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Publication of HMPC Documents on Essential Oils
Publication of HMPC Documents on Essential Oils |
| Essential oils used as API in herbal products lead to – from a regulatory view – a wide range of questions. At the moment, there is no EMA/HMPC Guideline. Now, the final “Reflection Paper” has been published. Moreover, current questions and answers about essential oils have been added to a Q&A document. Read more in the News. |
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Publication of HMPC Documents on Essential Oils |
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At the beginning of May 2014, the EMA’s HMPC (Committee on Herbal Medicinal Products) published the final “Reflection Paper” on quality of essential oils used for the manufacture of herbal medicinal products/traditional herbal medicinal products. The document was adopted on 25 March by the HMPC. This “Reflection Paper” should help consider aspects related to the nature and the specific production processes of essential oils. Moreover, the current HMPC quality guidelines don’t take into consideration the definitions of essential oils as laid down in the European Pharmacopoeia (Ph. Eur.). Essential oils used as API in herbal products lead to – from a regulatory view – a wide range of questions, especially as the current guidelines incompletely depict the specific aspects of essentials oils. In addition, a Q&A document containing questions and answers on herbal medicinal products/traditional herbal medicinal products was published on 30 April 2014. Four new questions and answers about essential oils have been added to this Q&A document. For more detailed information please see the complete “Reflection paper on quality of essential oils as active substances in herbal medicinal products/taditional herbal medicinal products” as well as the extended Q&A document “Questions & answers on quality of herbal medicinal products/traditional herbal medicinal products |
Pharmaceutical Packaging – New USP Proposal for Optimised Method of Measuring Moisture Vapour Permeation
| Pharmaceutical Packaging – New USP Proposal for Optimised Method of Measuring Moisture Vapour Permeation |
| An improved method of measuring water vapour permeation for solid oral dosage forms like tablets or capsules has been discussed during a USP – PQRI Workshop and presented in the Pharmacopeial Forum. See the detailed information. |
Revision of the USP Chapter on Spectroscopic Methods
| Revision of the USP Chapter on Spectroscopic Methods |
| A new concept for the representation of different analytical and spectroscopic methods (AAS, IR, UV, etc.) has been presented as general chapter in the USP. In the future, there should be two general chapters for each method. The concrete implementation is planned in the USP38/NF33. Read more here in the News. |
GMP News: Revision of the USP Chapter on Spectroscopic Methods
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EMA publishes New Process Validation Guideline
EMA publishes New Process Validation Guideline
After the publication of the Annex 15 draft at the beginning of February 2014, the EMA made a move towards the revision of its process validation guideline. The final document was published on 27 February 2014. For a long time now, the EMA had already announced this revision in a concept paper. What’s new? click here
After the publication of the Annex 15 draft at the beginning of February 2014, the EMA made a move towards the revision of its process validation guideline. The final document was published on 27 February 2014. For a long time now, the EMA had already announced this revision in a concept paper. The objective of the revision was to integrate modern GMP aspects:
- Integration of the ICH Q8, Q9 and Q10 Guidelines
- Incorporation of Process Analytical Technology (PAT), Quality by Design (QbD) and Real-Time Release Testing (RTRT).
- Extension with regard to an “enhanced approach” and integration of “continuous process verification”
- Integration of the Annexes to the current Note for Guidance
- Harmonisation with the current FDA Guidance on Process Validation
The deadline for comments on the draft for the revision of the process validation guideline ended in October 2012 already. Now, elements in accordance with the Annex 15 have also flowed into the final document. In the following, you will read a short evaluation of the document with regard to the original draft from March 2012, the (still) applicable Note for Guidance on Process Validation and FDA’s Guidance on Process Validation. The GMP relevant aspects of the documents will also be addressed.
The original 7-page long Note for Guidance on Process Validation has more than doubled and now contains 15 pages. Even the original revision draft had only 11 pages. The change in the title to “Guideline on process validation for finished products- information and data to be provided in regulatory submissions” is noticeable. The title itself gives indication about the content of the document, namely marketing authorisation matters.
