Inspections, Compliance, Enforcement, and Criminal Investigations
K.C. Pharmaceuticals, Inc. 19-Nov-02
Los Angeles District
19900 MacArthur Blvd.
Irvine, CA 92612-2445
November 19, 2002
RETURN RECEIPT REQUESTED
Pramuditya Oen, President
K. C. Pharmaceuticals, Inc.
3220 Producer Way
Pomona, CA 91768
Dear Mr. Oen:
During an inspection of your pharmaceutical and medical device manufacturing facility conducted during the period of May 29, 2002 to June 17, 2002, our investigators found significant deviations from the Current Good Manufacturing Practice (cGMP) for Finished Pharmaceuticals Regulations (Title 21, Code of Federal Regulations (CFR), Parts 210 and 21l), and Medical Devices: Current Good Manufacturing Practice, Quality System Regulations (Title 21, Code of Federal Regulations (CFR), Part 820). These deviations cause your drug products and medical devices to be adulterated within the meaning of Section 501(a)(2)(B) and/or Section 501 (h) of the Federal Food, Drug and Cosmetic Act as follows:
1. Failure to establish and follow adequate procedures to show that each lot of a component (purified water) that is liable to microbiological contamination that is objectionable in view of its intended use, is subjected to adequate microbiological tests before use [2l CFR 211.84(d)(6)]. Specifically, our investigators observed that the purified water system that is used for manufacturing sterile ophthalmic drugs is not adequately controlled or monitored. Your firm failed to investigate high microbiological counts on samples collected on 1/4/02. In addition, on 1/6/02, samples were collected from two locations not specified in procedures as sample locations, reportedly because the bacterial counts from two point of use outlets were "still high after sanitization".
2. Failure to establish laboratory controls that include the establishment of scientifically sound and appropriate specifications designed to assure that drug products conform to appropriate standards of identity, strength, quality and purity [21 CFR 211.160(b)]. Specifically, our investigator observed that practices for sterility testing of Eye Drop products are inadequate, in that your firm has not conducted any study to show that the process (submerging in bleach solution) used on bottles used to package eye drops does not compromise the final package integrity, and result in false negative microbiological test results. In addition, our investigators observed that your firm?s method of handling media used for sterility testing is inadequate, in that you failed to follow manufacturer?s storage requirements. Also, you are not adequately controlling the cooling of the Tryptic Soy Agar (TSA), and were using TSA at temperatures above 45 degrees C, thus potentially giving false negative sterility test results. (The United States Pharmacopeia requirements are that TSA be cooled to at least 45 degrees C. before use.)
3. Failure to follow procedures to assure each batch of drug product required to be free of objectionable microorganisms is tested through appropriate laboratory testing [21 CFR 211.165(b)]. Specifically, our investigators observed that your firm?s investigation into sterility failures is inadequate in that you failed to follow your own SOP, and failed to adequately ascribe the cause of the failure of the sterility test for Eye Drops.
4. Testing and release of drug product for distribution does not include appropriate laboratory determination of satisfactory conformance to the identity and strength of each active ingredient prior to release [21 CFR 211.165(a)]. Specifically, your firm is not testing the products Eye Drops, Advance Relief for the active ingredients Dexter a70, Polyethylene Glycol 400 and Povidone 1%. In addition, there is no testing for the active ingredient Polyethylene Glycol 400 1%.
5. Aseptic processing areas are deficient regarding the system for monitoring environmental conditions [21 CFR 2 11.42 (c) (10)(iv)] and [21 CFR 820.70 (c)]. Specifically, the investigation process used to investigate environmental monitoring excursions and to determine release of product is based partly on results from "in house challenge studies", but there is no approved procedure to define this test method.
6. Changes to written procedures are not drafted, reviewed and approved by the appropriate organizational unit and reviewed and approved by the quality control unit [21 CFR 211.100 (a)] and [21 CFR 820.40 (b)]. Specifically, changes that were not adequately reviewed and approved were made on 7/18/00 to change the frequency of sanitation of the purified water system, and on l/19/01 to change the frequency of microbiological testing of purified water.
