Inspections, Compliance, Enforcement, and Criminal Investigations
C & M Oxyfill, LLC 26-May-05
Department of Health and Human Services
Public Health Service
New Orleans District
May 26, 2005
WARNING LETTER NO. 2005-NOL-23
Mr. Kenneth H. Carver, II, Co-Owner
Mr. John M. Melvin, Co-Owner
C & M Oxyfill, L.L.C.
619A Highway 29
Wiggins, Mississippi 39577-8427
On January 12, 14, and 20, 2005, U.S. Food and Drug Administration (FDA) investigators inspected your Compressed Oxygen, USP, manufacturing facility, located at 619A Highway 29, Wiggins, Mississippi. Medical gases, such as Compressed Oxygen, USP, are drug products as defined by 21 USC 321(g), [Section 201(g) of the Federal Food, Drug, and Cosmetic Act (the Act)]. Our inspection found significant violations of the Current Good Manufacturing Practice (CGMP) regulations for drug products, set forth in Title 21, Code of Federal Regulations, (21 CFR), Parts 210 and 211. These violations cause your Compressed Oxygen, USP product to be adulterated within the meaning of 21 U.S.C. 351(a)(2)(B) [Section 501(a)(2)(B) of the Act],as the methods used in or the facilities or controls used for the manufacturing, processing, packing, storage or holding of your product do not comply with CGMP regulations. In addition, the Compressed Oxygen, USP, cylinders manufactured by your firm are misbranded within the meaning of 21 U.S.C. 352(c), [Section 502(c) of the Act], because the product's labels do not have the required statement "Rx Only" prominently placed so it is likely to be read and understood by an ordinary individual under customary conditions of purchase and use.
The CGMP violations include, but are not limited to, the following:
1. Failure to establish laboratory controls which include the calibration of instruments, apparatus, gauges and recording devices at suitable intervals in accordance with an established written program containing specific directions, schedules, limits for accuracy and precision and remedial action in the event the accuracy and/or precision limits are not met [21 CFR 211.160(b)(4)]. Specifically, your firm does not have a Certificate of Analysis (COA) for the Nitrogen calibration gas used to establish the zero point on the Servomex Oxygen analyzer. The manufacturer of the instrument recommends a minimum purity of 99.9% for the Nitrogen calibration gas. In the absence of this COA or any additional testing to verify the purity of the Nitrogen meets the manufacturer's minimum criteria, you have utilized an un-calibrated[redacted] Oxygen analyzer to determine the purity of your Compressed Oxygen, USP, drug product.
Additionally, your firm's procedures for calibrating the [redacted] Oxygen Analyzer are inadequate. For example, your procedure for the Oxygen Testing states the [redacted] Oxygen Analyzer will be "[redacted]" This procedure is unclear and is inconsistent with the manufacturer's recommendation which advises to calibrate the [redacted] Oxygen Analyzer each time the analyzer is moved. The manufacturer of the instrument also recommends the [redacted] Oxygen Analyzer be allowed to achieve equilibrium with the ambient temperature before taking a measurement. They also advise the user to note changes in the barometric pressure, as a 1% change in barometric pressure will result in a 1% error in the oxygen reading for 100% pure oxygen. Your procedure does not address any of these precautions.
We acknowledge your response to the Form FDA 483, dated January 25, 2005, stating you have ordered the COA for the Nitrogen Standard Gas. We also acknowledge your response dated March 25, 2005, stating your firm has purchased new Oxygen and Nitrogen calibration gases from [redacted] with the appropriate COA's for each gas, and the Oxygen COA lists the analytical method used to assay the standard. However, your responses are inadequate, because you fail to clarify whether the Nitrogen COA contained a reference to its analytical method. In addition, you have not provided any assurance the Nitrogen COA is for the exact unit of Nitrogen calibration gas you used to calibrate the [redacted] Oxygen Analyzer, observed during our inspection of your facility. Therefore, you have not provided any assurance the Nitrogen used to calibrate your [redacted] Oxygen analyzers meets the manufacturer's recommendation for purity (at least 99.9% pure Nitrogen). Please provide further explanation of how your firm plans to assure the quality of the Nitrogen calibration gas used to calibrate the [redacted] Oxygen Analyzer.
Additionally, during the inspection of your facility, you stated the supplier of your calibration gases was [redacted]. Based on your March 25, 2005, response, it appears as though your firm has changed the calibration standard supplier to [redacted]. However, your firm has failed to identify if there were any differences between each supplier's standards which could impact product quality.
2. Failure to routinely calibrate, inspect, or check automatic, mechanical, or electronic equipment according to a written program designed to assure proper performance [21 CFR 211.68(a)]. Specifically, your firm has not performed any equipment qualification on the "mobile" cryogenic pumping system which transfills your Compressed Oxygen, USP, drug product. The qualification of this system is especially crucial, because the system's manufacturer (a contract firm named [redacted] states in its documentation, it typically manufactures stationary pumping systems and "does not vouch for the operation of an Oxygen filling system in a portable trailer configuration." [redacted] also states C&M Oxyfill requested they fabricate and install this mobile cryogenic pumping system according to C&M Oxyfill's layout and design.
