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Gases as Excipients and Reagents in Pharmaceutical Manufacturing
The preface of the National Formulary, Volume 20, page 2494 , under the heading of “NF Admissions policies,” defines an excipient 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.” NF 20 specifically lists Nitrogen and Carbon Dioxide as excipients on page 2496.
The General Notices section of USP 25 on page 6 also discusses the use of gases in Pharmaceutical Manufacturing and includes references to Nitrogen, Carbon Dioxide and Helium as headspace gases. Oxygen, while frequently encountered in Pharmaceutical Manufacturing, is not an excipient; but rather because of its reactivity, is some sort of oxidizing reagent. Oxygen has its own USP monograph.
It is clear that USP 25/NF 20 teach that excipients have important potential significance to the Pharmaceutical Manufacturing process, particularly in regard to the potential for introducing adulterating contaminants.
Statutory Significance of the USP/NF Compendiums
The Preamble/Preface to USP 25/NF 20 includes a paragraph on page xlv which emphasizes the “Legal Status of the Official Compendia.” Included in this preface section are references to the various statutes which recognize, incorporate and use as a basis for enforcement, the Official Compendia. Essentially, the Food, Drug and Cosmetic Act provides, among other requirements, that a drug may be adulterated if it does not conform to USP/NF standards for strength, quality and purity. It is therefore important to ensure that all steps of the Pharmaceutical Manufacturing process incorporate processes, materials and equipment which minimize any possibility for the introduction of adulterating substances.
References: cGMP Requirements from 21 CFR 211.84 Testing and approval or rejection of components, drug product containers, and closures
(d) Samples shall be examined and tested as follows:
(2) Each component shall be tested for conformity with all appropriate written specifications for purity, strength and quality. In lieu of such testing by the[Pharmaceutical] 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 [Pharmaceutical] 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.
(5) Each lot of a component, drug product container, or closure that is liable to contamination with filth, insect infestation, or other extraneous adulterant shall be examined against established specifications for such contamination.
A. NF considers Nitrogen and Carbon Dioxide to be an excipient.
B. USP also discusses Oxygen, Nitrogen, Carbon Dioxide and Helium.
C. USP/NF provide compendial standards for these gases.
D. These gases have a history of use in other applications. Specifications developed for use in non-pharmaceutical industrial applications may differ from pharmaceutical standards, tests and specifications.
E. Linde USP/NF grade gases are manufactured under cGMP, and meet the applicable specifications of USP/NF, which include a certificate of analysis, validated analytical procedures, lot number assignment, traceability and recall procedures. Industrial grade gases have none of these cGMP attributes, and may be interpreted by FDA as a potential source of adulterants.
F. 21 CFR 211.84 (2) requires that a Pharmaceutical Manufacturer prepare written purity, strength and quality specifications for all components, then test each component for conformance to the written specifications. Alternatively, a certificate of analysis from the component supplier may be used if the Manufacturer validates the supplier’s analytical test results at appropriate intervals. All of these requirements are met for Linde’s USP/NF grade products, which are manufactured under cGMP by Linde. Therefore, the Manufacturer avoids most of the cost of conducting these regulatory compliance actions themselves by utilizing Linde USP/NF grade gases. Overall costs for the Pharmaceutical Manufacturer may actually be lower by utilizing Linde’s USP/NF cGMP grade gases in Pharmaceutical manufacturing.
G. A Pharmaceutical Manufacturer who has a bulk supply system for any of these gases, and who has a pipeline in their plant may have various locations throughout the plant which may access and utilize the pipeline supply in a variety of applications. It is conceivable that the bulk gas supply system, through the pipeline, may come into contact with the Pharmaceutical Manufacturer’s product.
H. Linde interprets the regulations as implying that the only uses for these gases which do not require USP/NF cGMP gases would be those applications where these gases do not come into contact with the Pharmaceutical Manufacturer’s product. An example of this would be the use of the gases for powering a pneumatic pump or motor. Linde interprets the regulations as requiring USP/NF cGMP grade gases whenever the gases come into contact with the Pharmaceutical Manufacturer’s product(s).
I. Linde also has the capability to produce Nitrogen, which meets the testing requirements of the European Pharmacopoeia (EP), thereby assisting the Pharmaceutical Manufacturer to comply with the EP requirements. This may have a beneficial effect on the Pharmaceutical Manufacturer’s ability to market their products in Europe.
J. FDA currently espouses the philosophy that USP/NF cGMP conformance CAN NOT be “tested into” a product. It was either manufactured under cGMP or it was not. Therefore a customer cannot “test into” an industrial grade product USP/NF cGMP conformance.
Linde Position Regarding Bulk Supply of Oxygen, Carbon Dioxide, Helium and Nitrogen to Pharmaceutical Manufacturers
Linde will recommend the supply of USP/NF cGMP grade gases to the maximum extent possible, whenever the gases have the potential of coming into contact with the Pharmaceutical Manufacturer’s product, i.e., as a reagent or excipient.
Linde takes the position that whenever a Pharmaceutical Manufacturer is faced with a choice between a USP/NF cGMP grade gas and a non- USP/NF cGMP grade gas, in order to maximize regulatory compliance, and minimize the potential for the introduction of adulterating materials into the Pharmaceutical product and to maintain an unbroken chain of cGMP documentation for the gases, that the USP/NF cGMP grade gas should be used.
Linde believes this course of action will also minimize overall costs for the Pharmaceutical Manufacturer. Linde, at its sole option, may and probably will, opt to not bid or not supply non USP/NF cGMP grade gases to Pharmaceutical Manufacturers for reagent, component or excipient applications.