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U.S. Department of Health and Human Services

Vaccines, Blood & Biologics

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Vaccines

Record of Telephone Conversation, March 20, 2012 - MenHibrix

 

Submission Type: BLA    Submission ID: 125363/0    Office: OVRR
Product:
Meningococcal Groups C and Y and Haemophilus b Tetanus Toxoid Conjugate Vaccine
Applicant:
GlaxoSmithKline Biologicals
Telecon Date/Time: 20-Mar-2012 12:50 PM        Initiated by FDA? Yes
Telephone Number:
Communication Categorie(s):
1. Information Request

Author: KIRK PRUTZMAN
Telecon Summary:
Lot Release Protocol IR and CMC review IR
FDA Participants: KIRK PRUTZMAN, JOSEPH TEMENAK, DAVID STATEN
Non-FDA Participants: JODY GOULD, NORRIS PYLE
Trans-BLA Group: No

Related STNs: None
Related PMCs: None
Telecon Body:
Dear Jody,

Please find attached an Information Request for the Lot Release Protocol and an Information Request regarding issues identified by the product reviewers. 

Regards,

Kirk Prutzman, PhD
Food and Drug Administration
Primary Reviewer/Regulatory Project Manager
CBER/OVRR/DVRPA/CMC3
1451 Rockville Pike (WOC2)
Room 2241
HFM-481
Rockville, MD  20857
Phone:  (301) 796-2640

IR Comments (DBPAP)

1.         In your response to Question 11a, you provide the validation data for the -----(b)(4)--- used at ---(b)(4)--- to quantify -------------(b)(4)---------------.  Please address the following concerns surrounding the validation.

a.         Identify each of the three major peaks shown in TT ------(b)(4)------ (Figures 1-3).

b.         Please provide a description of how ----------(b)(4)---------- is calculated from the validation data in Figures 1-3.

2. You propose a ---(b)(4)---.  You also propose a -------(b)(4)-------  release specification of not less than (b)(4) for Purified TT measured directly        -----------(b)(4)------------ in Belgium.  In your response to Question 12, you propose a -------(b)(4)------- stability specification of not less than (b)(4) for Purified TT manufactured at ---(b)(4)---. 

a. Please revise your stability specification to not less than (b)(4) so that it is in line with the specification needed to be used for further manufacture. 

b. You propose a (b)(4) month expiration date on Purified TT based on a ------(b)(4)-- stability specification of not less than (b)(4).  Using a stability specification for ------(b)(4)------ of not less than (b)(4), you only have data to support an expiration date of (b)(4) months.  Please revise your expiration date to ---(b)(4)---.

c.The -------(b)(4)------ results for Purified TT are known to decrease over time.  To ensure that a -------(b)(4)------ result of not less than (b)(4) is obtained at the end of expiry, the -------(b)(4)------ content at release should be closer to not less than (b)(4).  Please comment.

3. In your response to Question 14, you state that values for free polysaccharide are reported as a limit when the result is less than the first calibration point.  For consistency, if the value for free polysaccharide is below the limit of quantitation it should be reported as < LOQ value (i.e., ---(b)(4)--- for Hib-TT).

4. In your response to Question 16, you provide the statistical method (process performance indices) used to calculate specification.  Using this method for setting endotoxin specifications is not appropriate due to the high number of <LLOQ values.  Assigning the <LLOQ values to be equal to the LLOQ values makes the estimated mean and thus the upper specification higher than it should be.  Please set your ---(b)(4)-- specifications using a scientifically justified method to ensure process consistency.

5. You provided the validation data for the ---------(b)(4)--------- of Purified and        ---(b)(4)--- TT in this response.  We note that you had originally committed to provide as a PMC in response to Question 40b of the CR letter sent on June 11, 2010.  The validation submitted does not include an evaluation of intermediate precision.  Please provide data that demonstrate that the assay intermediate precision is adequate for its intended use.  

