
Information Request Email, September 10, 2014 - BEXSERO

 
 
RECORD OF TELEPHONE CONVERSATION

Submission Type: BLA     Submission ID: 125546/0     Office: OVRR 

Product:
 Meningococcal Group B Vaccine 

Applicant:
 Novartis Vaccines and Diagnostics, Inc. 

Telecon Date/Time: 10-Sep-2014 02:29 PM     Initiated by FDA? Yes

Telephone Number: 

Communication Categorie(s): 
1. Information Request

Author: KIRK PRUTZMAN

Telecon Summary: 
IR regarding the ---(b)(4)--- facility operations

FDA Participants: KIRK PRUTZMAN, ED WOLFGANG, RAMACHANDRA NAIK

Non-FDA Participants: PATRICIA STOEHR

Trans-BLA Group: No

Related STNs: None

Related PMCs: None

Telecon Body: 


From: Prutzman, Kirk C 
 Sent: Wednesday, September 10, 2014 2:30 PM
 To: Stoehr, Patricia (patricia.stoehr@novartis.com)
 Cc: Wolfgang, Edward; Naik, Ramachandra
 Subject: STN 125546 - Information Request 

Dr. Stoehr,

Please find attached a request for additional information regarding STN 125546 (Meningococcal Group B Vaccine). If you have any questions about this communication, please contact Kirk Prutzman, Ramachandra Naik, or Ed Wolfgang at (301) 796-2640.

Regards,

Kirk Prutzman, PhD
 Primary Reviewer/Regulatory Project Manager 
 CBER/OVRR/DVRPA/CMC3 
 Food and Drug Administration
 10903 New Hampshire Avenue
 Building 71 and Room 3041
 Silver Spring, MD 20993-0002
 Phone: (301) 796-2640
 Fax: (301) 595-1244 


CENTER FOR BIOLOGICS EVALUATION AND RESEARCH
 OFFICE OF VACCINES RESEARCH AND REVIEW
 DIVISION OF VACCINES AND RELATED PRODUCTS APPLICATIONS

DATE: SEPTEMBER 10, 2014       PAGES: 5

TO: NOVARTIS VACCINES AND DIAGNOSTICS, INC

ATTENTION: PATRICIA STOEHR, PH.D.
 Senior Group Manager Regulatory Affairs
 Novartis Vaccines & Diagnostics

350 Massachusetts Avenue
 Cambridge, MA 02139 
 USA

FAX: (617) 871-8060     TEL: (617) 871-4711

FROM: KIRK PRUTZMAN, PH.D.
 Regulatory Project Manager
 FAX: (301) 595-1244       TEL: (301) 796-2640

SUBJECT:   STN: BL 125546/0 – Request For Information 

MESSAGE:

Dear Dr. Stoehr:

We have the following request for additional information regarding STN 125546 (Meningococcal Group B Vaccine):

All Questions / Request are related to your -----(b)(4)---- operations

Regarding the HVAC Systems in ------------------(b)(4)--------------------

1. In 3.2.A.1.2.2 Drug Substance – Recombinant Proteins Manufacture, Section 3.2.A.1.2.2.4 HVAC Systems: You mention Room Classes -(b)(4)- and Class -(b)(4)-. You also make reference to “Zones.” And then in your PQ limits, you clearly reference Grades and ISO Classifications. Please clarify how do these “classes” (both numbered and lettered), zones, and grades relate to each other.

2. Please provide a list of the last qualification for all HVAC units (including protocol numbers and dates).

Regarding Equipment Cleaning 

3. In 3.2.A.1.2.2 Drug Substance – Recombinant Proteins Manufacture, Section 3.2.A.1.2.2.6.8 Equipment Cleaning: You state: “------------------------------------------------------------------------------------------------------------------------------------------------------------------(b)(4)------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------” 

a. Do you verify cleanliness after each batch?

b. What are the acceptance criteria for this cleaning after -------(b)(4)------- 

4. In 3.2.A.1.2.2 Drug Substance – Recombinant Proteins Manufacture, Table 3.2.A.1.2.2.6.8.2.1-4 Results for Purification Equipment (Run 1): 

Please provide a summary of the investigations for ---(b)(4)--- OOS (OOS80501 -Investigation report 80529), and the --(b)(4)-- OOS (OOE80028 - Investigation report 80034), including root cause and corrective action. 

5. Please provide a list of the most recent cleaning validation studies for the product contact equipment used in the production of the three Bexsero recombinant proteins (include protocol numbers and dates).

