Recovery from the surface is calculated as follows:
A recovery factor of 70% is usually acceptable; but factors as low 50% may be obtained. In cases where low results are obtained
in a reproducible manner, the sample surface area may be sampled again using a second swab,with the results obtained from
both swabs added together.
Initial Cleaning of New Equipment
Another important aspect to consider when establishing a cleaning validation program is the initial cleaning of new equipment.
Most commonly, the equipment included in a cleaning validation study is that which currently is in use for a specific operation.
Nevertheless, it could happen that new equipment purchased for any type of improvement or replacement is received and installed
at the site while the equipment validation study is being developed. In such case, this is the best time to include the new
equipment in the study.
Initial cleaning for new equipment requires some special considerations as noted here. This cleaning should be performed to
eliminate foreign matter or residues introduced through maintenance, fabrication, or installation.
Description of this initial cleaning procedure is as follows:
- Equipment should be passivated (if stainless steel material) as per current SOP.
- Remove passivation residues from equipment surfaces as per existing cleaning SOP.
- No detergent will be used during the cleaning process.
- Let equipment dry, rub a lint free piece of cloth (preferably white) over equipment surface and inspect the piece of cloth
for visible residues.
- Take rinse or swab samples to determine the absence of passivation agents by a validated methodology. Additional samples can
be taken for pH/conductivity or any organic reagent determination by TOC technique. In some cases, a sample for total plate
count determination is also included.
- The rinse sample for passivation agents will be collected in a 500 mL glass bottle and the sample for organic test by TOC
determination, in a 50 mL glass tube.
- The microbiological samples will be collected in sterilized sampling bottles. When swabbing is called for, a sterilized swab
should be used.
- Take samples as controls from the water source for chemical tests, TOC analysis, and micro-biological analysis, respectively.
- Submit the samples to the corresponding laboratories and analyze as per current SOP's.
- Acceptable limits:
- Passivation agents: ID test according to the chemical used in the passivation process
- TOC: Three log reduction of passivation agent's formulation or USP limits
- Conductivity: USP limits
- Total Plate Counts: The most important consideration in setting any limit here is that it have a scientific basis supported
by historical data.
CLEANING VALIDATION PROTOCOL
Once all the aforementioned aspects are considered, we are ready to develop the cleaning protocol. A protocol used to validate
the cleaning procedure contains the following basic elements:
A. Purpose: This section describes the intention of the validation protocol.
B. Scope: This lists the boundaries of the project to be validated.
C. Responsibilities: Tasks are listed for each person involved in executing the protocol.
D. Strategy: The following steps should be included in the strategy section:
1. Description of the product to be challenged:
- If two or more product presentations are used, the more concentrated should be challenged.
- Bracketing may be considered acceptable for similar products and equipment, provided appropriate scientific justification
2. Holding time period for equipment being cleaned:
- This is the time during which the equipment was soiled with the product.
- Let the residue dry for a specified length of time (hours), followed by cleaning the equipment.
3. Holding time for cleaned equipment:
- The rationale to establish this period of time should be based on microbiological challenges in equipment areas identified
as inaccessible locations or where the probability of stagnant water can exist.
5. Cleaning effectiveness measures (rinse or swab)
Measuring and Test Equipment
Check calibrations of instruments used during protocol execution for proper compliance.
1. Identify the procedure to be challenged.
2. List all safety precautions established for the affected area.
3. Indicate the number of runs that will be made
4. Describe the equipment to be cleaned, including:
- Equipment pictures
- Indicate equipment surface area calculations
5. List chemical tests (active, detergent, excipients, pH, and conductivity, as applicable to the method)
6. Indicate the number of samples to be collected, the volume of rinse (mL), the container (e.g., glass) material, etc.
Selection of Acceptance Criteria
For any new product, the owner should be consulted for details concerning the therapeutic potential and possible adverse reactions.
A determination should be made as to the appropriateness of the limits for that product. If the product is determined to be
highly potent or poses the strong possibility of adverse reaction, special limits must be determined. All special limits should
be determined on a case-by-case basis.
The lowest therapeutic dose (LTD) of 1/1000 is considered a safe level for residues of active ingredients. The same approach
will be adopted to calculate the contamination limit for the cleaning agent, using LD50 instead of LTD. For the products that
have excipients, (e.g., preservatives), the acceptable residual level should be set at not more than 1/1000 (three log reduction)
of TOC of the product formulation.
The maximum allowable carryover (MACO) limit for the active drug or cleaning agent in mg per swab for a specific piece of
equipment or for an equipment process train is as follows:
MACO (mg/swab) =
LTD = Lowest therapeutics dose (mg) or LD50 for cleaning agent (mg/kg)
D = Highest maximal daily dose (dose units)
= Smallest batch size (g)
= Highest unit dose weight (g)
= Swab area (cm2 or in2 )
= 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
- 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.
Collect any unexpected situations
that occurred during protocol execution.
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:
1. Table of Contents
- Include a brief description of the cleaning process that was validated.
3. Data analysis and results
- Summarize all validation outcome (use of tables is recommended)
- Any discrepancy found during protocol execution should be satisfactorily explained.
- 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.
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.
1. 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.
2. 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.
3. 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
4. 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.
5. 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.