Editorial: Documentation vs Opinion on Compounding Regulatory Activities III
This continues the series looking at some of the 483 observations and Board of Pharmacy activities and tries to provide documentation surrounding these specific activities. Comments are based upon complying with state board of pharmacy laws and regulations and United States Pharmacopeia (USP) standards.
Observation: Sterility testing is not routinely performed at the end of shelf-life or at the end of stability studies.
USP Standards:
General Notices 10.40.100.1 Compounded Preparations
"The label on the container or package of an official compounded preparation shall bear a beyond-use date [BUD]. The beyond-use date is the date after which a compounded preparation is not to be used. Because compounded preparations are intended for administration immediately or following short-term storage, their beyond-use dates may be assigned based on criteria different from those applied to assigning expiration dates to manufactured drug products."
U.S. Food and Drug Administration (FDA) Guides:
FDA Inspection Technical Guide
Expiration Dating and Stability Testing for Human Drug Products
10. Sterility Testing
Products manufactured as sterile must maintain that quality throughout the labeled expiration dating period as long as the product is unopened and stored according to labeled instructions. The ability of the product to retain its sterile condition is a function of the container-closure system. When qualifying the container-closure system, sterility testing should be performed initially and at the end of the expiration dating period. Once any particular container-closure system can be demonstrated to maintain sterility throughout the expiration dating period, it is unnecessary to revalidate its ability to maintain sterility for other ingredients that may be placed into the same container-closure system."
Comments:
The USP General Notices plainly state that compounded preparations must contain a BUD and this BUD can be determined differently than the procedures required by the FDA for establishing expiration dates. Expiration dates are applied to manufactured products with an expected shelf life of about 2 to 3 years. BUDs are for up to 6 months but generally much shorter than that. The requirement from the FDA for a sterility test at the end of the expiration period is for documenting that a container-closure system maintains sterility. There is nothing in <795> or <797> stating that sterility testing at the end of the BUD is required.
The only mention in <797> of a follow-up sterility test is in the case of Redispensed compounded sterile preparations (CSPs) where it states "Assignment of new storage times and BUDs that exceed the original dates for returned CSPs is permitted only when there is supporting evidence from sterility testing and quantitative assay of ingredients."
As a general rule for CSPs, after sterility is addressed, BUDs are based upon physical and chemical stability.
Also, in the majority of CSPs, there will be nothing left to analyze as only a minimum number of preparations to meet the needs are compounded and dispensed/administered.
Summary:
This is another example of the improper use of Good Manufacturing Practices (GMPs) inspection guidelines for inspecting a pharmacy that is subject to Good Compounding Practices, not GMPs. The costs to pharmacies in responding to these inspections are generally in the tens of thousands of dollars�or more! That is a lot of money for a small business.
Loyd V. Allen, Jr., PhD, RPh
Editor-in-Chief
International Journal of Pharmaceutical Compounding
Remington: The Science and Practice of Pharmacy
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