As efforts move forward to increased awareness and relay information for sterile compounding and hazardous drugs, it cannot go unnoticed that nonsterile compounding also presents with risk and potential harm for the patient. This blog will help with strategic assessment for assigning and extending Beyond-Use Dating (BUD) for nonsterile compounded preparations (CNSPs).
In the absence of stability information, USP <795> provides BUD guidance in Table 4 (see Diagram 1). Although Table 4 is based on sound scientific data on probability of microbial contamination and degradation, think of it as dealing with the unknown. Table 4 allows us to move forward and assign maximum BUD for CNSPs when there are certain unknowns. Even though unknowns may exist, this does not absolve us from doing our due diligence to find stability information and assigning the lesser BUD when information is present.
Table 4 BUDs are based on:
Potential for microbial growth from microbes introduced during compounding, proliferation during storage and/or introduction after dispensing
Potential for product degradation rendering the CNSP less effective or even dangerous because harmful byproducts
Table 4 categorizes final preparations based on the aqueousness of the dosage form. This aqueousness is determined on its water activity (Aw) of the final preparation. Water activity is not the measure of the total amount of water in a final preparation but instead the amount of water that lends itself to microbial proliferation and/or degradation to the final preparation.
Aw < 0.6 = nonaqueous CNSP
Aw ≥ 0.6 = aqueous CNSP
Thankfully, USP does not require us to measure water activity for any given CNSP. Instead, USP provides Table 3 that divides different CNSP dosage forms in two columns, aqueous and nonaqueous. Table 3 is not an all-inclusive list but is quite extensive.
Guidance for using Table 4 to assign BUD when stability is unknown:
Must attempt to find stability information and assign the lesser BUD (both physical and chemical stability of components and container)
May use to BUD indicated in Table 4 when unable to find stability
Antimicrobial testing (USP <51>) “should” be conducted on nonaqueous preparation but is not required
Required packaging must be tight and light-resistant to limit potential degradation from oxidation and light sensitivity
When assigning BUD from table 4, assuming no stability information could be found, the first step is to determine if the final preparation is aqueous or nonaqueous (again, refer to Table 3 to determine the aqueousness of the preparation).
Aqueous Preparations can be unpreserved or preserved:
Unpreserved aqueous preparations may receive a maximum BUD of 14 days under refrigeration. However, aqueous CNSPs “should” contain a preservative unless the preservative is contraindicated for the patient or the stability of the final preparation or if the facility is not equipped to add preservatives. Note that “should” in USP language is considered a recommendation and not a requirement but for this circumstance the “should” is backed with the statement “unless contraindicated”. Therefore, for patient safety, always consider using a preservative as a requirement for an aqueous preparation unless contraindicated or there is an inability to add a preservative. Many may fall into trouble with this concept, and it would be encouraged to document a reason for not adding a preservative to any given aqueous nonsterile preparation.
Furthermore, if an unpreserved aqueous CNSP is dispensed, the requirement is for it to be stored under refrigeration to slow microbial proliferation, unless there are stability issues with refrigerated temperatures. The maximum BUD of 14 days may still be assigned to a CNSP that is aqueous, unpreserved, and unable to be refrigerated but consideration should be made to what is best for the patient. Consider changing compounding process to more “sterile-type” manipulations to decrease microbial introduction during compounding, decrease BUD, dispense in unit-of-use, or patient education to ensure contamination is limited after dispensing (use of sterile swabs to remove product) to name a few.
Preserved aqueous preparations can be assigned a maximum BUD of 35 days at room temperature or under refrigeration. However, if combining multiple commercially available components that contain different preservatives, the final CNSP cannot be considered as preserved. The preservatives are potentially diluted out and there are unknowns to what interactions exists between preservatives, excipients, and API. There is no validation that the preservatives remain effective under these conditions. Therefore, the final CNSP should be assigned a BUD of 14 days refrigerated as if it were unpreserved. Although the CNSP itself may not be labeled as unpreserved since it does contain preservative, but the fact is that it is that the preservatives may no longer be effective.
