Record of Telephone Conversation, February 11, 2014 - RAGWITEK

Submission Type: BLA Submission ID: 125478/0 Office: OVRR
Product:
Short Ragweed Pollen Allergen Extract
Applicant:
Merck Sharp & Dohme Corp.
Telecon Date/Time: 11-Feb-2014 12:00 PM Initiated by FDA? Yes
Telephone Number: 
Communication Categorie(s):
1. Information Request
Author: Katie Rivers

Telecon Summary:
The purpose of this telecon is to discuss observations and request additional information in response to the inspection of the drug substance manufacturing facility, ALK-Abello, DK.

FDA Participants: 
Jay Slater
Jennifer Bridgewater
Taruna Khurana
Jon Daugherty
Elizabeth Valenti
Julie Vaillancourt 
Katie Rivers
Deborah Trout
Carolyn Renshaw

Non-FDA Participants: 
Merck
Scott Greenfeder
Scott Korn
Weining Hu
David Robinson
Patricia Valan
Hendrik Nolte
Sean Curtis
Judith Boice
Ann Niland
Julia Markusen

ALK-Abello, DK
Anne Lützhøft Aarbogh
Christian G. Houghton
John Witthøft
Katja B. Thaulund
Lars Dreiø
Maja Nøddekær
Tine Beck

Telecon Body:

CBER requested that the sponsor amend the BLA to provide additional information on the areas used to manufacture the drug substance (DS). Specifically, please identify the areas as new construction or pilot/development areas. In addition, please indicate that the areas used to manufacture the DS within –b(4)-------- at ALK are currently unlicensed in the US. The sponsor agreed.

CBER asked and Merck confirmed that –b(4)--- produced at ALK in 2007-2008 were used to make the Grastek drug product (DP) conformance lots (2009-2010). In addition, Merck confirmed that b(4) conformance lots were produced in 2010 and never shipped to Catalent for further manufacturing. CBER asked if this validation strategy was clearly outlined in the BLA. Merck stated that it was not, but Table 1 of section 3.2.S.4.4 of BLA125473 provided product characterization data. Merck confirmed that the –b(4)--- lots used to make the Grastek DP conformance lots were not identified as conformance lots in the table. Merck agreed to amend the BLA with additional information.

CBER asked whether the b(4) lots were manufactured using good manufacturing practices (GMP) and asked that additional information confirming GMP control (i.e., operator training, etc.) be submitted to the BLA. Merck stated that the b(4) produced for -b(4)---------- and U.S. markets are identical in terms of the facility and manufacturing process and agreed to submit additional information confirming GMP to the BLA.

CBER questioned the reasoning behind the use of b(4) manufactured for the –b(4)------ for the manufacture of the conformance lots of DP for U.S. licensure. Merck stated that they used data from over –b(4)------------------ to establish U.S. release specifications and the lots that were selected for manufacture of U.S. DP lots were chosen because they met US specification. CBER also questioned the need to manufacture –b(4)----------- lots for re-validation. Merck stated that the reason was because some analytical methods were revised to better adhere to strict International Conference on Harmonisation (ICH) guidelines. In addition, Merck noted that they did not anticipate significant manufacturing changes; therefore, felt it was appropriate to select the –b(4)--- lots. CBER stated that this was not clear in the BLA and requested that the BLA be amended to reflect the sequence of events and reasons for re-validation of the U.S. b(4). The sponsor agreed.

CBER requested that the sponsor provide additional information outlining the differences between the b(4) and U.S. b(4) specifications in order to determine that their equivalence. The sponsor noted that the manufacturing process for the b(4) and U.S. b(4) lots is identical. CBER asked the sponsor to amend the BLA to state this explicitly.

CBER questioned and Merck confirmed that additional lots of U.S. b(4) have been manufactured after the conformance lots. CBER requested that the BLA be amended to include a list of b(4) lots manufactured after the b(4) conformance lots. The sponsor agreed.

CBER asked and Merck confirmed that DP lots being submitted for lot release were manufactured for the U.S. market.

Merck asked and CBER agreed that the expiration date format listed in the lot release protocol (LRP) is acceptable at this time; however, for lots manufactured post-launch the expiration date format should be updated as previously communicated. In addition, CBER agreed that the product storage temperature language in the LRP was acceptable; however, minor edits would be provided and should be included on future lots manufactured post-launch.

Summary of information requests Merck agreed to respond to:
1.Provide additional information on the areas used to manufacture the b(4) Specifically, please identify the areas as new construction or pilot/development areas. In addition, please indicate that the areas used to manufacture the b(4) within Building b(4) at ALK are currently unlicensed in the US.
2.Provide additional information to identify the b(4) conformance lots.
3.Provide additional information to confirm that b(4) lots were manufactured under GMP.
4.Provide additional information to reflect the sequence of events and reasons for re-validation of the U.S. b(4)
5.Explicitly state that the manufacturing process for the b(4) and U.S. b(4) lots is identical.
6.Provide a list of b(4) lots manufactured after the b(4) conformance lots.
