Inspections, Compliance, Enforcement, and Criminal Investigations
Matheson Tri-Gas, Inc. 12-Sep-06
Department of Health and Human Services
Public Health Service
September 12, 2006
VIA CERTIFIED MAIL
RETURN RECEIPT REQUESTED
Mr. James Samples, President, COO
Matheson Tri-Gas, Inc.
South Texas Region
959 Rt. 46 E.
Parsippany, NJ 07054
Dear Mr. Samples:
The Food and Drug Administration (FDA) inspected your medical gas facility located at 2200 Houston Ave., Houston, TX 77007 on March 24, 30 and 31, and April 3 and 6, 2006. Medical gases are drugs as defined by Section 201(g) of the. Federal Food, Drug, and Cosmetic Act (the Act). [21 U.S.C. §321(g)]. The medical gases you distribute are drugs, and some of these products are intended for diagnostic. and treatment in conjunction with medical devices.
Our inspection found significant deviations from the Current Good Manufacturing Practice (CGMP) regulations for your drug products, set forth in Title 21, Code of Federal Regulations (21 CFR), Parts 210 and 211. These deviations cause your medical gas products to be adulterated within the meaning of Section 501(a)(2)(B) of the Act [21 U.S.C. §351(a)(2)(B)], in that the methods used in, or the facilities or controls used for, their manufacturing, processing, packing, storage, or holding, are not in conformity with CGMPs.
The deviations were listed on a Form FDA-483, Inspectional Observations issued at the conclusion of the inspection, and were discussed with management at the facility. A copy of the Form FDA-483 is attached for your information. We are in receipt of Matheson Tri-Gas, Inc.'s (Matheson) written response dated April 19, 2006, by Ms. Bonnie Stanage, Vice President Safety and Compliance, addressing the FDA-483 issued at the completion of the inspection. The CGMP violations discussed below have not been adequately addressed by your response.
Examples of these deficiencies are included as follows:
1. Failure to establish scientifically sound and appropriate specifications, standards, sampling plans, and test procedures to assure that components, in process materials, and drug products conform to appropriate standards of identity, strength, quality, and purity [211 CFR 211.160(b)].
For example, your firm fails to conduct adequate contaminant and impurities testing on incoming Carbon Dioxide (C02), LISP and Helium (He), USP medical gas products.
Your response states that you confirm the suppliers' test results. However, the confirmation is only for the United States Pharmacopeia (USP) assay of the active ingredient and the identity of contaminants and impurities included in the USP monograph. Your confirmation test does not establish whether the USP contaminants and impurities, and their established specifications constitute all appropriate contaminants and impurities, and their specifications for which the drug products should be evaluated. For example, C02 can be produced by any one of several processes, each with its characteristic impurity problems and He can have varying impurity profiles, depending on the product's source. The mere application of the USP monograph specifications, without any determination of other possible contaminants and impurities as a result of the particular source of the product, or the process used to obtain the product, does not constitute the establishment of "scientifically sound and appropriate specifications," as required by the regulations.
The "General Notices" section of~the USP states that impurities in compendial articles that may be introduced from extraneous -sources or may arise from changes in the material source or manufacturing process and are not covered by the monograph tests should also be tested. Thus, in the case of products like C02 and He, the testing of impurities should not be limited to those tests listed in the monograph unless it can be shown that the risk of additional contaminants arising from these events is sufficiently low.
2. Failure to establish and document the accuracy, sensitivity, specificity, and reproducibility of the test methods [21 CFR § 211.165(e)]. For example, since 2002, your firm has used a HP 6890 Series Gas Chromatograph, which has not been qualified, for assay of CO2 USP, and the test method has not been validated.
Your response states that all testing was completed for full validation in November 2005. Also, your response states that the qualification of the Gas Chromatograph and analyzers, and all other validation activities had been completed and reports were prepared and approved prior to April 14, 2005. However, your firm did not provide documentation either during the inspection or in your written response to support these statements. In addition, the unqualified chromatographic equipment is used for regulatory testing of He, USP and N2, NF.
3. Failure to establish an adequate quality control unit that shall have the responsibility and authority to approve or reject all components, drug product containers, closures, in-process materials, packaging material, labeling, and drug products, and the authority to review production records to assure that no errors have occurred, or, if errors have occurred, that they have been fully investigated [211 CFR § 211.22].
For example, the quality control unit failed to ensure a.) appropriate testing of the incoming finished drug product, and b.) the use of a validated testing method to assay the incoming finished drug products.
The above identification of violations is not intended to be an all-inclusive list of deficiencies at your facility. It is your responsibility to ensure adherence to all requirements of the Act and its implementing regulations for all Matheson Tri-Gas Inc. facilities involved in the manufacture of medical gases. Federal agencies are advised of the issuance of all Warning Letters about drugs so that they may take this information into account when considering the award of contracts.
You should take prompt action to correct these violations in this and ail other similarly operated Matheson medical gas facilities. You should establish procedures whereby such violations do not recur. Failure to do so may result in regulatory action without further notice. Possible actions include, but are not limited to, seizure and/or injunction.
Your corrective action which addresses observation 4 of the Form FDA 483, failure to have the initials or signature of a different person to document that laboratory records are accurate and complete, appears to be adequate. However, contrary to your statement in your response that ". . .this observation does not represent a violation of CFR. .., failure to have the initials or signature of a second person showing that the original records have been reviewed for accuracy, completeness, and compliance with established standards is a violation under 21 CFR § 211.194(a)(8) and is an important part of a your firm's ability to provide assurance of the quality and purity of marketed drug products.
Within fifteen working days of receipt of this letter, you should notify this office in writing of the additional steps to be taken to correct the noted violations and to prevent their recurrence. If corrective action cannot be completed within fifteen working days, state the reason for the delay and the time within which the corrections will be completed.
Your reply should be sent to the above address, to the attention of James R. Lahar, Compliance Officer. Should you have any questions concerning this letter, Mr. Lahar can be contacted by telephone at 214-253-5219.
Dallas District Director