Cleaning Validation and Analytical methods used for detection of residue

Cleaning Validation and Analytical methods

The specificity and the sensitivity of the method used for detection of contaminants after cleaning process are of great importance.
If the residues of previous product or the cleaning process is not detected in the analysis, which doesn’t mean that it is completely absent, it may be a case where the sensitivity of the analytical method and the limits may not be able to trace them in present concentration in the sample. The poor sampling method may be a cause of the absence of residue after cleaning as well. Therefore it is advisable that the analytical method must be challenged with different combination of sampling methods which are particularly used to demonstrate that the contaminant residue can be removed from an equipment surface at the level of 50% and 90% etc .Cleaning process evaluation and production in process quality control tests.
In process quality assurance tests can be used as tools to evaluate the efficacy of cleaning process, some of the indirect test like conductivity of last wash water can be used to predict and monitor the cleaning process. There must be a correlation between the in process test used to monitor effectiveness of cleaning, and during validation these tests should document that the the equipment not cleaned completely fail the in process tests employed. good manufacturing practices

Test for Total Organic Carbon (TOC) (TC ) for evaluation of efficacy of cleaning process:

Yes ! We can set this one of the test for evaluating cleaning effectiveness . in US FDA’S publication of the inspection guide on cleaning validation in 1993, a number of studies have been published to demonstrate the adequacy of TOC in measuring contaminant residues.

Total Organic Carbon (TOC) (TC ) will be an acceptable method for monitoring residues routinely and for cleaning validation. To make this test TOC to be functionally suitable, we should first establish with suitable study that a substantial amount of the contaminating material(s) is of organic origin which contains carbon that can be oxidized by conditions applied in TOC test. This is an important exercise because some organic compounds cannot be reliably detected using TOC.

Test for TOC may be used to for direct surface sample testing as well as indirect (rinse water) sample testing. In both cases. As TOC does not identify or distinguish between different compounds containing oxidizable carbon, any detected carbon is to be therefore attributed to the target compound(s) for comparing with the established limit. Thus, a pharmaceutical manufacturing firm should limit ‘background’ carbon (i.e., carbon from sources other than the contaminant being removed) as much as possible. If TOC samples are required to be stored for long periods of time before analysis, a pharmaceutical manufacturing firm should verify the impact of sample storage time on accuracy and limit of quantization.

What are the References for above discussion:

21 CFR 211.67: Equipment cleaning and maintenance.
21 CFR 211.160(b): General requirements (Laboratory Controls)
USP 643 Total Organic Carbon
Guide to Inspections of Cleaning Validation, 1993



Laboratory Validation / Analytical Method Validation. Laboratory Validation is a process that is employed to ensure that laboratory test data and results are consistent, accurate and precise. The validation process for test methods, as well as the instrumentation that is used to perform the analysis, have IQ, OQ and PQ protocols. There are eleven main principles to the PQ laboratory test validation protocol. These points are to be applied to each and every laboratory test that is critical to the pharmaceutical manufacturing process as well as the stability program and any process validation. Not all of the eleven principles may apply to each type of testing that is performed, however, a thorough review must be done in order to ensure a complete protocol has been written. VCI’s experience with a broad range of analytical methods can make your laboratory validation project run flawlessly.
The eleven PQ principles are listed below:

  • Specificity
  • Linearity
  • Accuracy
  • Precision
  • Robustness
  • Range
  • Detection Limit (LOD)
  • Quantitation Limit (LOQ)
  • Ruggedness
  • Selectivity
  • System Suitability

Cleaning Validation. This validation is used to show proof that the cleaning system consistently performs as expected and provides scientific data that consistently meets pre-determined specifications for the residuals.

The cleaning validation process must be written into protocols and standard operating procedures which are detailed and specific for the different pieces of equipment and instrumentation used by the facility for each type of drug product produced. Other protocols and SOP’s are also required based on the type of product manufactured or process used (such as a batch or bulk process or shared versus dedicated equipment).

A final report on the cleaning validation system will attest that the studies and data prove that the process is in control and cleans as expected. This report will also detail when and why revalidation needs to take place. Call on VCI to help you clean up your cleaning validation backlog.

Hazard Analysis and Critical Control Points (HACCP). The HACCP process is a prevention-based food safety system. These HACCP programs are to be designed to prevent the occurrence of potential food safety problems. The system appears to be simple at first glance, however, it requires a methodical, systematic approach. A pre-requisite to a well-developed and implemented HACCP system must be a solid current Good Manufacturing Practices (cGMP) program as well as strongly committed management.


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