An Introduction to the Accelerated Stability Assessment Program

Introduction

Stability studies are a time consuming and resource intensive task in the development of new drugs. Therefore products are tested under accelerated conditions to increase the rate of chemical and/or physical degradation. Based on the Arrhenius equation the chemical degradation increases with the temperature and therefore it should be possible to project the degradation rate at low temperature from the data generated under accelerated or stressed conditions. However, the predictive power of those experiments is not always sufficient. On the one hand, long-term studies or real-time studies are still needed and experience shows often different results between accelerated and long-term conditions. On the other hand, it is not possible to increase the temperature unlimited to get meaningful results at high temperature. Baking a cake at 160°C for 30 minutes is not the same as baking a cake at 240°C for 1 minute.¹

Current Limitations of Accelerated Stability Studies

So, why is it that the data generated from accelerated stability studies cannot be easily transferred to real time stability studies?

The first aspect is that in the Arrhenius equation only temperature is considered. But especially for solid state drug products the relative humidity is an important factor. In other drug products the oxygen level could play an important role.

The second aspect is that, for example, in solid state pharmaceuticals the API is in different micro-environments. It could be on the surface, it could be available as a crystal structure or as amorphous or it can be dissolved in other materials. Each of those states could have its own kinetics which leads to an overall complex kinetic .^2-3

Both aspects are potentially not relevant for solutions, since all molecules are in the same microenvironment having the same reactivity. However pH changes with temperature could lead to complex kinetics which makes the prediction from high-temperature data not accurate.⁴

Idea Behind the ASAP Concept

In general ASAP is a stability program that can be executed in a few days or weeks. A typical program involves 5-8 storage conditions with temperatures ranging from 50-80°C and a relative humidity ranging from 10 – 75%.⁵ The two basic and innovative concepts behind the ASAP are the isoconversion and the humidity-corrected Arrhenius equation.

Isoconversion can be described as time to “edge of failure”,⁶ which means the time a certain degradation product, the total degradants, the parameter potency or something else needs to reach the specification limit. Always chosen is the shelf life determining parameter. The assumption is that the degradation kinetics or the shape of the degradation curve is similar across different stability conditions and just the timescale changes with higher temperature.⁶

The difference between a conventional accelerated stability study and the ASAP is shown in Graphs 1 and 2. Under isoconversion the level of the shelf life determining parameter is fixed and the conditions are adapted to reach that level. The outcome is the time to reach the limit. This concept is shown in Graph 2. In a conventional accelerated stability study the time is fixed and the outcome are different levels of the shelf life determining parameter (in both graphs a degradant is chosen as the example for a shelf-life determining parameter). This is shown in Graph 1.

Graph 1. Conventional accelerated stability testing⁷

Graph 2. Accelerated Stability Assessment Program ⁷

The second concept is the usage of a humidity-corrected Arrhenius equation which is especially important for solid dosage forms since they are sensitive to humidity.

In Equation 1 the standard Arrhenius equation is shown, extended by the factor B(RH)

Equation 1: humidity adapted Arrhenius equation⁸

ln k: specification limit or isoconversion time
ln A: collision frequency
Ea: activation energy
RT: 1.986 cal/deg
B: humidity sensitivity factor
RH: equilibrium relative humidity

Typical B-values are between 0 and 0.10, where 0 indicates low moisture sensitivity and 0.10 indicates high moisture sensitivity.⁷ Typical Ea-values are between 10 – 45 kcal/mol.⁷ The degradation increases with the Ea value.

However even though the original intention of the ASAP was to assess the stability of solid drug products, it can be used also for solutions. In this case, the relative humidity is not a relevant factor.⁹ In dependence of the degradation pathways, this factor should be replaced by other factors, e.g. oxygen. But so far no practical example was found in the literature.

