A gravimetric analysis measures the weight of extracted residue. Concentrated extract is transferred to a crucible and evaporated. The crucible is reweighed, and the weight difference is the amount of extractable soluble and insoluble residue from the device.

Due to increased awareness of the potential dangers of residual manufacturing materials on medical devices, the FDA often requests documentation of a thorough validation of how residual materials were cleaned from newly manufactured devices. An essential part of this validation includes quantification or counting contaminants which may remain on the devices following the cleaning procedure.

There are several ways to analyze devices and possible contaminants as part of a cleaning validation. They include analytical, microbiological, and biocompatibility methods. This article examines total organic carbon (TOC) analysis, gravimetric analysis (ASTM 2459), and detergent residual analysis by ultraviolet/visible (UV/VIS) spectroscopy.

Start with a few questions

When formulating a plan for cleaning validations, start by answering questions, such as:

1. What is the purpose or goal of the cleaning?

2. How many devices must be tested to establish that the cleaning is reproducible?

3. To what types of contaminants are the devices exposed?

4. How can limits be established for the residual materials?

The obvious goal of a cleaning may be simply to produce a clean device, but it may also include manufacturing a biocompatible device, or reducing bioburden or endotoxin levels, or both. Understanding the purpose of the process brings the validation plan into clearer focus.

Demonstrating reproducibility in a cleaning validation is also an important step. Reproducibility should be two-fold: uniformity in a cleaning run and consistency from run to run. If there are variables in the cleaning operation which can significantly impact the cleanliness of the devices, it is advisable to test worst-case as well as nominal conditions.

A single device may be exposed to many contaminants during manufacturing and cleaning. How a team validates a cleaning operation is affected by the number and type of contaminants. Residues may be analyzed by direct surface analysis or measured after extraction. Extraction analysis is most common so the methods discussed here are all extraction-based.

Contaminants usually fall into one of three categories: water soluble and nonwater-soluble residue, and nonsoluble debris. Water-soluble residues are usually ionic compounds such as detergents and salts. Nonwater-soluble residues, such as oils, greases, and other hydrocarbons, are soluble in solvents other than water. Non-soluble debris includes residues such as metals, organic and inorganic solids, and ceramics.

There are no established regulatory limits for residual analysis, so it is important to justify an acceptable level. A few practical techniques for setting limits include comparing clean and unclean devices, evaluating a new process versus an old one, and assessing residue amounts based on the detection limit of the method. Residue limits are usually specified in micrograms or milligrams per device. When comparing devices with different surface areas, it is advisable to define limits based on surface area, such as µg/cm² or mg/cm².

Additional testing (such as for endotoxin, bioburden, or biocompatibility) may be required to justify established limits, demonstrate the effectiveness of the cleaning, or evaluate the risk of the detected residual levels on the clean devices. Specific risk assessment and justifications should be prepared for the validation file so regulatory reviewers can determine the rationale for a test plan and established limits for residual manufacturing materials.