Lot Release Sample Clarification Email, March 4, 2014 - RAGWITEK

From: Bridgewater, Jennifer
Sent: Tuesday, March 04, 2014 10:47 AM
To: Greenfeder, Scott; Rivers, Katie
Cc: Valenti, Elizabeth; Bridgewater, Jennifer
Subject: RE: BLA 125473 Lot Release Protocol

Hello Scott –
This email is in response to our previous exchange regarding the Canadian Ragwitek lots. To summarize, you stated that “Grastek (and Ragwitek) for distribution in Canada is identical to the US product with the exception of the blister label and the carton label. It is the applicant’s experience that CBER would need to release each DP batch for export regardless of final distribution and that we cannot apply 802 of the FD&C Act to export Grastek (and Ragwitek) to Canada for distribution since the identical product is approved in the US.

I have spoken to the CBER import group to address your questions. Please note that according to that group, which is located in OCBQ, CBER would not perform lot release testing on these drug product for export to Canada. You should not submit the b(4) Ragwitek lots (or any Grastek lots) intended solely for distribution in Canada to CBER for lot release testing. If you have submitted the lots already, please withdraw them. The import group informs me that Merck should export the product for Canada under Section 801(e)(1). I am definitely not an expert in these issues, I am only passing along to you the information that I have been given. So If you have any further questions on this matter, you really need to submit your questions directly to the import/export mailbox at: CBERImportInquiry@fda.hhs.gov . At this time, considering the above, I suggest that you submit your lots intended for the US for testing, no later than this week.

Thanks
 Jennifer


From: Bridgewater, Jennifer 
Sent: Wednesday, February 26, 2014 9:50 AM
To: Greenfeder, Scott; Rivers, Katie
Cc: Valenti, Elizabeth; Chattopadhyay, Rana; Lacayo, Juan
Subject: RE: BLA 125473 Lot Release Protocol

Dear Scott – 
I will talk to import/export about the issue of the lots for Canada. The –b(4)------------------------ is an important point you raise. I think the best approach is to submit all the lots as you originally intended until the issue is resolved so no time is lost. Thank you for providing the lot information. Can you please inform us when the lots are shipped?

Thanks
 Jennifer
 Jennifer L. Bridgewater 
 Associate Director for Regulatory Policy
 FDA/CBER/OVRR/DBPAP
 301-435-3011
Jennifer.bridgewater@fda.hhs.gov


From: Greenfeder, Scott [mailto:scott.greenfeder@merck.com] 
Sent: Wednesday, February 26, 2014 8:51 AM
To: Rivers, Katie
Cc: Valenti, Elizabeth; Bridgewater, Jennifer; Chattopadhyay, Rana; Lacayo, Juan
Subject: RE: BLA 125473 Lot Release Protocol

Dear Katie,
 Please find responses to this IR February 19, 2014 below.

CBER: As discussed in our teleconference on February 11, 2014, we have some questions in response to your emailed statements below regarding submission of samples. You have submitted b(4) lots of Grastek samples for testing. You stated during the telecon these are U.S. drug product (DP) lots made with U.S. drug substance (DS) lots. Please confirm that none of the DS lots used to make DP are EU lots.

Merck Response:
 All US Grastek DS commercial lots used to make US Grastek DP commercial launch lots were manufactured under the US material code and are not EU DS lots.

CBER: In your email you state that you plan to submit b(4) Ragwitek launch lots (b(4) lots for U.S. market and b(4) lots for CA market). Please clarify what you mean by b(4) lots for the CA market. Please note that if CA refers to Canada; we will not perform testing on lots intended for distribution only in Canada.