Step By Step Approach to ASAP

Determination of Isoconversion Time

First of all, the stability determining parameter of a substance or drug product must be known. The stability determining parameter is what first exceeds the limit. This could be due to a loss of potency (assay) or due to an increase of degradants.⁴

The assessment of the isoconversion time of a degradation product is an iterative approach. Based on screening studies there must be an estimation after which time points, under the several accelerated conditions, similar degradation levels are reached. Using the specification limit as the isoconversion point is most accurate for determining the shelf life.¹⁰

Performing the Study

The conditions must be determined for each product individually. Examples of the conditions and time periods are given in Table 1 and 2. It is recommended that all analysis are executed at the same time to minimize the analytical variation.¹¹ There are heterogeneous recommendations, if only at initial and endpoint samples should be drawn or at several timepoints.¹⁰ In the end, this is dependent on the accuracy the isoconversion point is matched. It is better to use interpolation than extrapolation for determining the isoconversion (time to spec) point.¹² If the isoconversion point is not found the data is increasingly inaccurate the more the point is extrapolated.

Table 1. Example for an ASAP protocol for solid oral dosage forms¹¹

Table 2. Example for an ASAP protocol for the stability of solutions⁹

Dependent on the sensitivity of the drug product to moisture, an ASAP study could be performed either as “open dish” studies or in the packaged product.¹³ In the open dish study, the product is placed openly in the stability chamber which leads to a direct exposure to the moisture.

For a packaged product the relative humidity inside a package is of importance. This relative humidity is a function of time and storage conditions (external RH and T) and can be calculated from the MVTR (moisture vapor transfer rate) through the packaging and moisture sorption isotherms from the product or a desiccant (if present) and the headspace volume.^7,9 Once a steady state is reached the moisture in the package equilibrates between the headspace and the internal components (sorption-desorption moisture transfer model). The assumption is that the transfer in and out of the packaging is in steady state, only dependent from the package permeability.⁶

At this point it is worth mentioning that the ASAP has its origin as the tool for the stability assessment of solid drugs and therefore humidity is mentioned beside temperature. But in case a product is for an example, oxygen or light sensitive the considerations have to be adapted accordingly.

Data Evaluation

A statistical, commercially available software is available which is named ASAPprimeTM. This software performs Monte-Carlo simulations to estimate confidence intervals for a projected shelf life.¹⁰ The company Amebis offers an integrated small chamber solution with wireless monitoring of the chamber conditions in combination with the ASAPprimeTM software.¹⁴ But for starting in the field of ASAP the usage of Excel seems to be sufficient.¹⁰

For the determination of the three unknown parameters Ln A, Ea and B at minimum three different combinations of temperature and humidity are needed.² The evaluation of the data is done in a three-dimensional adapted Arrhenius plot with ln k on the y-axis, 1/T on the x-axis and %RH on the z-axis. Ea/R is calculated from plotting the xy-dimension. B is calculated by adding the z-axis.²

Checking Goodness of Fit of Data

Garry Scrivens suggests two different approaches to verify the quality of the ASAP approach.² The first one is to compare the ASAP data against actual long-term data. This approach is not applicable during development but can be used for post-approval changes (see section: Application of ASAP). And the second one is an internal validation of the model by using four different ASAP conditions to predict the outcome of the fifth. This approach is more suitable during development.

Limitations of ASAP

ASAP does not work in some cases and in these cases, an accurate prediction of the stability cannot be expected.

First of all, the ASAP is designed for chemical degradation and not physical changes, like hardness or disintegration even though there is an example¹³ that shows the application of an ASAP to predict the dissolution rate. But in general physical properties show nonArrhenius behavior.¹⁰

As a consequence from this aspect ASAP is not accurate anymore when it comes to physical changes during the stability study for example melting or a change from the hydrate to the anhydrate form.¹⁰

Furthermore ASAP cannot be applied to large molecules such as proteins, because not all changes in the molecule structure are irreversible and not all changes affect the activity.⁴

Experience So Far – Predictive Accuracy

Scrivens presents several comparisons of real-time data vs. ASAP predictions.2 The data shows, in general, a good fit independent from the degradation reaction. In more cases there is a slight overestimation of the degradant in the ASAP model: in 23 examples there have been 4 exact matches, in 12 cases ASAP prediction was higher, in 7 cases ASAP prediction was lower. In 11 out of the 23 cases, the real-time data was outside the predicted range of the ASAP data.