Regarding Autoclave Qualification

 Reference 3.2.A.1.2.2 Drug Substance – Recombinant Proteins Manufacture, Section 3.2.A.1.2.2.3.4, Autoclaves:

6. Are any of the autoclaves newly installed? 

7. Please provide a summary of the IQ/OQ for all autoclave units used to sterilize equipment / components for Bexsero.

8. What are the requalification requirements for autoclaves (i.e. how often)?

9. Do you have all porous / hard goods loads or do you have any liquid loads?

10. Are all load configurations fixed (do not vary) for routine processing?

11. Please provide a comparison of Sterilization validation cycle(s) against your routine production cycle(s).

Regarding the Purified Water Systems

12. In 3.2.A.1.2.2 Drug Substance – Recombinant Proteins Manufacture, 3.2.A.1.2.2.5.1.1 Purified Water (PW) Distribution System; Table 3.2.A.1.2.2.5.1.1-1 Specification for Purified Water: You state the specification for ----------------(b)(4)-----------------------. Then in the table for routine operations you report acceptance criteria of Max. -----(b)(4)---- (Warning limit) and Max. ----(b)(4)--- (Action limit). Please explain the disparity. 

13. When were the PW systems installed in ----------------(b)(4)-------------, and when were they qualified (or most recently requalified)? 

14. Please provide a summary of the PW system routine monitoring requirements (i.e. how many samples?, how many sample points?, how often?, testing requirements?) for each Building (------------(b)(4)-----------).

Regarding the WFI Systems

15. Is there a WFI system in Building (b)(4)? If so, please provide a description of the system and a summary of its qualification and routine monitoring. 

16. When were the WFI systems installed in ---------------(b)(4)---------------, if applicable), and when were they qualified (or most recently requalified)?

17. Please provide a summary of the WFI system routine monitoring requirements (i.e. how many samples?, how many sample points?, how often?, testing requirements?) for each Building (-------(b)(4)-------- if applicable).

 Regarding the Clean Steam System

18. Is Clean Steam supplied to (b)(4)?

19. When were the Clean Steam systems installed in ------------------(b)(4)--------------- (if applicable), and when were they qualified (or most recently requalified)?

20. Please provide a summary of the Clean Steam system routine monitoring requirements (i.e. how many samples?, how many sample points?, how often?, testing requirements?) for each Building (-------------(b)(4)------------ if applicable).

Regarding the Compressed Air System

Reference 3.2.A.1.2.2 Drug Substance – Recombinant Proteins Manufacture, Section 3.2.A.1.3.2.5.2.1 Compressed Air Distribution System:

21. Please provide a summary of the uses of compressed air in ----------------(b)(4)-------------. 

22. When was the Compressed air system installed, and when was it qualified (or most recently requalified)?

23. Please provide a summary of the Compressed Air routine monitoring requirements (i.e. how many samples? how many sample points? how often? testing requirements?) in each Building (-----------(b)(4)------------ if applicable).

24. How did you establish the Microbial Limits?

Regarding the Nitrogen System

Reference 3.2.A.1.2.2 Drug Substance – Recombinant Proteins Manufacture, Section 3.2.A.1.2.2.5.2.2 Nitrogen Distribution System: 

25. When was the Nitrogen distribution system installed in ------------------(b)(4)----------- (if applicable), and when were they qualified (or most recently requalified)?

26. Is Nitrogen supplied or used in (b)(4)? If so, please provide a description of the system and a summary of its qualification and routine monitoring including acceptance criteria.

27. Please provide a summary of the uses of Nitrogen in -----------------(b)(4)------------- (if applicable).

28. Please provide a summary of the Nitrogen routine monitoring requirements (i.e. how many samples? how many sample points? how often? testing requirements?) for each Building (------------(b)(4)-------------- if applicable).

29. How did you establish the Microbial Limits?

Regarding Process Validation

30. Reference 3.2.S.2.5 Process Validation & Evaluation [rp287-953 – (b)(4)], Table 3.2.S.2.5.1-6 ---------------(b)(4)----------------- – Filling Validation:

a. Please clarify what Filling 1 through 7 refers to.

b. Why are there no results for samples 13 through 21 for Batches ---------------(b)(4)----------------------?

c. Why were samples for homogeneity testing not taken for Filling 4?

d. You note an observation of turbidity after --(b)(4)-- of the sample at the beginning of filling and a fresh (b)(4) bottle of ----(b)(4)---- was used for retesting. Did this turbidity warrant an investigation of the batch? Is “Clarity” a CQA required to be verified at Rosia for the ------------(b)(4)-------------- solution?

31. Reference the -------------(b)(4)------------ for rp287-953 and rp936-741: 

Were full production scale batches used to establish ----------(b)(4)--------?

32. Reference 3.2.S.2.5.5 ------------(b)(4)---------- (Both rp287-953, rp936-741, and rp961c):

a. Have you established a maximum --------(b)(4)------- filter membranes?

b. What solutions are the membranes cleaned/sanitized and stored in?

c. Besides the (b)(4), are you performing other tests to verify reduction of residues post cleaning and rinsing?

Regarding Shipping Validation

33. Were Shipping Validation studies performed with rp287-953 only? 

34. Were any quality attributes verified on the bulk material post shipping as part of the validation study?

Please provide your responses to this information request in an Amendment to STN 125546. We recommend that you restate each item and follow it with your explanation or clarification. Use of this format helps organize the relevant information and provides a self-contained document that facilitates future reference. If you have any questions about this communication, please contact Kirk Prutzman, Ramachandra Naik, or Ed Wolfgang at (301) 796-2640. 