Like in the draft, the document is composed of 8 numerated chapters, a summary, definitions, references, an Annex I (Process validation scheme) and an Annex II (Standard/non-standard processes) which is a new part compared to the draft. A sub section on “Design space verification” has been newly added to the chapter on process validation.
There haven’t been big changes to the draft document released in 2012. Only the chapter “Design space verification” is brand new, all other parts have been mostly updated. The chapter on ongoing process validation has been removed. Compared to the draft, indications about standard/ non-standard processes are now available in the Annex II – like in the currently applicable Note for Guidance.
What are the changes to the currently applicable Note for Guidance on Process Validation?
Compared to the current Note for Guidance, the revision remains in its final version pretty difficult to read and rather general. This is a marketing authorisation document, which is clearly addressed in the title and only applies to finished dosage forms of chemical medicinal products for human and veterinary use but not for old ones, which are already authorised and on the market. The introduction of a validation life cycle and the integration of continued process verification (CPV) are completely new although this approach is already acquainted from ICH Q8. The “traditional approach” remains accepted. Like in the Annex 15 draft the hybrid approach remains here in the final document “nebulous”. The idea to integrate modern elements from ICH Q8, Q10 (and Q11) into the document is clearly noticeable. Yet, far less concrete references are made to ICH Q9.
A stronger overlap of the FDA Guidance would have been desirable. FDA’s Guidance also deals with APIs and biologicals, and the process validation life cycle runs like a thread through the whole FDA document. FDA’s Guidance also contains GMP aspects. The FDA Guidance explicitly addresses old products which should be integrated to stage 3 of the life cycle. Yet, there is another big difference. The revised document doesn’t highlight statistical methods like the FDA Guidance.
Before the finalisation, a comparison with the Annex 15 has been made which is a nice thing. This explains the long period between the publication of the draft (March 2012) and that of the finalisation (February 2014).
What is significant for the GMP world? On the one hand almost nothing, on the other hand quite a lot: one may wonder why? Direct references to the Annex 15 can be found with regard to the “ongoing process verification” and “concurrent validation”, which is almost nothing looking at the whole document. Moreover, validation in general is required to be executed according to the GMP regarding “continuous process verification” and “change control”; these are the essential parts of the document, and (almost) the complete document should therefore be seen from a GMP perspective.
The new EMA guideline on process validation will apply by the end of August 2014.
FDA Secure Supply Chain Pilot Program: 13 companies prequalified
FDA Secure Supply Chain Pilot Program: 13 companies prequalified
In August 2013, the FDA initiated the so called Secure Supply Chain Pilot Program (SSCPP) to enhance the security of imported drugs. Now, the first companies have been listed. Read more.
In August 2013, the U.S. Food and Drug Administration (FDA) initiated the so called Secure Supply Chain Pilot Program (SSCPP) to enhance the security of imported drugs.
The goal was to enable qualified firms to expedite the importation of active pharmaceutical ingredients and finished drug products into the United States.
With this program, FDA wants to better focus its imports surveillance resources on preventing the entry of high-risk drugs that are the most likely to compromise the quality and safety of the U.S. drug supply.
The SSCPP is a voluntary program. Each firm accepted to participate in the program will be allowed to have up to five drugs subject to expedited import entry review. The SSCPP will be jointly administered by FDA’s Center for Drug Evaluation and Research (CDER) and Office of Regulatory Affairs (ORA).
Currently, the following companies have been accepted into the program:
- AbbVie Inc.
- Allergan, Inc.
- Astellas U.S. Technologies, Inc.
- Bristol-Myers Squibb Company
- Celgene Corporation
- GE Healthcare Inc.
- GlaxoSmithKline LLC
- Merck Sharp & Dohme Corporation
- Mylan Pharmaceuticals Inc.
- Novartis Pharmaceuticals Corporation
- Pfizer, Inc.
- Teva Pharmaceutcials USA, Inc.
- Watson Laboratories, Inc.