Also, our investigators observed your firm used a power drill to torque the valves of the Compressed Oxygen, USP, cylinders. However, your firm has not demonstrated, through equipment qualification, the drill does not over-torque the valve. Industry has informed the Agency of over-torqued valves which have blown from their cylinders, causing adulteration of the drug product, harm to the employees and significant damage to the facility. The industry typically hand tightens these cylinder valves using a specially designed chuck.
We acknowledge your response dated March 25, 2005, which states your firm will purchase a "Validation Gauge" to validate the pumping system can hold pressure and vacuum. You also stated a leak test would be performed on the system. Your response is not adequate in that these tests, by themselves, will not adequately qualify your mobile manufacturing equipment. Your firm should consider all of the critical aspects of your equipment such as the maximum sustained vacuum pull, cryogenic pump operation, cryogenic jacket temperature hold, electrical components, power generator, etc. It is your firm's responsibility to qualify the performance of your equipment and assure it is routinely calibrated, inspected and checked according to a written program designed to assure its performance.
3. Failure to assure all production and control records were reviewed and approved by the quality control unit to determine compliance with all established, approved, written procedures before the batch was released or distributed [21 CFR 211.192]. Specifically, the quality control review and approval is performed [redacted], prior to storing them at your firm's office in Wiggins, Mississippi and not after each transfilling at each home healthcare location prior to releasing finished Oxygen, USP. A comprehensive review of your production records dating back to May 12, 2004, when your firm began its operations, has revealed some prefill checks (such as the odor test), in-process checks (such as the heat of compression), and/or finished product tests (such as identity, purity, post-fill leak, and postfill odor) were not performed for ovef 35 lots of your Compressed Oxygen, USP, drug product.
We acknowledge your response dated March 25, 2005, which states quality control review and approval is performed [redacted] Oxygen, USP, product. Your response is not adequate, because you do not explain why or how your production records show over [redacted] lots of your Compressed Oxygen, USP, drug product, distributed to your home healthcare customers, were missing the critical prefill checks, in-process tests, and /or finished product tests
4. Failure to follow written procedures for production and process control functions and document at the time of performance [21 CFR 211.100(b)]. Specifically, during the inspection of your facility, our investigators observed the heat of compression and pre-fill odor tests were not performed, per your firm's Standard Operating Procedure (SOP), for each cylinder during filling operations.
Your response dated March 25, 2005, is not adequate because it does not describe, in any detail, the specific steps your firm has taken to assure all pre-fill, in-process testing will be performed for each cylinder of your Compressed Oxygen, USP, drug product.
Additionally, your procedure for operating the infrared thermometer states the instrument should be[redacted]. Our investigators observed the infrared thermometer was calibrated [redacted]. We observed your operators consistently reading temperatures calibrated during the transfilling of Compressed Oxygen, USP, by shining the infrared beam of the thermometer on the polished portions of the cylinders. Yet, the instrument's operations manual states taking temperature readings against shiny or polished surfaces results in an inaccurate measurement of temperature. The manual also recommends the optimal distance to take the temperature is at three (3) to 12 inches from the target. We observed your operators often took readings as close as one (1) inch from the cylinder. Obtaining an accurate cylinder temperature during the transfilling of Compressed Oxygen, USP, is critical. This value directly correlates to the volume of gas transfilled into the cylinder. Inaccurate temperature readings may result in under-filling of the cylinder, or worse, over-filling, which may cause dislodging of the cylinder valve, resulting loss of product, and harm to the employees.
We acknowledge your response dated March 25, 2005, which states a new digital thermometer with a NIST traceable calibration certificate will be purchased. You also stated you will purchase a "replacement" thermometer before the first digital therniometer certification expires. This response is not adequate, as your finn has failed to describe the type of digital thernlometer (i .e. probe, infrared beam, etc .) purchased, and how your firm will assure the unit will remain calibrated over its lifecycle . You also failed to provide any SOPs to demonstrate your procedures explain how to use, calibrate, dispose of, and replace the thermometer
5. Failure to establish adequate batch production and control records for each batch of drug product produced, including documentation each significant step in the manufacture, processing, packing, or holding of the batch was accomplished [21 CFR 211.188(b)]. Specifically, your firm's batch records failed to include the date and initials of the employee performing each step. Your batch records were also incomplete as several pre-fill checks, inprocess checks and final product tests were not performed on certain batches. Some of these records, despite their incompleteness, were approved by a supervisory operator.
We acknowledge your response dated March 25, 2005, which states a new batch record was designed, and is currently used, which "allows for complete recording of each lot to be documented." Also, your firm states the production procedures have been implemented to assure errors are not introduced, and the QA procedures specifically require a [redacted] Compressed Oxygen, USP, which is manufactured. In comparing the new batch production record (included in your response) to the old one (collected during the inspection of your facility), we note, other than the new spaces to record the [redacted] Oxygen analyzer calibration information, there is no difference between the new batch record and the old one. In addition, you have not provided the new production and the quality control unit procedures. Therefore, you have not adequately demonstrated your corrective actions will prevent your employees from approving incomplete batch records in the future.