 

  1. In the header, drop the phrase:  Licensed Name of the Product, and only list the product name.  Also, remove the trade name from the header section. 
  2. In the header, cc: should be completed. 
  3. On page 1, a line may be added before the date of manufacture to list the trade name of the product, if desired.
  4. On page 1, delete Virus strain.
  5. On pages 2 and 3, remove the word antigen from tables.
  6. On page 3, remove the word stabiliser from in front of TRIS.
  7. Please insert a Genealogical Tree similar to what was included on page 3 of STN125347 HIBERIX Lot Release Protocol.  Include strain and/or batch numbers.
  8. Pages 5-8 PURIFIED TETANUS TOXOID (TT) BULK:
    1. ---(b)(4)--- tetanus toxoid by (b)(4) should be added.  The specification proposed is not less than (b)(4), however, we are still discussing this.
    2. On page 8, the sodium chloride is stated as between -----(b)(4)----- mg per ml.  The BLA states the spec as -----(b)(4)----.
    3. On page 8, Absence of Tetanus Toxins in Guinea Pigs and Irreversibility of Tetanus Toxoid in Guinea Pigs, please use template provided.  (Another format is acceptable, as long as the suggested data in the table are provided).  See the templates at the end of the comments for the Irrevesibility of Tetanus Toxoid in Guinea Pigs and the Absence of Tetanus Toxins in Guinea Pigs.
  9. Pages 9-11  PURIFIED ------(b)(4)------ TETANUS TOXOID (TT) BULK
    1. ----(b)(4)----- tetanus toxoid by (b)(4) should be added.  Specification is not less than (b)(4) of the total surface as ---(b)(4)--- TT.
    2. ---(b)(4)--- should be added.  Specification is not more than ------(b)(4)--------.
    3. -----(b)(4)----- Content should be added.  Specification is ----(b)(4)-----.
  10. On pages 14, 25, 35 and 46, please spell out “µ” (----------(b)(4)----------).
  11. Page 16 HAEMOPHILUS INFLUENZAE TYPE B (PRR’P-TT) CONJUGATE (b)(4)
    1. The BLA calls this Purified Activated Hib.
    2. PRRP content by --(b)(4)-- should be added.  Specification is not less than ---(b)(4)---.
    3. Free (b)(4) Content should be added.  Specification (b)(4) of total surface.
    4. Activation Ratio should be added.  Specification is ----(b)(4)----.
  12. Pages 17-20 HAEMOPHILUS INFLUENZAE TYPE B (PRR’P-TT) CONJUGATE (b)(4)
    1. (b)(4) should be added.  Specification = ---(b)(4)---
    2. On page 18, the specification for Free PRPP polysaccharide by (b)(4) is not more than (b)(4).  The BLA states the specification is not more than (b)(4).
  13. Pages 21-22 and 31-32 PURIFIED --------------(b)(4)----------------- TETANUS (T) TOXOID BULK
    1. ---(b)(4)--- tetanus toxoid by (b)(4) should be added.  Specification is not less than (b)(4) of the total surface as ----(b)(4)----.
    2. Residual (b)(4) Content should be added.  Specification -(b)(4)- TT.
    3. ---(b)(4)--- should be added.  Specification is not more than -------(b)(4)---------.
    4. On pages 21-22 and 31-32 The test for Absence of Tetanus Toxins in Guinea Pigs and Irreversibility of Tetanus Toxoid in Guinea Pigs should be added, refer to comment 8.c. above, see template.
  14. Pages 23-27  MENINGOCOCCAL POLYSACCHARIDE TYPE C PURIFIED BULK
    1. ---(b)(4)--- specification is proposed as not more than --(b)(4)-- PS.  We are still reviewing this specification.
    2. ----(b)(4)---- by ----(b)(4)----.  Please spell out µ.
  15. Pages 28-30  NEISSERIA MENINGITIS POLYSACCHARIDE TYPE C - TETANUS TOXOID (Men C-TT) CONJUGATED BULK
    1. ---------(b)(4)----------- should be added.  Specification not less than --------(b)(4)----- PS.
    2. Identity by (b)(4) should be added.  Specification is positive.
  16. Pages 33-36 MENINGOCOCCAL POLYSACCHARIDE TYPE Y PURIFIED BULK
    1. ---(b)(4)--- specification is proposed as not more than ---(b)(4)--- PS.  We are still reviewing this specification.
    2. ---(b)(4)--- by ---(b)(4)---.  Please spell out µ.
  17. Page 37 MENINGOCOCCAL POLYSACCHARIDE TYPE Y ---------(b)(4)---------- – BULK
    1. ------------------(b)(4)------------------- should be added.  Specification is not more than (b)(4) before ---(b)(4)---.
    2. Assymetry by (b)(4) should be added.  Specification = ---(b)(4)---.
    3. Viscosity should be added.
  18. Pages 38-40 NEISSERIA MENINGITIS POLYSACCHARIDE TYPE Y - TETANUS TOXOID (Men Y-TT) CONJUGATED (b)(4)
    1. -(b)(4)- by -(b)(4)- should be added.  Specification not less than -------------(b)(4)------------------.
    2. Identity by (b)(4) should be added.  Specification is positive.
    3. On page 38, the specification for protein content by (b)(4) is not less than (b)(4) per mL.  The BLA states that the specification is not less than ------(b)(4)------.
    4. On page 38, the specification for polysaccharide Y content by ----(b)(4)----- is not -----------(b)(4)-----------.  The BLA states that the specification is not less than     -------(b)(4)------.

