Pharma: Stability Studies

Spotlight on stability: API and drug product testing

Stability studies are key to drug development. An integral part of any New Drug Application (NDA) is to perform stability studies on active pharmaceutical ingredients (APIs) and drug products to assess degradation and inform shelf-life prior to market release. For some programmes, further investigation is required to demonstrate stability of key raw materials, intermediates or excipients used in the manufacturing process. Anna Cousens, Business Development Manager at Almac Sciences, describes what studies need to be performed, and how, to ensure best product performance.


eveloping a drug is a long and complex process, and the stability requirements change depending on

the phase of development. At the early stage, little is known about the API and formulation, so this work is required to inform on the degradation profile of the compound. It is critical to know how the API degrades over time; if it is particularly sensitive to light, heat or humidity,and how best to store it to ensure that when it finally reaches a patient it is of the required quality and purity. When formulating a drug, studies must be conducted to demonstrate interactions between the API and any excipients used, and to confirm that these do not accelerate the degradation of the active ingredient. Once the final product is packaged, stability studies must also be undertaken to confirm that the finished product remains intact, and that the packaging selected is fit for purpose.

During the early stages of clinical development, every new batch of API or drug product should be placed on stability, and each new packaging presentation will also require supporting stability data. Once stability data has been generated it may not be necessary to place every new manufacture on stability provided that there is

-20˚C, 2-8C 25˚C/60%RH 40˚C/75%RH

Table 1: ICH stability conditions. 30

the analytical methods. For a GMP stability study, these methods will require validation prior to use. The inclusion of T = 0 testing of these batches can be used to perform a limited validation of the required methods by comparison of data with the releasing lab. This is a convenient and efficient way of bringing fully validated methods into the partnering company.

Dedicated stability chambers within Almac Sciences’ Craigavon, UK headquarters.

reasonable coverage from existing studies.

When performing stability studies there is much to consider:

• Analytical methods • Batches required to be set down • Conditions • Analysis required at each timepoint

• Transport studies • In-use stability • Reference standards

Analytical methods

When conducting stability testing, it is imperative that the analytical methods used are fit for purpose. Without a good understanding of the analytical testing, stability studies would be pointless. As an example, Almac was once provided with some client methods but was required to perform full ICH validation of the

30˚C/65%RH 30˚C/75%RH Photo stability

HPLC method. This was required for both the API and drug product, and because the methods were similar for both, the company found efficiencies in the project by conducting these two validations in parallel. Many outsourcing partners routinely perform ICH validations for methods developed in their own labs, or at client or third-party labs. When releasing a batch of API or drug product, a specification describing the full scope of testing is required. Often when setting down batches on stability, this release testing will be leveraged by the stability group. In some circumstances it is possible to leverage the release testing results for the T = 0 timepoint. This can save time and money by not duplicating these results. However, using release data for T = 0 is not always practical, and repeating this testing can add value to a project. In some instances, the stability partner will be setting down stability on products that are not manufactured on site and will have no previous experience of

Batches to be set down

As the drug proceeds through early clinical trials and moves towards commercialization, there may be multiple presentations to consider. A typical example of such presentations includes:

• Active ingredient (API) - 3 batches

• Drug product formulation (capsules) - 3 batches

• Drug packaging (capsules in blister) - 3 batches

• Drug packaging (capsules in bottle) - 3 batches

It is imperative that the stability team fully understands when samples need to be pulled. The project can be made more efficient by pulling stability timepoints together, reducing the time required to set up analytical equipment. However, there are standard requirements around the window for testing to be performed at each timepoint, so the length of the testing runs must be considered and samples pulled in line with the testing regimen. A dedicated stability team with sufficient equipment to prevent bottlenecks when large studies

March/April 2021 • Issue 2

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