Medical Gas - Good Manufacturing Practices Questions and Answers
The Medical Gas Good Manufacturing Practices (GMP) questions and answers presented below are designed to add further interpretation, and clarification, to guidance found in the document "Good Manufacturing Practices (GMP) for Medical Gases (GUI-0031) - 2006 Edition".
- Premises - C.02.004
- Equipment - C.02.005
- Personnel - C.02.006
- Sanitation - C.02.007 & C.02.008
- Raw Material Testing - C.02.009 & C.02.010
- Manufacturing Control - C.02.011 & C.02.012
- Quality Control Department - C.02.013, C.02.014 & C.02.015
- Packaging Material Testing - C.02.016 & C.02.017
- Finished Product Testing - C.02.018 & C.02.019
- Records - C.02.020, C.02.021, C.02.022, C.02.023 & C.02.024
Premises - C.02.004
Equipment - C.02.005
Q.1 Is the use of a hoke bomb acceptable for sampling gases from a storage tank?
A.1 Yes, provided the firm has validated the process. A hoke bomb is a stainless steel cylinder with a valve on each end which allows a gaseous product to flow through. The most significant step in the validation process is the time required to fully purge the cylinder which provides assurance that complete evacuation of the cylinder has been accomplished.
Q.2 What is the extent of calibration required for vacuum gauges?
A.2 Vacuum gauges are used during the essential evacuation of residual gas from high pressure cylinders, and therefore, need adequate calibration.
At periodic intervals, vacuum gauges should be calibrated to standards established by the National Institute of Standards and Technology or another recognized standard. The frequency of calibration should be based on manufacturer's recommendations. A firm could also establish its own frequency based on usage and experience. Vacuum gauges should be checked prior to use with no vacuum present to ensure that the needle on the gauge returns to the "zero." Records should be maintained.
Personnel - C.02.006
Sanitation - C.02.007 & C.02.008
Raw Material Testing - C.02.009 & C.02.010
Manufacturing Control - C.02.011 & C.02.012
Q.1 A firm receives liquid nitrogen from a supplier with a valid certificate of analysis for each delivery. The firm's operation involves the filling of high pressure cylinders via a heat exchanger or a vaporizer. Should a test for identity and assay be performed on one filled container from each manifold filling sequence or can we rely on the test results provided by the supplier with no further testing?
A.1 The liquid nitrogen received from a supplier should be tested as per the GMP requirements under Manufacturing Control. In addition, one filled cylinder from each manifold filling sequence should be tested in accordance with the GMP requirements under Finished Product Testing.
Q.2 Is cylinder colour an acceptable means of segregation between different products?
A.2 Product segregation by cylinder colour can be an acceptable method if there is evidence that the personnel involved are adequately trained. Additional measures are necessary to segregate quarantined and released cylinders.
Q.3 Is transfilling of medical gases considered a "package" activity or a "distribute" activity?
A.3 Transfilling of medical gases either at the facility or curbside is considered a "package" activity, pursuant to Section C.01A.001(1) of the Food and Drug Regulations, which defines the term "package" as "to put a drug in its immediate container", and section C.01.001, which defines the term "immediate container" as "the receptacle that is in direct contact with a drug".
Q.4 Can you provide examples of which operations at a medical gas facility is considered a "fabricate" activity and which are considered a "package" activity?
A.4 The following operations are considered a "fabricate" activity:
- medical gases produced via air liquefaction (i.e., meaning produced at air separation plants) and/or
- medical gas mixtures made by filling into cylinders
Transfilling of gases either at the facility or curbside is considered a "package" activity. If the company transfilling holds the drug identification number (DIN), the activity would be classified as both distribution and packaging/labelling, and must meet the requirements of Divisions 1A and 2 of the Food and Drug Regulations.
Medical gas facilities should have establishment licences that reflect what activity they are performing.
Quality Control Department - C.02.013, C.02.014 & C.02.015
Packaging Material Testing - C.02.016 & C.02.017
Finished Product Testing - C.02.018 & C.02.019
Q.1 When produced synthetically from oxygen and nitrogen raw materials, that respectively meet United States Pharmacopeia (USP) and National Formulary (NF) specifications, should medical air USP be exempt from the analysis for water/oil, carbon dioxide, nitric oxide/nitrogen dioxide and sulphur dioxide?
A.1 If compendial specifications require impurity tests, then they must be performed.
Q.2 When is oxygen exempt from being tested for carbon dioxide?
A.2 The USP exempts oxygen with purity of no less than 99% from the requirements of the tests for carbon dioxide and carbon monoxide when the oxygen has been produced by the air liquefaction method. Other Schedule B (compendial) monographs may have similar exemptions.
Documentation should be available indicating that the specific lot of oxygen has been produced by the air liquefaction process.
Q.3 Can mixtures of medical gases be labelled only as being a USP mixture?
A.3 Only mixtures of medical gases which meet USP monographs as mixtures may be labelled as USP.
Q4. A mixture of two gases is first filled into a series of storage buffer tanks. From the storage buffer tanks the mixture is then transfilled into finished product cylinders (cylinders labelled and ready for sale to clients). Can we only test each buffer tanks for one of the two gases (usually the active ingredient) and test only one cylinder after filling a series of cylinders or is it mandatory to test each cylinder after filling (usually for the active ingredient) as per C.02.018, interpretation 4?
A.4 When a mixture of two different gases is made in a tank, stratification may occur and each cylinder of the gas mixture must be tested as per interpretation 4 of C.02.018. This means every cylinder is tested to specifications of one of the gases, usually the active ingredient and an identity test for the other gas is performed on one cylinder from the manifold filling sequence. But if the mixing process of the gases in the buffer tanks can be validated to demonstrate that the mixture remains homogenous within the buffer tanks and during the filling process, then full testing of one cylinder per filling sequence or manifold could be acceptable.
Q.5 In terms of testing, what is expected when filling homecare units with liquid oxygen USP on company's premises?
A.5 If the source container is accompanied by a certificate of analysis, the filler for homecare units can perform identity testing only.
Q.6 Is an importer required to perform and identity test for gas mixtures of ethylene oxide?
A.6 Due to the carcinogenic nature of ethylene oxide, an identity test is not required to be performed on any medical gas mixtures of ethylene oxide by the importer as long as the importer sells the gas mixture "as is, in the same container" and does not perform any additional fabricating and/or packaging operations for this gas mixture. A certificate of analysis will be required from the fabricator of the gas mixture.
Q.7 In terms of testing, what is expected when a fabricator/packager/distributor supplies liquid nitrogen NF in an open-top dewar?
A.7 When a fabricator/packager/distributor supplies of liquid nitrogen NF in an unpressurized open-top dewar, no additional testing is required provided that the source container has been tested, met appropriate specifications and has been released and a certificate of analysis is available for the tank used to make the delivery.
Records - C.02.020, C.02.021, C.02.022, C.02.023 & C.02.024
Q.1 What is the extent of documentation required to be maintained by a medical gas distributor for new cylinders and valves?
A.1 Certification issued by Transport Canada may be acceptable as a means of compliance for new cylinders. Records may be maintained in a central location provided that the data is accessible or retrievable. It is expected that written specifications are available which outline the checks which are to be performed on empty cylinders prior to filling and that a record of those checks is maintained.
Valves on cylinders should be checked for functionality and records maintained.
Q.2 What is the retention time for Gas Chromatograms by a medical gas distributor?
A.2 Gas Chromatograms charts are considered to be records/evidence of testing and must be maintained for 5 years from the date of filling.
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