Complete Review of CMC-Product of BLA STN 125300, February 2, 2010 - Menveo

DATE:	February 2, 2010
FROM:	Che-Hung Robert Lee, Ph.D., Laboratory of Bacterial Polysaccharides, HFM-428, Division of Bacterial, Parasitic, and Allergenic Products, OVRR
SUBJECT:	Complete Review of CMC-Product of BLA STN 125300 Meningococcal (Groups A, C, W-135 and Y) Oligosaccharide CRM197 Conjugate Vaccine, Menveo®, Novartis
TO:	File, STN 125300 Cara Fiore, DVRPA, HFM-481 Willie Vann, Committee Chair, DBPAP
THROUGH:	Willie Vann, Ph.D., Chief, Laboratory of Bacterial Polysaccharides, DBPAP

ITEMS REVIEWED

BLA 125300

• 2.3.S. CRM197
• 2.3.S. MenA Polysaccharide
• 2.3.S. MenC Polysaccharide
• 2.3.S. MenW Polysaccharide
• 2.3.S. MenY Polysaccharide
• 2.3.S. MenA-CRM
• 2.3.S. MenC-CRM
• 2.3.S. MenW-CRM
• 2.3.S. MenY-CRM
• 2.3.P. MenCWY Liquid - Injection
• 2.3.P. MenA Lyophilized - Injection
• 2.3.S. CRM197
• 3.2.S. MenA Polysaccharide
• 3.2.S. MenC Polysaccharide
• 3.2.S. MenW Polysaccharide
• 3.2.S. MenY Polysaccharide
• 3.2.S. MenA-CRM
• 3.2.S. MenC-CRM
• 3.2.S. MenW-CRM
• 3.2.S. MenY-CRM
• 3.2.P. MenCWY Liquid - Injection
• 3.2 .P. MenA Lyophilized - Injection

Amendment 125300/0.3: Partial DI response
Amendment 125300/0.4: Partial DI response and additional information
Amendment 125300/0.5: Response to IRs
Amendment 125300/0.12: Stability Data for 24 months and packaging mock ups
Amendment 125300/0.13: Specifications and validation of specifications and
manufacture data
Amendment 125300/0.15: Complete Response
Amendment 125300/0.17: Stability Data for 36 months, batch data for pre-licensure
testing, PVP
Amendment 125300/0.19: Last minute BLA issues

• Response to CBER’s Requests on Formaldehyde Testing and --b(4)-------- Testing

SUMMARY

Novartis Vaccines and Diagnostics, Inc. is requesting licensure of Meningococcal (Groups A, C, W-135 and Y) Oligosaccharide CRM₁₉₇ Conjugate Vaccine (Menveo®).  Menveo® is copackaged as a vial containing lyophilized MenA Conjugate Component and a vial ---(b)(4)-- containing the liquid MenCWY Conjugate Component.  The selected final formulation contains 10-5-5-5 µg per oligosaccharide of N. meningitides serogroups A, C, W135 and Y, respectively, without adjuvant.  The pharmaceutical form is a powder and a solvent for solution for injection.  The dose is 0.5 mL (after reconstitution).  Menveo® consists of four drug substances: Meningococcal group A oligosaccharide to Corynebacterium diphtheriae CRM₁₉₇ protein (MenA-CRM Conjugate), Meningococcal group C oligosaccharide to Corynebacterium diphtheriae CRM₁₉₇ protein (MenC-CRM Conjugate), Meningococcal group W-135 oligosaccharide to Corynebacterium diphtheriae CRM₁₉₇ protein (MenW-CRM Conjugate), and Meningococcal group Y oligosaccharide to Corynebacterium diphtheriae CRM₁₉₇ protein (MenY-CRM Conjugate).  Each drug substance is prepared from materials purified from two starting products of bacterial fermentation origin: Corynebacterium diphtheriae Cross Reactive Material 197 (CRM₁₉₇) and capsular polysaccharide (A, C, W-135 and Y obtained from Neisseria meningitidis serogroups A, C, W-135 and Y, respectively).  There are a total of ----------b(4)--------------------------------------------------------------------------------------------------------

