Record of Telephone Conversation, May 29, 2008 - Flublok
Submission Type: BLA Submission ID: 125285/0 Office: OVRR
Product: Influenza Vaccine
Applicant: Protein Sciences Corporation
Telecon Date/Time: 29-May-2008 11:53 AM Initiated by FDA? Yes
Communication Category: Information Request
Author: RAKESH PANDEY
Telecon Summary: CMC manufacturing, validation.
FDA Participants: Rakesh Pandey
Non-FDA Participants: Manon Cox
As discussed this morning, here is the information request document regarding your BLA. Some of the facilities related comments may have been communicated to you already.
Please amend the original BLA submission and provide the following information for our review.
1. Please clarify, when in the manufacturing process bioburden samples are collected, including proposed action and alert limits for each sample point. Also, provide justification for the action limit of –b(4)---------- set for the -b(4)-------- step and include a detailed description of and justification for how and when future limits for all bioburden samples collected will be established.
2. Please provide a validation summary for the storage and shipment of samples to the –b(4)----- contract laboratory.
3. Please provide information on the locations of any Biosafety Cabinets (--b(4)---) used in the manufacturing process.
4. Please provide a complete description of the shipping validation plan including validation data.
5. Please provide a comprehensive list of any other products that are manufactured or manipulated in the same areas used to produce the drug substance and drug product. Information provided should include a brief description of the type and developmental status of the additional drug substances and products and indicate the areas into which these other products will be introduced.
6. Please provide a description, how product-contact equipment used to produce the drug substance and drug product is cleaned. In addition, please provide a summary of the validation and data to support cleaning procedures.
7. Please provide a validation summary for WFI system at the Protein Sciences facility. The validation summary should include the following information:
• A narrative of the validation process including acceptance criteria;
• Parameters monitored and tests performed; and
• Explanation of all excursions or failures.
8. Please provide a full description of the sterilization and depyrogenation processes used for drug product final containers, closures, and equipment. A description of the validation of these processes should be provided including, where applicable, heat distribution and penetration summaries, biological challenge studies and routine monitoring procedures.
9. Please provide a comprehensive list of all computer systems which control critical manufacturing processes for the drug substance and drug product. Please include a validation summary for each of these systems.
The following comments and questions pertain to Clinical Review of the study PSC04:
1. Please explain why planned investigational sites 9 and 18 had no enrollees.
2. Please indicate how the sample size for the safety analyses was determined. For each treatment group, please submit a table which describes the probability of detecting one or more events for assumed event rates in the range of 0.01% to 5.00%.
3. Please indicate where in Dataset 3, STN 125285\0\3, 5/16/08, Subject Disposition is located.
4. There appears to be a discrepancy between the text and Table 14.1.1 in Mod 5, Vol 19, p105. The number of subjects who completed study procedures through Day 28 is 4460 (96%) according to the applicant’s text in Module 5, Vol 19, pg 52, but the source table lists the number of subjects who completed the study as being 0 for both treatment groups and overall. Please comment on this apparent discrepancy and whether the source table lists the number of subjects completing the culture confirmation study endpoint.
5. Based on your Table 14.1.2, Subject Disposition by Center, Module 5, Vol 19, pp 106-129, it appears that a total of 21 subjects who were initially randomized to receive FluBlok were actually vaccinated with Placebo. In your Interim Clinical Study Report, Module 5, Vol 19, Table 6, p 56, you indicate that there were 11 protocol deviations due to incorrect randomization. Please explain why there are not 21 deviations due to randomization errors in this table.
6. Please provide a table or flow chart of Disposition of Subjects that accounts for Protocol Deviations and that depicts not only an Immunogenicity subset (Evaluable Population), but also a Per Protocol Population.
7. Please provide to us your primary and secondary immunogenicity analyses using the Per Protocol population.
Please provide a table that presents the day on which subjects in the immunogenicity subset had the post-vaccination/visit 2 serology drawn