PUBLIC HEALTH SERVICE
FOOD AND DRUG ADMINISTRATION
To:
Faud El-Hibri
Bioport Corporation
3500 N. Martin Luther King, Jr. Blvd
Lansing, MI 48906
District Address and Phone Number:
CBER, Office of Compliance and Biologics Quality, HFM-605
1401 Rockville Pike
Rockville, MD 20852
(301) 827-6191
Period of Inspection:
11/15-23/99
Type Establishment Inspected:
Biologics Manufacture
Name of Firm, Branch or Unit Inspected:
Same
Street Address of Premises Inspected:
Same
City and State (zip code):
Same
DURING AN INSPECTION OF YOUR FIRM (I) (WE) OBSERVED:
1. The manufacturing process for the production of Anthrax Vaccine Adsorbed is not validated. These process steps include:
a) the fermentation parameters/process;
b) the addition of and adsorption to ------- and the settling time in holding tanks;
c) the formulation operations (downstream processing) of sublots;
d) the pooling process. including mixing to formulate the final bulk drug product (repeat observation from 2/98). There is no validation of the actual mixing process. In addition, on Oct. 28, 1999 FAV053 was formulated with only ------- sublots, whereby ------- sublots are normally used.
e) the holding time for sublots prior to their use in final product bulk (repent observation from 2/98). In addition, the stoppers used to seal the ------- sublot bottles may be reused indefinitely based on visual examination. The integrity of the container/closure system has not been evaluated.
f) the hold time for the sterile formulated bulk drug product (repeat observation from 2/98)
g) the holding times for sterilized Alhydrogel.
2) Regarding assays used for in-process control and further processing decisions of sublots:
a) -------Sublots AV721 and AV744 have been deferred from further use due to
"unusual" ------- results. This assay has not been validated nor does it have
established specifications.
b) The ------- assay for, ------- determination is used to determine when to harvest ------- fermentors. This assay has not been validated. There are no lower limits established for the assay (spec. is stated as---------------) nor do the specifications reflect actual operational experience.
c) pH is recorded throughout the process, however there are no stated specifications.
3) The holding time for the following sterilized equipment has not been validated:
a) Bulk formulation tank;
b) -------- and ------- fermentors;
c) ------- harvest tank;
d) glassware used throughout the manufacturing.
4) Regarding validation of aseptic operations in Bldg 12:
a) The challenges did not include incubation of the media in the various vessels after sampling in order to test the integrity of the sampling process.
b) Out of---- media challenges for Train ----- there is not one single, whole, successful challenge.
c) During the downstream processing, samples are tested following the mock formulation of the sublot and following an overnight hold in the cold room. There is no incubation/testing of the entire formulation bottle.
5) Between May 3, 1999 and November 8,1999, ------- sublots have been discarded during processing, Only 5 lots had deviation reports. No investigations have been performed. Reasons for terminating manufacturing include contaminations in the fermentors, slow growth of the culture and equipment failures.
6) At least 11 sublots and 3 final lots have failed specifications for low -------
a) Determination of ------- by -----------------------------------was validated as of Dec. I997. For lots FAV049 and FAV052, initial tests done using this validated method gave readings of 0.72% and 0.73%, respectively (release specification 0.75%-0.95%). For lot FAV049, further ---- testing gave readings of 0.73% and 0.75%. Testing of FAV049 by USP titration gave a result of 0.78%. However, in the formulation batch record, page 2 of 15, the ---- result is reported as 0.79%. The LIMS report from QC lists the original 0.72% result with the following remark, "99-1124, 0.78% by USP titration." For 1ot FAV052, further ---- testing gave readings of 0.76% and 0.77%. Testing of FAV0S2 by USP titration gave a result of 0.76%. In the formulation batch record, page 2 of 15, the --------- result is reported as 0.76%. The LIMS report from QC lists the original 0.73% result with the following remark, "99-1123, 0.76% by USP titration." There is no investigation reported into the original OOS results, nor were these results determined to be invalid.
b) AV7I9 and AV724 were tested using the ------- method and gave readings at 0.70% and 0.74%, respectively. They were passed for formulation into lot FAV052 using results reported from the U.S.P. method. AV701 had results of 0.72% by the --------- method and 0.75% by USP. It was formulated into FAV051. Again, there has been no investigation into the original OOS.
c) AV700 failed the ------- specification using both the ------- method and the USP method (0.73% from both assays). It was formulated into lot FAV051.
d) FAV053 lists ------- as 0.73% as a passing result in the QA released batch record.
e) Starting with AV805, the sublot formulation has been adjusted to prevent low --- in the final formulation but this change has not yet been reported to CBER.
