Template for API Quality Agreement

BPTF or Bulk Pharmaceutical Task Force, a SOCMA organization has launched a template for preparing quality agreement to provide guidance for drafting agreements related to the manufacture and release of drug substances regulated by various regulatory agencies. The template is based on the experience of industry members.

For more information and downloading of the template, click here

Schedule L1, GLP on board !

Thanks to Mr Shirgaonkar for this wonderful information !
Knowledge of Good Laboratory Practices is very important in Pharmaceutical industry.
New GLP requirements as per Schedule L1 of Drug Rules will come into effect from 1st November 2010. Topics such as General laboratory requirements,instruments calibration, microbiological testing and internal audit will be covered in this statutory requirement.
It was announced that Ministry of Health has recently notified the Schedule L-1 of Rule 74,78 and 150 E under Drugs and Cosmetics Third Amendment Rule 2008 giving the pharmaceutical industry time till November 1, 2010 for compliance.
The implementation of GLP and the responsibility of companies to comply with them while carrying out quality analysis. GLP stresses on the maintenance of documented quality systems as per the quality manual laid down by the manufacturing unit, and on the technical audit of the quality control laboratory for GLP compliance by an expert/experts appointed by the top management other than the person in charge of the laboratory.
As Mr. Shirgaonkar organises a workshop on GLPs and highlight the incumbent Schedule L1, to know more visit Insight Systems website

Revision of Isopropylbenzene status from Class 3 to Class 2

Keyoor has forwarded an interesting information. The jumping of chemicals from one list to another will continue. The information says that ICH is revising the status of Isopropylbenzene to Class 2 from existing Class 3 ! This is somewhat a demotion of Isopropylbenzene which was previously in the safer Class 3. It also means that there will be an upper specification limit to Isopropylbenzene and which must be continuously monitord and controlled.

Although I could not verify the source of this information, but I am sure Keyoor's information is correct and precise. Please read the following text which is copy-paste version:

Due to new toxicity studies in rats and mice, the solvent Isopropylbenzene is meant to be categorised as Class 2 instead of Class 3. A corresponding ICH draft guideline has been published and released for commenting by the public.

The ICH Guideline Q3C defining the limits for residual solvents as impurities in active pharmaceutical ingredients (APIs) and finished medicinal products as well as the methods for establishing their exposure limits has already been revised four times. The revisions concern among others provisions for calculating the PDEs (PDE = permissible daily exposure, denoting the maximum amount of a solvent that may be taken in with a medicinal product) for the solvents N-Methylpyrrolidone and Tetrahydrofuran. Now the guideline is about to be revised once more, the reason being that new toxicological data have been collected on the solvent Isopropylbenzene (called "Cumene" in the guideline). Hitherto, this substance has been categorised as Class 3, i.e. as a solvent with low toxicity. In general, these solvents have PDE values of 50 mg per day or more. Recent toxicity studies conducted in rats and mice clearly showed a heightened carcinogenic potential so that it has become necessary to assign Isopropylbenzene to the higher Class 2 and to calculate the PDE accordingly.

On 26 March 2010, the ICH Draft Consensus Guideline "Impurities: Guideline for Residual Solvents - PDE for Cumene" was published (Step 2 in the ICH process) and has since been available for commenting by the public. This guideline now requires the calculation of the PDE for Isopropylbenzene according to the rules for Class 2 solvents. After two further steps in the ICH process, this guideline will be integrated into the core document, which will then bear the name ICH Q3C(R5).

This new regulation might require manufacturers of APIs and medicinal products using Isopropylbenzene to make a considerable effort in changing their registration dossier (e. g. as a consequence of changes to the manufacturing process, the analytical methods etc.).

CDSCO Website in its improved version with inclusion of Industry Guidance Documents

CDSCO website in new avatar. Since my last visit to the website, may be at a gap of a year, I realise, CDSCO has included various multidisciplinary topics. Navigation is made easy and search relatively better.
The best part is the inclusion of "Guidance to Industry" documents in the line of US FDA. The recent addition to this is a draft guidance for fixed dose combination.

There are separate sub-section for Medical devices and Diagnostics. Downloads having full text of Drugs & Cosmetics Law;

While all APIs registered as on date in India are listed, there are separate lists for formulations and vaccines registered for import.

