require significant sample numbers at a specific timepoint is hugely beneficial.

Test conditions

Table 1 highlights standard ICH conditions within stability chambers. Whilst there is often commonality, the conditions required are informed by the nature of the compound. For example, it is more likely that peptides, proteins and biologics will be stored at cold or frozen conditions due to their instability, and early-phase small-molecule studies typically follow a standard approach(Table 2). Results from this early data will inform later-phase studies.

A typical study runs between 3 and 5 years, and whilst these studies are used to obtain long- term shelf-life data, at early stages products will be exposed to harsher conditions – higher temperature, increased relative humidity – to stress them and increase the rate of degradation. This is important, as it provides an overall idea of the degradation profile of the compound and potentially highlights issues with analytical methods or the rise in level of certain impurities. Accelerated conditions can also be important when considering the infrastructure of the end user market. They can also be used to predict the shelf life of API or drug product in line with ICH guidelines.

Analysis at each timepoint

A limited testing schedule will be performed at each timepoint, and typical testing requires a purity method (likely by HPLC) that has been proven to be stability indicating. XRPD analysis can be included to demonstrate there has been no change in physical form, and a Karl Fisher technique is included to show the presence of moisture and indicate if the drug is hygroscopic. Microbiological testing can be included at some (but not necessarily all) timepoints to prove the absence of microbial contamination. For finished products, dissolution testing

Issue 2 • March/April 2021

Pharma: Stability Studies Condition 2ºC – 8ºC

25ºC/60% RH 40ºC/75% RH

Time point (months) 0 X

1 O X X

3 O X X

6 O X X

X = Scheduled testing, O = Optional testing on request Table 2. A typical stability schedule.

will be included to simulate the effectiveness of the drug in vivo.

Transport /temperature cycling studies Stability studies indicate degradation of products under fixed conditions, but in the real world it can be difficult to maintain these conditions when distributing worldwide. Logistically, planes can be delayed, trucks can be stopped at customs, or stuck in a long tailback on the motorway. To ensure that temperature excursions do not lead to wasted product, it is possible to conduct a transport study. This is where the drug is exposed to temperature cycling to mimic freezing and thawing of the drug. Typically, a drug will be exposed in its final packaged form to 3 cycles ranging from -20C to 40C/75% RH over 2 weeks, then set down onto a formal stability study for 36 months.This temperature cycling is performed prior to the set down of the main stability study, allowing the increase of efficiency by pulling these time points in parallel.

In-use stability

Depending on the dose regimen, in-use stability may be required. For tablets / capsules that are blisterpacked, each dose will remain sealed until point of use. For bottled tablets and products, as each dose is taken out, the remaining tablets will be exposed to the elements as the bottle is opened. For example, if the dosage is 2 tablets daily for 6 weeks, the final 2 tablets will have been exposed to changes in humidity, temperature and light daily for 42 days prior to ingestion. In-use

To ensure that temperature excursions do not lead to wasted product, it is possible to conduct a transport study. This is where the drug is exposed to temperature cycling to mimic freezing and thawing of the drug

standards can become depleted and an in-house strong synthetic chemistry group that can assist with remanufacture of reference standards is beneficial. This could be performed via chromatographic purification of API samples, extraction of/by degradation products from manufacturing mother liquors, or total synthesis.

In conclusion

stability studies have been designed to mimic this exposure, with bottles opened in controlled conditions of 25°C/60% RH conditions for 20 minutes each day, with 2 tablets removed at each timepoint. It is not necessary to perform the analysis on this daily, only on the final tablets to ensure that the final dose is fit for purpose.

Reference standards

Most stability studies will include purity/assay by HPLC as part of their testing regime. These methods will require the use of a reference standard – a highly purified and fully characterized sample of the API or impurity. These standards are typically small quantities stored in vials with a need for recertification, most likely on an annual basis. Over a 5 year stability study it is probable that standards will need recertification multiple times. Over a prolonged period of time it is possible that reference

There is much to consider when addressing stability studies. Typical conversations include capacity, and the conditions available, but as discussed there are a wider number of factors to consider. It is therefore critical when partnering to consider lab footprint, experience and supporting capabilities to ensure your product is in the safest hands. Almac have significant expertise

in stability studies; its team has over 20 years’ experience, with 350 studies currently active. Across the company’s three global sites, it sets down 60-70 studies each year covering small molecules, peptides, biologics, active ingredients, tablets, capsules, vials, blisters, bottles and devices. Each month Almac’s dedicated team processes 30 pull points, each of which includes sampling, analysis, QA review and reporting, making the company a leading global partner for stability studies.

Further information Anna Cousens

Business Development Manager

Almac Sciences E: anna.cousens@


9 O X

12 O X

18 O X

24 O X

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