7) SOP AL00-021-01 addressing OOS results allows for retesting without a predetermined limit to that retesting. In addition, under this SOP a single passing retest value may be substituted for an OOS that has not been determined to be invalid due to an error. For example FAV046 failed
at the one year stability time point at 0.74% (specification:--------------). A single retest is reported at 0.77% (repeat observation from 2/98 and 10/98).
8) The LIMS system used for tracking and trending of QC testing results is not validated. LIMS reports are used by QC and QA for lot release and stability decisions.
9) The deviation system does not:
a) have an established time limit for resolution of investigations (repeat observation: 2/98 and 0/98);
b) define when deviation reports should be included in the batch records. The listing of deviations in the batch records and in the deviation database do not correlate and were frequently found not to match. For example:
l) Sublot AV701 has the following deviations included in the BPR: 99-0538, 99-0561, 99-0722, 99-0792, 99-0775, 99-1284, and 99-0739. However, for sublot AV701, the deviation database lists the following: 99-0538, 99-0561, 99-1284, and 99-0563.
2) There are no deviations included with the BPR for Sublot AV764; However, the deviation database lists deviation 99-0943.
c) adequately address when deviation reports should be written. For example:
1) Sublots AV746, AV800, and AV801 failed purity at the SI sample, but processing continued based on subsequent purity samples. No deviations or investigations were initiated as a result of the failures of the S1 samples.
2) During processing of sublot AV793, the --- fermentor, Train ----- was re-sterilized three times (4 sterilizations total). No deviations or investigations were initiated.
l0) Centrifuge bottles are re-used, cleaned and sterilized up to five times for downstream processing. The integrity of the seal through the centrifuge process over the life time or the bottles and the lids has not been validated.
11) During validation of the sterilization of the filter transfer carts, there was no direct monitoring of the steam penetration into the filters to assure sterilization. Monitoring of the sterilization process was limited to the condensate drains, The ---- micron filter is the sterilization step for the product.
12) Media fills do not reflect operations in that all possible interventions during filling are not modeled.
13) Interventions of less than l0 minutes during filling are not recorded in the batch record. On
11/15/99, three adjustments were made to the filling head positions during the first 43 minutes of filling lot FAV053. These adjustments were not recorded. There is no place on the batch record to record interventions. (repeat observation)
14) The aseptic connection of the ---- bulk final product tank to the filling line is made below the level of the work surfaces in filling room 319, Bldg. 16. There is no assurance of laminar airflow at that level. In addition, once the connection is made, the connected tubing is allowed to rest on the floor.
15) There is no formal document defining the fill volume for the final Anthrax Vaccine multidose vial (l0 doses). By practice, the vials are filled to 5.2 mi. Fill adjustments are reported to be made if the fill level drops to 5.1 mi or below. Fill volume checks are performed using an un-calibrated syringe graduated to 0.2 mis.
16) Final lot FAV053 was pooled on Oct 28.1999 with only ---- sublots due to the breaking of the bottle for sublot AV746 during the pooling process.
a) ---- sublots are normally used and were planned for use in FAV053. There is no indication in the batch record of the cause for using only --- sublots.
b) The remaining sublots AV743, AV748, and AV749 were re-stoppered and returned to the storage and subsequently used in the formulation of FAVO54. The process of removing tile siphons from the sublot bottle and re-stoppering was not included in the aseptic process validation for the pooling and formulation process. There are no deviation reports for this operation.
17) The batch record for final drug product pooling and formulation is filled out after the formulation process.
18) Validations of sterilization processes have not demonstrated a ----- reduction of possible
microbiological load. The validations were performed based on accumulated lethality (F-0) as the primary acceptance criteria. Validations were run using cycles at or near the operating cycle times, using Bls with spore populations of <2.0 x l0^6 CFUs.
