A cleaning validation protocol format shall be developed for the ‘worst case’ product selected for cleaning validation programme.
Following information (but not limited to) the following included in the cleaning validation protocol.
Numbering of protocol shall done through of respective SOP of Cleaning Validation Protocol Numbering.
Cleaning Validation Protocol Format –
A brief description of the purpose of the validation study.
This section must include an extent of the cleaning validation protocol.
This section includes the different responsibility for completing the cleaning validation programme.
Provided to all personnel involved in the cleaning validation
Records of training of all personnel involved in the cleaning validation program for understanding and cGMP requirement.
Protocol signature log:
Signature (specimen) of all the person involved in the cleaning validation program mention here for proper identification of person for future reference.
Brief description of equipment used for selected product & relevant SOP for equipment cleaning. provide the complete details of cleaning procedure in this part of cleaning validation protocol format.
Swab samples shall taken after final cleaning of the equipment and once the equipment qualifies the visual inspection test. Sampling procedure should be defined in the protocol.
- Visual Inspection
- Preparation of swab
- Dimension of swab sample area.
- Swab Sampling point
Sampling strategy shall be defined in this part of cleaning validation protocol format.
While performing each activity, documentation of the required details shall be done in appropriate attachment of this protocol.
Analytical and microbiological test method:
This section will give references for the adopted analytical and microbiological test method to analyse the samples.
The analytical method must validated for the residue levels, or bio-burden as per the specification given in the protocol. Testing performed by.
All test results must calculated and reported to correspond with the predetermined acceptance criteria.
Validation report addressing the cleanliness of each piece of equipment shall generated after compilation of three batch validation.
The acceptance criteria for the cleaning validation will mentioned in the
specific protocol and will decided based on product matrix.
Any deviation taken during execution of the protocol shall documented in this section.
Justification for the deviation will be authorized by Quality Assurance (QA) Head and Factory Head (Plant Head).
ANALYTICAL METHOD DEVELOPMENT AND VALIDATION
- The development and validation of analytical procedure for the purpose of analyzing cleaning validation sample requires the selection of appropriate tests.
- Definition of test :
- Limit of Quantification:
- The limit of quantification of an individual analytical procedure is the lowest amount of analyte in a sample, which can be quantitatively determined with suitable precision and accuracy.
- RSD of area of triplicate injections, Not more than 10.0%
- Limit of Detection:
- The limit of detection of an individual analytical procedure is the lowest amount of sample concentration till the peak detects in all of the triplicate injections.
- The linearity of an analytical procedure is its ability (within a given range) to obtain test results, which are directly proportional to the concentration of analyte in the sample at LOQ level.
- Limit of Quantification:
Correlation coefficient in the range of LOQ to 150% of sample concentration should be less than 0.990 and graph shall be visually linear.
- Instrument Precision and Accuracy and Precision at LOQ Level.
- This study to check instrument repeatability, method repeatability and accuracy. RSD of area from six replicate injections of standard preparation (at LOQ): Not more than 10%. RSD of % recovery calculated from six replicate sample preparation at LOQ concentration is not more than 10 %.
- Recovery from placebo at LOQ concentration should be between 80.0 % and 120.0 % .
- Stability in Analytical solution at room temperature:
- Analytical solution stability at room temperature shall performed.
- Stability in analytical solution at room temperature for standard and sample preparation between Initial and specified stability time interval is not more than 10 %.
- Recovery from spiked swabs:
- The recovery from spiked swab at LOQ (100%) to different concentration is Not less than 80%.
- Recovery Study from SS Plate:
- This study is performed for efficiency checking of swab sampling procedure from the surface by applying the known concentration of standard solution on surface at target and LOQ level. Mean recovery from SS plate is not less than 70.0%. Recovery factor should be considered for evaluation of cleaning validation results.
- Note : Limits for the carryover of product residues should be based on a toxicological evaluation. The justification for the selected limits should be documented in a risk assessment which includes all the supporting references. Limits should be established for the removal of any cleaning agents used. Acceptance criteria should consider the potential cumulative effect of multiple items of equipment in the process equipment train.
MYTH AND FACTS OF CLEANING VALIDATION.
Myth 1 : “You can’t validate manual cleaning”
Automated and manual Cleaning Procedure can be validated.
Actually manual cleaning variability is more as compare to the automated cleaning processes,
Consistency of manual cleaning is depends upon
- the complete details mentioned in cleaning procedures,
- trend manpower and
- adequate cleaning steps.
If cleaning procedure steps are robust, cleaning variability will be minimum. It requires more vigilant to validation maintenance. Design a comprehensive, dependable cleaning validation program.
Myth 2 : During recovery at different spiked level should linear.
Fact : Recovery (in %) are highly variable. It is not reasonable to expect linear response, Swabbing is a manual procedure so variability will be there.
Myth 3 : Any residue is unaccepted.
In the current methodology (by TOC or By HPLC) of evaluation of residue content, there will always be some residue obtained in result.
Detection limits of Analytical procedure actives the lower levels.
If the residue obtained is below the acceptable level, and medically safe and it don’t impact on product quality, same quantity of residue can be accepted.
Myth 4 : For Evaluation of Samples, Always use HPLC instead of TOC.
Perform the Evaluation through validated TOC analyzer
No need to re perform the evaluation with HPLC separately and no need to correlate the result generated by TOC with HPLC.
Method validation of TOC with appropriate standards is sufficient to run the sample on TOC.
No need to perform the test individually, both Analytical procedure by HPLC and by TOC can accepted.
Myth 5 : Always correlate rinse sample results with swab sample results.
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The rinse samples are different with swab samples, there will be no correlation among the both.
Actually swab focus on small area and rinse focus on larger area, where simulation of surface is not possible for swab sample or difficult to reach areas,
Rinse sample for the same. Swab measures worst case and rinse measures average.