Liquid sampling plays a crucial role in contamination control strategies, ensuring that particulate contaminants are kept out of injectable pharmaceutical products and, ultimately, the bodies of end-users. In this article, we will delve into the essentials of sampling within USP 788 compliance, including validation techniques and requirements to ensure adherence to these critical standards.
Understanding USP 788
We are all acutely aware of the potentially severe consequences of particulate matter contamination in parenteral injectable pharmaceutical products. In this context, particulate matter refers to small, subvisible particles that can have detrimental effects on patient safety. The United States Pharmacopoeia, specifically USP <788>, offers two tests for detecting such particulates: light obscuration and microscopic assay. Both of these methods are widely accepted for testing large volume parenteral (LVP) and small volume parenteral (SVP) products to determine subvisible particulate matter. Typically, samples are first subjected to the light obscuration method. If a sample fails to meet the specified limits, the microscopic assay method can be employed.
The Importance of USP 788 Compliance
Injectable drug products undergo multiple processes to meet or exceed the standards set by USP, which are enforced by the Food and Drug Administration (FDA). Particulate matter in injections is defined as extraneous, mobile, undissolved particles unintentionally present in the final product. These contaminants can originate from various sources, including the environment, packaging materials, cleanroom personnel, and formulation ingredients.
The introduction of particulate matter into the bloodstream can have severe consequences for patients, including vein irritation, local tissue infarction, anaphylactic shock, and, in the worst cases, death. Most injectable products are not thermally sterilised, which poses a risk that must be mitigated to ensure patient safety.
USP <788> sets limits on the allowable amount of subvisible particles in injections. These limits are harmonised with the European Pharmacopoeia (EP) and Japanese Pharmacopoeia (JP) and are outlined in USP <788> “Particulate Matter in Injections.” Recent advances in particle counter liquid sampling technology, coupled with sampling software that adheres to 21CFR Part 11 (the FDA’s regulations on electronic records and electronic signatures), have made the testing process less burdensome and more compatible with current Good Manufacturing Practices (cGMP). Understanding how this technology aligns with USP <788> and why it should be utilised by injectable drug manufacturers is essential.
Before we dive deeper into liquid particle counter technology and its alignment with USP 788, let’s summarise a few key points:
- Particulate matter in injectable products can have severe health consequences when introduced into the bloodstream.
- Recent advances in liquid sampling technology have simplified the process of complying with USP 788.
- USP 788 standards are harmonised with international pharmacopoeias, such as the European Pharmacopoeia and Japanese Pharmacopoeia.
Liquid Particle Counter Technology: How It Works
Light obscuration stands out as the preferred method listed in pharmacopoeias for analyzing subvisible particles in parenteral products. The process involves drawing a sample into the system’s sensor through a needle or sample tube. Particles passing through a laser beam obstruct a specific amount of light, creating a “shadow” on a light-sensitive detector. The area of this shadow is then converted into the equivalent diameter of the particle.
One of the liquid particle counters that adhere to USP 788 standards is the LS-20 Liquid Particle Counter. This equipment is designed for batch sampling and comes complete with user-friendly 21 CFR Part 11 compliant software.
How to Sample Within USP 788 Compliance
To sample within USP 788 compliance, certain protocols and considerations must be followed. The current methods for light obscuration require a sample volume of 25ml. The number of individual units to be tested for LVP and SVP units with a volume of 25ml or more depends on “statistically sound sampling plans.” These plans should take into account factors such as product volume, historical particle counts in comparison to limits, particle size distribution, and count variability between units.
The liquid particle counter typically withdraws three samples, each not less than 5ml. It calculates various parameters, including average cumulative counts, average differential counts, average cumulative counts per ml, and average differential counts per ml. As per USP <788>, data from the first run is automatically omitted. The size ranges used for USP <788> testing are ≥10 and ≥25 μm. Liquid particle counters are capable of sizing and counting particles ranging from 2μm to 200μm.
Validation Requirements and USP 788
The validation of a liquid particle counter is a critical aspect of compliance and should be performed every six months. Commonly used validation materials in the industry are known as Count-Cal particles, manufactured by Thermo Scientific. These particles have National Institute of Standards and Technology (NIST) traceable diameters, making them ideal for calibrating and documenting the reproducibility of liquid particle counting instruments. Count-Cal particles typically come with an accuracy of 3000/ml ±10%.
The validation process involves several essential steps, including:
- Sample volume verification
- Volume accuracy test
- Sample flow rate verification
- Sensor calibration
- Sensor resolution test (using 10μm test particles)
- Count ratio test using clean, particle-free water (blank test)
- Count ratio test using 15μm Count-Cal reference particles (3000/ml ±10%)
Validation is considered successful when the liquid particle counter passes the count ratio test using 15μm particles, with counts falling within the range of 2,700 and 3,300 particles. This range adheres to a ±10% tolerance at 3,000 particles per milliliter, validating the accuracy of the liquid particle counter sensor.
USP 788 and other pharmacopoeial standards for testing particulate matter play a pivotal role in managing the safety and quality of injectable products. By integrating quality testing into their processes, manufacturers can address the potential sources of contamination in the environment where sterile products are produced. Patient safety remains the paramount concern in this context.
Recent advances in liquid sampling technology have made compliance with USP 788 more straightforward and less burdensome. Liquid particle counters, such as the LS-20, are designed to meet these standards and simplify the testing process. Ensuring USP 788 compliance not only safeguards patients but also upholds the reputation and credibility of pharmaceutical manufacturers.