 

  1. Pages 42-49 FINAL CONTAINER
    1. Sucrose by (b)(4) should be added.  Specification = ---------(b)(4)---------.
    2. ---(b)(4)--- should be added.  Specification = ------(b)(4)------.
    3. ----(b)(4)---- by (b)(4) should be added.  Specification = --------(b)(4)---------.
    4. On page 43, the test is written as polysaccharide C content by ---(b)(4)--- with a specification of not less than (b)(4) of the target value.  The BLA states that polysaccharide C content is determined by calculation with a specification of not less than (b)(4).
    5. On page 44, please add the word “Total” in front of polysaccharides PSC-PSY content by (b)(4).
    6. On page 46, the ------(b)(4)------ is stated to be determined by -------(b)(4)-------.  The BLA states -----(b)(4)------.
    7. On page 48, the ---(b)(4)--- specification is not more than ------(b)(4)--------.  We are currently reviewing a specification of -------(b)(4)--------.
    8. On page 49, please include the information in the format suggested for Abnormal Toxicity-General Safety.  (Another format is acceptable, as long as the suggested data in the table are provided.) 
  2. Throughout the Lot Release Protocol, inconsistent names are used for the manufacture steps.  In bold is what is at the top of each section, after the hyphen is at the top of the subsequent pages, this is not enough information to know clearly what is being reviewed.  In red is what we could find that corresponds in the BLA submission, those highlighted definitely need to change.

As much as possible please be consistent with the terminology of the ---b(4)--------used in the BLA to avoid confusion. 

Pages 5-8  PURIFIED -----(b)(4)------- TETANUS TOXOID (TT) BULK - Concentrated  
BLA – GSK Bio b(4). Purified Tetanus toxoid specifications

Pages 9-11  PURIFIED ------(b)(4)----- TETANUS TOXOID (TT) BULK – Purified Bulk  
BLA – Purified and ----(b)(4)---- tetanus toxoid

Pages 12-15 HAEMOPHILUS INFLUENZAE TYPE B (Hib) – Purified Bulk 
BLA – Purified polysaccharide (Hib)

Page 16  HAEMOPHILUS INFLUENZAE TYPE B (PRR’P-TT) CONJUGATE BULK – Purified Bulk Activated
BLA - Activated polysaccharide

Pages 17-20 HAEMOPHILUS INFLUENZAE TYPE B (PRR’P-TT) CONJUGATE BULK – Bulk Conjugate
BLA – Hib TT bulk conjugate

Pages 21-22 and 31-32 PURIFIED --------------(b)(4)--------------- TETANUS (T) TOXOID BULK –Purified Bulk
BLA – Purified and ---------(b)(4)---------- tetanus toxoid

Pages 23-27  MENINGOCOCCAL POLYSACCHARIDE TYPE C PURIFIED (b)(4) – Purified Bulk
BLA – N. meningitides Serogroup C Polysaccharides

Pages 28-30  NEISSERIA MENINGITIS POLYSACCHARIDE TYPE C - TETANUS TOXOID (Men C-TT)
CONJUGATED BULK – Bulk Conjugate
BLA – Purified MenC-TT bulks

