Coupons cleaning validation
The low formulation gave the highest recovery on average, suggesting that the excipient was enhancing the recovery of the drug from the coupon. Based on the types of variability discussed above, the initial approach to improve recovery was to redevelop the extraction method and the experimental conditions to obtain consistent and high recoveries.
The average recoveries on four different coupons along with relative standard deviation are shown in Figure 1 for some experiments. The main conclusion was that none of the aforementioned changes eliminated the previously observed variability in Table 2. Within experimental error, almost all of these experiments were not considered statistically different. It is clear that the average recovery is different from one coupon surface to another.
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Therefore, the coupon surface is expected to be a major contributor to the observed variability. There was a high probability that the previously observed variability in recovery was due to coupon-to-coupon variability. Moreover, some differences were observed between coupons at this formulation Figure 2. The observed variability suggested that the surface of the various coupons was not identical and interacted differently with the matrix.
The first approach to minimize the difference among the coupons was to thoroughly clean the surfaces of the coupons. Coupons used for obtaining recovery in Figure 3 were cleaned according to the procedure presented in the experimental section. The recovery results after cleaning the coupons are presented in Figure 3.
It is clear that the recovery is virtually reproducible from one trial to another and that the difference in recovery between coupons is minimized. Table 2 shows a comparison of the recovery results before and after cleaning the coupons under the same experimental conditions. Coupons cleaned with CIP solutions were then used for cleaning verification of compounds B another small molecule C and D large molecules, i.
The same conclusions drawn from experiments for drug A were applicable for drug B, C, and D detailed results shown in reference High recoveries were obtained across molecular size and physicochemical properties by applying a systematic cleaning approach for the coupons.
cleaning validation - Chromatography Forum
Figure 1. Average Recovery Obtained from Four Coupons. Error bars represent relative standard deviation from four trials on four coupons. Please click here to view a larger version of this figure. Figure 2. Figure 3.
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Variability in Recovery of Drug A at 2. Solid triangles correspond to recovery values before cleaning the coupons, while open symbols correspond to the recovery values after cleaning the coupons. Table 2. The major contributor to low and variable recoveries of API residues from stainless steel coupons was traced to the lack of a well-defined procedure for cleaning of the coupon surfaces.
Cleaning the surface of the coupons resulted in consistent, accurate spiked recovery and reproducible results.
Cleaning validation sampling methods...
With the demonstration of high recoveries from stainless steel coupons, the actual cleaning verification results obtained from the manufacturing equipment using validated method s should be accurate and precise, reflective of the residue level on the equipment with minimum risk of false negatives for product to product carryover that could jeopardize patient safety. The initial approach followed by the analyst to troubleshoot the low and inconsistent recovery was by modifying the experimental conditions such as: percent of organic in the diluent, the spiking process, the type and strength of acid used in the spiking solution, etc.
This approach did not solve the low and inconsistent recovery issue. Nonetheless, this aforementioned problem was completely solved when the stainless steel was adequately cleaned using clean-in-place solution. This achievement results in vastly increasing the chances of the successful pass of cleaning verification of the manufacturing equipment. It is important to note that the CIP solutions used here are limited to the pharmaceutical industry and thus suitable CIP solutions should be selected for other types of industries processed food, dairy, cosmetics, etc.
Correspondence to: Andrei Blasko at moc.
Abstract The aim of this work is to identify the parameters that affect the recovery of pharmaceutical residues from the surface of stainless steel coupons. The borosilicate glass surface was used in the construction of the viewing endcap on the final formulation compounding tank, so the higher VRL observed was not critical. The visual inspection procedure as well as the inspector qualification study consisted of precleaning and visual inspection of the coupons before spiking. This procedure is used to try to eliminate phantom residues or false positives.
The coupons were placed flat on a table in front of a fume hood in groups of three, and the inspector stood back approximately 0. The lighting in the room was between and lux. Rinse sampling is commonly used to evaluate surface cleanliness of closed production equipment, hoses, and piping commonly cleaned by CIP systems 23— The advantages of rinse sampling are that the entire surface can be sampled, with no disassembly of equipment and no direct sampling of the surface, and that rinse sample analysis via conductivity, TOC, UV, and other methods in-line or on-line can be adapted to PAT technologies.
The disadvantages of rinse sampling are that the analyte measured may not be soluble in the rinse solution, rinsing may not pick up the residue due to poor coverage during rinsing, and the analyte may be too diluted in the rinse solution volume. Rinse recovery studies can be used in addition to assessing the solubility of the active ingredient in the rinse solution. The studies are performed by adding a specified concentration, around the acceptable limit, of the residue on the surface.
