FDA Approves Spiriva Respimat (tiotropium) for the Maintenance Treatment of COPD

New Drug Approvals

Ridgefield, Conn., September 25, 2014 – Boehringer Ingelheim Pharmaceuticals, Inc. announced today that the U.S. Food and Drug Administration (FDA) approved Spiriva Respimat (tiotropium bromide) inhalation spray for the long-term, once-daily maintenance treatment of bronchospasm associated with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and emphysema and to reduce exacerbations in COPD patients. Boehringer Ingelheim anticipates Spiriva Respimat to be available in January 2015.

Spiriva Respimat provides a pre-measured amount of medicine in a slow-moving mist that helps patients inhale the medicine. Spiriva Respimat was developed to actively deliver medication in a way that does not depend of how fast air is breathed in from the inhaler.







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QP Declaration: EMA publishes Comments

QP Declaration: EMA publishes Comments


More than three years ago, the EMA has published two draft documents for a template for the QP’s declaration concerning GMP compliance of the API used as starting material and verification of its supply chain called “The QP declaration template“:

1. The draft template for the Qualified Person’s declaration


2. the respective draft Q&A on the template for the Qualified Person’s declaration

The QP Declaration should be provided in support of an application for a new marketing authorisation, variation or renewal of a medicinal product(s) authorised in the Community, using EU or national procedures within the scope of the respective Directives.

The consultation for the template ended on 30 April 2011. In June 2014, the final version was published together with a template guidance. Now, three months after publication of the final document, the comments from 2011 have been published.

The answers to these comments also give some useful and interesting background information on EMA’s expectations when it comes to API supplier auditing and qualification.

The 93 page document shows that some comments provided by the various interest groups – like the European QP Association – have been taken into consideration, and a few suggestions for improvement have been implemented. When it comes to audit information, fewer details are requested now. Confirmation of the supply chain traceability has been deleted; the API “supply chain should be established, qualified and documented and addressed through GMP”.

The wording of the draft declaration ”I have evaluated each of the named contract acceptors… …. Audit(s) was/were conducted by properly qualified and trained staff….” has been changed to a more formal phrase, not implying the necessity for a personal check by the QP.

But EMA also declined many industry proposals for the QP Declaration:

Some stakeholders thought that most of information being requested in the template should be part of GMP audit or supplier qualification programme rather than to inclusion in a regulatory dossier submission. But the template is still part of the regulatory submission. And EMA still considers a maximum three year period for API audits as good practice. Exceptions to this standard might only be possible on a case by case basis, which cannot be generalised.

The wish that GMP certificates from a relevant Competent Authority can replace audits by the company will remain a wish. EMA refers to its Q&A document*  where it is stated that audits should be performed by or on behalf of the Marketing Authorisation Holder or acceptable third party auditors. However “API manufacturing sites, which have been inspected by an EU Competent Authority and found GMP non-compliant, should not be used as sources of API”. Audits by accredited audit bodies who audit on behalf of the contract acceptor are also not accepted. Furthermore the API supplier needs to be assessed and deemed satisfactory before purchase of the material. Only in exceptional cases, e.g. atypical actives, where the QP Declaration is not based on an on-site audit, then other documentation (not the QP template) will need to be submitted according to the guidance document and considered on a case by case basis. It will be possible to share API audits and audit reports, if supported by appropriate contract arrangements.

The fear of the European QP Association and other stakeholders, that disclosing (internal) audit reports during inspections by the Competent Authorities might trigger a process of parallel audit reports (one for the official part to show during inspection and in parallel a second one used internally) was not acknowledged. So GMP inspectors might request these audit reports during regulatory GMP inspections.

The request for a sufficient transition period of 24 months for the implementation of the QP declaration was declined (“not considered necessary”).

EMA emphasises that the QP Declaration should cover the designated starting material, as shown in the summary of the route of synthesis given in the DMF. Some stakeholders thought it might be better to refer to an Active Substance Master File (ASMF) and limit the QP Declaration only to the API manufacturing site involved in the last quality relevant manufacturing step.

* Q&A: Good Manufacturing Practice (GMP), EU GMP guide part II Basic requirements for active substances used as starting materials: GMP compliance for active substances (Q2)

Pharmaceuticals; Make in India

New Drug Approvals

Indian PM Narendra Modi: Understanding an enigma PM,  MODI
Brand India Pharma aims to make the most of a booming domestic pharma industry
India’s pharma exports stood at 90,000 crore rupees ($15 billion) for the year 2013-2014, and are set to cross the 1 lakh crore rupees ($16.4 billion) mark in the current financial year. The Brand India Pharma campaign aims to tap into this value proposition, under the guidance of the Indian Ministry of Commerce and Industry, aiming to showcase the strengths of the Indian pharma industry.