6. Failure to assure each employee engaged in the manufacture, processing, and holding of Oxygen, USP, has the education, training, and experience required to perforn-i their assigned duties [21 CFR 211.25(a)]. Specifically, you do not have a detailed training program to adequately train your employees concerning Current Good Manufacturing Procedures, quality control, SOPs, quality assurance, transfilling operations, distribution, record keeping, and traceability.
We acknowledge your response dated January 31, 2005, which states all operators were retrained on January 24, 2005, on "Current Good Manufacturing Practices, SOPs, Quality Control, filling cylinders, record keeping and distribution ." We also acknowledge your response dated March 25, 2005, provided a resume of your outside consultant, [redacted] who apparently conducted the CGMP training for your employees. However, you have not provided any documentation discussing topics such as the contents/topics of the training program, the length of the training program, whether the program included the managerial staff at your finin, when refresher courses might be held for employees, etc.
7. Failure to establish and follow written procedures designed to assure correct labels and labeling are used for the Compressed Oxygen, USP, drug product. In particular, you failed to identify the quantity of contents of each unit of Compressed Oxygen, USP, [21 CFR 211.130(b)]. Specifically, there is no statement of quantity of contents on your Compressed Oxygen, USP, drug product label as required by this regulation. As a result, your drug product is misbranded within the meaning of 21 USC 352(b)(2), [Section 502(b)(2) of the Act].
We acknowledge your response dated March 25, 2005, which states the "Quality Control Procedures now mandate all labels be examined by QA personnel who compare the new labels to a master label before being accepted into stock for distribution." This response is not adequate. Our concern with your firm's labeling operation is not that the Compressed Oxygen, USP, product labels deviated from the master label, but the master label does not comply with the CGMP regulations or the Act, as stated above.
In addition, given your drug product is distributed to[redacted] it is unlikely an elderly patient will be able to read the contents of your label, which is written in a very small text size.
8. Your firm does not have written procedures for equipment cleaning and maintenance [21 CFR 211.67(b)], nor for complaint handling (21 CFR 211.198).
9. Your firm does not have adequate written procedures for product returns (21 CFR 211.204).The procedure advises to vent the returned cylinder to atmosphere, and to follow standard operating procedures when refilling the cylinders with Compressed Oxygen, USP. The procedure makes no reference to recording key information such as the lot number of the returned product, and performing an investigation to determine why product was returned or if there were any other lots which may have been affected . In refilling the cylinders, the procedure does not clarify which SOPs the operator should follow.
10. Failure to establish a quality control unit, which has the responsibility and authority to approve or reject all components, drug product containers, closures, in-process materials, packaging materials, labeling, and drug products, and the authority to review production records to assure no errors have occurred [2l CFR 211.22(a)]. The presence of a properly functioning quality control unit would increase your firm's ability to meet the CGMP requirements impacting the identity, strength, quality and purity of your drug products.
Your response dated March 25, 2005, is not adequate because you have not provided any documentation to support the corrective actions you state have been made. The above violations are not intended to be an all-inclusive list, as other deficiencies may exist at your facility. It is your responsibility to assure your facility is operated in compliance with each requirement of the CGMP regulations and applicable statues enforced by the FDA. Federal agencies are advised of the issuance of all warning letters about drugs so they may take this information into account when considering the award of contracts.
We recognize at the close of the inspection, Mr. John M. Melvin, Co-Owner, made a verbal commitment to correct the observed deficiencies. Also, we acknowledge receipt of your firm's letters dated January 25 and 31, 2005, and March 25, 2005, written in response to the inspeetional observations. The corrective actions described in the letters are inadequate for the reasons stated in the "CGMP violations" section above. We remain concerned your corrections have been implemented without first performing a thorough evaluation of all your production and records systems.
You should take prompt action to correct all of the violations noted in this letter, and you should establish procedures whereby such violations do not recur. Failure to promptly correct violations may result in regulatory action without further notice, such as seizure and/or injunction.
During the inspection, our investigators also observed your finn does not have any procedures for stability testing or any records showing stability testing has been performed to justify the five (5) year expiration date which appears on each Compressed Oxygen, USP, cylinder manufactured by your firm. Currently, we require adherence to 21 CFR 211.166, regarding the development of a stability program, if a finrn incorporates an expiration date on their Compressed Medical Gas drug products.
You should notify this office in writing, within fifteen (15) working days from your 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 recurrence of similar violations. You should include in your response documentation, such as validation of the thermometer and the cryogenic pumping system, corrected SOPs for process control procedures, and corrected labels or other useful information to assist us in evaluating our corrections. If you cannot complete all corrections before you respond, you must explain the reason for your delay and state when you will correct any remaining deviations. Your responses will be reviewed and any corrective actions will be verified during our next inspection at your facility.
You can find guidance and information for the regulated industry regarding regulations for drug products through links at FDA's website at http://www.fda.gov/oc/industry Your reply should be directed to the U.S. Food and Drug Administration, Attention : Nicole F. Hardin, Compliance Officer, at the address above. If you have questions regarding any issue in this letter, please contact Ms. Hardin at (504) 253-4519.
H. Tyler Thornburg
New Orleans District