Source of Beyond-use date

{{Infobox concept | name = Beyond-use date | subtitle = Dating of compounded and opened preparations | image = coa-sheet.svg | caption = A beyond-use date is assigned by the person who prepares or opens a preparation, and is recorded on the container rather than derived from it. | Abbreviation = BUD | Assigned by = The compounder or the person opening the container | Basis = Compendial default tables, or product-specific testing | Contrast = Expiration date, assigned by the manufacturer from stability data <!-- Compendial framework --> | Sterile compounding = USP <797> | Nonsterile compounding = USP <795> | Container and storage definitions = USP <659> | Stability in dispensing practice = USP <1191> <!-- Selected defaults --> | Multiple-dose container after first puncture = 28 days unless otherwise specified | Single-dose container entered in ISO Class 5 air = 12 hours | Single-dose container entered in poorer air = 1 hour | Nonaqueous nonsterile preparation = 180 days }} {{hatnote|Not to be confused with the manufacturer expiration date, which is established by a formal stability programme under ICH Q1A(R2).}} {{accuracy|date=February 2026|talk=RfC: conflation of beyond-use date and expiration date}} A '''beyond-use date''' ('''BUD''') is the date, or date and time, after which a compounded preparation or an opened container is not to be used. It is assigned by the person who prepares or opens the preparation, using compendial default tables or, where available, testing specific to the preparation. It is distinct from an '''expiration date''', which is assigned by a manufacturer on the basis of a formal stability programme conducted on the finished product in its final container.{{r|usp797,usp1191}} The distinction is one of evidence rather than of vocabulary. An expiration date rests on long-term, intermediate and accelerated stability studies conducted under the conditions specified in ICH Q1A(R2), analysed statistically, and submitted to a regulator; it is a claim about the specific product in the specific container. A beyond-use date generally rests on a table of conservative defaults chosen to be safe across a wide range of preparations, and it is a claim about a class of preparations rather than about the one in hand. The two are therefore not comparable quantities, and a short beyond-use date does not imply a preparation degrades quickly.{{r|ich_q1a,usp797}} Beyond-use dates in sterile compounding are limited principally by microbiological risk rather than by chemical degradation. The default periods in USP <797> are graduated by how the preparation was made, by whether sterility testing was performed and passed, and by storage temperature — not by the chemistry of the active substance. Chemical stability is a separate constraint, and where it is shorter it governs.{{r|usp797}} The distinction between the two kinds of date is imperfectly maintained in secondary sources and in ordinary usage, where both are called an expiry. On this wiki the conflation has been the subject of a request for comment, and the resulting convention is that ''expiration date'' is reserved for manufacturer dating supported by a stability programme, and ''beyond-use date'' for everything else.{{r|ppbud}} == Definition and contrast with the expiration date == An expiration date is the output of a defined regulatory process. Under ICH Q1A(R2), a manufacturer conducts long-term studies at the intended storage condition, intermediate studies where required, and accelerated studies at elevated temperature and humidity, on at least three primary batches in the container closure system intended for marketing. The results are evaluated — under ICH Q1E — to establish a retest period or shelf life, and the date is stated on the label. It applies to the unopened product stored as labelled.{{r|ich_q1a}} A beyond-use date has none of that apparatus behind it. It applies to a preparation that the manufacturer's stability programme never examined: a container that has been opened, a solution that has been diluted, a lyophilised solid that has been reconstituted, or a preparation compounded from components. The chemistry may be identical; the container's history is not. |+ Two kinds of date | !Property | Expiration date | Beyond-use date | |---|---|---| | Assigned by | Manufacturer | Compounder or dispenser | | Evidence base | Product-specific stability programme | Compendial default table, or preparation-specific testing | | Applies to | Unopened product, stored as labelled | Compounded or opened preparation | | Principal limiting factor | Chemical and physical degradation | Microbiological risk, then chemical stability | | Regulatory status | Submitted and approved | Assigned under a compendial standard | | Typical magnitude | 12–60 months | Hours to 180 days | Two consequences of the table are worth drawing out. Because the two dates are limited by different things, they respond differently to storage: refrigeration extends a microbiologically limited beyond-use date substantially and generally extends an expiration date not at all, since the expiration date already assumes the labelled condition. And because a beyond-use date is assigned rather than measured, it can be assigned correctly to a preparation that has in fact already degraded, if the degradation route was one the default table does not contemplate.{{r|usp797,usp1191}} Where both dates apply, the earlier governs. A preparation compounded on a date that would yield a 45-day beyond-use date, from a component whose own expiration date falls in 20 days, has a usable life of 20 days.