For healthcare products that have a shelf life, stability studies play a central role in their development. These stability assessments of the active substance (for example, the active pharmaceutical ingredient) and the finished healthcare product are mandated by international regulatory agencies. Before a healthcare product can be studied in a clinical trial or be placed on the market, the appropriate shelf life (that is, storage condition and duration) and expiry limits must be established. These stability data must be submitted for regulatory evaluation to ensure that over its proposed shelf life and storage conditions, the product in its packaging will continue to meet the required identity, strength, quality, purity and impurities that support the safety and efficacy claims of the product.1,2

Stability studies: What the data yields

In general, stability studies are conducted to1,2:

  • Establish shelf-life and storage condition(s): This identifies the storage period under a set of specified conditions within which the healthcare product will meet its established end-of-shelf-life specifications.
  • Permit understanding of product and formulation development: This includes understanding the chemical characteristics of the active substance (for example, the degradation pathway that may yield toxic by-products over time). It also includes understanding the chemical stability, which is important to evaluate as the product may become less effective as it undergoes degradation over time (for example, its antimicrobial activities may decrease).
  • Assist in formulation development: Studies can, for example, evaluate if there is any change in the physical properties, such as hardness, phase separation and change in dissolution rate, in the developed formulation.
  • Aid in the development of analytical methods: Sometimes, the physical and chemical properties of the product may change over time (for example, a gel used in a matrix may harden) and the analytical methods will need to be modified accordingly.
  • Identify appropriate packaging: Data from stability studies can confirmthe right packaging for the active substance as well as the final product (for example, the packaging must protect the product from environmental factors such as light, moisture and shipping conditions). Having an appropriate container closure system (that is, packaging) is particularly critical for sterile products, and it should be designed and evaluated over time to ensure no penetration of microbes can be made into the product.

Designing and conducting stability studies

Key considerations in designing and conducting a stability program in accordance with regulatory requirements include 3-7:

  • Identify and follow the relevant regulatory guidance documents in designing your stability program. In addition to general stability requirements, consult product-specific guidance documents to ensure you evaluate and capture the required parameters in the stability program. Examples of these documents may include:
    • International Conference on Harmonisation (ICH): Q1 and Q6 Topics
    • U.S. Food and Drug Administration (FDA): Container and Closure System Integrity Testing in Lieu of Sterility Testing as a Component of the Stability Protocol for Sterile Products
    • ASTM F1980 – 07: Standard Guide for Accelerated Aging of Sterile Barrier Systems for Medical Devices
    • U.S. FDA: Shelf Life of Medical Devices
  • Submit stability protocols and data together with the stability commitment statement (if relevant) for both accelerated and long-term studies.
  • In general, conduct studies using three different batches of both the active substance and finished product for each formulation in their respective containers or packaging.
  • Provide a justification if bracketing and matrixing designs are used in the stability program.
  • Collect long-term data under temperature and relative-humidity conditions in line with the storage recommendations.
  • For products intended for the global market, consider the environmental conditions in different climate zones (fo example, zones III and IV).
  • Support long-term data with accelerated and intermediate stress testing at a higher temperature and relative humidity. Verify the photostability using a single batch.
  • Remember that an accelerated stability study alone does not suffice to support the product shelf life.
  • Beyond considering reasonable analytical and manufacturing variability, justify your acceptance criteria with development data, pharmacopoeial standards, test data for the active substance and finished products used in the toxicology and clinical studies, as well as stability results.

Did you know?

It is common to have a stability program for an investigational healthcare product run in parallel with the clinical trial. Depending on the amount of stability data submitted in the initial clinical trial application (CTA), manufacturers who wish to extend a product shelf life need to evaluate the relevant requirements and determine whether a submission is required to the regulatory agency prior to extending the shelf life of the investigational product.

In Canada, for example, if the CTA-approved shelf life for a biological product is less than 18 months, a CTA-amendment approval would be required before the company can extend its product shelf life. If the product is approved with more than 18 months of shelf life, then a CTA-notification must be submitted to Health Canada within 15 days of implementing the extended shelf life; no prior approval from Health Canada is required.8

Disclaimer

The information presented in these articles is intended to outline the general processes, principles and concepts of the healthcare product development lifecycle. Since regulatory requirements are ever-changing, it is current only as of the date of publication and not intended to provide detailed instructions for product development. Every healthcare product is unique and therefore so is its associated product development lifecycle. Specific advice should be sought from a qualified healthcare or other appropriate professional.

Published: October 17, 2012

References

  1. Kuwana, R. (2011, January). Stability testing. World Health Organization. [Slides]. Retrieved August 28, 2012, from http://www.slideserve.com/judson/stability-testing.
  2. Murphy, J.R. & J.D. Hofer. (2002). Establishing Shelf Life, Expiry Limits, and Release Limits. Drug Information Journal. 36:769-81.
  3. International Conference on Harmonisation. (2002, September 12). The common technical document for the registration of pharamceuticals for human use: Quality M4Q(R1). Quality overall summary of Module 2. Module 3: Quality. Retrieved September 26, 2012, from http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/CTD/M4_R1_Quality/M4Q__R1_.pdf.
  4. International Conference on Harmonisation. (2002, February 7). Bracketing and Matrixing Designs for Stability Testing of New Drug Substances and Products: Q1D. Retrieved September 26, 2012, from http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q1D/Step4/Q1D_Guideline.pdf.
  5. International Conference on Harmonisation. Quality guidelines. Stability guidelines Q1A – Q1F. Retrieved September 26, 2012, from http://www.ich.org/products/guidelines/quality/article/quality-guidelines.html.
  6. International Conference on Harmonisation. Quality guidelines. Specifications Q6A- Q6B. Retrieved September 26, 2012, from http://www.ich.org/products/guidelines/quality/article/quality-guidelines.html.
  7. Tobin, J.J. & Walsh, G. (2008). Chapter 4. Non-clinical studies. In Medical product regulatory affairs. Pharmaceuticals, diagnostics, medical devices. Weinheim: Wiley-VCH Verlag GmbH & Co. KGaA.
  8. Health Canada. Clinical Trial Application – Amendments (CTA-As). Retrieved September 26, 2012, from http://www.hc-sc.gc.ca/dhp-mps/prodpharma/applic-demande/guide-ld/clini/cta_amendment-eng.php.