The presentation of clinical trial supplies can play a crucial role in creating a professional image, influencing subject compliance and ensuring the quality of the investigational product. Barry Mansfield looks at how the existence of stability data is often the deciding factor when selecting a particular type of packaging.
In pharmaceutical packaging, stability data can be used to guide the manufacturer in its decisions as to how the final product should be presented or stored. Long-term stability studies involve myriad sophisticated techniques depending on the special criteria relating to the specific drug and necessary storage conditions. These should meet International Conference on Harmonisation (ICH) guidelines for drug development, but third-party specialists often include follow-up stability studies for all ICH-standard storage conditions, as well as low-temperature storage (-20°C), special temperatures, relative humidity or container orientation.
Based on specific needs, pharmaceutical stability testing protocols outlining all details of a study can be written by a third-party expert and approved by the customer in the run-up to commencing the actual stability study. Manufacturers typically consult a third party because they have the know-how and experience to deal with unexpected situations during the stability study, such as the appearance of new degradation products, access to a more complete analytical equipment base and more extensive in-house expertise. Usually, either a full stability report or only analytical data is provided.
Stress tests and forced degradation studies can be performed to aid in the method development of stability-indicating methods and give an idea of compound stability. Using an established forced-degradation standard operating procedure, consultants like Onyx Scientific provide the customer with valuable stability testing data, which helps in early-phase container and closure system design. The typical stress tests performed consist of pH, oxidative, thermal and photostability stress testing.
During stress testing, analytical methods are checked and optimised to be stability indicating; if they are relevant, customised stability-indicating methods will be used. Pharmaceutical stability testing of an active pharmaceutical ingredient (API) is a necessary requirement during lead optimisation and following selection of a clinical candidate. Most third parties provide solid-state services and analytical laboratories, and often a range of tests according to ICH-harmonised tripartite guidelines. Stability offerings usually encompass solid and solution forms, testing in a range of conditions using state-of-the-art stability and photocabinets.
Jon Beaman, senior director of analytical development at Pfizer, has been outspoken about the need to improve the design of stability strategies during development and proposes more innovative approaches that he believes are more scientifically rigorous than those traditionally used. Alternative methods would bring enhanced product understanding and robustness, as well as a reduction in the number of scientifically redundant stability studies, he argues. These alternatives can also have implications as to the choice of packaging used.
Most pharma professionals who have spent time working in the stability field will be well aware of the time spent clock-watching as the stability studies draw on, even if the stability characteristics of the API or drug product are already determined. Although real-time stability studies are critical during development – if only to double-check the validity of any alternative models – by following a science and risk-based approach to stability, a stronger comprehension of stability performance can be realised and a number of unnecessary studies may be avoided.
An appropriate science and risk-based approach can be achieved by applying the principles of quality by design (QbD) to stability. Actions arising from QbD should be based around generating scientific understanding and manipulating any attributes that impact the stability performance of the pharma product.
Taking an API as an example, the developer must determine the type of packaging needed to achieve a minimum feasible shelf life, usually at room temperature, although refrigerated and frozen conditions may be acceptable.
The only remaining attributes that may affect stability are those that are typically determined during manufacture: polymorph, surface area and water content being probably the three attributes of most pressing importance. Those considered to have an effect on the stability performance of the item are often termed as ‘stability-related material attributes’ (SRMAs). These can be mapped out in a dimensional space alongside storage temperature and shelf life – in other words, defining the ‘stability space’.
At this point, the developer can figure out which controls they wish to place on these SRMAs during manufacture to ensure the target shelf life. It may not be necessary to test for the SRMAs during the stability study; only shelf-life-limiting qualities – for example, degradation products are required to be tested from a scientific perspective. Clearly, test findings are highly likely to impact the decision as to the type of packaging material used, which then affects ink choice, printing and anti-counterfeit technology.
Spot the difference
When organising and carrying out stability studies, several testing factors must be considered over and above the analytical method, time points tested and storage conditions. With liquid products, container orientation must be included to calculate any differences between upright and inverted storage. Container extractables such as label components (adhesives and ink) are significant tests performed as part of packaging development to ensure the container is not contributing unacceptable levels to the pharma product.