REVIEW

----b(4)------------------------------------------------------------------------- ---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------

5 Pages determined to be not releasable:
b(4)

 -------------b(4)------------------------------------------------------------------------- ------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------

Drug Product: Menveo®, MenA Lyophilized and MenCWY Liquid (Vial -(b)(4)-      -------------).  The proposed shelf life for the reconstituted product vaccine is up to -b(4)--- stored at both 2-8 °C and -b(4)--

MenA Lyophilized or MenA Lyo (lyophilized powder, vial, single dose) – The composition of Men A Lyo is MenA-CRM₁₉₇ (10 ug MenA oligosaccharide, -b(4)---- CRM₁₉₇) formulated in a ----b(4)--------------------------------------------------------------------------------------------------------------  There are no overages in terms of content to account for loss or degradation.  There is a -b(4)- overfill in the vials to allow the withdrawal and administration (after reconstitution) of 0.5 mL of MenA Lyo.  --b(4)-------------------------- ---------b(4)------------------------------------------------------------------------------------------------------------------------------------ -----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------  The proposed shelf life for MenA Lyo is 24 months when stored at 2-8 °C.

MenCWY Liquid (vial ----(b)(4)---) – The composition of MenCWY Liquid (vial or syringe)  is MenC-CRM (5 µg MenC oligosaccharide, -b(4)--------- CRM₁₉₇), MenW (5 µg MenW oligosaccharide, -b(4)---- CRM₁₉₇), MenY (5 µg MenY oligosaccharide, -b(4)-------CRM₁₉₇) in a ----b(4)---- ------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- There are no overages in terms of content to account for loss or degradation.  There is a b(4) overfill in the vials to allow the withdrawal and administration of 0.5 mL, after reconstitution of the lyophilized MenA Lyo with the MenCWY Liquid.  ---b(4)----- -------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------.  The proposed shelf life for MenCWY Liquid is 24 months when stored at 2-8 °C.

COMMENTS

Global
1.  All the specifications for the drug intermediates, drug substances and drug products are provisional.  They need to be re-evaluated when enough lots have been produced.  Please comment

2.  -b(4)------- of each (MenA, C, W-135 and Y) polysaccharide, each conjugate, and Menveo® MenA Lyo needs to be included in their lot release specifications.

3.  Please provide the SOP --b(4)--------------- determination of each (MenA, C, W-135 and Y) conjugate and Menveo® MenA Lyo.

4.  Please clarify the storage temperature --b(4)----------- for each (MenA, C, W-135 and Y) polysaccharide and each conjugate throughout the entire BLA submission.

5.  3.2.S.2.5 Process Validation and/or Evaluation, MenA polysaccharide, Page 15 of 29, Line 16; MenC polysaccharide, Page 18 of 33, Line 16; MenW-135 polysaccharide, Page 18 of 31, Line 11; MenY polysaccharide, Page 18 of 29, Line 11:  Please indicate that -----b(4)-------------------------------------------------. 

6.  3.2.S.2.5.Process Validation and/or Evaluation, MenA-CRM Conjugate,
Page 24 of 46, Lines 4 and 5; MenW-CRM Conjugate, Page 22 of 43, Lines 3 and 4 from Bottom; MenY-CRM Conjugate, Page 22 of 43, Lines 3 and 4 from Bottom:  Please confirm the numerical values for the volume of -------b(4)-----------------------------------------

7.  3.2.S.2.5 Process Validation and/or Evaluation, MenA-CRM Conjugate, Page 27 of 46, Line 15; MenC-CRM Conjugate, Page 29 of 48, Line 17; MenW-CRM Conjugate, Page 26 of 43, Line 15; MenY-CRM Conjugate, Page 26 of 43, Line 15:  
-----------b(4)----- -----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------