There is also a list of all WHO GMP  certified facilities in India which are 817 in number. This information will be useful for foreign manufacturers which wanted to have contract manufacturing or any other kind of in-licensing business from India.

However, still I feel that there could be a better ways of segregation of different categories under the headings of drug products, drug substances, cosmetics, medical devices etc.

Anyway, to start and improve is still better to wait and watch !

To reach the website, click here

What is AIP ?

AIP is Application Integrity Policy. The policy focuses on the integrity of data and information in applications submitted for Agency (FDA) review and approval.
The AIP described Agency's approach regarding the review of applications that may be affected by wrongful acts that raise significant questions regarding data reliability.
Although the guidance document does not create or confer any rights for or on any person and does not operate to bind FDA or the public, it does represent the Agency's current thinking on consistent implementation of the AIP.
The AIP is invoked when a company’s actions raise significant questions about the integrity of data in drug applications including falsification. Under the AIP, FDA asks the company to cooperate with the agency to resolve the questions of data integrity and reliability. This includes implementing a Corrective Action Operating Plan (CAOP) to provide assurance of the integrity.
To download policy document, click here

Has FDA invoked AIP for any Indian company?
To best of my knowledge, there is no other company from India for which AIP has been invoked, except the Japanese-Indian company - Ranbaxy Laboratories Limited.

Given below is a Case Study on AIP invoked to a company, its consequences and handling of events.
U.S. Food and Drug Administration announced that a facility owned by India-based Ranbaxy Laboratories falsified data and test results in approved and pending drug applications. The facility, Paonta Sahib, was already under an FDA Import Alert since September 2008. To address the falsified data, the FDA has invoked its Application Integrity Policy (AIP) against the Paonta Sahib facility. The AIP is invoked when a company’s actions raise significant questions about the integrity of data in drug applications. Under the AIP, the FDA has asked Ranbaxy to cooperate with the agency to resolve the questions of data integrity and reliability. This would include implementing a Corrective Action Operating Plan (CAOP) to provide assurance of the integrity.

What led FDA to invoke AIP to Ranbaxy?
In the backdrop, when two facilities of Ranbaxy Labs were audited by US FDA Inspectors in the February 2006, the inspections reveal significant deviations from cGMP. Ranbaxy issued three responses (March 20, April 20 and May 25) to these observations. However, the FDAs review of Ranbaxy response didn’t helped much and FDA said in its letter about the still valid concerns.
As these responses and the supporting documentation from Ranbaxy continued to be examined by CDER against the filed applications, it was reveled that apart from significant GMP deviations, the company falsified data and test results in approved and pending drug applications.
The AIP memorandum issued by CDER dated February 25th, 2009 says that CDER has determined that “Ranbaxy submitted untrue statements of material fact in abbreviated and new drug applications filed with the Agency. These findings concern the submission of information, such as from stability test results in support of pending and approved drug applications, from the Ranbaxy Laboratories Limited site located at Paonta Sahib”.

The AIP copy can be downloaded from here
For the benefit of readers it is worth to mention that FDA has stated in its website that

“To date, the FDA has no evidence that these drugs do not meet their quality specifications and has not identified any health risks associated with currently marketed Ranbaxy products.”

EMEA is revising Process Validation guidelines

At the end of February 2010, the European Medicines Agency (EMA) published a draft paper revising their process validation guidelines
Elements from the guidelines ICH Q8 (Pharmaceutical Development), ICH Q9 (Quality Risk Management) and ICH Q10 (Pharmaceutical Quality Systems) are to flow in, particularly in the process areas of Analytical Technology (PAT), Quality by Design (QbD) and Real Time Release Testing (RTRT).
It is planned that the final document will be ready in the 4th quarter of 2011.

The concept paper on this guideline can be downloaded here

Eudralex revises Part II of the GMP guide

An amendment is made to Part II of the GMP Guide to incorporate principles of Quality Risk Management in line with the ICH Q9 guideline on Quality Risk Management. Amendments correspond to similar changes made to Part I Chapter 1 of the Guide and published in February 2008. A new section on Quality Risk Management is
introduced as section 2.19. The remaining sections of chapter 2 are renumbered. A minor change is made to section 2.21. No other changes have been made.

Deadline for coming into operation 31 July 2010
 
Authors Note:- Eudralex Part II to GMP guide is an adoption of ICH Q7 and gives comprehansive view of GMPs for APIs. To download, click the title of the post !