Merck Response:
 Please note that CA refers to lots designated for distribution in Canada. Grastek (and Ragwitek) drug product (DP) intended for distribution in Canada is manufactured at Catalent Pharma Solutions in the UK. Following manufacturing, the drug product will be imported into the US, --b(4)--------------------------------------------------- followed by export to Canada for sale and distribution. Grastek (and Ragwitek) for distribution in Canada is identical to the US product with the exception of the blister label and the carton label. It is the applicant’s experience that CBER would need to release each DP batch for export regardless of final distribution and that we cannot apply 802 of the FD&C Act to export Grastek (and Ragwitek) to Canada for distribution since the identical product is approved in the US. Given the intended supply chain for the import and export of Grastek (and Ragwitek) DP from the US to Canada, the applicant would like to confirm that CBER lot release is not required for the lots intended for sale and distribution in Canada. Additionally, guidance is requested regarding appropriate export laws that can be employed to send Grastek (and Ragwitek) to Canada if CBER will not perform lot release for lots intended for sale and distribution in Canada.

CBER: As discussed in the telecon, please do not submit Ragwitek lots in support until requested. Please provide the following information with respect to the Ragwitek lots you propose to submit for release: the lot numbers, whether you are sending both the sample/physician presentation and the 30 day treatment presentations, and whether the physician sample packs have different lot numbers from the 30 day treatment packs. In other words, if we are looking at one lot of product, please clarify if that would include both the physician and the treatment pack presentations.

Merck Response:
 The physician presentation and the treatment pack presentations are manufactured as separate lots and are not part of the same lot; therefore, separate lots will be submitted for lot release for the physician presentations (Sample) and the treatment pack presentations (Trade). Our updated plan is to submit b(4) Ragwitek launch lots (b(4) lots for U.S. market and b(4) lots for CA market (if required)) to CBER for lot release.

Ragwitek US launch lots: 
 US Sample image lots (Physician presentation): ---b(4)---------------------------- 
 US Trade image lots: --b(4)--------------------------------- 
 Ragwitek Canadian launch lots: 
 CA Sample lot: --b(4)-------------
 CA Trade lot: --b(4)------------
 Regards,
 Scott
Scott Greenfeder, Ph.D.
 Director and Liaison
 Global Regulatory Affairs
 T: +1 732-594-1021
 Fax: +1 732-594-1030
scott.greenfeder@merck.com
 Merck Research Labs
 126 East Lincoln Ave.
 MS RY33-204
 Rahway, NJ 07065
www.merck.com



From: Rivers, Katie [mailto:Katie.Rivers@fda.hhs.gov]
Sent: Wednesday, February 19, 2014 9:40 AM
To: Greenfeder, Scott
Cc: Valenti, Elizabeth; Bridgewater, Jennifer; Chattopadhyay, Rana; Lacayo, Juan
Subject: RE: BLA 125473 Lot Release Protocol

Dear Scott,
 As discussed in our teleconference on February 11, 2014, we have some questions in response to your emailed statements below regarding submission of samples. You have submitted b(4) lots of Grastek samples for testing. You stated during the telecon these are U.S. drug product (DP) lots made with U.S. drug substance (DS) lots. Please confirm that none of the DS lots used to make DP are EU lots. In your email you state that you plan to submit b(4) Ragwitek launch lots (b(4) lots for U.S. market and b(4) lots for CA market). Please clarify what you mean by b(4) lots for the CA market. Please note that if CA refers to Canada; we will not perform testing on lots intended for distribution only in Canada.

As discussed in the telecon, please do not submit Ragwitek lots in support until requested. Please provide the following information with respect to the Ragwitek lots you propose to submit for release: the lot numbers, whether you are sending both the sample/physician presentation and the 30 day treatment presentations, and whether the physician sample packs have different lot numbers from the 30 day treatment packs. In other words, if we are looking at one lot of product, please clarify if that would include both the physician and the treatment pack presentations.

Please respond to these issues so we can provide further guidance on submission of lots. You may respond to this request via e-mail.
 Thank you,
 Katie
 Katie H. Rivers, M.S.
 Regulatory Project Manager, CMC1
 FDA/CBER/OVRR/DVRPA
 1401 Rockville Pike, HFM-481
 Rockville, MD 20852
 Phone 301-796-2640
 Fax 301-827-3532

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