What the 2023 revision changed

The previously published chapter sorted compounded sterile preparations into low, medium and high risk, and the question was how complicated the preparation was. The revised chapter, official since November 2023, sorts them into Category 1, Category 2 and Category 3, and asks different questions: where the preparation was compounded, whether it was sterility tested, and whether any starting component was nonsterile. A simple transfer made in a segregated compounding area now carries a shorter limit than a harder preparation made in a cleanroom suite and tested.

Category 1 is made in an ISO Class 5 or better primary engineering control that may sit in an unclassified segregated compounding area. Category 2 requires a cleanroom suite. Category 3 is a Category 2 suite operating under a longer list of standing requirements that apply to the room on every day, not to the batch on the day it is made.

One line decides more schedules than any other: the beyond-use date is determined from the date and time the preparation is compounded. It does not start at release, and it does not start when the sterility result comes back.

The USP 797 beyond-use date chart, by category

The limits below are the chapter's maximums. A shorter date is always permitted, and a component's own expiration or retest date can force one. Read down the room temperature column and the argument is visible. One day becomes 4 by starting from only sterile components. Four becomes 30 by passing a sterility test. Thirty becomes 60 by meeting every Category 3 condition. Two of those steps are bought with a test; the third is bought with a facility, and never for a single lot.

If a Category 3 condition is not met, the preparation does not get a reduced Category 3 number. It falls back to the Category 2 limits in Table 13. Immediate-use preparations sit outside the categories: not more than 3 different sterile products, and use begins within 4 hours following the start of preparation.

What a sterility test buys, and what it costs in days

At controlled room temperature the sterility test is worth 26 days on an aseptically processed preparation made from only sterile components, 29 days when a nonsterile component is involved, and 31 days on a terminally sterilized one.

The chapter accepts the test under 71, or a validated alternative shown to be noninferior to 71 under 1223. Under 71 the media are incubated for not less than 14 days: Fluid Thioglycollate Medium at 30 to 35 degrees C, Soybean-Casein Digest Medium at 22.5 plus or minus 2.5 degrees C. The calendar cost is therefore 14 days whatever a laboratory quotes for turnaround, and because the date runs from compounding, a 30 day room temperature preparation has half its life spent by the time the result exists. A laboratory quotes per lot against the method and the sample count; the numbers that govern planning are the 14 days and the units consumed.

Those units are specified, not estimated. Section 12.2 caps a batch requiring sterility testing at 250 final yield units. Below 40 units, additional units must be compounded for the test, 10 percent of the number prepared, rounded up to the next whole number. Above 40, the sample sizes in 71 Table 3 apply. The Method Suitability Test in 71 also has to be performed.

Releasing before the result is known is a documented position, not an exception to the test. Section 18.1 requires written procedures to notify the prescriber immediately of a failure with the potential to cause harm, recall unused dispensed units, quarantine remaining stock, and investigate whether other lots are affected. A facility that dispenses against a pending sterility test needs that procedure written before the first lot ships.

• Not more than 100 containers: 10 percent or 4 containers, whichever is greater.
• More than 100 and not more than 500 containers: 10 containers.
• More than 500 containers: 2 percent or 20 containers, whichever is less.
• Large volume parenterals: 2 percent or 10 containers, whichever is less.

Endotoxin testing is not only a Category 3 question

Section 12.3 is read too narrowly. A Category 2 injectable compounded from one or more nonsterile components and assigned a date that requires sterility testing must be tested for bacterial endotoxins. The same preparation assigned a shorter date that does not require sterility testing should be tested. Every Category 3 injectable compounded from one or more nonsterile components must be tested. Endotoxin testing follows the nonsterile starting component, not the category label.

Where no USP-NF monograph or other formula source sets a limit, the limit is calculated under 85 for the applicable human route: the endotoxin limit equals K divided by M. K is 5 USP-EU per kilogram of body weight for parenteral routes other than intrathecal, and 0.2 EU per kilogram for intrathecal. M is the largest quantity of the preparation a patient may receive per kilogram of body weight in a single hour, and it comes from the order, not from the material.

The arithmetic is the part people skip. If the largest hourly quantity is 0.5 mL per kilogram, the limit is 5 divided by 0.5, or 10 EU per mL. Halve M and the limit doubles. Move the same preparation to an intrathecal route and K falls by a factor of 25, which is why a limit calculated for one route is never carried across to another.

Category 3 is a facility standard, not a test panel

The most expensive misreading is that Category 3 is Category 2 plus a sterility test and a stability study. The added requirements bind the buffer room and everyone who enters it, on every day, whether or not a Category 3 preparation is made that week.

The stability requirement in 14.4.3 is the one that most often stops a program. The date has to be supported by stability data from a validated stability-indicating method that separates the active ingredient from its degradants and impurities and quantifies the active ingredient, validated against characteristics such as those in 1225. The preparation has to match the exact formulation the data came from, including ingredient grade, and be packaged in a container closure of the same materials used in the study. A stability study on a different vial is a study about a different preparation.

Two conditions apply outside this table, to every category alike. Under section 14.5, the container closure system used to package a multiple-dose preparation must be evaluated for and conform to container closure integrity under 1207, whatever the category. And section 12.1 requires a visual inspection before release: a preparation must be free of inappropriate visible particulates or other foreign matter, discoloration, or other defects.

