During early stages of the cleaning method validation or after introduction of the new process equipment or cleaning equipment the egg and hen dilemma (Cleaning SOP first or cleaning validation first) is normally observed.
To start the cleaning method validation, the approved cleaning method (Standard operating procedure for cleaning of the equipment) is required and to write the Standard operating procedure for cleaning (SOP), the validation is required.
Imagine a new drug product manufacturing facility, or new equipment train or introduction of the new process equipment and still not in use. The seeding of the cleaning method shall be done at this stag itself to have the strong pillar for the cleaning method with the aid of the accessories installed on the process equipment for the cleaning (e.g. Spray ball for the tank cleaning) or by using the dedicated equipment required for the cleaning like Cleaning in Place (CIP) unit, or ultrasonic bath for the very small product contact surface accessories.
The right approach to resolve the Hen and Egg dilemma would be, to incorporate the study in the performance qualification protocol of the CIP or Process equipment or the cleaning accessories, The qualification of the cleaning equipment may be performed in two stages. Each stage will be data base for writing the SOP for the cleaning.
Stage: 1: Rinse policy determination :
The First would be using the dummy chemical for batch manufacturing and using the Riboflavin. e.g. use of the sodium chloride or Sucrose or other appropriate chemical having lower detection unit ( We will write the Sodium Chloride in further write up as the representative of these chemicals ).This stage will help to write the approach to the rinse sampling ( Performed during normal production run ) and the use of the riboflavin will have the basis for the swab sampling methodology for writing the SOP for the cleaning of the equipment.
Let us see it stage wise. During first stage of the qualification of the cleaning equipment or process equipment installed with the cleaning accessories, prepare the batch of the sodium chloride or spread the solution of the sodium chloride on the on the product surface of the equipment. Clean the equipment by using the cleaning devices by using measured quantity of the water. Take the rinse sample for the analysis and analyze the sample for the presence of the sodium chloride. Clean till the sodium chloride does not appear in the rinse sample.
That’s it, now we the data base for the quantities of the solvent to be used for the cleaning and the number of the cycles required for the cleaning. This database will help in writing the cleaning method and the rinse sampling for the cleaning method validation.
Stage: 2: Swab Policy determination
Now we are ready to decide the swab sampling, The most important part of the swab sampling is the swab sampling be done on the hard to clean location. Now we have to decide the hard to clean surface. This will be stage 2 of the Performance qualification of the equipment or accessories used for the cleaning.
Overlay the Riboflavin on whole inner surface of the equipment including the crevices and the remote parts and run the first cycle of the cleaning (Decide the cycle parameters of cleaning here itself). With the aid of the UV light observe carefully the whole surface of the equipment after completion of the first cycle (The riboflavin gives fluorescence under UV light). If no fluorescence is observed on any of the product contact locations, Good!
The cleaning accessory or cleaning equipment can clean the equipment overlaid by the riboflavin by using the decided cycle parameters If after completion of the first cycle the riboflavin is observed on the equipment then mark the locations on the drawing or photograph of the equipment where the riboflavin is observed. Run the similar cycles till the riboflavin is completely eliminated and go on marking on the drawing or photograph of the equipment (Modification in the cycle parameters like qty of the solvent used, or the cycle time etc may be done to have effective cleaning, but this will lead to repetition of the entire process of cleaning again, right from the overlaying surface of the equipment with the riboflavin and rinse procedure).
Determine the hard to clean locations by observing the photographs marked for the presence of the Riboflavin. The repeated cycles will determine the hard to clean locations. Normally the remote locations or crevices of the process equipment are hard to clean surfaces. If the determined “Hard to clean surfaces” are surprisingly not obvious surfaces which shall have been observed cleaned, then we may have to modify the cycle parameter.
If specialized equipment like CIP is used we have ample of parameters to modify and if the simple cleaning accessory attached to the process equipment (Like spray ball) is used then we have limited parameters to manage. After varying these parameters I it is concluded that the cleaning can not be performed by this cleaning accessory, the performance of the same is in question and we have to look for the accessory with higher capacity or different design.
Writing the Standard Operating Procedure
After completion of the study, all the study data shall be addressed in the performance qualification report of the equipment. This report will stand as the basis for writing the Standard operating procedure for the cleaning of the equipment. After performing all the above exercise, we have following data in hand.
- Number of the rinse required to clean the equipment with no detectable sodium chloride and riboflavin.
- Quantity of the solvent used for each cleaning cycle
- Hard to clean surfaces for the given process equipment by using the said cleaning accessory.
Now, we are ready to draft the SOP for the cleaning of the equipment.
While writing the SOP for the cleaning, mention the following things in the SOP as determined after the above mentioned study.
- Write the quantity of the solvent and cycle parameters in the SOP as set during the above study
- Write the number of cycles in the SOP required for cleaning, the number of cycles shall be the maximum cycles as performed during the rinse analysis (Stage : 1) or swab analysis (Stage :2) in above study. Since we have used the sodium chloride and riboflavin, it may be easier to clean than the planned products. Hence while writing the SOP consider the number of cycles one or two more than performed during the study, this will help to minimize the further revision of the SOP after introduction of the more hard to clean product
- Mention the hard to clean surface in the SOP, so that swab sampling of the same location will be performed
Now we will have the good SOP for the cleaning of the equipment with the sound background and we are ready to use the process equipment and cleaning equipment for production purpose. On introduction of the new product we will check the feasibility of the current procedure (Validated on the Sodium chloride and the riboflavin with one or two extra cycles) to clean the product. This will be a continuous process as the products go on adding.