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Question: In the revised USP <795> Pharmaceutical Compounding—Nonsterile Preparations, what is the scientific justification and documentation for the use of USP <1112> and water activity for defining compounded preparations and beyond-use dates (BUDs)?
Answer:
First, let's see what USP <795> says:
10. ESTABLISHING BEYOND-USE DATES
10.3 Establishing a BUD for a CNSP
The BUDs in Table 3 [of USP <795>] are based on the ability of the CNSP to maintain chemical and physical stability and to suppress microbial growth...
The aqueous and nonaqueous dosage forms in Table 3 are defined based on the water activity (Aw) of the most similar drug product described in Application of Water Activity Determination to Nonsterile Pharmaceutical Products [USP] <1112>. In general, the use of Aw aids in assessing the susceptibility of CNSPs to microbial contamination and the potential for API degradation due to hydrolysis...
Comments:
- The use of Aw to define dosage forms and categorize their "chemical stability" is not applicable, as Aw was never detailed/described for this purpose in USP <1112>.
According to USP <1112>:
The determination of the water activity of nonsterile pharmaceutical dosage forms aids in the decisions relating to the following:
- (a) optimizing product formulations to improve antimicrobial effectiveness of preservative systems,
- (b) reducing the degradation of active pharmaceutical ingredients within product formulations susceptible to chemical hydrolysis,
- (c) reducing the susceptibility of formulations (especially liquids, ointments, lotions, and creams) to microbial contamination, and
- (d) providing a tool for the rational for reducing the frequency of microbial limit testing and screening for objectionable microorganisms for product release and stability testing using methods contained in the general test chapter Microbial Enumeration Tests <61> and Tests for Specified Microorganisms <62>.
- Throughout USP <1112>, the discussion relates ONLY to (a), (c) and (d) above, and there is NO further mention of (b). The sole purpose of USP <1112> involves microbial growth and testing related to Aw; it has nothing to do with chemical drug degradation.
- Table 2 in the chapter, ?Microbial Limit Testing Strategy for Representative Pharmaceutical and OTC Drug Products Based on Water Activity? is just what it says, a "strategy for microbial limit testing," not for chemical analysis/stability testing. A footnote to the table states:
"[Note-The water activities cited in Table 2 for the different dosage forms are representative, and companies are urged to test their individual products before developing a testing strategy.]"
This note refers to companies doing microbial limit testing on their pharmaceutical products utilizing a water activity testing method, as different products will have different Aw values.
- Where is the reference/documentation for Table 2 in USP <1112>? Chemical stability is not discussed in this chapter; so it should not be used in USP <795> to establish BUDs.
- Tracing USP <1112> back to when it was originally introduced, we find the following:
2004 Pharmaceutical Forum (PF) Sep/Oct
Title changed from:
"<1112> Microbiological Attributes of Nonsterile Pharmaceutical Products–Application of Water Activity Determination"
TO
"<1112> Application of Water Activity Determination to Nonsterile Pharmaceutical Products."
The "Briefing" notes stated the following:
<1112> Microbiological Attributes of Nonsterile Pharmaceutical Products–Application of Water Activity Determination, page 2009 of PF 28(6) [Nov-Dec. 2002]. This new chapter, which previously appeared in Pharmacopeial Previews, is now moved to In-Process Revision with the following changes on the basis of comments received:
- (1) The title of the chapter has changed.
- (2) The importance of container-closure integrity in maintaining the water activity level during the product shelf life is emphasized.
- (3) Reduced microbial limits testing must be justified through risk assessment and not solely on water activity determinations.
- (4) The ability of more resistant microorganisms to persist in drug products of low water activity is acknowledged.
Editor's Note: As can be seen above, there is NOTHING related to chemical stability.
2006 USP 29 Suppl 2 Chapter Added to USP Supplement
2007 USP 30 Chapter included in hard volume
In summary, USP <1112> does not appear to include any aspect of "reducing the degradation of active pharmaceutical ingredients within product formulations susceptible to chemical hydrolysis" other than the mention in the first paragraph of USP <1112>. There appears to be no basis in USP <1112> for its use in establishing USP <795> chemical stability BUDs or defining dosage forms.
For those state boards of pharmacy that are not adopting the USP chapters and are preparing their own or using their own modifications of the chapters, easily-modifiable alternative versions of <795>, <797>, and <800> have been prepared and will be available starting Monday of next week (June 24, 2019) as a FREE DOWNLOAD at the following website for use in modifying their individual states:
CompoundingToday.com
You may wish to download and send to your state board of pharmacy for consideration.
Loyd V. Allen, Jr., PhD, RPh
Editor-in-Chief
International Journal of Pharmaceutical Compounding
Remington: The Science and Practice of Pharmacy Twenty-second edition
EDITOR'S NOTE: The complete "Initial Impressions of the Recently Released Final Revision of USP <797>" prepared by Rad Dillon is now available on the CompoundingToday.com website for a FREE DOWNLOAD.
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https://www.nytimes.com/2019/06/14/health/drug-prices-tv-ads.html
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Tip of the Week
Common Sense (CS) lived by simple, sound financial policies and reliable strategies:
- Don't spend more than you earn
- Adults, not children, are in charge
The health of CS began to deteriorate rapidly when well-intentioned but overbearing regulations were set in place:
- Reports of a 6-year old boy charged with sexual harassment for kissing a classmate
- Teens suspended from school for using mouthwash after lunch
- A teacher fired for reprimanding an unruly student
All these and more, only worsened CS's condition.
(More next week)
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