From: Rana. Pratlbha
Sent: Tuesday, November 03, 2009 11:44 AM
To: 'Paula.Hines@cslbehring.com'; PauI.Hartmann@cslbehring.com'
Subject: STN 125350/0 Information Request
To: Paul Hartmann
CSL Bebring AG
Date: November 3, 2009
This is regarding your BLA submission STN 125350/0 for Immune Globulin Subcutaneous (Human), 20% Liquid, submitted to the Agency on April 30, 2009. FDA continues with the review of the referenced submission and requests CSL Behring AG to provide the following information.
1. The proposed specification for Appearance "...light brown solution (b)(4)" represents a reduction in product quality standards compared to the current IgPro10 specification. Please provide an appropriate justification for the lowering of this specification. Also, please provide additional information on the following related items:
2. Please provide appropriate justifications for the lack of final container specifications for the following physicochemical and biological requirements:
- (b)(4) redaction
- (b)(4) redaction (at release and at end of shelf life)
- (b)(4) redaction (upper and lower limits)
- (b)(4) redaction
- Pryogen test
In addition, please provide the method SOPs and validation reports for each of the test methods used.
3. Please specify the following "other characteristics/batch-related requirements":
- Visual inspection (100% of the bottles are controlled)
- Date of manufacture
- Transport conditions
4. When using Reference Immune Globulin Lot 176 (a 16.5% IgG solution) for purposes of meeting the minimum potency requirements for anti-measles and anti-polio type 1 in IgPro20 (a 20% IgG solution), the potency ratios should be adjusted to correct for the difference in IgG concentration. Thus, the adjusted minimum ratio for anti-measles for lot release of IgPro20 should be (b)(4) if the required ratio for a 16.5% IgG solution is set at (b)(4). Please use the adjusted ratio in the lot release protocol.
5. For diphtheria antitoxin, the specification listed in Table 3 (Batch analysis report, pg 8 of 10) is (b)(4). Please use the US Standard Diphtheria Antitoxin for validation and express the specification for lot release as U (units)/mL. The minimum ratio for a 16.5% IgG solution is 2 units (U)/mL and hence the adjusted ratio for IgPro20 is close to (b)(4). Please provide the conversion ratio between IU and U.
6. New WHO Reference Reagents (RR) for testing (b)(4) in immune globulin products were established recently, along with the reference test, (b)(4) (b)(4). Because FDA CBER is harmonizing with the EDQM to adopt these new (b)(4) standards, we recommend that you revise your (b)(4) testing with the following measures:
- Replace your current (b)(4) test method (the (b)(4) method) with the recommended reference test (the (b)(4). To support this change, please provide your methods SOP and methods validation data.
- Use the WHO Reference Reagents, CBER Lots (also known as (b)(4) (b)(4) respectively) to standardize your testing. (FDA CBER can provide you a few vials of these standards upon request.)
- Revise your (b)(4) specifications to "(b)(4) (b)(4)"
7. In your validation of your : (b)(4) test method, you were able to demonstrate a linear range of (b)(4) IU/mL, which was adequate for testing IgProl0losts, but not IgPro20 lots. Please re-validate your method's linear range with (b)(4) amounts that will adequately cover IgPro20's proposed specification of (b)(4).
8. You submitted method summaries and validation reports for the Parvovirus B19 NAT methods of the (b)(4) however, their intended uses were not specified.
- Please clarify which methods will be used to test Bl9 in:
i. (b)(4) and manufacturing pools
ii. Source Plasma and recovered plasma
- Please provide additional information regarding the testing sensitivities for (b)(4) NAT screening and cut-off levels in terms of original plasma donations being excluded from manufacturing.
9. There are conflicting reports in your submission regarding your endotoxin test method and specification. In the Biological Requirements section, the method and specification are listed as Q000443D and,(b)(4) respectively. Meanwhile, in the Characterization of Impurities section, the method and specificalion are listed as Q000081D and (b)(4) (if using (b)(4) test), respectively. Please clarify.
10. For your anti-Polio Type 1 method validation, please tabulate the validation results (in IUlmL) side-by-side with the equivalent values in "x Ref 176 CBER" for easier comparison.
Please submit a response to this request as an amendment to the file by November 25,2009.
Pralibha Rana, M,S.
Regulatory Project Manager
Division of Blood Applications
1401 Rockville Pike
Rockville. MD 20852
Office: (301) 827-6124
Fax: (301) 827-2857