The Food and Drug Administration (FDA) classifies oxygen and other medical gases used to treat disease as prescription drugs. If you fill high-pressure medical oxygen cylinders at your facility—either by the cascade method (gas to gas filling)—or by using a pump and vaporizer (liquid to gas filling), or if your employees move liquid oxygen from one container to another (either at your facility or at the patient’s residence), the FDA considers your company a drug manufacturer. You must register your “manufacturing” facility with the federal FDA and the appropriate agency in your state—usually the Board of Pharmacy—and comply with the applicable federal and state regulations.

One of the regulations a medical gas “manufacturer” must comply with is the Current Good Manufacturing Practice (CGMP) for Finished Pharmaceuticals regulation. The CGMP regulation’s purpose is to assure that manufactured drugs meet all quality characteristics. However, the requirements are broad and nonspecific for medical gases. As the name of the regulation infers, the characteristics are “current.” In essence, this means that what may have been acceptable practice in the past may not be acceptable now, and similarly, what is currently acceptable may not be acceptable in the future.

The applicability of CGMP provisions is contingent on the type of operations performed by the medical gas manufacturer. To assist medical gas firms in understanding what the FDA considers acceptable CGMP compliance, it has published guidance documents and papers. In May 2003, the FDA published a draft “Guidance for Industry—Current Good Manufacturing Practice for Medical Gases.”

Guidance documents are not requirements, and you must still be knowledgeable of and comply with all the applicable CGMP requirements that impact your operations. Links to the CGMP regulation, the draft guidance, and other information related to medical gases are available via the FDA’s Medical Gases Web site: www.fda.gov/cder/dmpq/gases.htm.

Usually, home care oxygen fillers require only basic medical gas manufacturing controls, because they handle just one product. This is especially true if the company fills only liquid oxygen home units. When a company fills high-pressure cylinders or handles more than one product, the FDA becomes concerned with potential quality problems and product mixups. With proper controls, however, these problems can be minimized and/or eliminated.

The FDA’s Quality Expectations
The FDA expects a home care company’s management team to have the necessary controls to assure a quality system functions properly. This includes qualified employees, proper facilities and equipment, written procedures, documentation covering all aspects of medical gas operations, and adequate equipment testing to assure the final product meets specifications. The CGMP regulation requires a firm to establish a quality control unit (QCU) capable of functioning independent of operations.

Depending on the size and complexity of the firm’s operations, the QCU may be a separate organizational unit, but generally, even for larger home care firms, an individual wears both an operations hat and a QCU hat at the branch level. While wearing the QCU hat, the individual must act as the consumer advocate and not permit the release of any product not physically or technically meeting specifications. Any condition found out of conformance with company specifications, including any paperwork discrepancies, requires a fully documented investigation.

As with all aspects of business, having qualified personnel is a key ingredient for success. The CGMP regulation requires firms to have employees with the proper education, training, and experience. Personnel associated with any medical oxygen filling or distribution operation must be trained on the specifics of their job to assure they follow the company’s standard operating procedures (SOPs), and understand the “whys” behind the “have to dos,” including the applicable portions of the CGMP regulation itself.

A firm also needs to consider any employee ailments or conditions that may affect product quality. For example, color blindness may influence an individual’s capability to determine the an oxygen cylinder’s color code, or a cold may prevent detection of an odor during a pre- or post-fill check.

Vehicles should be organized to prevent mix-ups between empty and full cylinders, and designed to prohibit delivery of products not properly approved by your QCU. The FDA allows each firm to determine how it will comply with the requirement for “separate areas.”

Some firms use painted lines on a floor, others use elastic ropes or movable carts in conjunction with signage to segregate products. Lighting in production and distribution areas should be sufficient to read all process-monitoring equipment.

High-pressure and liquid oxygen filling equipment should be designed, constructed, cleaned, and maintained to assure production of a consistent product that meets both product quality and quantity characteristics. In addition, process-monitoring and testing equipment requires periodic calibration to assure reliability and confidence in output readings. Generally, the equipment manufacturer’s recommendations for tolerance specifications, appropriate calibration standards, calibration frequency, and calibration methodology can be followed, provided the equipment’s use is also consistent with the manufacturer’s instructions. Surfaces directly exposed to gaseous or liquid oxygen must be “oxygen clean” and free of cleaning agents. Once properly cleaned and installed by qualified individuals, high-pressure filling equipment would not require routine internal “cleaning.”

All liquid filling equipment should be maintained in a way to prevent the introduction of foreign material. Properly designed, cleaned, and maintained high-pressure and liquid-oxygen equipment—used consistent with recommended safety practices—both protects filling personnel and assists in assuring product quality.

If you use computers for automated filling operations or for documenting filling or distribution activities, those systems would require validation to assure they consistently function properly. In addition, computer documents may also be subject to the FDA’s “electronic records, electronic signatures” regulation.

