From a pharmaceutical development point of view, stability studies are frequently on the critical path to starting patient studies and registration stability studies, as described in the International Conference on Harmonisation (ICH) guideline Q1A (R2), are commonly the activity on the critical path to regulatory filing and approval [1]. Stability studies are also a significant resource commitment in both pre and post-approval phases.
This article examines the decisions to be made regarding the design of a stability strategy during development and some alternative approaches, compared to those traditionally followed, are proposed as being more scientifically rigorous. Following these approaches would lead to better product understanding and robustness as well as to a reduction in the number of scientifically redundant stability studies.
Traditional stability studies overview
The development of the ICH stability guidelines led to a significant degree of harmonization of expectations and, more recently, the World Health Organization (WHO) stability guideline has extended the reach of these efforts [2,3]. However, although the guidelines state that alternative approaches can be used when scientifically justified, pharmaceutical companies may be reluctant to propose any significantly different approaches when subsequent long delays may be incurred to a development program if a regulatory body refuses to accept the alternative approach followed. Additionally, in some regions details from the ICH guidelines have been either written into, or are referred to in, local regulations [4,5]. It is therefore usually considered ‘safer’ to conservatively follow the guidelines along the paths mapped out.
The first stability studies performed are usually forced degradation studies [1]. These are carried out to understand the primary degradation products of the molecule and to aid analytical method development (stability-indicating methods to be subsequently used during long-term stability studies). The next stage is to perform accelerated stability testing for excipient compatibility studies during formulation development and to support assignment of initial shelf lives/storage conditions for early toxicological and clinical studies. Long-term stability studies will also be initiated on both the active pharmaceutical ingredient (API) and the drug product, generally following many of the principles contained in the ICH stability guidelines, with storage at accelerated and long-term conditions.
Unless the expectations outlined in ICH guideline Q1A(R2) have been met as part of the clinical stability program, registration stability studies are traditionally performed before filing a Common Technical Document (CTD). Q1A(R2) also states that if the registration stability batches are not made at commercial scale, then the first three commercial batches need to be placed on stability. Furthermore, after this point batches are usually placed on stability annually, an expectation which has been included in the WHO stability guideline [3]. In addition, when changes are made (e.g. to manufacturing process or synthetic route), repeat stability studies are frequently undertaken in both the pre and post-approval phases.
Alternative Scientific Approaches
Anybody who has worked in the stability arena will be familiar with time spent ‘clock-watching’ as stability studies progress – even though the stability characteristics of the API/drug product may be fully understood. Although real-time stability studies are an absolute necessity during development (at the very least in order to confirm the validity of any alternative models), by following a science and risk-based approach to stability a better understanding of stability performance can be achieved and a number of unnecessary studies may be avoided [6].
An appropriate science and risk-based approach can be achieved by applying the principles of Quality by Design (QbD) to stability. The application of these principles should be based around generating scientific understanding and controlling the attributes affecting the stability performance of the API and drug product. Taking an API as an example, what the developer needs to determine is what packaging is required 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 essentially determined during manufacture: polymorph, surface area and water content being probably the three most important attributes. Those that are determined to have an effect on the stability performance of the entity may be defined as ‘stability related material attributes’ (SRMAs). If these are then mapped out in a dimensional space alongside storage temperature and shelf life (i.e. defining the ‘stability space’), then the developer can determine what controls need to be placed on these stability related material attributes during manufacture to ensure a target shelf life. It should be noted that it may not be necessary to test for the stability related material attributes during the stability study; only shelf life limiting attributes (e.g. degradation products) are required to be tested from a scientific perspective.
Another area of increasing interest in the stability world is in the use of accelerated predictive models for stability determination. Waterman et al. have developed and used a humidity-corrected Arrhenius equation to give reliable estimates for temperature and relative humidity effects on stability performance [7]. They have combined an experimental design that decouples temperature and relative humidity effects with an isoconversion paradigm to predict shelf lives at long-term storage conditions using data gathered over a relatively short period of time. This tool allows faster and more accurate prediction of shelf lives than current one-condition accelerated stability studies (e.g. at 40°C/75% Relative Humidity) which is particularly useful during the early clinical phases. The model can then be used to underwrite the stability of an API or drug product during the continuous improvement phase of synthetic route or process/manufacturing development by comparing the stability of an API or drug product before and after the change. In addition, the combination of an accelerated predictive model with a science and risk-based approach allows the determination of a scientifically sound, robust stability space to be developed which could be used to underwrite future changes to factors such as manufacturing process, scale or site.