The selection of the residue, conditioning of the residue, surface material, roughness of the surface, rinse solution, volume of rinse solution per surface area, rinse solution temperature, and flow rate should all be considered in setting up a rinse solution recovery study.
Two rinse recovery studies are discussed as examples. Figure 6. First rinse recovery study; linearity between conductivity to concentration of a formulated alkaline cleaning agent. Figure 7. Second rinse recovery study; linearity between total organic carbon TOC and concentration of a formulated alkaline cleaning agent. Conductivity and pH results, hour air-dried samples.
Total organic carbon TOC results, hour air-dried samples.
Three lots of the formulated alkaline cleaning agent were diluted at various concentrations between 1 and ppm by volume using DI water and tested at ambient temperature. Temperature compensation was not used for this testing. Three lots of the formulated alkaline cleaning agent were diluted at various concentrations between 0. Solution was applied in drops to provide a uniform coverage. Samples were air-dried on the coupons in a horizontal position. After drying, mL of DI water at ambient temperature was poured from a squeeze bottle over the coupon so that the flow cascades down the face of the coupon for approximately 30 seconds.
Surface cleanliness is crucial in ensuring that process residue, cleaning agent residue, and bioburden do not adversely affect the safety, quality, and potency of the drug manufactured. Surface cleanliness can be determined through surface sampling, rinse sampling, and visual inspection. The preferred method is surface sampling through swabbing, wiping, or direct measurement.
Surface sampling can add production delays, increased sampling costs, and often increased safety risk to the analyst. If the engineering of the equipment, coverage testing of the equipment, and cleaning agent and analytical method selection have been well vetted during the design and qualification stages of the lifecycle approach, then rinse sampling or visual inspection can be successfully used to demonstrate surface cleanliness. Attention to detail and application of a risk-based approach during the design stage can provide justification for using either rinse sampling or visual inspection in determining surface cleanliness.
The authors are grateful to Amanda Deal for excellent technical assistance in performing the VRL study as well as the first and second rinse recovery case studies. Verghese and P. Pluta Ed. Verghese and N.
Kanesgsberg and E. Kanesgsberg, Eds. Kaiser, J. Tirey, and D. Kaiser and B. Lopolito and E. Madsen and J. Moldenhauer, Eds. Gietl, B. Meadows, and P. Forsyth, J.
Fourman and M. Bethesda, MD, Forsyth, V. Van Nostrand, and G. Bunimovich, P. Lopolito, and B. Bader, et al. When referring to this article, please cite it as E. Rivera and P. Tags: surfac , FDA , risk-based , validation , cleaning.
Evaluating Surface Cleanliness Using a Risk-Based Approach Rinse sample analysis or visual inspection can be correlated to surface cleanliness to replace surface sampling. Each element of the justification needs to be reviewed and evaluated during the cleaning process design stage to defend a lean approach in continuously monitoring the cleaning process. Averaging Swab Sample Results? More on Limits for Formulated Cleaning Agents.
Issues in Limits for Formulated Cleaning Agents. Revisiting Cleaning Validation for Medical Devices. Setting Limits Based on Process Capability? Objectionable Microorganism Concept in Cleaning Validation. Cleaning Validation for Packaging Equipment: Part 2. Cleaning Validation for Packaging Equipment: Part 1. Dealing with Unknown Peaks. Understanding the Cleaning Process. Is Rinse Sampling Alone Acceptable? Selecting Worst-Case Products for Grouping. Issues in the Visual Examination of Equipment Surfaces.
More on Specificity of Analytical Methods. Cleaning After a Media Fill. Endotoxin Issues in Cleaning Validation. Monitoring a Validated Cleaning Process. PAT and Cleaning Validation. Correlation of Swab and Rinse Sample Results? Why TOC is Acceptable. Limits for Drugs with Multiple Actives.
Using Sampling Recovery Percentages.
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Additional Considerations in Recovery Studies Part 2. Additional Considerations in Recovery Studies Part 1. Recovery Studies for Rinse Sampling. Sampling the Sampling Rinse. Selecting Swab Sampling Sites. Worst-case Process Conditions. Recovery Studies for Microbial Sampling? Cleaning Validation for Medical Devices. The Use of Default Limits. Cleaned Equipment Hold Time. Dirty Equipment Hold Times. Handling Sampling Recovery Results. Equipment Grouping Strategies for Cleaning Validation. Product Grouping Strategies for Cleaning Validation.
Water Quality for Validated Cleaning Processes. Validation of Analytical Methods. Specificity of Analytical Methods. Happy Holidays. Campaigns and Dedicated Equipment. The Applicability of Cleaning Validation. Specific Documents. Site Links. Supplier Sites. June September December Cleaning Agents. CIP Equipment.