Internationally Recognized Stability Criteria

With the 2019 revision to <797>, the USP eliminated the ability to extend Beyond Use Dates (BUDs) using stability indicating methods, citing there was more discussion and considerations required for developing new resources.

There are some good resources out there that point out what criteria is necessary for a valid stability study (see references). In my own attempt to establish and extend BUDs I worked with an analytical lab to figure out exactly what we should include in our studies.

What is a Stability Study?

The key to what a stability study is and isn’t has much to do with whether a stability indicating assay is being used. A stability indicating assay in simple terms uses forced degradation (usually heat) of your product to determine if any excipients or by-products will alter the way the assay is able to detect the drug.

A good resource for this can be found here, an article by Loyd Allen et al and is featured on the USP website. One key paragraph and distinguishing feature of a stability study:

The most common flaw in determining stability is failure to use an analytical method that has been demonstrated to be a stability-indicating method. The most important aspects of determining strength and stability are the methods used in the process. A stability-indicating method must be used to determine stability. Although stability-indicating methods have the capability of also determining strength, the reverse is not so—not all strength tests are capable of determining stability. The purpose of this communication is to explain the difference between strength and stability, why they are of importance, and how they are determined. The method used to determine the concentration of the active pharmaceutical ingredient (API) is the most critical step in the process and takes into account other variables, such as solubility, polymorphic forms, and others.

Strength and Stability Testing for Compounded Preparations

Also, in the FAQs section for compounding on the USP website, it also references the above document:

Q. Is there a difference between testing stability with a strength (potency) or a stability-indicating method?

A. Yes, a strength (potency) over time test determines the amount of active ingredient in a preparation, however, it may not be able to separate the active ingredient from its degradation products and impurities for quantitation depending on the analytical methods used for the test. A stability-indicating method will be able to quantitate the active ingredient and its degradation products or related impurities in the preparation by separating the active ingredient from its degradation products and impurities, and to show a change in the concentration of the active ingredient with increasing storage time. A stability-indicating method is used to determine stability of a drug and used to establish the Beyond-Use Date. (See article, “Strength and Stability Testing for Compounded Preparations.”)

USP Compounding FAQs

In order to validate your stability method let’s look to an FDA Guidance called “Expiration Dating and Stability Testing for Human Drug Products“

While 211.166 (a) (3) merely requires that test methods be reliable, meaningful, and specific, section 211.165 (e) gives more guidance by stating that the accuracy, sensitivity, specificity, and reproducibility of test methods employed by the firm shall be established and documented. Section 211.194 (a) (2) further requires that all testing methods used shall be verified under actual conditions of use. Testing procedures must include a stability indicating test which will distinguish the active ingredient from any degradation products and be able to make a reliable estimate of the quantity of any degradate. The stability indicating test does not have to be the assay method used to determine product strength.

Expiration Dating and Stability Testing for Human Drug Products

Number of batches

Per International Council for Harmonization (ICH) guidelines, specifically Q1A (R2), it states 3 batches/lots are used for a valid stability study. Also, in the FDA document, “Expiration Dating and Stability Tasing for Human Drug Products,” it confirms this idea of using at least 3 primary batches:

Generally, the placing of three initial batches into the long term stability program is considered minimal to assure batch uniformity for establishing an expiration date. Since a dosage form is a complex unit and there are continued variables in the production process, such as change in personnel, raw material lots and suppliers, and equipment, it is imperative that stability studies are not limited only to initial production batches but a portion of annual production batches be the subject of an ongoing stability program.

Expiration Dating and Stability Testing for Human Drug Products

Container Closure Integrity Testing (CCIT)

Also in ICH Q1A (R2) section 2.1.4 talks about the container closure system for a product as it relates to stability:

The stability studies should be conducted on the drug substance packaged in a container closure system that is the same as or simulates the packaging proposed for storage and distribution.

Guidance for Industry Q1A(R2) Stability Testing of New Drug Substances and Products

Time Points

If you’re looking to extend your BUD to 180 days you would want to pick time points that would allow you to see if the product is going to degrade at any points in between zero and 180. Typically you’d perform testing at 0, 14, 30, 60, 90, 120, 180. Using 30 day intervals (after day 30) would ensure that if you start to lose potency at day 90 and don’t make it to 120 you can stop the study at that point and you’d still be able to claim your dating for 90 days. It’s recommended to do a minimum of 5 time points in any study to determine linearity.

Other components of a stability study

• pH
• potency
• container closure integrity
• particulate matter (visual inspection)
• sterility
• endotoxin

Do these all need to be done at every time point? Maybe not. You may be able to do an initial and final for some of these. However, keep in mind if any of the key factors fall out of spec (sterility, endotoxin, potency) you will not be able to claim the dating. The point here is that you should think carefully about which tests to include at each time point while trying to minimize costs; unfortunately that’s a fine line to walk. Be conservative, but smart about what may affect the stability of the product (pH would be one that you may consider doing at each time point, since this can affect stability).

Other considerations

If you have multiple vial sizes for your product (10 and 30 mL vials) you may consider cutting that down to one; each of these would need to have it’s own stability study done because the containers are different and may affect the stability of the compound.

If you have multiple strengths of the same product consider bracketing. This simply involves doing a stability study of the highest concentration and lowest concentration; with all other factors being equal (the vial, closure, excipients must all be the same). Again, with all things being equal you can claim stability of all of the strengths in between your two extreme concentrations.

Validations

Everything above needs to have a validated method in order to prove that it’s working and is able to detect what it’s supposed to.

• USP <71> for sterility (method suitability)
• USP <85> for endotoxin
• USP <51> antimicrobial effectiveness
• Validation extension (Also known as specificity – USP <1225>)
• Possibly USP <61>, <62> and <81>

Costs

If you’re looking to perform a stability study on a single ingredient product for 6 month to 1 year dating the cost will more than likely be over $15,000. This is highly dependent on the lab you choose and which tests you select to perform at each time point. I’ve tried to lay out in simple terms the absolute minimum that’s required to claim and defend your beyond use dates against any board of pharmacy that may inspect your pharmacy. More importantly, you can assure your patients that the product has the stability that’s claimed on the label with scientifically backed data.

References

1. STRENGTH AND STABILITY TESTING FOR COMPOUNDED PREPARATIONS
2. FDA Guidance Container Closure 
3. FDA Guidance Q1A (R2) Stability Testing
4. FDA Guidance: Drug Stability Guidelines
5. Identifying the criteria for a valid stability study (IJPC)
6. FDA Guidance Q1D Bracketing and Matrixing
7. Expiration Dating and Stability Testing for Human Drug Products