Stability refers to a product’s ability to maintain its original properties and characteristics throughout its shelf life.
Stability testing is a crucial aspect of in-vitro diagnostic (IVD) reagents, calibrators, and controls, ensuring their performance and functionality throughout their intended shelf life. It is vital for accurate diagnosis and effective patient care.
Failure to comply with FDA stability requirements can lead to regulatory actions, product recalls, and potential threats to patient safety.
Manufacturers must provide strong scientific evidence to support their claims about product stability, as these claims directly impact clinical reliability and patient safety.
The Code of Federal Regulations (CFR) and the Centre for Biologics Evaluation and Research (CBER) both have regulatory requirements for stability testing of IVDs.
Real-time testing involves storing an IVD under labelled conditions and monitoring its performance over time. Accelerated stability studies expose IVDs to extreme conditions to predict their shelf life in a compressed timeframe, often used for preliminary claims or validating modifications. In-use stability testing evaluates the IVD’s performance in real-world conditions to ensure product reliability.
IVD manufacturers must prioritize stability in the design control phase to align the device’s intended use and key features with established expiration dates. User requirements, including onboard stability, storage conditions, and preservative effectiveness, are crucial for microbially controlled or sterile IVDs.
Mathematical extrapolations, like the Arrhenius equation, calculate the predicted shelf life. However, not all IVDs follow a predictable degradation rate, and real-time testing is only acceptable in certain situations.
Key principles of FDA standards for IVD stability testing include:
1. Reliable and Specific Test Methods: FDA 510k submission process mandates that stability claims must be supported by reliable, meaningful, and specific test methods. This means using validated procedures that accurately reflect the IVD’s performance under defined conditions. For example:
Physical Testing: Verifying that the IVD retains its physical properties, such as appearance or viscosity.
Chemical Testing: Assessing the chemical integrity of reagents, calibrators, and controls.
Functional Testing: Ensuring the IVD performs according to its intended use, such as delivering accurate diagnostic results.
2. Controlled Testing Conditions: Stability testing must replicate the product’s labelled storage conditions, such as temperature, humidity, and light exposure. For real-time testing, the FDA 510k submission process requires storage in the same container-closure system used for the marketed product.
3. Minimum Lots Required: Stability studies must include at least three independent production lots to ensure the data is representative of manufacturing variability. These lots should be produced under finalized manufacturing conditions.
4. Predefined Acceptance Criteria: Manufacturers must define acceptance criteria before initiating the stability study. These criteria should correlate with the product’s label claims and provide clear pass/fail thresholds for each tested attribute for FDA 510k Submission.
5. Adequate Sampling and Testing Intervals: stability testing for a minimum of one interval beyond the labelled expiration date must be conducted to thoroughly evaluate the product’s quality and performance during its intended shelf life. This validates the accuracy of expiration date assertions.
The FDA’s Office of In Vitro Diagnostic Device Evaluation and Safety follows ISO 23640:2011 standards for assessing the stability of in vitro diagnostic medical devices, including reagents, calibrators, control materials, diluents, buffers, and reagent kits.
The standard covers establishing IVD reagent shelf life, ensuring stability after opening the primary container, monitoring market stability, and verifying stability specifications after potential modifications.
Premarket notification FDA 510k submissions process should include a summary of accelerated data, while premarket approval (PMA) submissions should include real-time study data along with stability protocol. Real-time stability data are accepted for biologics license application submissions.
All IVD components must be tested to meet final manufacturing specifications, and the intended label and containers should also meet finalized packaging specifications.
The FDA does not mandate ongoing stability studies for in vitro diagnostics (IVDs), but manufacturers licensed by the Clinical Biomarkers Agency (CBER) are typically exempt from post-approval stability studies.
However, FDA investigators may cite manufacturers for not performing these studies if they are a condition of their license. If a potential stability issue is identified, manufacturers should immediately initiate a thorough failure investigation, including impact analysis to determine affected product lots. Various techniques, including statistical methods, can be used to identify potential issues.
Conclusion
The FDA 510k submission process mandate compliance with regulatory standards for stability testing of in vitro diagnostics (IVDs). Manufacturers must assess the necessity and extent of stability monitoring, considering risks and regulatory obligations. Implementing a comprehensive IVD stability testing as early as possible in the product development process, along with timely and detailed responses to any identified stability concerns, assures that IVDs will consistently fulfil user requirements throughout their designated expiration period.
Author:
Ms Suman Mishra (M. Pharm)
Regulatory Consultant, FDA Compliance | Medical Device
I3CGlobal