With more than 10,500 manufacturing units and more than 3,000 pharma companies, India is ranked among the top six producers of pharmaceuticals worldwide, and is well-positioned to take advantage of its place in a global landscape.



List of WHO Approved Pharma Plant in India


India’s spacecraft cost $74 million, a fraction of the $671 million spent by NASA’s MAVEN ……….SEPT 24 2014

Indian Pharma Sector

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WHO publishes New Version of the Draft on “Hold-Time” Studies

WHO publishes New Version of the Draft on “Hold-Time” Studies


The 2nd revision for comment was published already in February this year (we reported). Now, a 3rd version is available – also for comment. The document describes the design of hold-time studies for the determination of time limits which have to be determined according to the generally applicable intermediate and bulk products. This should avoid that the storage of intermediate or bulk products from having any negative influence on their quality or the quality of a finished before processing to the next stage.

Chapter 2 which defines what intermediate and bulk products are has been added. It is now explicitly pointed out that hold-time investigations are part of the process validation. In turn, the reference to retrospective observation has been removed from the current version as well as – fortunately – the incomprehensible paragraph on the ‚most probable / worst case approach’.

Still, the different stages of production are explained with the example of solid forms. A flow chart for better understanding has been newly added.

The second part of the last chapter has been completely revised. In the second version, it contained proposals for hold-times of different process materials (in contradiction with the statement according to which data have to be collected for the determination). The quite vague information about cumulated hold-times has also been removed. Instead, the new version now contains a table with proposals of stages and respective tests that may be considered to certain study times.

Revision 3 of the draft can be found in the Members Area.

How to identify Out-of-Trend Results in Stability Studies?


How to identify Out-of-Trend Results in Stability Studies?

An article in PharmTech from June 2013 (by Trajkovic-Jolevska et. al) deals with the methods to identify Out-of-Trend (OOT) results in ongoing stability studies.

With regard to stability studies, it is important to make the difference between Out-of-Specification (OOS) and Out-of-Trend (OOT). Both the pharmaceutical industry and authorities often misuse these two terms.

The article defines OOT results as those results which don’t follow the expected trend, either in comparison with other stability batches or compared to previous results collected during a stability study. OOT results aren’t necessarily OOS, but they don’t look like a typical data point.
Although OOT results are a serious problem, neither the scientific literature nor regulatory guidelines fully address them.

The aim of the study described in this Pharmtech article by Trajkovic-Jolevska et. al was to perform a statistical evaluation of the statistical methods used in the identification of OOS results.

The authors of this article present 4 statistical methods for the identification of OOT results:
•The regression control-chart-method
•The by-time-point method
•The slope-control-chart method
•The z-score method

The conclusion of this article is the statement that there is a tremendous need for a regulatory Guideline on OOT results in stability studies. This is exactly the next objective of ECA’s QC working group: an SOP on the handling of OOT results. On 22-23 October 2014, the OOT Forum in Prague will present the Draft of ECA’s SOP on OOT results.

The complete article can be found with the title “Methods for Identifying Out-of-Trend Results in Ongoing Stability Data”.


Australia: Orphan Drug Designation For Kalydeco + Lumacaftor For Cystic Fibrosis

Orphan Druganaut Blog

Australia’s Therapeutic Goods Administration (TGA) on September 22nd, designates Lumacaftor (VX-809) as an orphan drug in combination with Kalydeco (Ivacaftor), for the treatment of Cystic Fibrosis (CF) in patients who are homozygous for the F508del mutation in the CFTR (Cystic Fibrosis Transmembrane Conductance Regulator) gene.

The combination of Lumacaftor + Kalydeco has the following Orphan Drug Designations:

•   FDA ODD in June 2014

•   EMA COMP recommendation in July 2014.