However, it is not mentioned in the presentation, if in all comparisons the isoconversion point was found or interpolated. It is known that the predictions are less accurate if the isoconversion point is not found.¹⁵ But it seems that the statistical model used in the ASAP leads in general to an underestimation of the shelf life.¹⁶

Application of ASAP and Regulatory Acceptance

ASAP can be applied through the whole lifecycle of the drug product, from development up to post-approval changes.

In development, the ASAP can be used for the selection of an appropriate packaging concept⁶ or to compare between prototypes.¹⁵ Furthermore, it helps to compare options in formulation, processes or to assess the compatibility of the API with the excipient.¹⁷ And finally ASAP helps to generate an initial understanding of the stability, to give shelf life predictions and to quantify the effect of temperature and/or humidity.² It can therefore help to shorten drug product development.

In early clinical trials, it was possible to use ASAP data as a bridging stability study¹⁵ or as only stability.¹² So it was possible to start the supply of a clinical trial with the results of an ASAP and a concurrent real-time stability program. This approach was accepted by the FDA, Health Canada, the German BfArM and other countries in the EU. The authorities from South Korea, Czech Republic, and Ukraine required data out of long-term studies.¹⁸

For registration purposes ASAP was only used as supportive data. As a single source of data for the determination of the shelf life, it is currently not suitable, but it could help to reduce stability commitments.²

At a post-approval stage ASAP was useful for assessing process, packaging or formulation changes.^5,9,12 Results from ASAP were accepted by Egypt, France, Italy, Kenya, Lebanon, Turkey, UK and USA.¹² In a root cause investigation, an incompatibility between an API and an excipient was realized by means of ASAP.5 In some publications ASAP is mentioned as an annual commitment replacement,^2,5 but no source of acceptance by an official authority was found.

Outlook

ICH Q1A states that “alternative approaches can be used when there are scientifically justifiable reasons.¹⁹ ASAP could be such an approach. Reports from interactions with health authorities’ show that the authorities are receptive to the idea but right now need more evidence and experience.¹⁶ At this point in time, it seems that, beside the pharmaceutical industry, also regulatory agencies have to become more familiar with the concept.

Conclusion

ASAP is much faster than conventional stability or package screening studies at a higher accuracy. ASAP is capable of reducing costs to a fraction of conventional stability studies, especially if you consider all the infrastructure that is needed to run and maintain stability chambers. It could allow a faster clinical entry and it also could lead to fewer stability activities for post-approval changes. With ASAP it is possible to link the Critical Quality Attributes of a development project more direct with long term stability effects in contrast to standard accelerated studies.

Nevertheless ASAP has its limitations when it comes to physical stability or large molecules. Furthermore, the development of a program requires initially some work in assessing the isoconversion point. The data assessment itself requires specialized stability experts, experienced in multifactorial data analysis. From a regulatory, perspective ASAP is currently only considered as a supportive tool.

In conclusion ASAP and its applications show that this program could be a powerful tool in the future with a variety of applications. Current shortcomings, e.g. regulatory acceptance, the main focus on solid dosage forms and chemical degradation will vanish with an increased application of the technique.

The above article represents a personal view and is not necessarily that of B.Braun.