A review of Traditional Stability Expectations and a Comparison with the Science and Risk-based Approach
As discussed in the previous section, once the packaging and storage requirements for the API/drug product have been fixed, the only variables that can affect the stability of that API/drug product are the stability related material attributes. Once these are identified then any subsequent changes to other factors such as site, scale, process or synthetic route only need to be assessed in terms of their potential effects on the stability related material attributes identified for the API or drug product in question. For example, if polymorph is determined as the only stability related material attribute for a particular API, then any effects that a change in scale may have on stability can be determined simply by determining the polymorph after manufacture of the scaled-up batches, negating the need to perform further stability studies.
Highlighted in Table 1 are some of the statements from available guidance and expectations for registration stability batches which could be challenged from a scientific point of view if a science and risk-based approach is followed for determining stability.
In the following sections these traditional registration stability expectations, plus those expectations covering subsequent stability studies, are discussed in the context of their relevance if science and risk-based and accelerated predictive approaches are followed.
Representative Nature of Batches
The ICH guideline states that 3 batches at a certain scale need to be placed on stability and that they are representative. The science and risk-based approach outlined essentially renders the registration stability study an unnecessary activity. However, even if a more traditional approach to stability was followed and batches conforming to the requirements in Table 1 were to be placed on stability, then the term ‘representative’ is only relevant in terms of the stability related material attributes of the API or drug product. The batches would not need to be made by a certain synthetic route or process (or scale) to be representative in terms of stability performance. Certainly from a manufacturing validation point of view when making process changes other representative properties such as process related impurity levels may need to be determined; however these would not affect the representative nature of earlier batches as far as stability performance is concerned. Repeat stability studies (from those previously performed) would not be scientifically justified/required if the stability related material attributes remained within the stability space defined, regardless of what changes had been made to synthetic route or manufacturing process.
Scale
As discussed, scale is not a stability related material attribute. Once these are determined and the specification developed, further stability studies are unnecessary as long as the API/drug product meets requirements for the stability related material attributes included on the specification during release testing, i.e. stability knowledge combined with release testing underwrites unlimited scale-up from the perspective of shelf-life allocation.
Duration of Data
The ICH stability guideline Q1A(R2) recommends that 12 months data should be available at time of filing. Increasingly, some agencies appear willing to accept data of a shorter duration when combined with a scientific rationale or other relevant justification. The WHO stability guideline states that a minimum of 6 or 12 months data may be provided; 6 months if API is known to be stable and no significant changes occur at long term or accelerated conditions. Analysis we have performed on data from stability studies demonstrated that 6 months acceptable accelerated data can accurately predict whether a minimum 18 or 24 month shelf life for a drug product can be applied [8]. The use of accelerated predictive models should challenge the traditional duration of data expectations still further.
Annual Commitment Stability Expectations
The Code of Federal Regulations part 21CFR 211.166 states that: “There shall be a written testing program designed to assess the stability characteristics of drug products” and part 21CFR 211.170 states that: “reserve samples from representative sample lots or batches selected by acceptable statistical procedures shall be examined visually at least once a year for evidence of deterioration unless visual examination would affect the integrity of the reserve sample….The results of the examination shall be recorded and maintained with other stability data on the drug product” [8]. There is no explicit requirement for annual lot stability studies. However, the FDA Inspection Guide on “Expiration Dating and Stability Testing for Human Drug Products” states under Stability Testing, B.1: “it is imperative that stability studies are not limited only to initial production batches but a portion of annual production batches be the subject of an ongoing stability program” [9]. Although the Inspection Guide is dated October 1985, the webpage was last updated April 2009. Outside of the US, the WHO stability guideline states: “Unless otherwise justified, at least one batch per year of product manufactured in every strength and every primary packaging type, if relevant, should be included in the stability program” [3]. A similar statement is made for API. As discussed in previous sections, confirmation that batches continually conform to the stability related material attributes should be an acceptable scientific justification to negate the need to do further routine (including annual) stability studies.
Post-approval Changes
The United States Food and Drug Administration (FDA) and European Medicines Evaluation Agency (EMEA) provide guidelines on additional stability studies for post-approval changes in site, scale, manufacturing and process for dosage forms. As an example, Table 2 contains a summary of the stability studies outlined in the FDA guideline for scale-up and post-approval changes for immediate release solid oral dosage forms [10].
The FDA guidelines on post-approval changes are essentially pragmatic risk management matrices classifying the risks associated with changes in a way to give a simple common position for all products in the absence of any specific data. However, there is a danger that stability studies become ‘box-ticking’ exercises if the guidelines are applied literally to a particular API/drug product and change. For example, a change in mixing times may have no effect at all on any of the stability related material attributes but a batch would be placed on long-term stability regardless. Site, manufacturing and process, in addition to scale (as previously discussed), are not stability related material attributes.
The European guideline on variations states for API batches that if the quality characteristics (e.g. physical characteristics, impurity profile) of the active substance are changed in such a way that stability may be compromised, comparative stability data are required, i.e. this infers that an assessment can be first made as to whether the stability is likely to be compromised by a change before performing long-term stability studies [11].
