Food and Drug Administration
Center for Biologics Evaluation and Research
DATE: January 23, 2003
FROM: Michael Schmitt, Ph.D.
Committee Chair for Aventis Pasteur Inc. (API) supplement 103919/5018
SUBJECT: Recommendation for approval of supplement
After having reviewed all documents relating to API supplement STN 103919/5108, I recommend approval of the supplement. In this supplement, API requested approval of a preservative-free (pf) single dose presentation for Diphtheria and Tetanus Toxoids Vaccine Adsorbed, for Pediatric Use [DT (pf)]. Information and data provided in support of approval for DT (pf) includes a description of the manufacturing process, the results of validation studies, and complete six-month stability data for one lot of the product (lot # ----------). All stability tests performed by API met required specifications for bulk vaccine and final container. CBER tested bulk lot -------- for Hg and Al content, and both compounds met specifications. CBER did no other testing. An updated package insert was also included in the original submission, which was later revised as requested by CBER. A letter detailing five post-approval commitments was also submitted to the file.
The ------------- components in ------------- are manufactured using the same process as that employed in the DT (pf) vaccine, and the current supplement contains much of the same information that was used to support the approval of -------------. The shared information and data between the earlier ------------ supplement and the current DT supplement is extensive and includes portions of the manufacturing process, and validation studies for manufacturing, cleaning, testing, and aseptic processing. The method by which thimerosal is removed from the final vaccine formulations as well as the final Hg specification is also identical between -------- -------- and DT (pf). Additionally, the --- months of stability data that has so far been accumulated for ------------, provides additional supporting data for approval of DT (pf). Much of the new information in the current supplement that was not present in the ------------ supplement describes process validation studies that were done in support of the ------------ and DT manufacturing process, however much of this information was also reviewed in an earlier submission (July 16, 2002).
During the process validation studies for DT (pf) it was noted that ----------------- tanks in which the bulk lot was dispensed had aluminum specifications outside of the acceptable range (tanks --and --). The firm suggests that the --- ml sample taken from the tanks was not a representative sample and was the reason for the OOS result (usually a ----- sample is taken from the bulk prior to dispensing into the ----- tanks). A new protocol was subsequently written for sampling from the tanks, and tanks ------- were re-sampled and met Al specifications. Tank - could not be re-sampled since it had already been filled. In a telecon with the firm on December 19, 2002, the firm was asked about the OOS result, and CBER requested that API submit the protocol that was used for sampling from the tank (protocol B002569, submission received on January 10, 2003). The firm was also informed in a subsequent telecon on January 13, 2003 that the final container sublot that was filled from tank 1 could not be released until aluminum testing was done on those final containers. API agreed not to release this sublot (----------) until aluminum testing on final containers was done, and this agreement was included as part of a post-approval commitment (see below).
In a telecon with API on January 15, 2003, CBER representatives requested that API submit a revised package insert (PI) that contains only language related to the reduction of thimerosal. A couple of other minor changes to the PI, including a statement that indicated that all meat used for growth medium was US sourced, was also accepted. Additional minor modifications to the PI were requested by CBER in a telecon with API on January 21, 2003, and in a brief follow-up telecon later that day, API representatives stated that documentation that supported the US sourcing of meat used for their growth medium was submitted to CBER on 6/21/00.
During the telecon on January 15, 2003, CBER representatives requested that API submit the following five post-approval commitments to the file:
- Real time stability data on final containers for lot --------------, will be accumulated at the following intervals: 9, 12, 18, 24, 30, and 36 months, and these stability data will be provided to CBER as they become available. In addition, stability data from bulk vaccine lot -------- will be provided to CBER at the 9, 12, and 15-month time points as soon as those data are made available.
- Two additional lots of single dose preservative-free DT Adsorbed will be added to your current stability program as they are manufactured. You have indicated that the approximate dates of manufacture for these lots are ---------------------- and -----------------------------.
- Validation studies on the manufacturing process for the DT Adsorbed vaccine will be conducted as outlined in the protocol contained in your submission of October 4, 2002. These validation studies will be conducted for two additional lots of single dose preservative-free DT Adsorbed vaccine with approximate dates of completion in the second quarter of 2003.
- Final container lot ----------- will not be released to the market until after assay results for aluminum content have demonstrated that this lot meets aluminum specifications, and the results of the aluminum assay have been submitted to CBER for review.
- A revised package insert for single dose preservative-free DT Adsorbed vaccine will be submitted as a Prior Approval Supplement following the approval of the revised ---------- package insert that is currently under review at CBER.
A letter containing these post-approval commitments along with the revised package insert was submitted to the file on January 21, 2003.