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.
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.
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.
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.
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”.
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…
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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