{{r|usp795}} == Sterile preparations under USP <797> == USP <797> classifies compounded sterile preparations into categories by the conditions under which they are made, and assigns default beyond-use dates by category, by whether sterility testing was performed, and by storage temperature. Category 1 preparations are made in an unclassified segregated compounding area and carry the shortest dating. Category 2 preparations are made in a cleanroom suite meeting the chapter's requirements. Category 3 preparations meet additional requirements — including sterility and endotoxin testing and more extensive personnel qualification — and may carry substantially longer dating. |+ Default beyond-use dates for Category 2 preparations, USP <797> 2023 revision | !Preparation method | Sterility tested and passing | Controlled room temperature | Refrigerated | Frozen | |---|---|---|---|---| | Aseptically processed, from sterile components only | No | 4 days | 10 days | 45 days | | Aseptically processed, one or more nonsterile components | No | 1 day | 4 days | 45 days | | Aseptically processed | Yes | 30 days | 45 days | 60 days | | Terminally sterilised | No | 14 days | 28 days | 45 days | | Terminally sterilised | Yes | 45 days | 60 days | 90 days | Periods are those tabulated in the 2023 revision of the chapter, which differs from earlier revisions; the earlier low-, medium- and high-risk classification has been replaced by the category scheme.{{r|usp797}} Three structural features of the table repay attention. Sterility testing buys a large extension — from 4 days to 30 at room temperature for an aseptically processed preparation from sterile components — which reflects that the untested default is a bound on the probability of undetected contamination rather than an estimate of when contamination occurs. Introducing a nonsterile starting component shortens the dating sharply, because the bioburden and endotoxin history of that component is unknown. And frozen storage flattens the differences, because microbial growth is suppressed and the residual limit becomes chemical.{{r|usp797}} The chapter states throughout that the defaults are maxima and that a shorter date must be assigned where the chemical or physical stability of the preparation, or the compatibility of its components, requires it. The defaults bound microbiological risk; they say nothing about whether a peptide in the preparation remains intact.{{r|usp797,usp1191}} == Nonsterile preparations under USP <795> == Nonsterile compounded preparations are dated under USP <795>, which in its 2023 revision assigns defaults by dosage form and water activity rather than by a calculation from component expiry. | Preparation type | Default beyond-use date | |---|---| | Nonaqueous dosage forms | 180 days | | Water-containing oral formulations | 14 days, refrigerated | | Water-containing topical, dermal and mucosal liquid and semisolid formulations | 30 days | Periods are those in the 2023 revision.{{r|usp795}} The revision removed a widely known earlier provision under which a preparation made from a manufactured product could be assigned a beyond-use date of not later than 25% of the time remaining until that product's expiration date, or six months, whichever was earlier. That ''25% rule'' remains in circulation in secondary sources and in older references, and is no longer the compendial position; sources quoting it should be checked against the current revision.{{r|usp795,trissel2022}} The 2023 chapter also permits longer dating where supported by a stability-indicating study on the preparation, or by published stability information for the same formulation in the same container and storage condition. The qualification about container and condition is not incidental: published stability data for a solution in a glass vial does not transfer to the same solution in a plastic syringe, because sorption and permeation differ.{{r|usp795,trissel2022}} Water activity is the organising principle behind the dosage-form distinctions. Preparations in which water is available support microbial growth and hydrolytic degradation; those in which it is not, or is bound, support neither to the same degree. This is the same principle that makes a lyophilised solid far more stable than its reconstituted solution, and it connects the compendial framework to the physical chemistry set out at [[Lyophilisation]].{{r|usp795}} == Opened containers == Entering a container ends the applicability of its expiration date, because the container closure system on which that date depended has been breached. Dating from that point follows the rules described at [[Multi-dose vial|multiple-dose containers]] and summarised here. ; Single-dose containers : Entered in ISO Class 5 air or better, usable for up to 12 hours; entered in poorer air, up to 1 hour. The dependence on air quality reflects that the risk is airborne and personnel-borne contamination at the moment of entry. ; Multiple-dose containers : 28 days after initial puncture, unless the manufacturer specifies a shorter period. The preservative, not the environment, is what permits the longer period. ; Pharmacy bulk packages : As stated on the label, conventionally a small number of hours after entry.{{r|usp797,usp659}} The 28-day figure derives from the antimicrobial effectiveness testing in USP <51>, whose challenge protocol runs over 28 days, together with infection-control practice. It is not a chemical stability figure and was never derived as one, a point on which this wiki has had to correct several articles.{{r|usp51,ppbud}} Reconstitution of a lyophilised product is the case most relevant to this wiki. Where the manufacturer has established a period for the reconstituted product, that period appears in the labelling and governs. Where no such period exists — the situation for essentially all peptides distributed for research use — no compendial default is directly applicable either, because the default tables in <797> govern preparations compounded under the chapter's conditions and not preparations made outside any such framework.