The CGMP subpart titled “Control of Components, Containers, and Closures” covers the procedures and controls for liquid or gaseous oxygen received and used to fill cylinders and liquid containers. This subpart also covers the procedures and controls used for assuring the high-pressure cylinders and the liquid containers themselves are acceptable for use prior to fill.

When you receive liquid product to fill other containers, you should receive a certificate of analysis (COA) specific to the lot numbered product in the received container. If you witness the testing documented on the COA, and the person witnessing the testing is qualified and trained in the methodology used by the supplier for testing, then no additional testing of the supply is needed. If you do not see the testing of the supply vessel, you will be required to do an identification test on the supplied product.

In the case of a storage tank, you will need to assay and identification test the commingled product in your storage or stand tank—after your supplier off-loads the certified product contained in the supplier’s bulk trailer. As a home care company, if you fill other supply vessels (such as a vehicle-mounted vessel from your qualified storage tank), you would not normally need to test the commingled product in your filled vehicle-mounted vessel. Currently, the FDA does not require the receipt of a COA or testing on incoming high-pressure supplies—if the supply cylinders are labeled Oxygen, USP.

50 Years and Counting
Some medical gas cylinders in the field today have seen more than 50 years of safe use. The repeated use of cylinders and containers makes medical gases unique in the pharmaceutical industry and dictates the need for stringent controls. Perhaps the most critical step to assure both the quality of the oxygen provided to patients and the safety of the filling personnel is the proper performance of prefill inspections and proper handling of high-pressure cylinders and liquid containers. Through its guidance documents, the FDA stresses the importance of high-pressure cylinder and liquid container control. The Compressed Gas Association (CGA) publishes several pamphlets, detailing the prefill inspections and tests required to assure a cylinder is safe and acceptable to fill. To assure the proper functionality of both large- and patient-use liquid oxygen containers, conduct the appropriate pre-fill inspections and maintenance recommended by the liquid container manufacturer and stipulated in the FDA’s guidance documents.

All filled cylinders and containers, including liquid oxygen home units, must bear a drug product label in compliance with the FDA’s label regulation (21CFR Part 201). Among other items, medical oxygen must bear the statement “Rx only,” and indicate the net quantity of contents, usually in gaseous liters or cubic feet for high-pressure cylinders, and liquid liters or gallons for liquid containers. Documenting the net quantity, per current industry practice, places the information directly on the product label or, alternatively, on the lot number sticker.

Liquid oxygen base units are unique in the fact that they must also bear the unit manufacturer’s device label. Although there is CGA-recommended wording for cryogenic oxygen labeling applicable to large cryogenic vessels, not all of the wording is applicable for home use operations. Per discussions with the FDA, once the CGMP guidance is finalized, one of the next priorities will be to work on medical gas labeling guidance and regulation.

The product label is the primary means of identifying any drug, therefore the FDA expects a firm to exercise strict control and document oxygen label issuance, application, and return. The FDA expects reconciliation between the number of labels used and the number applied to cylinders and liquid containers. Maintain your medical oxygen labels in a secure limited-access storage area, such as a lockable cabinet. A unique lot number assigned to every manifold of high-pressure cylinders, every large cryogenic container filled, and every liquid oxygen base unit filled and placed into stock is required on each container. A liquid oxygen base unit, filled for a specific patient at a facility or patient’s residence, would not require an assigned lot number. However, the production paperwork, among other things, should identify the patient’s name and the supply lot used to fill the unit. As of this writing, the issue (raised in the draft guidance) that requires medical gas containers to bear an expiration date has not been fully debated.

The CGMP contains a “production and process control” requirement that translates into the need to have step-by-step procedures and an SOP for filling high-pressure cylinders and liquid containers. Referencing manufacturer’s instructions in an SOP is acceptable if the instructions are available to the filler and followed exactly. It is imperative to follow all procedures and document all significant steps on a fill record at the time they are performed. Design your procedures to assure a container has 100% of its label claim at the conclusion of filling operations.

All high-pressure cylinders must be evacuated before fill. During the fill process, cylinders heat up and fillers use temperature-pressure charts to tell when to stop filling. These charts, however, generally reflect the proper “settled” pressure when the cylinder has reached temperature equilibrium with its environment—and not necessarily during the fill process.

Perform leak checks and heat-of-compression checks during the fill process to detect leaks and assure that cylinders are filling correctly. Once filled, each cylinder undergoes a second leak check to assure the cylinder valve is closed and is leak free. After filling, one cylinder per manifold must be tested for odor, and also tested for identity and strength (assay)—typically using a calibrated paramagnetic analyzer. The QCU must review and approve all records associated with the production and testing of each high-pressure cylinder lot prior to its distribution.

John K. Willenbrock, RAC, is president of Gas Regs Inc, Jamestown, NC, a quality assurance/FDA regulatory affairs and compliance consulting firm for companies that fill and/or distribute medical gases. Willenbrock is a member of AAHomecare’s Medical Gases Committee, the Compressed Gas Association, and other quality and regulatory associations. He can be reached through the Internet at www.gasregs.com, or via email: john.willenbrock@gasregs.com.