systems and life-cycle management.

Further clarifications concern the framework of the ASMF procedure. The API has to be “well defined” in an ASMF. Biological APIs used in vaccines or cell therapeutic medicines or APIs obtained from blood are not “well defined” chemical entities in this sense and thus the ASMF procedure is not applicable to them.

6 Drugs Whose Dangerous Risks Were Buried So Big Pharma Could Make Money

New meds are rushed to the market so industry can start making money even before safety has been determined.
January 15, 2014  |

Editor’s note: The following article is a follow up to a previous AlterNet piece about drugs whose dangerous side-effects emerged only after the pharmaceutical industry’s patents ran out.


Most Influential Blogger Award, thanks Brigid and Eye-Dancers!

Dear Kitty. Some blog

Most Influential Blogger Award

Thank you, Brigid of the blog aristonorganic, and Eye-Dancers of the blog Eye-Dancers for nominating this blog for the Most Influential Blogger Award!

The rules of this award are:

1. Add the award logo to your blog.

2. Answer the following questions.

3. And pass the award on to 11 other blogs and let them know.


1) What makes you happiest?

Seeing birds.

2) Do you love the Oceans or Mountains more?

I love mountains near oceans 🙂

3) What has been a special moment in 2012?

My journey to the Gambia.

4) What’s your favorite quote?

“The great appear great to us, only because we are on our knees: LET US RISE.” By James Connolly. Written in 1897, but still very fitting in 2013.

5) Do you like yourself?


6) Do you stay up till midnight on New Year?


7) Something…

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Glenmark conferred with Best Biotech New Molecular Entity Patent award

New Drug Approvals


IDMA best biotech NEW MOLECULAR ENTITY patent award to Glenmark

YEAR 2012-2013 YEAR in Mumbai India

PATENT  US 8236315



Elias LazaridesCatherine WoodsXiaomin FanSamuel HouHarald MottlStanislas BleinMartin BertschingerALSO PUBLISHED ASCA2712221A1CN101932606A,EP2245069A1US20090232804,WO2009093138A1
Publication numberUS8236315 B2
Publication typeGrant
Application numberUS 12/358,682
Publication date7 Aug 2012
Filing date23 Jan 2009
Priority date23 Jan 2008

USPTOUSPTO AssignmentEspacenetUS 8236315

The present disclosure relates generally to humanized antibodies or binding fragments thereof specific for human von Willebrand factor (vWF), methods for their preparation and use, including methods for treating vWF mediated diseases or disorders. The humanized antibodies or binding fragments thereof specific for human vWF may comprise complementarity determining regions (CDRs) from a non-human antibody (e.g., mouse…

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FDA Warns Against High-Dose Acetaminophen : severe liver injury with acetaminophen

TGI: Thrive Health

The U.S. Food and Drug Administration (FDA) is recommending health care professionals discontinue prescribing and dispensing prescription combination drug products that contain more than 325 milligrams (mg) of acetaminophen per tablet, capsule or other dosage unit.

“Limiting the amount of acetaminophen per dosage unit will reduce the risk of severe liver injury from inadvertent acetaminophen overdose, which can lead to liver failure, liver transplant and death.”

Cases of severe liver injury with acetaminophen have occurred in patients who:
  • took more than the prescribed dose of an acetaminophen-containing product in a 24-hour period;
  • took more than one acetaminophen-containing product at the same time; or
  • drank alcohol while taking acetaminophen products.


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Helping keep pharmaceuticals safe:metal detection overview and guidelines

Sanjay Muley uploaded a file in the group Global Pharma Connection.
Helping keep pharmaceuticals safe:metal detection overview and guidelines :
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New Drug Approvals


105826-92-4 (HCl)

 ICF 205-930, Navoban™
Molecular Formula: C17H20N2O2   Molecular Weight: 284.3529

Novartis (Originator)

Tropisetron (INN) is a serotonin 5-HT3 receptor antagonist used mainly as an antiemetic to treat nausea and vomiting following chemotherapy, although it has been used experimentally as an analgesic in cases of fibromyalgia.[1] The drug is available in a 5 mg oral preparation or in 2 mg intravenous form. It is marketed by Novartis in Europe, Australia, New Zealand, Japan, South Korea and the Philippines as Navoban, but is not available in the U.S. It is also available from Novell Pharmaceutical Laboratories and marketed in several Asian countries as Setrovel

Tropisetron is a 5-hydroxytryptamine receptor 3 (5-HT3) antagonist that was launched in 1992 by Novartis for the oral and injection treatment of chemotherapy-induced emesis. The drug has also been approved for the prophylaxis and treatment…

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