8.  3.2.S.2.5 Process Validation and/or Evaluation, MenW-CRM Conjugate, Page 19 of 43, Line 13; 3.2.S.2.2 Manufacturing Process and Controls, Page 9 of 18, First Column, Line 12; 3.2.S.2.2 Manufacturing Process and Controls, Page 14 of 18, Line 1; 2.3.S.2 Manufacture, Page 7 of 39, First Column, Line 12; 3.2.S.2.5 Process Validation and/or Evaluation, MenY-CRM Conjugate, Page 19 of 43, Lines 12-13; 3.2.S.2.2 Manufacturing Process and Controls, Page 9 of 18, First Column, Line 12; 3.2.S.2.2 Manufacturing Process and Controls, Page 14 of 18, Line 1; 2.3.S.2 Manufacture, Page 7 of 40, First Column, Line 12:  ----b(4)---- -----------------------------------------------------------------------------

9.  3.2.S.2.5 Process Validation and/or Evaluation, MenW-CRM Conjugate, Page 22 of 43, Line 11; MenY-CRM Conjugate, Page 22 of 43, Line 11:  Please confirm the mass of “--b(4)--------------

CRM₁₉₇
10.  2.3.S.1. General Information, Page 2 of 2, Line 8; 3.2.S.1.3 General Properties, Page 5 of 5, Line 6:   Please confirm that CRM197 contains a --b(4)--- ----------------------------------------------------------------------------------------------------------------------
11.  2.3.S.2. Manufacture, Page 9 of 33:    Line 16    Please confirm “-b(4)-----” instead of -b(4)----

12.  2.3.S.2. Manufacture, Page 14 of 33:    Line 14   Please confirm the Measure unit “mg/ml” and the Acceptance criteria --b(4)-----

MenA-CRM Conjugate
13.  2.3.S.2 Manufacture, Page 10 of 38, First Column, Line 2:  Please confirm the concentration of “-b(4)-” instead of “-b(4)--“

14.  3.2.S.2.5. Process Validation and/or Evaluation, Page 17 of 46:  Table 3.2.S.2.5.1.1-4    Please provide a copy of SOP b(4) 07.189.

15.  3.2.S.2.5.Process Validation and/or Evaluation, Page 24 of 46, Lines 2:  Please confirm that “-b(4)-” instead of “-b(4)----” is used to --b(4)--------.

MenC-CRM Conjugate
16.  3.2.S.2.2 Manufacturing Process and Controls, Page 17 of 20, Line 4:  Please confirm the concentration “-b(4)-” instead of “-b(4)---”.

17.  3.2.S.2.5 Process Validation and/or Evaluation, Page 29 of 48, Lines 15-16; 3.2.S.2.2 Manufacturing Process and Controls, Page 11 of 20, First Column, Lines 5-6; 3.2.S.2.2 Manufacturing Process and Controls, Page 17 of 20, Line 4; 3.2.S.2.3 Control of Materials, Page 8 of 11, First Column, Lines 11-14; 2.3.S.2 Manufacture, Page 9 of 39, First Column, Lines 5-6:  Please clarify the condition of the --b(4)--------------------------------------------
18.  3.2.S.2.5 Process Validation and/or Evaluation, Page 30 of 48, Line 10:  Please clarify the use of “------------b(4)--------------------------------------------------------------” instead of “-----------b(4)-------------------------------------------------------------------.
19.  3.2.S.2.5 Process Validation and/or Evaluation, Page 33 of 48, Line 11:  Please confirm “------------b(4)--------------------------------------------------------------------------” instead of “-----------b(4)--------------------------------------------------------------------- was performed”.

MenW-CRM Conjugate
20.  3.2.S.2.5 Process Validation and/or Evaluation, Page 11 of 43:  Please provide a copy of SOP --b(4)-------.

MenA Lyophilized or MenA Lyo (lyophilized powder, vial, single dose)
21.  2.3.P.3 Manufacture, Page 5 of 8, Figure 2.3.P.3.2-1, Middle Column, Line 3; 3.2.P.3.3 Manufacture, Page 6 of 11, Middle Column, Line 3:  Please confirm the temperature -b(4)- instead of -b(4)-
RECOMMENDATION

Based on the complete review of the submitted CMC information and the Company’s responses to the above comments in the submitted Amendments, I recommend that this BLA be approved.