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.
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:
- 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 is present.
- 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.
- 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.
- Cleaning effectiveness measures (rinse or swab)
Measuring and Test Equipment
Check calibrations of instruments used during protocol execution for proper compliance.
- Identify the procedure to be challenged.
- List all safety precautions established for the affected area.
- Indicate the number of runs that will be made
- Describe the equipment to be cleaned, including:
Indicate equipment surface area calculations
- List chemical tests (active, detergent, excipients, pH, and conductivity, as applicable to the method)
- 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) =