Container or closure systems can also adversely affect product stability via the absorption of drug substances or preservatives. Hence, assay of these ingredients during primary stability is critical for the appropriate dosage forms. After completion of all steps, if the item still shows an unacceptable level of change, then a redesign or reformulation of the package may be needed. Labelling statements like ‘Protect from light’ may be applied and, in cases where secondary packaging is used, additional statements like ‘Retain in carton until contents are used’ may be applicable.
Another area of growing interest in the stability world is in the use of accelerated predictive models for stability determination. Waterman has developed and used a humidity-corrected Arrhenius equation to give accurate estimates for temperature and relative humidity impact on stability performance. The team combined an experimental design that decouples temperature and relative humidity effects with an ISO conversion paradigm in order to predict shelf life in long-term storage conditions using data collected over a relatively short period of time.
This tool allows faster and more accurate prediction of shelf life than the present one-condition accelerated stability studies – for example at 40°C or 75% relative humidity – which is especially convenient at the time of the early clinical phases. The model can then be used to ensure the stability of the API or pharma product in the continuous improvement stage of synthetic route, or process and manufacturing development, by contrasting the stability of the product before and after the change.
In addition, the blending of a higher-paced predictive model with a scientific and risk-based approach allows the development of a scientifically vigorous, robust stability space. This can then be used to build towards future changes to factors such as manufacturing process, scale or site.
When the packaging and storage requirements for the pharma product have been determined, the only variables that can impact the stability of the item are the SRMAs. Once these are pinpointed, then any later alterationsto factors, including process, scale, site, process or synthetic route, must be evaluated only in terms of the possible effect on said attributes used in that product.
For example, if polymorph is the only stability-related attribute, then any effects on stability caused by changes in scale can be calculated using the polymorph after manufacture of the scaled-up batches, removing the need to perform further stability studies.
Science versus risk-based model
Beamon emphasises that scale is not a SRMA. Once these are determined and the specification developed, further stability studies are unneeded as long as the item meets requirements for the SRMAs included on the specification during release testing; for instance, stability knowledge combined with release testing allows unlimited scale-up from the perspective of shelf-life allocation.
FDA guidelines on post-approval changes are, in essence, a set of pragmatic risk-management matrices; the idea is to categorise the risks associated with changes in a way to give a simple catch-all position for every product, in the absence of any specific data. However, there is a risk that stability studies become box-ticking exercises if the guidelines are applied literally to a specific product and change. For example, a change in mixing times may have no effect at all on any of the SRMAs, yet a batch would be placed on long-term stability regardless.
As well as scale, factors like site, manufacturing and process are not SRMAs. The European guideline on variations states that if the quality characteristics – say, physical characteristics or the impurity profile – for API batches of the active substance are changed in such a way that stability may be threatened, comparative stability data is required. This suggests that an assessment can be first made as to whether the stability is likely to be endangered by a change prior to the commencement of long-term stability studies.
Although the arrival of a number of quality guidelines in the past decade has guided the industry towards a more harmonised approach − and allowed a highly productive exchange between industry and regulatory bodies – Beamon has long held concerns over the danger that both sectors can become overdependent on following these guidelines to the letter, while neglecting the science and risk-based approach.
If a science and risk-based approach to stability is followed, then the stability characteristics of the item will be properly understood and mapped out. Although the resource and economic expense of this approach may be greater at first, it should ensure that product failures due to unanticipated stability results are avoided as development proceeds. Development activities should be focused on determining those quality attributes that affect the stability performance of a pharma product and fixing in place appropriate controls, either through manufacturing controls or release testing.
Adopting a science and risk-based approach, combined with accelerated predictive models, would negate the need to conduct more routine, non-value-added stability studies during the development and commercial phases, and would allow continuous improvement of processes − without the need to wait for superfluous long-term data before these changes could be applied. Avoidance of product failure also gives more leeway in selection and design of packaging, with more effective decisions made at an earlier stage.