References

1. Scrivens, G. ASAP: Theory and Fundamentals. Presentation available at: http://www.stabilityconference.com/wp-content/uploads/2016/02/Garry-Scrivens_ASAP-Fundamentals-SOS-2015.pdf
2. Scrivens, G. Predicting the Long-Term Stability of Solid-State Pharmaceuticals. Presentation available at: http://freethinktech.com/wp-content/uploads/2016/11/GarryScrivens_ASAP_London_March2015.pdf
3. Waterman, KC. The Application of the Accelerated Stability Assessment Program (ASAP) to Quality by Design (QbD) for Drug Product Stability. AAPS PharmSciTech. 2011; 12 (3): 932 - 937
4. Waterman, KC. Stability of Parenteral Drug Products. Presentation available at: https:// www.pda.org/docs/default-source/website-document-library/chapters/presentations/ new-england/stability-of-parenteral-drug-products.pdf?sfvrsn=6
5. Llurellyn, M. ASAP Applications. Presentation available at: https://www. stabilityconference.com/wp-content/uploads/2016/02/Llurellyn-Malcolm-ASAPApplications-101215.pdf
6. Waterman, KC. Drug Product Stability—Accelerated Decision Making for Selecting a Package. Presentation available at: https://zerista.s3.amazonaws.com/item_files/9a5e/ attachments/59253/original/224.pdf
7. Waterman, KC. Advanced Modeling (Accelerated Stability Assessment Program, ASAP) for Shelf-Life Determinations. Presentation available at: http://www.cbinet.com/sites/ default/files/files/Session%2013_pres.pdf
8. Chen, J et al. Comparison of Shelf Life Estimates Generated by ASAPprimeTM with the KingKung-Fung Approach. Presentation available at: http://www.mbswonline.com/upload/ presentation_6-5-2014-9-51-16.pptx
9. Ensing, JM. Accelerated Stability Assessment Protocol (ASAP). Presentation available at: http://www.cosmoscience.org/archives/2011/Accelerated%20Stability_Janice%20 Ensing.pdf
10. Hyzer, CH. Implementing an Accelerated Stability Assessment Program: Case Study. Presentation available at: http://freethinktech.com/wp-content/uploads/2016/11/LillyImplementing-an-Accelerated-Stability-Assessment-Program_Case-Study-1.pdf
11. Thielges, S. ASAP concept and case studies. Presentation available at: http://freethinktech. com/wp-content/uploads/2016/11/Janssen-ASAP-21-MAR-2013-london.pdf
12. Williams H. Predictive Stability in Pharmaceutical Development, focusing on ASAP Studies. Presentation available at: http://www.ddfevent.com/wp-content/uploads/2016/11/ Helen-Williams-AstraZeneca.pdf
13. Li H et al. Prediction of the changes in drug dissolution from an immediate-release tablet containing two active pharmaceutical ingredients using an accelerated stability assessment program (ASAPprime ®). AAPS Open. 2016, 2 (7)
14. Amebis. Amebis ASAP Brochure. Brochure available at: http://amebisltd.com/images/pdf/ Amebis_ASAP_Brochure.pdf
15. Qiu, F. Application of ASAP in Early API and Formulation Development. Presentation available at: https://www.stabilityconference.com/wp-content/uploads/2016/02/ FengheQui-applicationofASAPinearlyAPIdevelopment.pdf
16. Williams, H. ASAP Regulatory Strategy, Acceptance and Feedback - AstraZeneca perspective. Presentation available at: http://freethinktech.com/wp-content/uploads/2017/02/HelenWilliams-SOS-2016-1.pdf
17. Thompson, J. Excipient Compatibility as Predicted by ASAP. Presentation available at: http://freethinktech.com/wp-content/uploads/2016/12/Excipient-Compatibility.pdf
18. Freed, L et al. Regulatory responses to the use of various lean stability strategies in early drug development. Regulatory Rapporteur. 2014. Vol 11, No. 7/8, July/August
19. International Council for Harmonisation. Quality Guidelines. Stability Testing of new Drug Substances and Products Q1A(R2). Guideline available at: http://www.ich.org/ fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q1A_R2/Step4/Q1A_ R2__Guideline.pdf

Author Biography