Source: FDA press release
Japanese Pharmacopoeia and Japanese GMP Regulations available online
Japanese Pharmacopoeia and Japanese GMP Regulations available online
On Japan’s Pharmaceuticals and Medical Devices Agency (PMDA) website, you can download documents on GMP as well as on marketing authorisations for medicinal products. An English version of the Japanese Pharmacopoeia (JP) is also available. You will find the direct links in the News.
On Japan’s Pharmaceuticals and Medical Devices Agency (PMDA) website, you can find in the section “Regulations and Procedures” under the heading “GMP” requirements regarding the inspection of manufacturers of medicinal products and APIs who want to introduce their products into Japan.
Now, a document was supplemented in January 2014 which describes which documents have to be submitted to the Japanese Agency within a pre-approval inspection and/ or a periodical post-approval inspection.
Go to the PMDA webpage to get more information.
There, you can also access the current Japanese Pharmacopoeia Sixteenth Edition in English.
Source: PMDA, Japan
Indian Regulators promote two levels of GMP
GMP deviations and even data falsification have been identified in a number of companies in India. How is it possible that interpretation of FDA and EU authorities on one side and the Indian authority on the other side come to a completely different picture? Read more in our GMP News
GMP deviations and even data falsification have been identified in a number of companies in India. The FDA has issued numerous Warning Letters, the EU has published GMP Non Compliance Reports in its EudraGMDP database and EDQM has withdrawn various CEPs because of GMP inspection findings.
In an article published by Regulatory Focus on 28 January 2014 the question has been raised whether Indian companies have a chronic data falsification problem. The article lists 7 companies in India which have received a Warning Letter in the past months – all of them because of GMP deviations and because of “actually or potentially tampering with their data”. In addition to the 7 companies the Ranbaxy case is a story of its own. Not only one facility was found to manipulate data but several sites of the company are involved. For this reason the US FDA has issued a consent decree of permanent injunction against Ranbaxy. All manufactured products in the facilities concerned are now subject to an FDA import alert. In a press release the FDA states: “Because this company continued to violate current good manufacturing practice regulations and falsify information on drug applications, the FDA took these actions in an effort to protect consumers.” Dara Corrigan, FDA associate commissioner for regulatory affairs goes on: “The FDA continues to be committed to protecting consumers from potentially unsafe products that may be offered on the market.” On January 23, 2014 the FDA added an additional facility of Ranbaxy to the existing consent decree.
So far, the Indian Authority did not initiate the same measures like US and European counterparts. This also questions the supervision system in India. If inspections have been performed by Indian Inspectors at the concerned facilities why did they fail to make the same findings? The Drug Controller General of India, Mr. G.N. Singh, gave an interesting interpretation: According to an interview published by live mint & Wall Street Journal he said: “…it must be stated that every country has different measures and we cannot judge Ranbaxy by standards set up by the American drug regulator“. When Mr Singh was asked about the problems identified at three Ranbaxy plants he stated: “Some of those were found to be true and my office had told Ranbaxy to take corrective measures. Similar procedures will be followed in this case as well. But I do not think this is a situation which will warrant withdrawal of drugs from the domestic market. Our biggest objective is to maintain good quality of medicines and we are doing that. There are no drugs in the Indian market that are not up to the standards stated under the Drugs and Cosmetics Act.” In a final statement in the interview he also mentioned that he is “not worried about issues of quality.” In another interview with the Business Standard Press Mr Singh made an alarming statement for all customers of medicinal products and APIs in Europe and the US. “If I follow US standards, I will have to shut almost all drug facilities“. If this is the truth EU and US customers are in big trouble because products not complying to EU/US GMP standard (e.g. ICH Q7 GMP for APIs) would need to be taken from the market immediately.
This all looks like it will not fit together. How is it possible that interpretation of FDA and EU authorities on one side and the Indian authority on the other side come to a completely different picture? It can only mean that dual standards exist. This would result in two quality levels, an international and a domestic quality level. Such a policy possibly causes questions by Indian patients who have to accept a different and probably lower quality standard.
It does not look like the Indian Regulators will re-think the GMP inspection approach and the quality standard in their country. Instead of acting in his own country the Drug Controller General of India announced inspections in the US and the EU.
