Vaccines, Blood & Biologics

October 2, 2000 Approval Letter - CroFab

Public Health Service
Food and Drug Administration
1401 Rockville Pike
Rockville, MD 20852-1448

October 2, 2000

Ms. Carol P. Clark-Evans
Protherics Inc.
(a wholly-owned subsidiary of Protherics PLC)
1207 17th Avenue S., Suite 103
Nashville, TN 37212

Dear Ms. Clark-Evans:

Your Biologics License Application for Crotalidae Polyvalent Immune Fab (Ovine) for the treatment of minimal and moderate North American Crotalidae envenomation is approved effective this date. Protherics Inc. (a wholly-owned subsidiary of Protherics PLC), is hereby authorized to introduce or deliver for introduction into interstate commerce Crotalidae Polyvalent Immune Fab (Ovine), manufactured at Protherics Inc. (a wholly-owned subsidiary of Protherics PLC) under U.S. License No. 1575.

Under this license you are authorized to introduce or deliver for introduction into interstate commerce Crotalidae Polyvalent Immune Fab (Ovine), in a single nominal dosage strength, with minimal potency determined as neutralizing activity against venom from the pit viper species C. atrox, C. adamanteus, C. scutulatus, and A. piscivoris, of 1350, 800, 5210, and 460 ED50 units/vial respectively. Under this authorization, you are approved to manufacture Crotalidae Polyvalent Immune Fab (Ovine) drug substance at your Wales, United Kingdom facility and drug product, including filling and packaging, at your [----------------------------------------------------------------------------]. Changes to the product, production process, location of production process, 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.

The dating period for this product shall be 30 months from the date of manufacture when stored at 2-8C. The date of manufacture shall be defined as the date of the initial sterile filtration of the formulated bulk. Results of ongoing stability studies should be submitted throughout the dating period as they become available.

We acknowledge the following actions you have committed to take following licensure of Crotalidae Polyvalent Immune Fab (Ovine):

Regarding continued clinical studies:

  1. Protherics commits to conducting a Phase 4 study to monitor a surrogate clinical endpoint to determine whether it can be used as a quality control parameter to detect changes in product quality that are clinically important. If appropriate, Protherics commits to trend and evaluate results for commercial batches in a subsequent monitoring phase of the study. A copy of the protocol for this study was electronically mailed to the Agency on September 28, 2000.

    Regarding process validation:


  2. [-------------------------------------------------------------
    ------------------------------------------------------------------------------------------------] for residual papain. Protherics acknowledges that this erratic behavior does not provide sufficient assurance of consistent performance. Protherics is currently [-----------------------------------------
    -------------------------------------------------------]. Protherics commits to completing this validation and submitting the results in its first annual report.


  3. Protherics confirms its commitment to carrying out Validation Plan No.CRO/PrP/005, "Validation of Column Lifetime [----------------------] CroFab" (refer to Amendment 013, pages 016 - 022). Cumulative study results will be submitted in annual reports, as data become available.


  4. Protherics agrees to perform a lifetime validation study of [------------------------------------------------------------------------------]. This study will be done concurrent with use of the ---------------------------------] will be performed prior to processing of each batch, which translates to approximately every 6 to 7 runs, as well as post storage. A [---] method will be developed and validated within 2 months, at which point lifetime testing will be initiated. The cumulative study results will be submitted in the annual reports, as the data becomes available.


  5. Protherics commits to validating the proposed reprocessing procedures, [---------------------------------------------------------------------------------------------------------------------------------], in the following way. For the first three lots to be reprocessed by each method, Protherics will submit a supplement to the BLA for a one-time exemption for each lot. The first lot reprocessed by either method will be included in the stability program. The supplement for the third lot processed by either method will include a request for approval of the reprocessing method itself, and will include both the final container analysis results for all three lots made using that method, and the results from lots placed on the stability program.

    Regarding affinity matrix storage solution:


  6. Protherics commits to continue seeking an affinity [---------------------------] that does not contain thimerosal. Specifically, they will perform the studies described in Protocols QCM/DSP/001, [----------------------------------------------------------------------------------] and CRO/DSP/002, "Sanitization of CroFAb® Venom [-------------------------------------------------]", as submitted in Amendment 007 (Volume 3, pages 241 - 252).

    Further characterization will also be done of Fab, [-------------------------------------------------
    --------------------------------------------------------------------------------------------------------- --------------------------]. The maximum validated storage time for manufacturing use will be determined by the results of the study. This characterization will be performed on the formulated bulk solution and will include assessment of Fc, papain, and albumin content, and of specific activity as ED50 (mg/mouse). As a condition of implementation of the alternate sanitizing solution, the acceptance criteria will be the approved in-process specifications for the formulated bulk product.

    Regarding final container product specifications:


  7. Protherics commits to re-evaluating the batch results for impurities in the final product (papain, albumin, and mercury) for a period of one year post-licensure. This data will be used to determine if production lots consistently contain amounts of these impurities, which are significantly lower than the final product specifications. In that case, specifications will be made more stringent (i.e., tightened). The results will be submitted in the first annual report.


  8. Protherics commits to continuing the stability studies for lots 200058 and 200135 through 30 months, and will submit the results of testing to CBER, for each lot, when such testing is complete.


  9. CBER acknowledges the commitments made in the August 30, 2000 letter to:


    1. evaluate the in-process microbial specifications and environmental monitoring limits at the next annual review, and


    2. perform enhanced testing of the lyophilized final product on the next 3 production runs.

Please be advised that the data submitted on August 30, 2000 do not support the 16 hour claim for a prolonged filling time for this product. The data submitted to date supports a 4 hour filling time only.

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

Please submit three (3)copies of final printed labeling at the time of use accompanied by Part II of FDA Form 2567 with completed implementation information. In addition, you may wish to submit your proposed introductory advertising and promotional campaign. If so, please submit three (3) copies of the proposed material in draft form with Part I of the FDA Form 2567/2253 to CBER, Advertising and Promotional Labeling Staff (APLS), HFM-602, 1401 Rockville Pike, Rockville, Maryland 20852-1448. Promotional claims should be consistent with and not contrary to the approved labeling. No comparative claims or claims of superiority over other similar products should be made unless data to support such claims are submitted to and approved by the Center for Biologics Evaluation and Research. Final copies of advertising and promotional materials should be submitted at the time of use with Part II of FDA Form 2567/2253 to APLS. Please include copies of the approved labeling with your proposed or final copy of advertising and promotional materials submitted to CBER.

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


Sincerely yours,


--- signature ---

Jay S. Epstein, M.D.
Office of Blood Research and Review
Center for Biologics Evaluation and Research

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