Inspections, Compliance, Enforcement, and Criminal Investigations
CPG Sec. 435.100 Compressed Medical Gases - *Warning Letters for Specific Violations Covering Liquid and Gaseous Oxygen*
*This CPG provides guidance for issuing warning letters to firms processing compressed medical gases in violation of the adulteration, misbranding, and/or new drug provisions of the Federal Food, Drug, and Cosmetic Act.*
Compressed medical gases, *including compressed medical oxygen and liquid oxygen, *are drug products regulated under 21 CFR 210 and 211.
*Section 201.100 requires that the labeling for prescription drugs (e.g., Oxygen U.S.P.) bear adequate directions for use. In this regard, the requirements of 201.100 would be satisfied if the article meets the labeling requirements described in the Federal Register of March 16, 1972, (37 FR 5504) entitled "Oxygen and Its Delivery Systems, Proposed Statement of Policy." Although this proposal was not finalized and is being revoked, the Agency continues to use it as a labeling guideline for medicinal oxygen.
Oxygen, U.S.P. would be misbranded if its label fails to indicate whether or not it has been produced by the air-liquefaction process as required by the United States Pharmacopeia (USP XXII).
All other compressed medicinal gases should meet the requirements of 21 CFR 201.161.
All medical gas drug labels must bear the following information: (1) name and address of the manufacturer or distributor, (2) official product name (for single-component gases), (3) contents, in units of measure commonly used, e.g., liters, cubic feet, (4) lot number, and (5) statement of ingredients (for gas mixtures).*
Section 211.160(b) requires the establishment of scientifically sound and appropriate specifications and test procedures that are designed to assure that components and drug products conform to appropriate standards of identity and strength.
Section 211.160(b)(4) requires the calibration of laboratory instruments, apparatus, and gauges at suitable intervals in accordance with an established written program containing specific directions, schedules, limits for accuracy and precision, and provisions for remedial action in the event accuracy and/or precision limits are not met.
Section 211.165(a) requires that each batch of a drug product be tested to determine satisfactory conformance to final specifications for the drug product, including the identity and strength of each active ingredient, prior to release.
Section 211.165(e) requires that the accuracy, sensitivity, specificity, and reproducibility of the test methods employed by a firm shall be established and documented.
The Center for Drug Evaluation and Research *(CDER) "Compressed Medical Gases Guideline" (revised February, 1989) provides guidance to industry for compliance with these regulations. Many firms that fill high pressure cylinders with medical gases do not assay the finished product for identity and strength. In some instances, the testing performed is inadequate, due to failure to: 1) establish appropriate finished product test procedures and specifications, and/or 2) maintain the test apparatus, e.g., the United States Pharmacopeia Orsat test apparatus, or calibrate the oxygen analyzer according to the analyzer manufacturer's specifications.
Of particular concern is the transfilling (cascading) of smaller high pressure cylinders (e.g., E or D) from larger high pressure cylinders (e.g., H or K). The smaller high pressure cylinders may be transfilled individually, or more than one may be filled at a time by connecting them to a manifold with multiple outlets. The firms may fail to perform any finished product testing and to vacuum evacuate or double purge each cylinder prior to filling. Many of the firms have not been registered and are unaware of their responsibility to comply with the current good manufacturing practice regulations.
HOME RESPIRATORY CARE:
The revised guideline (February 1989) includes guidance for home respiratory care companies (HRC). In practice, an HRC may pick up or receive a shipment of liquid oxygen (LOX) in a cryogenic container and transport the container to a patient's home to fill a cryogenic home unit. Another common practice is for the HRC to exchange a full unit with the empty home unit. The empty units are returned to the HRC facility for filling. In both scenarios, no testing of the cryogenic home units is required, provided all of the following three elements are met:
1. The incoming LOX has been adequately tested for identity and strength by one of the methods outlined in the guideline,
2. no other liquid (gas) is being transfilled on the premises, and
3. the cryogenic home units are retained by the HRC.
However, if any other liquid (gas) is being transfilled, then ALL cryogenic home units would require full USP testing.
Furthermore, in accordance with Section 211.87, the contents of units sent out for repair/maintenance, must be retested at the least for identity, prior to redistribution.
Occasionally, an HRC will use a supplier's Certificate of Analysis (COA) to reduce the amount of testing the HRC needs to perform. In this situation, the following minimum information should be provided in the COA:
1. supplier's name
2. name of product (gas)
3. air-liquefaction statement
4. lot number or other unique identification number
5. actual analytical results obtained for identity and strength
6. test method used for analysis (Note: In lieu of indicating the test method on each COA issued, a general letter from the supplier, maintained on file with the HRC, which indicates the test method used for all supplied product is acceptable)
7. supplier's signature/date.
If the HRC relies on a COA to reduce the amount of testing it needs to perform, the HRC should establish the reliability of the supplier's analysis at appropriate intervals (once a year would be sufficient) by taking a recently delivered and tested vessel to a third party for full USP testing.
Most medical gas firms receive their bulk oxygen from an intrastate source. If they receive LOX from an interstate source, document the interstate movement of the bulk LOX. If the LOX is from an intrastate source, document the interstate movement of 1) the stand tank, 2) the large cryogenic vessels, 3) the high pressure cylinders, and/or 4) the home units, by determining the location of the manufacturer of the articles.*
REGULATORY ACTION GUIDANCE:
*District offices should consider issuing warning letters under any one of the following circumstances, provided interstate movement of the gas or the various containers (cryogenic or high pressure cylinders) has been documented:*
1. Firm has no written specifications or test procedures, or if such documents exist, they are not in the possession of, or are not followed by the individual(s) performing the assay.