Although the ICH Q8(R1) Pharmaceutical Development, ICH Q9 Quality Risk Management and ICH Q10 Pharmaceutical Quality System guidelines do not directly deal with stability per se, a similar approach to risk management could be considered [12-14]. In Table 3 an alternative approach to change control (of site/scale/manufacturing/ processes) is outlined that combines the science and risk-based and accelerated predictive stability approaches described previously.
Summary
Although the introduction of a number of quality guidelines has helped industry move to a more harmonized approach and allowed constructive dialogue between industry and regulators, there is a danger that both can become over-reliant on following the letter of these guidelines at the expense of applying science and risk-based approaches.
If a science and risk-based approach to stability is followed during development, then the stability characteristics of an API and drug product will be properly understood and mapped out. Although the resource and cost requirements of this approach may be greater initially, it should ensure that product failures due to unexpected stability results are avoided as development proceeds. Development activities should be focused on determining those quality attributes that affect the stability performance of an API and product and putting in place appropriate controls, either through manufacturing understanding and controls and/or release testing.
Adopting a science and risk-based approach, combined with accelerated predictive models, would lead to the need to do less routine, non value-added stability studies during the development and commercial phases and would facilitate a continuous improvement of processes without the need to wait for unnecessary long-term data before these changes could be implemented.
The above article represents a personal view and is not necessarily that of Pfizer Ltd.
Acknowledgements
PhRMA Stability Expert Team, Ron Ogilvie, Steve Colgan, Allan Edwards, Bob Whipple and Liz Coulson for useful discussions and input.
References
1. International Conference on Harmonisation Guideline Q1A(R2): Stability Testing of New Drug Substances and Drug Products. http://www.ich.org/LOB/media/ MEDIA419.pdf
2. International Conference on Harmonisation Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) guidelines. http://www.ich. org/cache/compo/276-254-1.html
3. Stability testing of active pharmaceutical ingredients and finished pharmaceutical products. In: WHO Expert Committee on Specifi cations for Pharmaceutical Preparations. Forty-third report. Geneva, World Health Organization, 2009, Annex 2 (WHO Technical Report Series, No. 953). http://www.who.int/medicines/ publications/pharmprep/pdf_trs953.pdf#page=101
4. Panama Ministry of Health Executive Decree No.504, dated 9 November 2005, published in the Gaceta Oficial 16 November 2005.
5. Resolution RE No.1, dated 29 July 2005, published in the Official Gazette of the Union, Supplement to No.146, Section 1Brasilia – DF 1 August 2005.
6. J.V.Beaman. QbD Approach to Stability… a science and risk-based approach. Proceedings of Optimising Stability Testing Conference, Visiongain, September 2008.
7. K. C. Waterman, A. J. Carella, M. J. Gumkowski, P. Lukulay , B. C. Macdonald, M. C. Roy, S. L. Shamblin. Improved protocol and data analysis for accelerated shelf-life estimation of solid dosage forms. Pharm. Res. 24 (4):780-790 (2007).
8. J. Beaman, M. Whitlock, R. Wallace, A. Edwards. The scientific basis for the duration of stability data required at the time of submission. J. Pharm. Sci. 99 (6):2531-2925 (2010).
9. Code of Federal Regulations 21CFR Part 211: Current Good Manufacturing Practice for Finished Pharmaceuticals. http://www.access.gpo.gov/nara/cfr/ waisidx_09/21cfr211_09.html
10. The FDA Inspection Guide on “Expiration Dating and Stability Testing for Human Drug Products. http://www. fda.gov/ICECI/Inspections/InspectionGuides/ InspectionTechnicalGuides/ucm072919.htm
11. FDA CDER Guidance for Industry: Immediate Release Solid Oral Dosage Forms Scale-Up and Postapproval Changes: Chemistry, Manufacturing, and Controls, In Vitro Dissolution Testing, and In Vivo Bioequivalence Documentation Center for Drug Evaluation and Research (CDER), November 1995. http://www.fda.gov/downloads/Drugs/ GuidanceComplianceRegulatoryInformation/Guidances/ucm070636.pdf
12. EMEA CPMP (2005) Guideline on stability testing for applications for variations to a marketing authorisation. CPMP/QWP/576/96 Rev.1. http://www.emea.europa.eu/ pdfs/human/qwp/057696en.pdf
13. International Conference on Harmonisation Guideline Q8(R1): Pharmaceutical Development. http://www.ich.org/LOB/media/MEDIA4986.pdf
14. International Conference on Harmonisation Guideline Q9: Quality Risk Management. http://www.ich.org/LOB/media/MEDIA1957.pdf
15. International Conference on Harmonisation Guideline Q10: Pharmaceutical Quality System. http://www.ich.org/LOB/media/MEDIA3917.pdf
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