• The Addl DGHS & Director i/c, NIB welcomed the participants to the meeting.She said that NIB was ready to start the testing of recombinant insulin and the meeting had been convened to clarify matters related to the receipt of samples for testing, finalize production protocol which is to be submitted with each batch sent for testing and also to work out the modalities for the preparation of national reference standard for rec-insulin.She requested the manufacturers and regulatory authorities to send all the necessary documents along with the samples to enable NIB to test the products expeditiously and avoid delays in seeking clarifications etc.She assured the manufacturers that the Institute would monitor turnaround time and make all efforts to send the test reports within 45 working days or earlier.The turnaround time would start after all documents and required number of vials had been received and therefore it would be in the interest of the party sending the samples to see that the laid down criteria were met. She informed that the Institute had also taken steps to prepare national reference standards and thanked the manufacturers for sending bulk material.Since the preparation of the standard required collaborative studies and cooperation of regulatory authorities and the manufacturers,the modalities and timelines would be discussed during the course of the meeting.

Dr GN Singh appreciated the steps taken by NIB. He said that the national reference standard of insulin was a felt need.He assured the full cooperation of IPC in the efforts being made in this regard.

Dr AK Tahlan briefly reiterated the criteria for the acceptance of samples for testing at NIB.  He said that the information in this regard had already been circulated by DCG(I) to all state drug controllers, regional drug control authorities and others.He said that care should be taken to lift samples randomly so that the entire batch was covered.He said that the batch should be interpreted as given in the Drugs and Cosmetics Act, 1940 and Rules there under (amended 2006).  If the filling was done on the same day it was considered as one batch; however if filling was done on different days, the same should be reflected in the production protocol and sterility tests recorded.The criteria laid down at NIB for the acceptance of samples and communicated to all concerned were:

• Name and designation of the person sending the sample should be on a letterhead and clearly mentioned
• Box containing the samples should be sealed and intact
• Production protocol and other related documents such as valid manufacturing/ import license, insert/leaflet should accompany the samples
• Required number of vials/ampoules/pre-filled syringes
• At recommended storage and transportation temperatures
• Within 3 months of date of manufacture for indigenous products and imported products to have at least 60% shelf life

Dr. Tahlan mentioned that for imported products, import licence, CoA of the country of origin, name of the countries where this product was being used and production protocol with results of necessary tests conducted should be provided.

NIB had indicated that 14 vials of insulin in 10 ml vials and 28 prefilled syringes (3 ml) were needed for testing and an equal number was required to be kept as retained samples.The manufacturers, however, felt that the number may be increased to 18 vials if sterility test was also to be done according to their experience in the QC department.

Shri Kukraty said that the information provided in the production protocol was very important to assess the quality of the product.He suggested that information on flow process and critical steps should be included in the protocolHe mentioned that the detailed information should be provided in a dossier which should be submitted only once.  If any changes were made, the production protocol should reflect these changes.  Otherwise, the production protocol should include a statement that ‘no deviations from standard/ established procedures were made during production or filling of the formulation. He appreciated that the Institute was monitoring the turnaround time and agreed that delay could be minimized if the samples were sent as per requirement and that the production protocols, insert/leaflets, valid license etc were sent with the samples and unnecessary correspondence avoided.He said that necessary instructions had been issued to the regional offices and others concerned and that the CDSCO would also monitor and ensure that the guidelines were followed.

Dr Renu Jain, Scientist Grade II and Head of the Recombinant Laboratory requested the participants for feedback on the draft production protocol which had been circulated along with the notice of the meeting.She said that attempt had been made to keep the protocol simple and include only the critical information needed for assessing the production steps and results of various tests during production and in the finished product.The suggestions made during the meeting were minor and incorporated.She said that that the revised protocol would be circulated and posted on the website.

The criteria for acceptance for biphasic isophane insulin preparations ie. 30:70 and 50:50 as per IP 2007 and EP was raised.Ms Suman said that acceptance limits followed at Biocon are 5% +_  of 30% and 50%.Since the acceptance criteria had not been mentioned in IP 2007 this may be agreed upon in consultation with CDSCO and IPC.

Shri Mithlesh enquired about the need for Rabbit Bio-identity test for bulk as per USP.  He was advised that the mandatory tests given in the concerned pharmacopoeia were required to be done.If there were other validated alternate tests, the matter for revision in the IP 2007 could be taken up with the IPC along with the relevant data.

Dr Jain thanked the manufacturers for sending bulk material which had been received from 3 manufacturers in powder form and from one in liquid form.She said that the tests performed for calibration using certified reference material showed that the results were in conformance to the COA provided by the manufacturers.She said that to produce national reference standard, it was necessary that the international guidelines were followed.She described these requirements in brief.Copy of the power point presentation is attached.

The modalities were discussed in detail.The representatives of the manufacturing institutions agreed to participate in the study as availability of national reference standard was a felt need.  It was suggested that NIB may follow up with the other manufacturers also who could not be present in this meeting.It was agreed that 10 gm would be sufficient for calibration and characterization by five collaborating laboratories.The national reference standard would be prepared from one lot.  The total quantity would be 5000 vials x 50/100 mg.It was considered necessary that the bulk material required for preparing the national reference standard (500-600 gm) be obtained from each manufacturer participating in the collaborative study to ensure that adequate quantities of the bulk material was available after characterization and calibration had been completed as this may take a few months.NIB will code the material and send it to the collaborating centres along with the protocol.

.Each laboratory will generate data on potency by calibration using certified reference material (CRM) of the highest metrological traceability.The time line for testing and generating data would be 6 weeks.The test method would be as per IP 2007.NIB will prepare the protocols and communicate to all the laboratories participating in the study.A meeting will be organized at NIB to discuss the results of the study and selection of the candidate reference material.

The representatives of the manufacturers said that they did not have the required infrastructure to freeze dry and final filling of small quantities of insulin to be used as national reference standard.They suggested that NIB may explore with institutions engaged for this specific purpose.

The meeting ended with a vote of thanks to the Chair.

LIST OF PARTICIPANTS