Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2022 Oct 28;14(11):2324.
doi: 10.3390/pharmaceutics14112324.

Drug Stability: ICH versus Accelerated Predictive Stability Studies

Olga González-González  1 , Irving O Ramirez  1 , Bianca I Ramirez  1 , Peter O'Connell  1 , Maria Paloma Ballesteros  1   2 , Juan José Torrado  1   2 , Dolores R Serrano  1
Affiliations
Review

Drug Stability: ICH versus Accelerated Predictive Stability Studies

Olga González-González et al. Pharmaceutics. .

Abstract

The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH), along with the World Health Organization (WHO), has provided a set of guidelines (ICH Q1A-E, Q3A-B, Q5C, Q6A-B) intended to unify the standards for the European Union, Japan, and the United States to facilitate the mutual acceptance of stability data that are sufficient for registration by the regulatory authorities in these jurisdictions. Overall, ICH stability studies involve a drug substance tested under storage conditions and assess its thermal stability and sensitivity to moisture. The long-term testing should be performed over a minimum of 12 months at 25 °C ± 2 °C/60% RH ± 5% RH or at 30 °C ± 2 °C/65% RH ± 5% RH. The intermediate and accelerated testing should cover a minimum of 6 months at 30 °C ± 2 °C/65% RH ± 5% RH (which is not necessary if this condition was utilized as a long-term one) and 40 °C ± 2 °C/75% RH ± 5% RH, respectively. Hence, the ICH stability testing for industrially fabricated medicines is rigorous and tedious and involves a long period of time to obtain preclinical stability data. For this reason, Accelerated Predictive Stability (APS) studies, carried out over a 3-4-week period and combining extreme temperatures and RH conditions (40-90 °C)/10-90% RH, have emerged as novel approaches to predict the long-term stability of pharmaceutical products in a more efficient and less time-consuming manner. In this work, the conventional ICH stability studies versus the APS approach will be reviewed, highlighting the advantages and disadvantages of both strategies. Furthermore, a comparison of the stability requirements for the commercialization of industrially fabricated medicines versus extemporaneous compounding formulations will be discussed.

Keywords: ASP; extemporaneous compounding; stability.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
ICH codes and titles.
Figure 2
Figure 2
CPMP Guidelines. Modified from: [8].
Figure 3
Figure 3
ICH climatic zones. Key: climate zone I (blue color), climate zone II (green color), climate zone III (orange color) and climate zone IVa and IVB (red color).
Figure 4
Figure 4
Objectives of Stability Testing. Adapted from: [8].
Figure 5
Figure 5
APS characteristics. Modified from: [16,17].
Figure 6
Figure 6
Recommended shelf life for extemporaneous compounding formulations. Modified from: [20].
Figure 7
Figure 7
Forced degradation studies. Modified from: [24].
Figure 8
Figure 8
Used conditions for forced degradation studies. Modified from: [25,26,27].
Figure 9
Figure 9
Drug shelf-life prediction derived from the extrapolation of degradation rates from the Arrhenius equation. Modified from [29].
Figure 10
Figure 10
Three-dimensional representation of the degradation rate (Lnk), temperature (1/T) and relative humidity (%). Modified from [29].
Figure 11
Figure 11
Schematic representation of the stages of an APS study.
Figure 12
Figure 12
Types of stability chambers for ICH and APS studies. (a) Industrial stability chamber for ICH studies. (b) Simple hermetically closed jar for APSs, (c) Amebis Ageing System with WiFi controllers for APSs and (d) Cuspor Ageing System for APSs.
See this image and copyright information in PMC

References

    1. WHO . Annex 10. Stability Testing of Active Pharmaceutical Ingredients and Finished Pharmaceutical Products. WHO; Geneva, Switzerland: 2018.
    1. Sun M.F., Liao J.N., Jing Z.Y., Gao H., Shen B.B., Xu Y.F., Fang W.J. Effects of polyol excipient stability during storage and use on the quality of biopharmaceutical formulations. J. Pharm. Anal. 2022 doi: 10.1016/j.jpha.2022.03.003. - DOI - PMC - PubMed
    1. USP Stability Considerations in Dispensing Practice (1191) 2020. [(accessed on 12 September 2021)]. Available online: http://www.uspbpep.com/usp32/pub/data/v32270/usp32nf27s0_c1191.html#usp3....
    1. Jato J.L.V. Tecnologia Farmaceutica Volumen I: Aspectos Fundamentales de los Sistemas Farmacéuticos y Operaciones Básicas. Editorial Sintesis; Madrid, Spain: 2001. Estabilidad; pp. 317–362.
    1. Carstensen J.T. Drug Stability, Principles and Practices. Elsevier; New York, NY, USA: 2000.

LinkOut - more resources