{{r|usp797,ppbud}} What is left is analogy. Community practice generally assigns about 28 days to a vial reconstituted with a preserved diluent and a much shorter period to one reconstituted with an unpreserved diluent, both refrigerated. The shape of that practice matches the compendial framework, and its numerical values are borrowed from it rather than derived. Its weakness is not the borrowing, which is reasonable, but the absence of any check: no sterility testing, no preservative-effectiveness testing and no assay of the reconstituted solution have been published for such preparations, so a beyond-use date so assigned is untested at both ends.{{r|ppbud}} == Assignment in the absence of data == Where a preparation-specific stability study is unavailable — the usual case — the compendial approach is to apply a conservative default and to shorten it where any consideration suggests it should be shorter. The considerations enumerated in <795> and <1191> include the nature of the active substance and its degradation mechanism, the container and its potential for sorption or permeation, the storage condition, the expected duration of use, and the presence of water.{{r|usp795,usp1191}} Date arithmetic is simple and worth stating explicitly, because errors in it are common and consequential. A lyophilised vial is reconstituted on 12 March and stored refrigerated. A 28-day period gives a beyond-use date of 9 April: the count runs from the day of preparation, and the beyond-use date is the last day on which the preparation may be used, not the first on which it may not — a convention on which sources differ, so that a stated date without a stated convention is ambiguous by a day. The ''shorter-of'' rule then applies. If the lyophilised material carried a manufacturer's expiration date of 30 March, that date governs and the beyond-use date is 30 March, not 9 April, because a preparation cannot outlive the component it was made from. If instead the expiration date were 30 June, the 28-day beyond-use date of 9 April governs. A second worked case illustrates the same rule with a percentage. Under the superseded 25% provision in the older <795>, a preparation made on 12 March from a product expiring on 12 September — 184 days remaining — would have received 25% of 184 days, or 46 days, giving 27 April, since 46 days is less than six months. Under the 2023 revision that calculation is not performed at all and the dosage-form default applies. The two approaches give different answers, which is why the revision status of a cited source matters.{{r|usp795,trissel2022}} {{note|Both dates are properties of a record, not of a container. A vial whose reconstitution date was not written down has no determinable beyond-use date, and compounding practice treats that as equivalent to an expired preparation rather than as a documentation lapse to be corrected retrospectively.}} === Where testing is available === A beyond-use date may be extended beyond the defaults where supported by evidence, and the evidence expected is specific. For chemical stability, a [[Analytical method validation|validated]] stability-indicating assay applied to the actual preparation, in the actual container, at the actual storage temperature, over the proposed period, with the acceptance criterion stated in advance. For sterility, testing under USP <71> on a statistically defensible sample, together with endotoxin testing under USP <85> where relevant.{{r|usp797,usp795}} The requirement that the study match the container is the one most often violated in practice, because published stability data are abundant for common combinations and scarce for unusual ones. Sorption of peptide onto container surfaces, permeation of water or oxygen through a polymer wall, and leaching from a closure are all container-specific, and none is detectable in a study performed in a different container.{{r|usp795,usp1191}} For material distributed outside regulated channels, third-party purity testing of a reconstituted solution after storage is occasionally reported and is a genuine improvement on assertion. Without a matched baseline result on the same lot before storage, however, it cannot distinguish degradation during storage from a purity deficit present at manufacture — the same limitation described at [[Temperature excursion]].{{r|ppbud}} == Labelling and records == A beyond-use date exists only as a record, which makes labelling part of the standard rather than an administrative addition. USP <797> requires that a compounded sterile preparation be labelled with, among other items, the assigned beyond-use date and the storage condition to which it applies, because the date is conditional on that condition and is meaningless without it.{{r|usp797}} Three items make a beyond-use date interpretable, and the omission of any one makes it uninterpretable: * the date, with the convention stated or evident; * the storage condition assumed; * what the preparation is, at what concentration, in enough detail to identify the applicable default. For an opened manufactured container the equivalent record is the date of first entry, annotated on the container. Guidance treats an unannotated multiple-dose container as undatable and therefore to be discarded, on the ground that no evidence exists that it is within its period.