But what are the international implications of this strategy? European Regulators need to react as they require from the Indian Authority to issue Written Confirmations of GMP compliance. Without a Written Confirmation APIs can not enter EU market. Currently more than 200 Written Confirmations have been issued by Indian Authority. If the inspections which have been performed as a prerequisite for issuing a Written confirmation were not based on the international standard ICH Q7 (GMP for APIs) the Written Confirmations are no longer valid documents. This issue might be raised by an EU court if a substandard API in a medicinal product will cause a health risk to patients in Europe.
FDA Issues Draft Guidance on NCE Exclusivity Determinations
| Feb 25, 2014 |
Source: FDA.gov
see below
The Food and Drug Administration (FDA or the Agency) is issuing this guidance to set forth a change in the Agency’s interpretation of the 5-year new chemical entity (NCE) exclusivity provisions as they apply to certain fixed-combination drug products (fixed-combinations).
Historically, FDA has interpreted these provisions such that a fixed-combination was ineligible for 5-year NCE exclusivity if it contained a previously approved active moiety, even if the product also contained a new active moiety (i.e., an active moiety that the Agency had not previously approved).
The Agency recognizes that fixed-combinations have become increasingly prevalent in certain therapeutic areas (including cancer, cardiovascular, and infectious disease) and that these products play an important role in optimizing adherence to
dosing regimens and improving patient outcomes.
As further discussed below, we are therefore revising our historical interpretation of the 5-year NCE exclusivity provisions to further incentivize the development of certain fixed-combination products.
If the new interpretation is adopted, FDA intends to apply the new interpretation prospectively.Therefore, this guidance does not apply to fixed-combination drug products that were approvedprior to adopting the new interpretation.
FDA’s guidance documents, including this guidance, do not establish legally enforceable responsibilities. Instead, guidances describe the Agency’s current thinking on a topic and should be viewed only as recommendations, unless specific regulatory or statutory requirements are cited. The use of the word should in Agency guidances means that something is suggested or
recommended, but not required. read at
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM386685.pdf
FDA publishes new Guidance on Validation of Analytical Methods
The FDA has published a new Guidance on the validation of analytical methods which shall replace the 14 years old existing Guideline on the topic. More details about the contents of this highly topical document can be found here.
A new FDA Guidance for Industry entitled “Analytical Procedures and Methods Validation for Drugs and Biologics” was published a few days ago. This Guideline replaces the Guidance for Industry “Analytical Procedures and Methods Validation” from 2000 (this document has never been finalised and has had a draft status 14 years long) and – when finalised – should also replace the “Guidelines for Submitting Samples and Analytical Data for Methods Validation” which came into force in 1987.
Unlike the previous Guideline from 2000, the new document explicitly mentions biologics in its title. The objective of the Guideline is to inform applicants about what data are expected by the FDA in marketing authorisation dossiers. The provisions of the Guideline apply to new drug applications (NDAs), abbreviated new drug applications (ANDAs), biologics license applications (BLAs), and variation applications regarding these types of application, as well as to Type II Drug Master Files. The Guideline can’t be directly used for investigational new drug applications (INDs) as the scope of data with regard to analytical procedures and methods validation varies with the development phase. Nevertheless, IND applicants should orientate themselves to the provisions of the new Guideline.
When comparing it with the former and now invalid “Methods Validation” Guidance, it is apparent that the Draft Guidance has been kept much shorter. There are no detailed descriptions available: for example the table about recommended validation parameters for different analytical tests has been deleted without substitution. Yet, new chapters have been added, like chapter “VIII. Life cycle management of analytical procedures” and its following chapter on the verification of analytical methods in FDA’s own laboratories (“IX: FDA methods verification”).
The document contains plenty of cross-references to corresponding 21 CFR paragraphs and provides – in the last chapter “X. References” – an extensive list of essential FDA Guidelines which also have to be considered in this context, as well as references to corresponding USP chapters, and technical literature on statistical topics. The fact that many aspects of methods validation are addressed in those referenced Guidelines explains the reason why the new Guidance has become shorter.
The document can be commented within 90 days.
read all at
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