Stability studies supporting marketing authorization submissions

Introduction

The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for
Human Use (ICH) has published several quality or ‘Q’ guidelines for stability testing of active substances and drug products, e.g. ICH Q1A(R2), which can
be accessed via the ICH website (http://www.ich.org).

International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use stability guidelines for chemical and biological products

  • Q1A(R2):  Stability Testing of New Drug Substances and Products (second revision 2003).
    • This guideline provides recommendations on stability testing protocols including temperature, humidity and trial duration for climatic zones I and II. Furthermore, the revised document takes into account the requirements for stability testing in climatic zones III and IV so as to minimize the different storage conditions for submission of a global dossier
  • Q1B: Stability Testing: Photostability of New Drug Substances and Products (1996).
    • This guideline forms an annex to Q1A(R2), and gives guidance on the basic testing protocol required to evaluate the light sensitivity and stability of new drugs and products
  • Q1C: Stability Testing for New Dosage Forms (1996).
    • This guideline extends Q1A(R2) for new formulations of already approved medicines and defines the circumstances under which reduced stability data can be accepted
  • Q1D: Bracketing and Matrixing Designs for Stability Testing of New Drug Substances and Products (2002).
    • This guideline describes general principles for reduced stability testing and provides examples of bracketing and
      matrixing designs
  • Q1E: Evaluation of Stability Data (2003).
    • This guideline extends Q1A(R2) by explaining possible situations where extrapolation of retest periods/shelf lives beyond the real-time data may be appropriate. Furthermore, it provides examples of statistical approaches to stability data analysis
  • Q1F: Stability Data Package for Registration Applications in Climatic Zones III and IV.
    • This guideline was withdrawn in 2006, leaving the definition of storage conditions in climatic zones III and IV to the
      respective regions and WHO
  • Q5C: Stability Testing of Biotechnological/Biological Products (1995).
    • This document augments guideline Q1A, and deals with the particular aspects of stability test procedures needed to take account of the special characteristics of products in which the active components are typically proteins and/or polypeptides

The ICH Q guidelines aim to harmonize the quality and testing methods for pharmaceutical products, including conducting stability studies and evaluating the data. ICH is composed of the regulatory authorities of the EU, Japan, the USA, Switzerland and
Canada, together with pharmaceutical industry representation from Europe, Japan, the USA and the rest of the world.

The Asia-Pacific Economic Cooperation (APEC), Association of Southeast Asian Nations (ASEAN), East African Community (EAC), Gulf Central Committee for Drug Registration (GCC), Pan-AmericannNetwork for Drug Regulatory Harmonization
(PANDRH) and Southern African Development Community (SADC) regional harmonization initiatives, and regulatory authorities from Australia, Brazil, China, Taiwan, India, the South Korea, Russia and Singapore are also involved in the ICH process for developing guidelines. The WHO also participates in the process as an observer.

In addition to ICH guidance, countries and regions may have specific additional or supplementary stability guidance which also needs to be taken into consideration when a product is being developed, e.g. Committee for Human Medicinal Products (CHMP) stability
guidance (available from http://www.ema.europa.eu) and ASEAN stability guidance.

Stability guidelines essentially describe how formal stability studies on the active substance and the drug product should be conducted. Stability testing should
be performed on at least three primary batches of the pharmaceutical product so as to measure any batch-to-batch variability. A primary batch should
be at least pilot scale (typically 10% commercial manufacturing scale, or at least 100 000 units for tablets or capsules, whichever is larger) and should be representative of the commercial product (same synthetic process and critical control steps for active substances and same composition and manufacturing process for drug products).

In certain situations, such as where the active substance is considered stable, the number of batches that need to be included in a stability study can be reduced.

The container closure system should simulate the commercial packaging for active substances and should
be identical to that used for the drug product. Liquid products packaged in containers with separate closures
will need to be stored inverted and laid on their side to allow any interaction between the product and the container closure to be monitored (e.g. sorption
into a rubber vial closure).

Where there are multiple presentations of the drug product (e.g. different strengths or bottle pack sizes), stability testing will be required for each possible
presentation. However, the concepts of bracketing and/or matrixing can be used to reduce the amount of testing.

Bracketing is where only the samples on
the extremes of certain factors (e.g. strength, container size and/or fill) are tested at every time point.

Matrixing is where a selected subset of all the possible samples at a particular time point is tested. Reduced
designs have pitfalls in that they may lead to shorter shelf-life estimation, or the stability studies have insufficient power to detect some main or interaction
effects.

At least 12 months’ long-term stability data (and/ or intermediate data) and 6 months’ accelerated data need to be provided to regulatory authorities by
companies seeking a marketing authorization.

However, in certain cases (e.g. generic products) the data requirement may be reduced to 6 months. ICH also provides guidance on the length of intervals
between testing – a typical ICH stability study protocol is described in Table 49.1.

Photostability testing

Photostability of the active substance is initially studied as part of stress testing to elucidate degradation pathways, but can also be used to indicate whether there might be a need for light protection
of the formulated product. Photostability testing of the drug product may be done during formulation and container closure development studies (using
open and closed container studies).

Photostability studies of the pharmaceutical product and the container closure system intendedt o be marketed will need to be performed to confirm the product is not affected by light exposure. Thisi s typically achieved by an overall illumination of notl ess than 1.2 × 106l ux hours within a temperature controlled light cabinet with use of light sources thatr eplicate daylight (both visible and UV light).

Typically, the product’s appearance, assay and impurities are investigated, as are other Critical Quality

Attributes (CQAs) that may be affected by light; for example, some polymers may cross-link in light, resulting in changes of viscosity.

The drug product may need to carry a label warning to advise that the product should be stored protected from light.

This may also extend to its use by the
health care professional or patient; for example, nitroprusside degrades to cyanide on exposure to light, therefore infusion bags need light-protecting
over-bags and opaque giving sets should be used.

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