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Conducting stability testing on APIs/finished drug product helps ensure shelf-life storage.
Stability testing is essential for maintaining the integrity and quality of biopharmaceuticals and for assessing an accurate shelf-life. It is an important aspect of quality control and is an important step in evaluating product safety and efficacy. It is also important for examining how critical quality attributes (CQAs) of a drug substance vary with time under different environmental factors.
Through stability testing, pharmaceutical companies can ensure the most suitable packaging and/or container closure for the storage and distribution of biopharameutical products, according to Russell Crothers, supervisor, Sample Control Unit, Alcami.
“With the right storage, appropriate shelf life determined, and distribution methods in place, the quality of active pharmaceutical ingredient (API) and drug products is safeguarded,” Crothers says.
In addition, understanding potential degradation routes in relation to storage environment is an important factor in establishing the CQAs of a pharmaceutical or biopharmaceutical, according to Ashleigh Wake, director, Biological Services, Intertek Pharmaceutical Services.
“Ultimately, this understanding ensures that the optimal quality control strategy is in place to monitor the continued efficacy and safety of any therapeutic,” Wake says.
“Imagine the situation where, in the first instance, the degradation route of a molecule had not been assessed through forced or ‘stressed’ studies. Not understanding this pathway could lead to failure in identifying pertinent degradation products [that] impact the safety and/or efficacy of the product and thus need to be controlled during product release,” says Wake.
Wake goes on to note that if the potential formation of impurities is not evaluated prior to the release of the product, then methods will not be in place to monitor levels. This could lead to a rise or change in profile, which might not be detected until an “effect” in patient population is observed.
“More so, without understanding the stability both of drug substance and drug product, the shelf life cannot be effectively established. This may not only risk the safety and efficacy of a product supplied to patients but can lead to unrealistic or even untenable pricing, especially for biologic molecules, which are expensive to produce, thus impeding their availability,” she adds.
There are several important factors to consider when designing and conducting stability studies.
“Safety, quality, and product efficacy work together in stability studies of APIs and finished drug products. Through stability testing, pharmaceutical companies have the ability to identify and trend shelf life and their effects on efficacy as samples are exposed to time, light, and temperature,” Adam Keisker, supervisor, Laboratory Support Services, Alcami, states.
Degradation factors that are fundamental to consider for the efficacy and shelf life of APIs/finished drug products include physical, chemical, and microbiological factors. Physical factors encompass changes to the physical nature of the drug, such as appearance, properties, hardness, brittleness, and particle size, that occur in tablets, capsules, and semisolids.
From a chemical perspective, scientists look for separation of the chemical compound into elements or simpler compounds or a change in the drug’s chemical nature via hydrolysis, oxidation, isomerization, polymerization, or photodegradation, according to Keisker.
Finally, microbiological contamination of a product, depending on the type of microbe and its level of toxicity, can also play a role in the design and functions of the studies, he adds.
The strategy used for testing product stability is the most important consideration in the design of a pertinent study, according to Wake.
“If, prior to a formal stability evaluation, work is not performed to understand all potential degradation routes of the molecule through stressed studies, methodologies cannot be effectively chosen for inclusion in the formal study to encompass assessment of degradation product formation and thus all such species monitored,” says Wake.
“For any drug substance or product, an effective stability study cannot be designed on a ‘tick box’ approach for analytical assessments to be included for testing at timepoints,” she adds.
Wake adds that all stability programs should include methods to confirm identity, assay, purity, and impurities. “However, the choice of the actual analysis and number/mode of methods utilized cannot be a ‘standard set’, but should be designed on a bespoke basis.”
“Choice of storage condition or conditions should also be carefully determined prior to initiation. [International Council for Harmonization (ICH)] Q1 and Q5C (1,2) provide guidance on study design for pharmaceutical and biopharmaceutical products and should be the basis for all design; however, the eventual program requires considered input,” explains Wake.
As an example, Wake points out that, if the intended storage condition is refrigerated, this condition should be considered as the long-term storage condition to be evaluated for a minimum of 12 months, typically longer. An accelerated condition would then, in most instances, relate to storage at 25 °C/60% relative humidity (RH) for six months and, importantly, the need for assessment at 40 °C/75% RH, would not typically be required.
“Logistically, the amount of material, drug substance, and/or drug product required to support what can be as long as a five-year program with multiple time points needs to be considered at onset. Not only should this include a realistic amount for the defined program, but should incorporate a minimum of an additional 25% to act as back-up material in case of re-test,” Wake says.