At the upcoming North American Cystic Fibrosis Conference (NACFC), October 9-11 in Atlanta, Vertex Pharmaceuticals will present the following Abstracts on the Phase III TRAFFIC and TRANSPORT studies of Lumacaftor in combination with Kalydeco (Ivacaftor), in CF patients with two copies of the F508del mutation:

•   “Effect of Lumacaftor in combination with Ivacaftor in patients with cystic fibrosis who are homozygous for F508del-CFTR: Phase 3 TRAFFIC & TRANSPORT studies.” An oral presentation of these data will be delivered as…

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EU OK’s Gilead’s rare blood cancers drug

New Drug Approvals

EU OK's Gilead's rare blood cancers drug

SEPT 21 , 2014

Patients with the incurable blood cancers chronic lymphocytic leukaemia (CLL) and follicular lymphoma (FL) have gained access to a new treatment option in Europe with the approval of Gilead’s Zydelig (idelalisib).

For CLL, the drug can now be used alongside Rituxan (rituximab) in patients who have received at least one prior therapy, and it has also been green lighted for first-line use in those carrying a 17p deletion or TP53 mutation who are unsuitable for chemo-immunotherapy.




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Glenmark’s TRPA1 antagonist ‘GRC 17536’ shows positive data in a proof of concept study

New Drug Approvals

MUMBAI, India, Sep 17, 2014

- Glenmark's first in class TRPA1 antagonist, GRC 17536, has shown positive data in a Phase 2a proof of concept study in patients with painful diabetic neuropathy

Glenmark Pharmaceuticals today announced that its first in class Transient Receptor Potential Ankyrin 1 (TRPA1) antagonist, GRC 17536 has shown positive data in a Phase 2a double blind, placebo controlled, multi-centre, proof of concept study conducted on 138 patients in Europe and India.

A statistically significant and clinically relevant response was seen in a prospectively-identified, substantial sub-group of patients with moderate to severe pain who had relatively intact sensory responses as detected by a standardized testing methodology. GRC 17536 was well-tolerated with no evidence of CNS or other drug related side effects.

Patrick Keohane, Chief Medical Officer, Glenmark stated “Diabetic neuropathy remains a difficult to manage chronic clinical condition with limited therapeutic options. These initial efficacy and safety…

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Complaints and Recalls: new EU-GMP Chapter 8 published

GMP News: Complaints and Recalls: new EU-GMP Chapter 8 published


the European Commission has published the final Chapter 8 of the EU Guidelines for GMP (Complaints, Quality Defects and Product Recalls). The chapter has been revised completely. Whereas the current one has less than two pages focusing on complaints and recalls only, the revision is six pages long, defining expectations for:

  • Personnel and Organisation
  • Procedures for handling and investigating complaints including possible quality defects
  • Investigation and Decision Making
  • Root Cause Analysis and Corrective and Preventative Actions
  • Product Recalls and other potential risk-reducing actions

Throughout its chapters, the new version of Chapter 8 introduces Quality Risk Management principles and appropriate root cause analysis work when investigating quality defects and complaints. The scope includes complaints including quality defects (this is also new) and recall issues with respect to marketed medicinal products and investigational medicinal products (IMPs) that have been released to clinical trials. The new chapter 8 is better aligned with the wording of Directive 2003/94/EC with regard to when a quality defect/complaint should be reported to the competent authority.

Besides investigating and determining the cause(s) of quality defects/complaints, the revised chapter 8 also wants to ensure that appropriate corrective and preventative actions are put in place to avoid recurrence of the issue. CAPA has already been introduced in the revision of chapter 1 and is now also be recognised in chapter 8. The effectiveness “should be monitored and assessed”.

When it comes to product recalls, the new chapter also addresses risk mitigation and risk-based thinking into the recall decision-making process. In this context, the Manufacturer and Marketing Authorisation Holder shall ensure continuity of supply for critical medicinal products where alternative products may not be readily available. Consultation with the Competent Authority is inevitable.

The Qualified Person (QP) who is involved in the certification for release of the concerned product will play an important role. If the QP is not directly responsible for managing complaint and quality defect investigations and for deciding the measures to be taken, he or she “should be made formally aware of any investigations, any risk-reducing actions and any recall operations, in a timely manner”. For all respective actions like for example handling, reviewing and investigating complaints, sufficient personnel and resources should be made available.

The revised chapter details the requirements for written procedures like SOPs. They should at least address the following:

  • The description of the reported quality defect.
  • The determination of the extent of the quality defect.
  • Handling of samples
  • The assessment of the risk(s) posed by the quality defect.
  • How decisions and assessments are made
  • Notification to the relevant authorities and other internal and external communications
  • Root cause analysis and CAPAs.