{{r|usp797,cdc_injection_bud}} For reconstituted research peptides the recording problem is compounded by the labelling problem discussed at [[Vial|vial]]: a vial that carries no manufacturer label offers nowhere obvious to write, and a vial whose contents are identified only by a discarded outer package cannot be annotated meaningfully at all. Community practice of marking the closure or the ferrule with the reconstitution date is the common workaround and is recorded here as practice rather than recommended.{{r|ppbud}} Terminology on labels is a further source of confusion. Manufactured products carry ''EXP'' or ''Expiry'', compounded preparations carry ''BUD'' or ''Discard after'', and the two are visually similar and semantically different. Where a compounder relabels a manufactured product — repackaging into a smaller container, for instance — the resulting label carries a beyond-use date and the original expiration date is no longer applicable, a transition that [[Repackaging|repackaging]] practice is required to make explicit.{{r|usp795,usp1191}} == Terminology and the conflation problem == The two kinds of date are conflated pervasively, and the conflation is not merely pedantic to correct, because the two respond differently to the questions readers ask. Asked whether a date can be extended, the answers differ. An expiration date can be extended only by the manufacturer on the basis of further stability data, and in specific circumstances by a regulator, as has occurred during shortages. A beyond-use date can be extended by whoever assigned it, if they obtain evidence supporting a longer period — because it was a conservative default and not a measurement.{{r|ich_q1a,usp795}} Asked what happens on the day after, the answers differ. Passing an expiration date means the manufacturer's assurance of conformance to specification has ended; the product is very often still within specification, and stability studies extending past labelled shelf life routinely show that. Passing a beyond-use date on a preserved multiple-dose container means a microbiological risk bound has been exceeded, which is a different kind of statement and not one about assay values.{{r|usp1191,usp51}} Asked whether refrigeration helps, the answers differ, as set out in §Definition and contrast with the expiration date. The convention adopted on this wiki after a 2026 request for comment is that ''expiration date'' is used only for manufacturer dating supported by a stability programme; ''beyond-use date'' for dating assigned by a compounder, dispenser or user; and ''in-use period'' for a manufacturer-specified period after first use or reconstitution, which is a third thing again — it is manufacturer dating, supported by stability data, but applying to an opened container.{{r|ppbud}} That third category is where most of the residual confusion sits. The 56-day in-use period on a semaglutide pen and the 28-day default on an unpreserved reconstituted vial look superficially alike and rest on entirely different evidence: one is a labelled claim from a stability programme, the other a borrowed convention. The distinction is developed at [[Temperature excursion]] and at [[Multi-dose vial]].{{r|ppbud}} {{seealso|Multi-dose vial|Temperature excursion|Repackaging}} == References == {{reflist}} <ref name="usp797">United States Pharmacopeia, General Chapter <797>, "Pharmaceutical Compounding — Sterile Preparations", 2023 revision, including the beyond-use date tables for Category 1, 2 and 3 preparations.</ref> <ref name="usp795">United States Pharmacopeia, General Chapter <795>, "Pharmaceutical Compounding — Nonsterile Preparations", 2023 revision.</ref> <ref name="usp659">United States Pharmacopeia, General Chapter <659>, "Packaging and Storage Requirements". USP–NF, current revision.</ref> <ref name="usp51">United States Pharmacopeia, General Chapter <51>, "Antimicrobial Effectiveness Testing". USP–NF, current revision.</ref> <ref name="usp1191">United States Pharmacopeia, General Chapter <1191>, "Stability Considerations in Dispensing Practice" (informational). USP–NF, current revision.</ref> <ref name="ich_q1a">International Council for Harmonisation, ''Q1A(R2): Stability Testing of New Drug Substances and Products'' (2003), read with ''Q1E: Evaluation for Stability Data'' (2003).</ref> <ref name="trissel2022">Trissel LA. ''Handbook on Injectable Drugs''. 21st edition, American Society of Health-System Pharmacists (2022). The standard compilation of published stability and compatibility data.</ref> <ref name="cdc_injection_bud">Centers for Disease Control and Prevention. ''Guide to Infection Prevention for Outpatient Settings: Minimum Expectations for Safe Care'', with associated injection-safety guidance on dating opened vials.</ref> <ref name="ppbud">PeptidePedia community dating-practice tally and the 2026 request for comment on dating terminology (self-reported practice; weak evidence — see [[Project:Sourcing_guidelines]]).</ref> == Further reading == * American Society of Health-System Pharmacists. "ASHP Guidelines on Compounding Sterile Preparations." ''American Journal of Health-System Pharmacy'' 71(2):145–166 (2014). * United States Pharmacopeia, General Chapter <825>, "Radiopharmaceuticals — Preparation, Compounding, Dispensing, and Repackaging" — a parallel dating framework for a different product class. == External links == * [https://www.usp.org/ USP compounding compendium (index)] — Chapters <795>, <797> and <825>; text is paywalled, revision status is public. == See also == * [[Multi-dose vial]] * [[Vial]] * [[Bacteriostatic water]] * [[Reconstitution of lyophilised peptides]] * [[Temperature excursion]] * [[Cold chain]] * [[Peptide stability table]] {{DEFAULTSORT:Beyond-use date}} [[Category:Preparation and handling]] [[Category:Cold chain and stability]] [[Category:Pharmacy compounding]] [[Category:Clinical practice]] [[Category:Drug regulation]]