Where:
LTD = Lowest therapeutics dose (mg) or LD50 for cleaning agent (mg/kg)
D = Highest maximal daily dose (dose units)
W b = Smallest batch size (g)
W t = Highest unit dose weight (g)
S s = Swab area (cm2 or in2 )
S e = Equipment product contact surface area (cm2 or in2 )
R = Recovery factor of active ingredient or cleaning agent
LD50 = Lethal dose of 50% of animal population
Microbiological Limits
Depend on the type of product (e.g., injectable, etc.)
The most important consideration in setting any limit is that there be a scientific and historical basis.
Discrepancies
Collect any unexpected situations that occurred during protocol execution.
Approvals
List approvers will vary with each firm. At the very least, the following should be included: a validation specialist, head management of the affected area, appropriate representatives of the microbiological and chemistry laboratories, and appropriate QA representatives. The protocol must be approved before execution begins.
FINAL REPORT AFTER PROTOCOL EXECUTION
The final report will include the following:
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Table of Contents
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Introduction
Include a brief description of the cleaning process that was validated.
- Data analysis and results
Summarize all validation outcome (use of tables is recommended)
- Deviation
Any discrepancy found during protocol execution should be satisfactorily explained.
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Conclusions
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Approvals
The same personnel who approved the validation protocol should approve the final report. These individuals included a validation specialist, head management of the affected area, appropriate representatives of the microbiological and chemistry laboratories, and the appropriate QA representatives.
MONITORING SYSTEM
The purpose of monitoring is to assure the adequacy of the equipment cleaning process. It is important to verify that the cleaned equipment performs as it was intended and that it remains in a validated state. Monitoring may be achieved through taking representative samples, and evaluation of product non-conformances; by following through on quality alert notifications and complaints and by conscientiously completing “Annual Products Reviews.” Any or all of these should be followed by revisions to change controls as needed.
Failures in any of these areas might indicate the need for revalidation. Revalidation is also required when there is a significant change in product formulation, change, or modification to a process or equipment and change of cleaning agents.
COMMON ERRORS AND RECOMMENDATIONS
The section is based on the author’s experience during his 13 years of dealing with cleaning validations.
Common Errors
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Failing to perform a good process flow, beginning with the raw material sampling process and focusing on obviously important stages such as the compounding or filling process.
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Failing to train operators well, and failure to instill a sense of high commitment:
Most common mistakes, such as not following procedures, not taking samples at the time specified, improper handling of samples, not reporting discrepancies observed during the specific process executed, etc., undermine high quality performance and contribute to poor results. It is highly recommended to have representation from the validation department present throughout all runs.
- Missing or inaccurate documentation:
In addition, to the common errors noted above in #2, a lack of documentation also causes difficult situations during future audits, because important key information will be missing during investigations. This is often the basis for general misunderstanding of data.
- Lack of good coordination and communication between the different areas involved in the validation process:
Examples of poor coordination and communication include samples not being taken on time, required materials not being available, disputes within departments, lack of cooperation, and bad working environments based on placing blame rather than on cooperation.
- Failing to understand the criticality of the sampling process:
It is very important to take the samples at the time(s) established and for the proper durations (stability), taking correct quantities and volumes, attending to the proper handling and storage of samples, using the correct equipment, and other special considerations for samples requiring microbiological testing.
- Failure to properly train persons in charge of sampling:
This can have a major impact on the accuracy of microbiological sampling.
- Not having an effective change control program:
Once the validation process is completed, internal procedures impacted by the validation outcomes must be revised accordingly. It is frequently observed that the communication and follow up systems fail at some point and impacted procedures and activities are not modified.
- Not having an adequate cleaning monitoring system:
It is frequently observed that changes are made to an already validated system, disregarding the impact those changes might have on the validation state of the total system. Constant communication between manufacturing and the validation department is critical.
- Failure of manufacturing areas to consider the validation department in internal changes and procedure approval:
Due to lack of technical knowledge in the validation area personnel in manufacturing might overlook or be unaware of important aspects that have impact from a validation point of review.
- Failure of plant personnel primarily focused on the manufacturing operation, to require compliance with the cleaning validation procedures.
José A. Morales Sánchez is a technical services senior scientist at Janssen Ortho LCC a Johnson ’ Johnson Company; 787.272.7463; jmoral12@janpr.jnj.com
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REFERENCES
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FDA. “Guide to Inspectors of Validation of Cleaning Procedures,” 1993.
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Technical Tip #3020. “Pharmaceutical Product Contact Surface Sampling.” Steris Corporation (Calgon Vestal Division), 410-200-3020. 4/97.
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PDA Pharmaceutical Cleaning Validation Task Force, “Points to Consider for Cleaning Validation,” Journal of Pharmaceutical Science and Technology, Technical Report No. 29, Volume 52, Number 6, 1998.
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Maria J. Capote, “Documentation For Cleaning Validation: A Protocol Template,” pgs 261-271, Volume 2-Number 3, Journal of Validation Technology.
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Gil Bismuth and Shosh Neumann, “Cleaning Validation: A Practical Approach,” Interpharm Press, 2000.
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Health Products and Food Branch Inspectorate, “Good Manufacturing Practices - Cleaning Validation Guidelines,” Spring 2000.
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Destin A. LeBlanc. “Equipment Cleaning Validation: Microbial Control Issues,” Journal of Validation Technology, Volume 8, Number 4, August 2002.
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Herbert J. Kaiser and Maria Minowitz. “Analyzing Cleaning Validation Samples: What Method?” (
http://www.ivthome.com/free/analyzing_cleaning_validation_samples.htm
, accessed July 16,2003). -
Code of Federal Regulations Title 21, Volume 4, Section 211.67, April 2004.