There should also be established written procedures in relation to recall activities or the implementation of any other risk-reducing actions, so that recall operations can be initiated promptly and at any time.

So called Mock Recalls are now also described in more detail. Evaluations of the effectiveness “should extend to both within office-hour situations as well as out-of-office hour situations and, when performing such evaluations, consideration should be given as to whether mock-recall actions should be performed. This evaluation should be documented and justified. ”

Overall, the goal is to achieve information-based and scientific decisions in relation to risk-mitigating actions. It should also be highlighted that there may be more than one cause associated with a quality defect/complaint. However all likely causes should be thoroughly investigated leading to more effective preventative actions being identified and put in place.

To find more details please see the final Chapter 8: Complaints, Quality Defects and Product Recalls.

If a Facility stores Medicinal Products for more than 36 Hours GDP will apply

GMP News: If a Facility stores Medicinal Products for more than 36 Hours GDP will apply


Since the EU Good Distribution Practice (GDP) Guide has been revised, a number of questions regarding its interpretation have been raised. One of these questions relates to storage facilities and so called distribution hubs. In the past, many facilities which have been involved in the supply chain were not managed under GDP and didn’t posses a licence for their activities.

The British Medicines Authority MHRA published a press release on 18 August 2014 to explain what they consider to be a facility which must be licensed and which needs to implement the GDP requirements. According to the MHRA: “The GDP Inspectorate is raising awareness of the impact of the new regulations to those parties that are either directly or indirectly affected and any freight consolidator or freight forwarder either in the air, sea or road transport sector that is either holding ambient medicinal products on site for more than 36 hours or has cold room facilities will require a Wholesale Distribution Authorisation WDA(H) in order to comply with the Human Medicines Regulations 2012 [SI 2012/1916] (as amended) and with the Falsified Medicines Directive 2011/62/EU.”

Source: MHRA Press Release: MHRA position on freight consolidation depots (freight forwarders)

FDA publishes ICH Q4B – Annex 6 on Uniformity of Dosage Units

GMP News: FDA publishes ICH Q4B – Annex 6 on Uniformity of Dosage Units


On 16 June 2014, the FDA published the ICH harmonised Guideline entitled “Evaluation and Recommendation of Pharmacopoeial Texts for Use in the ICH Regions on Uniformity of Dosage Units General Chapter (Q4B Annex 6)”. This ICH Guideline thus came into force in the USA, too.

The objective of the ICH Q4B Working Group is to reach mutual recognition by regulatory authorities in the ICH regions for all testing methods listed in the ICH Q6A Guideline on Specifications. Through this, comparable testing laid down in the different pharmacopeias shouldn’t be performed separately when it has been assessed by the authorities that those are similar and interchangeable.

The Annex 6 states that the following official texts :

  • Ph.Eur. 2.9.40 (Uniformity of Dosage Units
  • JP 6.02 Uniformity of Dosage Units
  • USP General Chapter <905> Uniformity of Dosage Units

can be used as interchangeable. Nevertheless, certain restrictions listed under the section “Analytical Procedures” have to be considered.

To get more details please see the complete FDA “Q4B – Annex 6 Uniformity of Dosage Units General Chapter“.

PS: At the QbD/PAT Conference from the University of Heidelberg from 15-16 October 2014, Dr Øyvind Holte from the Norwegian Medicines Agency will present the uniformity of dosage units using large sample sizes (Ph.Eur. 2.9.47). Dr Øyvind Holte is a member of both the EDQM PAT working party and the EMA PAT team.

Piramal Drops Drug Discovery,…………. Pharmaceuticals: Risks and regulations convince the Indian company to reallocate resources

New Drug Approvals

A Piramal scientist at work in Mumbai last month.
Credit: Danish Siddiqui/Reuters/Newscom

In a move that raises questions about the future of drug research in India, Piramal Enterprises will end its drug discovery activities. The decision—which involves possible job losses—will affect several hundred scientists, many of whom were recruited internationally to work in Mumbai in one of India’s most sophisticated pharmaceutical labs.
The company has been considered an Indian leader in drug research since opening its discovery labs in 2004. Within the firm, drug discovery was championed by the vice chairman, Swati A. Piramal, a medical doctor who also holds a master’s degree from the Harvard School of Public Health.
“After reevaluating the risk-benefits of new chemical entity research, the company decided to focus resources on our other areas of R&D with shorter development timelines and different risk profiles,” Piramal tells C&EN.

read all at


Piramal Enterprises, which sold…

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