Proactive approaches to mitigate stability failures

Quality assurance programs are essential to establishing standards for compounded preparations. One of the most important elements in a QA program is identifying the root cause of a failure and implementing a corrective action to prevent a future failure, also known as CAPA (Corrective and Preventative Action).

USP <795> states that compounders shall adhere to general principals of compounding which includes adequate procedures and records exist for investigating and correcting failures or problems in compounding, testing, or the preparation itself. 

Potential sources of product stability failures and quality problems include:

  • The drug and its degradation mechanism
  • The dosage form and its components
  • The potential for microbial proliferation
  • The container in which the preparation is packaged
  • The expected storage conditions
  • The intended duration of therapy

Corrective actions that 503A, 503B, and hospitals can take to prevent failures include:

  •  Check the raw material certificate of analysis (CoA) and consider the purity, salt form, and water content into the formulation sheet calculation.
  • Check whether the raw material is sensitive to light, heat, or absorbing moisture easily.
  • If a filtration step is involved in compounding process, confirm no significant filter binding before large batch production.
  • Confirm content uniformity (sample to sample variability) before large batch production for suspension and cream.
  • Confirm the package used (vials, syringe, etc.) is particle free for injectable formulation. Stability studies fail due to particle detected in vials.
  • Confirm integrity of intended container before large batch production. Regulatory bodies put container closure integrity testing as a requirement for stability. Even if pharmacies and outsourcing facilities are not notified of an adverse event due to container closure, this does not necessarily indicate the package will pass a CCIT test. 
  • Confirm the pH and if there is a pH requirement for the product. The pH can change significantly based on batch to batch of the ingredients. Example: many ingredients are HCI salt forms but can vary in HCI content if the formulation doesn’t have sufficient buffer strength.
  • Beside active pharmaceutical ingredient (API), other components such as preservatives are critical to stability of the API or antimicrobial properties.
  • Compatibility (physical such as solubility or chemical such as color change) is critical for multiple API formulations such as multiple vitamin and amino mixtures. Some APIs can make other APIs more or less soluble/stable.
  • Nonspecific binding can cause unexpected potency loss even for repackaging practice.

For more information on root cause of stability failures, watch this recent Quality Compounding Summit session from Dr. Thomas C. Kupiec: