Qualifying “Excipient” Gases (Nitrogen, Carbon Dioxide, Oxygen) In the Drug Manufacturing Process

In strict adherence to the Good Manufacturing Practices (GMP) as required in the development of drug products, it is important to ensure that all steps utilize processes, materials and equipment that minimizes and eradicates the possibility for the introduction of contaminated substances. Add to this requirement that the National Formulary section of the United States Pharmacopeia defines excipients as “any component other than the active substance(s), intentionally added to the formulation of a dosage form. It is not defined as an ‘inert’ commodity or an ‘inert’ component of the dosage form.” The USP goes on further to specifically lists Nitrogen and Carbon Dioxide as excipients. Not to add even more fuel to the fire, the general notices section of the USP also discusses the use of medical gases and also references Nitrogen, Carbon Dioxide and Helium as headspace gases and mentions Oxygen as an oxidizing agent. All of these gases have their own USP Monographs. In 2003, the Food and Drug Administration issued a draft guidance document entitled “Current Good Manufacturing Practice for Medical Gases”.

Based upon all of the above referenced facts, if medical gases such as Nitrogen, Carbon Dioxide, Helium and Oxygen are being used in any aspect of the drug development and manufacturing process, it is imperative, and a regulatory requirement, that they meet (as any excipient is required to) the USP defined qualification process. Based upon my experience in the area of gas qualification testing that has spanned the past 13 years, the qualification of USP grade gases has been an area often overlooked by manufactures. If this is an area that your company has struggled with, this article will hopefully provide some insight in to how best to address the medical gas qualification issue.

To begin, you must verify that your gas supplier vendor is providing your company with USP-NF grade materials. In most cases the supplier will include of “Certificate of Compliance” (CofA) with each specific lot of the specific gas purchased. The C of A should reference USP-NF qualification test procedures. As referenced in the Code of Federal Regulations (21 CFR 211.84 “Each component shall be tested for conformity with all appropriate written specifications for purity, strength and quality. In lieu of such testing by the Manufacturer, a report of analysis may be accepted from the supplier of a component, provided that at least one specific identity test is conducted on such component by the Manufacturer, and provided that the

[Pharmaceutical] Manufacturer establishes the reliability of the supplier’s analyses through appropriate validation of the supplier’s test results at appropriate intervals.” In essence, the C of A as provided by the vendor is acceptable but there remains a requirement that the receiving manufacturing company perform at least one specific identity test. Non-performance of the required identity test is a typical pitfall of many companies.

The second area many companies fall short of regulatory requirements deals with inline gas systems. In many large scale manufacturing plants, large volume gas supply tanks feed an internal pipeline system with numerous extraction points. Upon receipt of the large bulk delivery, the vendor can supply the C of A to confirm USP-NF compliance, but the supplier cannot guarantee the quality or integrity of the gas as it makes its way through the internal pipeline. It is in this distribution process that contamination can become an issue. To address this issue, the manufacturing plant must take steps to implement a plan of action that required some form of quality control testing on a periodic basis. This program typically required a defined schedule of sample pulls and testing from the various outlet points. Typically, a service provider who specialized in USP-NF gas testing can help you define the most appropriate plan that will insure FDA compliance.

Medical gas testing, while not a high profile area in the eyes of the FDA, is something that has become more prevalent over the past ten years. Taking the time to insure compliance before the FDA needs to address the issue with your company, will not only insure you are meeting the CFR/USP requirements, but will also help to show the inspectors that you understand all of the critical areas (even small ones) defined by the regulations.