The two records that carry the date

A master formulation record is written before the preparation exists. Section 11.1 requires one for any preparation made from nonsterile ingredients or made for more than one patient. Box 9 asks for the name, strength or activity and form; the identities and amounts of all ingredients, with relevant characteristics such as particle size, salt form, purity grade and solubility; the type and size of the container closure system; complete instructions and any special precautions; the date and storage requirements; a reference source supporting stability; and the quality control procedures.

A compounding record is evidence about one lot. Section 11.2 requires one for all Category 1, Category 2 and Category 3 preparations, and for immediate-use preparations made for more than one patient. Box 10 asks for the date and time of preparation, the assigned internal identification number, a method to identify who compounded and who verified, the name, weight or volume and strength of each component, the vendor, lot number and expiration date of each component where the preparation is made from nonsterile ingredients or for more than one patient, the total quantity compounded, the final yield, the assigned date and storage requirements, and the result of each quality control procedure. The nonsterile chapter carries the same pair at 795 sections 7.1 and 7.2.

One field cannot be produced by anything the compounder does. The vendor, the lot number and the expiration date of each component arrive with the material or not at all, and if they do not, the record is incomplete when the preparation is made rather than when an inspector asks. GradeBio files the incoming certificate of analysis against the incoming lot number and carries that number onto the filled lot, because a compounding record field is only as retrievable as the document it was copied from.

Where the chart stops

The chart above is what a state board reads against a 503A pharmacy. An outsourcing facility registered under section 503B of the Federal Food, Drug, and Cosmetic Act, 21 U.S.C. 353b, is on a different regime. Section 503B exempts it from new drug approval under section 505, from the adequate directions for use requirement of section 502(f)(1), and from the supply chain security requirements of section 582, but not from current good manufacturing practice, which reaches it through section 501(a)(2)(B). Its label carries an expiration date under section 503B(a)(10)(A)(iii)(VI), which 21 CFR 211.137 and 211.166 establish through a stability program.

FDA's draft guidance for those facilities, revision 2, describes conditions under which the agency does not intend to take action if a beyond-use date is used in place of a full stability program. Two studies are still required once for each formulation and container closure system before a batch is released: container closure integrity testing on samples aged to or beyond the intended date, referencing 1207, and antimicrobial effectiveness testing where the container is intended for more than one withdrawal. The guidance is draft and nonbinding, and says so on every page.

Its default table for sterile products at an aggregate batch size of 1,000 units or less does not track the compounding chapter in either direction. An aseptically processed, unpreserved product with a completed, passing sterility test before release sits at 28 days at controlled room temperature, 42 days refrigerated and 45 days frozen, against 30, 45 and 60 in the chapter. The same product with no completed sterility test sits at 6 days at controlled room temperature, against 4 days in the chapter where every starting component was sterile and 1 day where one was not. The same preparation carries two different numbers depending on the regime it was made under, so asking for the beyond-use date without naming the chapter or regulation reliably produces the wrong one.

What this means for a buyer

The date is decided before the material is ordered. A preparation made in a suite qualified to Table 13 is a Table 13 preparation whatever was bought for it. If a 60 day room temperature date is the requirement, the commitment is monthly viable air sampling, weekly surface sampling, competency every 3 months, and a validated stability-indicating method for that exact formulation in that exact container.

Three things are worth asking of any material before it arrives, because all three land in a record that is difficult to reconstruct later: the certificate of analysis for the lot actually shipped rather than a representative one, the lot's own expiration or retest date, which caps the date of anything made from it, and the storage condition the material is released to, which decides which column of the chart applies.

GradeBio does not assign a beyond-use date and does not tell a compounder which category applies. That decision belongs to the compounder and to the environment and testing the compounder can evidence. What travels with the material is narrower: the identity confirmed before the container was opened, the assay against the floor set for that entry, the storage condition, and the lot's own certificate, filed against the lot number it was issued for.

Sources

1. United States Pharmacopeia USP General Chapter <797> Pharmaceutical Compounding - Sterile Preparations, official since November 2023. Sections 1.3, 5, 6.2.1, 6.3.1, 11.1 and Box 9, 11.2 and Box 10, 12.2, 12.3, 14.3 and Tables 12 and 13, 14.4 and Table 14 18.1.
2. United States Pharmacopeia USP Compounding Standards and Beyond-Use Dates, USP Healthcare Quality and Safety, as posted by the Mississippi Board of Pharmacy.
3. Washington State Department of Health USP <797> Sterile Compounding Self-Inspection Addendum, DOH 690-296, which quotes the chapter language section by section.
4. United States Pharmacopeia USP General Chapter <71> Sterility Tests, Table 3, Minimum Number of Articles to be Tested; media and incubation conditions.
5. United States Pharmacopeia USP General Chapter <85> Bacterial Endotoxins Test, USP-NF, endotoxin limit expressed as K divided by M.
6. U.S. Food and Drug Administration Pyrogen and Endotoxins Testing: Questions and Answers, Guidance for Industry, level 2 revised guidance.
7. U.S. Food and Drug Administration Current Good Manufacturing Practice - Guidance for Human Drug Compounding Outsourcing Facilities Under Section 503B of the FD&C Act, draft guidance for industry, revision 2, section III.K and Appendix B including Table D.
8. United States Code 21 U.S.C. 353b, section 503B of the Federal Food, Drug, and Cosmetic Act, including 503B(a)(10)(A)(iii)(VI).
9. Code of Federal Regulations 21 CFR 211.137, Expiration dating, and 21 CFR 211.166, Stability testing.
10. Washington State Department of Health USP <795> Nonsterile Compounding Addendum, DOH 690-326, quoting section 7.1 Box 2 and section 7.2 Box 3.