7. Written procedures for production and process controls designed to assure that the drug products have the identity, strength, quality, and purity they purport or are represented to possess are inadequate [21 CFR 211.100 (a)]. Also, your firm failed to validate with a high degree of assurance a process, the results of which cannot be fully verified by subsequent inspection and test [21 CFR 820.75(a)]. Specifically, the performance qualification for the purified water system used in the manufacture of sterile ophthalmic OTC drug products and medical devices is not adequate. There is no statistical basis for the acceptance criteria utilized, and the final "Report on Performance Qualification of the Purified Water System" was signed and approved, but deviations reported in the document impacting the performance of the system were not adequately evaluated.
8. Deviations from written production and process control procedures are not justified. [21 CFR 211. 820.100 (a)(2)]. Specifically, a deviation from the approved procedure [redacted] Sterile Filtration of Product" was not appropriately recorded and justified. The process was changed to include in each of the-nozzles used in the aseptic filling of saline solution in room Y-4, with no assessment of the impact of the change on sterile finished products.
9. Written procedures are not adequately established for the cleaning and maintenance of equipment, including utensils, used in the manufacture, processing, packing or holding of a drug product [21 CFR 211.67(b)]. Specifically, the "Artificial Tears Process Equipment Cleaning Validation Protocol" was deficient in that there was no specified evaluation for microbial contamination of product contact surfaces. In addition, the protocol failed to identify and require residue sampling of difficult to clean locations (i.e. nozzles, filter housings),
10. The production area air supply lacks an appropriate air filtration system [21 CFR 211.46(c)] and [21 CFR 820.70 (c)1. Specifically, your firm?s specification states that HEPA filters used for clean rooms are to have an air flow between a high and low flow specification. Five HEPA filter velocities in a clean room were recorded to have average flows outside of the specification. The HEPA filter in another clean room was observed to have flow less than the specification during air handling certificates testing conducted on 6/7/2002.
11. There are inadequate washing facilities and toilet facilities for employees involved in laboratory and manufacturing operations (21 CFR 211.52) and [21 CFR 820.70 (d)].
Specifically, there was no hot water available for hand washing in both women?s bathrooms and soiled toilet tissue was observed in wastebaskets in the bathrooms.
12. Persons engaged in manufacturing, processing or packing of drug and device products do not have adequate training to enable those persons to perform the assigned functions. [21 CFR 211.25 (a)] and [21 CFR 820.25 (b)]. F or example, personnel should have been trained to report the lack of hot water in bathroom facilities, personnel were observed in class 100 clean rooms to be using buckets with rust residues, splattering isopropyl alcohol with rapid movements of tongs during cap handling, and unnecessary social interaction (talking) among technicians performing the filling operation. These actions are prohibited by your firm?s approved procedures.
The above identification of violations is not intended to be an all-inclusive list of deficiencies at your facility. A list of observations (form FDA-483) was issued and discussed with you at the conclusion of the inspection. It is your responsibility to assure adherence with each requirement of the Good Manufacturing Practice regulation and other applicable regulations. Federal agencies are advised of the issuance of all warning letters about drugs and medical devices so that they may take this information into account when considering the award of contracts.
We are in receipt of your responses to the FDA-483 dated July 2, 2002; July 8, 2002, and August 2, 2002, and acknowledge that corrective actions you listed in those responses address some of the above specific issues, It will not be necessary for you to submit again those revised documents already provided. However, we are concerned of the apparent system deficiencies that have allowed the unacceptable practices cited herein to occur. Such system deficiencies appear to involve internal quality auditing, corrective and preventive actions, management controls relating to quality planning and resource allocations (staffing of appropriately qualified individuals), and/or training of personnel.
You should take prompt action to correct these deviations by identifying not only specific corrective actions but also the systems improvements you have made or will make to assure that such deviations will not reoccur. Failure to do so may result in regulatory actions being initiated by FDA, including product seizure and/or a permanent injunction requiring you to cease manufacture of drug or device products. You should notify this office within fifteen (15) working days of receipt of this letter, of the specific steps you have taken to correct the noted violations, including an explanation of each step taken to prevent the recurrence of similar violations. If corrective action cannot be completed within (15) working days, state the reason for the delay and the time within which the corrections will be completed.
If you have any questions regarding this letter, please contact Mr. J. Lawrence Stevens, Compliance Officer at 949-798-7732. Your written reply should be addressed to:Thomas L. Sawyer, Director of Compliance
U. S. Food and Drug Administration
19900 MacArthur Blvd, Suite 300
Irvine, CA 92612
Alonza E. Cruse