Nonaqueous Preparations can be unpreserved or preserved:
This is where it gets a bit simpler. For nonaqueous ORAL LIQUIDS a BUD of 90 days may be given at room temperature or under refrigeration and for all other nonaqueous dosage forms, they may be assigned a maximum of 180 days. It should be noted that the more conservative BUD for nonaqueous oral liquids is because many API/ingredients are not stable in oil. Oils can also be corrosive to many plastics used as containers for CNSPs. Nonaqueous preparations may be preserved or unpreserved since the lack of water content essentially serves to better resist microbial growth.
Note again, the requirements for using Table 4 to assign BUD to CNSPs when stability is unknown:
Must attempt to find stability information and assign the lesser BUD (both physical and chemical stability of components and container closure)
May use to BUD indicated in Table 4 when unable to find stability
Antimicrobial testing (USP <51>) “should” be conducted on nonaqueous preparation but is not required
Required packaging must be tight and light-resistant to decrease potential degradation from oxidation and light sensitivity
Extending BUD beyond those in Table 4: USP <795> does allow for extending BUD beyond the limits of Table 4 by using USP-NF Monographs or stability studies if with very specific requirements are in place.
USP-NF Monographs supersede USP General Chapters and may be used in place of the USP <795> minimum standards. Therefore, if there isn’t any deviation from the monograph formulation and container then the BUD in the monograph may be used. This BUD may go beyond the maximum 180 days (mentioned below) and allow for unpreserved aqueous preparations. The Designated Person’s discretion may be used to determine what is acceptable for each patient need.
Stability Studies may be used to extend BUD but only to a maximum of 180 days. The stability information may be obtained through a private (unpublished) study or from a reputable study if the study contains very specific criteria:
Formulation must be followed
Container must be identical
Must have a stability-indicating analytical method
This blog won’t go into detail for stability-indicating methods. This information can be obtained by following the link https://go.usp.org/Proposed_2021_Revisions_795_797, which will direct to a document on stability-indicating analytical methods on the USP website. Keep in mind that this document was published prior to the finalization of 2023 USP <797> (sterile compounding) and should not be read for total content but instead for the information of stability-indicating methods.
Special Requirements for Extending BUD for Aqueous CNSPs: If extending BUD of any aqueous CNSP there are further requirement to have USP <51> antimicrobial testing done due to the danger of microbial contamination for these products. Note, USP <51> testing is a recommendation when using BUD from Table 4 but is required to extend BUD of aqueous CNSPs.
USP <51> antimicrobial testing can be obtained once through a private study and only needs repeating if there is deviation from the formulation or the container used. The compounder may also rely on USP <51> antimicrobial testing information obtained through and FDA-registered facility or through published peer-reviewed literature where no deviation from the formulation or container used. Bracket studies with USP <51> testing may be used as well where testing is done at a low and high concentration. If this is used, then the concentrations in-between the low and high values is an acceptable source if there isn’t any deviation in formulation or preservative amount.
USP <795> serves as the minimum standard for compounding nonsterile preparations to ensure patients are not harmed from excessive microbial exposure, inconsistent ingredients, and harmful incompatibilities and contaminants.
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About the author: Steve Milstead is a Board Certified Sterile Compounding Pharmacist (BCSCP) and the founder of Soigner Solutions (Soigner Universal, LLC). Collectively, Steve has over 20 years experience in sterile compounding of non-hazardous and hazardous preparations (including non-sterile to sterile using API). He is also experienced in non-sterile compounding and has fully developed and implemented all-inclusive compounding programs including USP <800> hazardous drug programs since the release of <800> in 2016. Steve received his Doctor of Pharmacy degree from McWhorter School of Pharmacy and holds two other degrees from Samford University and Université Sorbonne.
Thank you for visiting my site. For more information please visit www.SoignerSolutions.com or email me directly at smilstead@SoignerUniversal.com
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