19) There are no SOPs addressing the following:
a) Error and Accident reporting;
b) retesting due to OOS results;
c) reject limits from visual inspection of final filled product vials (repeat observation
from 2/98);
d) the one week expiry on the sterilized fermentors and holding tanks for Anthrax Vaccine;
e) the "First-in-First-Out" procedure for the selection of sublots for formulation of' final bulk lots; and
f) redating of lots (repeat observation from 2/98)
20) SOPs and BPRs lack specificity for time frames regarding completion of critical operations. For example:
a) there are no time limits for the Sterile filtration of product between the ----- fermentor and the holding tank, and
b)there is no maximum lime limit for "stirring" to mix sublots in the formulation tank.
21) Limits for exposure of sublots and final product to temperatures above 8°C have not been established. Starting with the formulation of FAV049 in June 1999 tracking of exposure to temperatures above 8°C began for the pooling and formulation process. Previously tracking began with the filling process. Currently the temperature tracking system docs not track individual sublots. For example, the normal formulation operation includes bringing the sublots to room temperature for approximately --- hours prior to the pooling process. Sublots AV743, AV748, and AV749 were originally designated for FAV053 but were returned to the cold room after the operation on Oct 28, 1999. These sublots were subsequently used to formulate FAV054 on Nov. 18,1999. The only record of the repeated warming of these sublots for the two formulation operations is the coldroom log.
22) Regarding the Stability program:
a)The firm is using an as yet unapproved method for calculating potency. (Potency calculation methods currently under review. Ref. No. 91-0079.)
b) Lot FAV040 failed potency at the --- month time point by both the currently approved and the unapproved methods of potency determination. There has been no investigation as required under the Stability SOP QA02-M01-02, nor has an Error and Accident report been filed to CBER
c) Lot FAV044 failed potency by the approved method at the --- month time point. As the firm is using the unapproved method, they did not report this as a failure.
d) Lot FAV046 failed potency by the approved method at both the ~ and ...==- month time points. As the firm is using the unapproved method, they did not report these as failures. Lot FAV046 also failed the NaCl at 1 year.
(This observation relates to the 2/98 observations that addressed the failure to appropriately investigate and report stability testing failures and potency test results.)
23) The environmental monitoring program does not require the identification of isolates if more than ------- colonies are found on a plate, regardless of whether the number of isolates causes an action limit to be exceeded.
24) Manual cleaning of the fermentors and holding tanks is not monitored after every cleaning process.
25) The filters used to sterilize the saline/preservative solution, containing -------- and -------, have not been tested for compatibility with this solution.
26) Calibration of the impellers and recorders for mixing in the ------- fermentors was not in the operational range. The calibrations were performed between -------- and ------- RPM. The batch record calls for the culture to be stirred at ----- RPM.
27) Performance evaluations of the BSCs in Room 212 used for aseptic downstream processing of sublots did not evaluate conditions similar to actual operations. During operations, ------- carboys, ------- 1L centrifuge bottle, two operators, l0 blood agar plates, a number of 50 mL pipettes and a pipette aid are contained in a 6 foot BSC. Performance qualifications ate done under static (empty) conditions.
28) Glove monitoring is not representative of operations for the Downstream processing in Bldg. 12. On 11/17/99, an operator was observed sampling her gloved palm for her glove touch plate sample. During the operation she had been observed using mostly her finger tips to handle containers and other materials. SOP VP02-004-01, covering environmental monitoring in Bldg. 12, specifies that glove samples must be taken, without further instruction
29) SOP 11472.000, effective 2/7/99, "Gowning for Room 307. Building 16" has not been updated to reflect the additional gowning instituted for the main hallway Building 16, third floor.
30) On 11/16/99 carboys of sterilized, prepared, ------- were observed in Refrigerators in room 206, Bldg. 12. These carboys were not labeled for their content. They were labeled only with a sublot number and their expiration date.
The observations noted in this FDA-483 are not an exhaustive listing of objectionable conditions. Under the law, your firm is responsible for conducting internal self-audits to identify and correct any and all violations of the GMP regulation.