“In addition, ICH guidance requires that a minimum of three batches of material be included in formal stability studies, again this can put pressure on sample requirement and timely availability,” she adds.
Having a strategic approach and considering a plan for a “worse-case” scenario is important to addressing the challenges of stability testing and to conducting a successful testing program. It is also important to approach each study with a bespoke, considered design for storage and testing, rather than a “tick box” approach, Wake says.
“Perhaps the biggest challenge is to ensure that the testing program incorporates sufficient analytics to ensure all potential and known degradants are continually monitored. When considering complex molecules, such as biologics, the complexity of degradation and the number of potential routes makes this assignment extremely difficult,” Wake explains.
If a potential impurity is missed and later seen to appear, this may detrimentally affect the integrity of the stability study. In a worst-case scenario, the missed impurity may require re-testing, which would introduce significant delay to product registration, Wake notes.
“Knowing all the ways a finished product or API could be affected by degradation is crucial in performing successful stability tests. For instance, stability studies are executed to simulate climatic effects. The studies are based on where the products are going to be sold. From those studies, scientists are able to better establish a shelf life of the medicine, determine the best way to store the medicine, and ultimately help ensure the safety of the consumer,” says Keisker.
Analytical methods for effective stability testing vary from drug product to drug product. The design of stability studies must take into account the product form, container type, and packaging, Keisker notes. “For example, commercial drug product testing would include studying the degradation effects from the conditions on both the drug product and the container it is sold in,” he says.
“There are many variables but it ultimately depends on the client and their interests as well as requirements for the climate zone they intend to sell their product,” Keisker adds.
In terms of methodology, most small-molecule pharmaceutical stability study programs are typically based around the need for some analysis that is dependent on the presentation of the substance or product, such as, for example, water content only being necessary on lyophilized or solid material, Wake says. Not all analytics will be required at each timepoint, their inclusion would be driven by the likelihood of change, for example, sterility is typically assessed at six-month intervals, unless a specific indication warrants more frequent analysis.
Typical methodologies for certain quality attributes are illustrated in Table I.
In comparison, for biologics, the nature of the stability testing to be included in any program differs, driven by the complexity of biologic molecule structure. In many ways, biologics require a more diverse analytical capability, according to Wake. Defining a typical stability testing protocol is consequently more difficult, but as a minimum would include assessment of the quality attributes shown in Table II.
“Other criteria such as process related impurities, solvents, metals, etc. are typically not included in a stability program but determined on product release. Again there can be exceptions where there is a potential for the amount of such species to increase on storage,” says Wake.
In the case of multi-dose product types, in-use stability testing can be used. The intent of an in-use stability study is to simulate the use of the product in practice, taking into consideration the filling volume of the container, any dilution/reconstitution before use, the hold-time before use, and various diluents that could be used for administration, Crothers says.
The purpose of conducting in-use stability testing is to establish a period of time during which a multi-dose product may be used while retaining quality within an acceptable specification, once the packaging is open or broached, Wake says, citing the European Medicines Agency’s definition of the term (3).
“In-use stability testing can therefore be considered for multi-dose product types, as assessment of the continued efficacy and safety (as defined through critical quality attribute testing) of a pharmaceutical (or biopharmaceutical) drug product once in its final administration form,” Wake says.
Typically, an in-use assessment is performed on a minimum of two batches of material, with, ideally, one batch taken from a near end-of-shelf-life product. The protocol involves reconstituting the drug product to its administrative form and testing over a pre-defined storage period at the condition recommended.
“The analytics performed will be in line with those identified for long-term and accelerated storage studies with perhaps a greater influence on microbial criteria and potential impurities derived from pertinent environmental factors, for example, impurities formed through oxygen exposure which is unavoidable in a multi-dose format,” according to Wake.
Establishing an effective in-use shelf-life is of significant benefit. Without such, a multi-dose product design becomes significantly less practical in terms of ensuring patient safety and product efficacy in this format. “This can lead to huge product wastage which, specifically in the case of biological materials, has huge consequence in terms of product cost and maintaining supply which can lead to the product being non-viable in terms of patient access,” says Wake.
1. ICH, Q1 (A-F) Stability, Step 5 version (ICH, 2003).
2. ICH, Q5C Quality of Biotechnological Products, Stability Testing of Biotechnological/Biologic Products, Step 4 version (ICH, 1995).
3. EMA, Note for Guidance on In-Use Stability Testing of Human Medicinal Products (EMA, September 2001).
Volume 31, Number 1
When referring to this article, please cite as F. Mirasol, “Stability Testing Ensures Proper Packaging for Drug Storage,” BioPharm International 31 (1) 2018.