Pages 33-36 MENINGOCOCCAL POLYSACCHARIDE TYPE Y PURIFIED BULK –Purified Bulk
BLA - N. meningitides Serogroup Y Polysaccharides

Page 37 MENINGOCOCCAL POLYSACCHARIDE TYPE Y ---------(b)(4)----------- - BULK – Bulk
BLA – ------(b)(4)------- MenY

Pages 38-40 NEISSERIA MENINGITIS POLYSACCHARIDE TYPE Y - TETANUS TOXOID (Men Y-TT)
CONJUGATED BULK – Bulk Conjugate
BLA – Purified MenY-TT bulk

Page 41-  FINAL BULK  BLA – Hib-MenCY-TT Final Bulk

Pages 42-49 FINAL CONTAINER                BLA - Hib-MenCY-TT Final Container

 

  1. For Sterility and (b)(4) tests, use the full template presentations for the drug substance (conjugates) and final container.  We recognize that (b)(4) testing is not done on the bulk conjugates.  In this case the template presentation is only needed for final container.  For Sterility and (b)(4) tests on intermediates the results may be presented in table format similar to that shown in comment 22.
  2. Except for tests where more information has been requested, the following format may be used to present the data throughout Lot Release Protocol.  (Another format is acceptable, as long as the suggested data in the table are provided):

Example:


Test

Analytical Method

Test Date

Results

Specifications

pH

 

 

 

 

Identity

 

 

 

 

Protein

 

 

 

 


 

 

Absence of toxin for tetanus toxoid on Guinea pigs

Method Reference:                                     ---(b)(4)--. 
Weight of Guinea Pig (G.P.)                        xxx-xxx g:
Route of injection                                        Subcutaneously


Toxoid conc.
Lot Number

Date injected

Number of G.P.

Dose
(mL)

Lf/mL

Days
Obs.

Number of G.P. survive

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Observation (obs.) End Date:

 

Result:
Specification: No tetanus toxicity

 

 

Irreversibility of test for tetanus toxoid on Guinea Pigs

Method Reference:                                     ---(b)(4)--. 
Weight of Guinea Pig (G.P.)                        xxx-xxx g
Route of injection                                        Subcutaneously
Date of end of observation (obs.):

Toxoid conc.
Lot Number

Lf/mL

Incubation Temperature (°C)

------(b)(4)------- (beginning and end)

Number of G.P.

Date Injected

Days
Obs.

Number of G.P. survive

 

 

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

 

 

 

 

 

 

 

(b)(4)

 

 

 

 

 

 

 

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

 

 

 

 

 

 

 

(b)(4)

 

 

 

 

 

 
Result:
Specification:  No reversion to toxicity

 

 Sterility

Method used:                                                            
Type:   for example, Viral Harvests, Bulk, Final Container
-b(4)- Test Date:                                         
Media Growth Promotion Test Date:          b(4)____________________
b(4)_____________________

On Test Date

Medium/Temperature

Tested Quantity

Off Test Date

 

 

 

 

 

 

 

 

Result:
Specification:

 

General Safety Test

Method used:                                                 Specification:

On Test Date

Animal

Route of

Amount

Weight

(gm)

Off Test Date

 

Species

Inoculation

Inoculated

Initial

Final

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Result:


 

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

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

 

Test date                                                                     

Name of Lysate Manufacturer                                                 
           
Lysate Lot number                                          

 

Standard Curve Information

Endotoxin lot number                                                             

Endotoxin Mfr/Supplier                                                           

Standard Curve (performed for each analytical session)

 

Standard Endotoxin Concentration
EU/mL

Mean Onset Time
(seconds)

CV%

1

 

 

 

2

 

 

 

3

 

 

 

4

 

 

 

5

 

 

 

6

 

 

 

 

Correlation coefficient (r): ___________   Intercept: _________           Slope: ___________

Product Test Summary

MVD                            

 

Results
EU/mL

Test Dilution

Mean Onset Time

CV%

% Spike Recovery

Beginning

 

 

 

 

 

Middle

 

 

 

 

 

End

 

 

 

 

 

Results (EU/mL): ___________________ Specifications: _______________________________

Calculations or additional comments