Charge: 501(a)(2)(B); 21 CFR 211.160(b)
2. *Firm is using a Servomex Oxygen Analyzer <>, for example, or other testing instrument for oxygen analysis and fails to adequately calibrate the instrument according to the manufacturer's directions, i.e., daily or more often, using the calibration gases specified.
Charge: 501(a)(2)(B); 21 CFR 211.160(b)(4)
<> Since oxygen is the only gas that will provide a significant reading on the scale of a calibrated Servomex Oxygen Analyzer, the strength reading obtained also serves as an identity test.
3a Firm is using a manifold to fill high pressure cylinders with a single compressed medical gas such as Oxygen, USP, or Nitrogen, NF, from a bulk storage tank containing commingled lots of the gas and fails to assay the contents of the cylinders for both identity and strength prior to release. (Instead of testing each cylinder, it is acceptable to perform an assay for identity and strength on one filled cylinder per manifold filling sequence.)
3b Firm is filling small high pressure cylinders individually or one at a time from larger high pressure cylinders, but fails to assay at least one cylinder per uninterrupted filling sequence for both identity and strength, provided the same equipment, personnel, and lot of bulk is used.
3c HRC fails to test the incoming liquid oxygen for both identity and strength according to one of the methods outlined in the February, 1989, Compressed Medical Gases Guideline.
Charge: 501(a)(2)(B); 21 CFR 211.165(a)
4. Firm is using a non-official test procedure for the assay of Oxygen, USP, and has no documentation that the sensitivity and accuracy of the test procedure will produce identity and strength results equivalent or superior to those obtained using the official test procedure.
Charge: 501(a)(2)(B); 21 CFR 211.165(e)
5. The article is misbranded in that its labeling fails to contain a statement of the quantity of the contents.
Charge: 502(b)(2); 21 CFR 201.51
6. The article is misbranded in that it is regarded as a prescription drug and its labeling fails to bear adequate directions for use in accordance with 21 CFR 201.100(c).
Charge: 502(f)(1); 21 CFR 201.100(c)
7. The article, Oxygen USP, is misbranded in that its labeling fails to indicate whether or not the oxygen has been produced by the air-liquefaction process as required by the United States Pharmacopeia (USP XXII).
8. The article is misbranded in that it was manufactured in an establishment not duly registered under section 510 of the Act and the article has not been listed as required by section 510(j).
Charge: 502(o); 21 CFR 207.20
9. The article is a drug within the meaning of section 201(g) of the Act which may not be introduced or delivered for introduction into interstate commerce under section 505(a) of the Federal Food, Drug, and Cosmetic Act, since it is a new drug within the meaning of section 201(p) of the Act and no approval of an application filed pursuant to section 505(b) is effective for such drug.
Examples of the wording to be used in the warning letter to any filler of medical gas are as follows:
501(a)(2)(B) Your product, (name of medical gas), is adulterated in that the controls used for the manufacture, processing, packing, or holding of this product are not in conformance with current good manufacturing practice regulations (Title 21, Code of Federal Regulations, Parts 210 and 211), such as:
Failure to establish scientifically sound and appropriate test procedures for the assay of (name of medical gas(es)) 21 CFR 211.160(b)].
Failure to properly calibrate the Oxygen Analyzer used for the assay of Oxygen, USP, in that your firm did not have the high purity nitrogen standard required to calibrate the "zero" on the meter [21 CFR 211.160(b)(4)].
Failure to assay the filled high pressure cylinders of (name of medical gas) for identity and strength, prior to release [21 CFR 211.165(a)].
Failure to establish that the test procedure used to determine the strength and identity of (name of medical gas) will provide test results that are equivalent or superior to the official test procedure. (Give example of why it isn't equivalent or superior to the official test procedure) [21 CFR 211.165(e)].
In addition, the following is an example of the wording for HRCs that fill liquid home units:
Failure to assay the incoming liquid oxygen for identity and strength prior to filling the liquid home units [21 CFR 211.165(a)].
In addition, the following violations, if noted during the inspection may be included in the District's letter:
Failure to test each lot of bulk oxygen to determine conformance with appropriate specifications for identity and strength [21 CFR 211.84(d)(2)].
Failure to perform adequate prefill operations on each high pressure cylinder, prior to filling [21 CFR 211.84(d)(3)].
Failure to establish written procedures designed to assure that the drug products have the identity and strength they purport or are represented to possess [21 CFR 211.100(a)].
Failure to establish written procedures for the reconciliation of the quantities of labeling issued, used, and returned [21 CFR 211.125(c)].
Failure to establish written procedures designed to assure that correct labels and labeling are used, including identification of the drug product with a lot or control number that permits determination of the history of the manufacture and control of the batch [21 CFR 211.130(b)].
Failure to establish adequate batch production and control records for each batch of drug product produced, including documentation that each significant step in the manufacture, processing, packing, or holding of the batch was accomplished [21 CFR 211.188(b)].
Failure to maintain complete records of the periodic calibration of the oxygen analyzer, CFR 211.194(d)].
Failure to establish written procedures for the receiving of any complaints [21 CFR 211.198].
When issuing a warning letter to a firm with multiple locations, the original should be sent to the most responsible head residing at the headquarters location, with a copy sent to the plant manager. The warning letter should include a statement that this will serve as official notification to management that FDA expects all locations to be in compliance.
Once a firm as been issued a warning letter, the next course of action, provided the firm continues to operate out of compliance, is to consider submitting a seizure recommendation to CDER. Do not to issue a second warning letter.
Send a copy of the warning letter that issues to the firm to Duane S. Sylvia, HFD-322, Sterile Drugs Branch, Division of Manufacturing and Product Quality, CDER.
*Material between asterisks is new or revised*
<> Indicates material has been deleted