March 21, 2003 Corrected Approval Letter - Aralast

Our Reference No.:BL 125039/0

James Sesic
Alpha Therapeutic Corporation
5555 Valley Boulevard
Los Angeles, California 90032-3520

Dear Mr. Sesic:

This letter corrects our approval letter of December 23, 2002 regarding Alpha-1-Proteinase Inhibitor (Human) [Aralast].

Our approval letter should have included the following:

Your Biologics License Application for Alpha-1-Proteinase Inhibitor (Human) [Aralast] was approved effective December 23, 2002. Alpha Therapeutic Corporation was authorized to introduce or deliver for introduction into interstate commerce Alpha-1-Proteinase Inhibitor (Human) [Aralast], manufactured at Alpha Therapeutic Corporation, Los Angeles, California, under U.S. License No. 0744.

Under this license, you are authorized to manufacture Alpha-1-Proteinase Inhibitor (Human) [Aralast] at your Los Angeles, California location, in dosage strengths of 0.5 gram and 1.0 gram per vial. Alpha-1-Proteinase Inhibitor (Human) [Aralast] is indicated for augmentation therapy in patients having congenital deficiency of alpha-1-proteinase inhibitor with clinically evident emphysema.

Changes to the product, production processes, location of production processes, equipment, facilities, or responsible personnel are required to be reported to FDA as specified in Title 21 Code of Federal Regulations (CFR) Section 601.12.

All adverse experience reports should be submitted according to 21 CFR 600.80 to the Center for Biologics Evaluation and Research, HFM-210, Food and Drug Administration, 1401 Rockville Pike, Rockville, Maryland 20852-1448. In addition, safety related information obtained in the course of ongoing clinical studies should be reported to BB-IND ---- in accordance with 21 CFR 312.32. It is also requested that distribution reports be submitted according to 21 CFR 600.81.

As agreed upon in your letter, dated December 23, 2002, the following post-marketing commitments must be fulfilled:

 

1. Alpha Therapeutic Corporation will conduct a phase IV study, in part, to further verify changes in levels of alpha-1-proteinase inhibitor in epithelial lining fluid. A study protocol will be submitted for review by the FDA no later than April 1, 2003, and the final study report will be submitted to the FDA within one year after approval of the study protocol.

    

2. Alpha Therapeutic Corporation will place the first three lots of Aralast manufactured post-licensure on stability study. Two of the three lots will be the same fill size (either 0.5 gram or 1.0 gram ) and one (1) of the lots will be the other size.

    

3. Alpha Therapeutic Corporation will submit a post-marketing report every six months that will include: a list of all bulk and final container lot numbers assigned; the disposition of every bulk and final container lot; a copy of deviation report(s) issued for any bulk lot or any final container lot that is not released; and for each training lot, an identification of the step in the process at which the production was halted and an indication of any in-process intermediate not meeting acceptance criteria. In addition, the six month report will include the final container tri-n-butyl phosphate level for each lot that is taken to final container.

    

4. Alpha Therapeutic Corporation will include in its periodic, post-commitment reports the stability data from Lot Nos. ---------------, and ------- to support the Fraction IV1+IV4 paste dating period (-- months when stored at --°C or colder).

    

5. With regard to post-licensure stability studies, Alpha Therapeutic Corporation will implement a ----------------------------------- method and submit these data with other stability data. If --- test results are obtained by using a method not yet validated, a note to this effect will be added to the data sheet. It is expected that this test method will be validated within 6 to 8 weeks of licensure.

    

6. Alpha Therapeutic Corporation will annually place a lot of Aralast on stability study. The fill size of the lot (0.5 gram or 1.0 gram) will vary on alternate years.

    

7. Full stability protocol testing will be conducted at all time points for all lots of Aralast on test post-licensure until such time that Alpha Therapeutic Corporation submits a pre-approval supplement requesting a deletion of some time points. Stability studies will reflect a worst case scenario for labeled storage conditions.

You are required to submit reports of biological product deviations in accordance with 21 CFR 600.14. All manufacturing deviations, including those associated with processing, testing, packaging, labeling, storage, holding, and distribution, should be promptly identified and investigated. If the deviation involves a distributed product and may affect the safety, purity, or potency of the product, which meets the other criteria in the regulation, a report must be submitted on Form FDA-3486 to the Director, Office of Compliance and Biologics Quality, Center for Biologics Evaluation and Research, HFM-600, 1401 Rockville Pike, Rockville, MD 20852-1448.

Please submit all final printed labeling at the time of use and include implementation information on FDA Form 2567. Please provide a PDF-format electronic copy as well as original paper copies (ten for circulars and five for other labels). In addition, please submit two draft copies of the proposed introductory advertising and promotional labeling with an FDA Form 2253 to the Center for Biologics Evaluation and Research, Advertising and Promotional Labeling Branch, HFM-602, 1401 Rockville Pike, Rockville, MD 20852-1448. Final printed advertising and promotional labeling should be submitted at the time of initial dissemination, accompanied by an FDA Form 2253.

All promotional claims must be consistent with and not contrary to approved labeling. No comparative promotional claim or claim of superiority over other products should be made unless data to support such claims are submitted to and approved by the Center for Biologics Evaluation and Research.

We acknowledge your commitment to have third party review performed on every fourth lot of Alpha-1-Proteinase Inhibitor (Human) prior to submission for lot release. FDA further reminds Alpha Therapeutics Corporation that manufacture of this product is subject to the terms and conditions of the Consent Decree of Permanent Injunction, entered on February 3, 1998.

It is recommended that a copy of this letter be available for review at the time of FDA inspections.

Sincerely yours,

--- signature ---

Basil Golding, M.D.
Acting Director
Division of Hematology
Office of Blood Research and Review
Center for Biologics Evaluation and Research