Priya Poduval | April 28, 2020
The regulations in the pharmaceutical industry are constantly being updated to include aspects of various processes that were considered unimportant before. Similarly, the pharmaceutical industry itself is trying to be one step ahead by implementing procedures that ensure maximum quality and efficiency of the final pharmaceutical product.
Cleaning of the product contact parts is one such aspect that was often neglected and age-old cleaning methods were used that led, not only to extensive usage of manpower for scrubbing, but also failures such as cross-contamination and microbial contamination due to incorrect cleaning practices. Because of this, the pharmaceutical industry turned to the sophisticated semi-automated and automated cleaning hoping that their cleaning issues would be taken care of, and although cleaning was improved, all the cleaning issues in the pharma industry were far from being sorted out.
The main reason for the Pharmaceutical industry struggling with unexpected cleaning issues is that little to no attention is paid to the science-based development of a cleaning procedure for a given product.
The solution to this is that cleaning development should start at the Formulation and Development stage. Along with product development, a scalable cleaning process should be a part of technology transfer for each product. For existing products that are in commercial manufacturing already, a change of cleaning agent or process could be difficult due to the re-validation requirement but if there is a good return on investment by increased capacity and profits due to reduced downtime, it must be considered. Here, the paradox is that without making sure if the change in cleaning will be beneficial, the company wouldn’t want to invest in the development of analytical methods for the residual detergent analysis, without which, the cleaning agent cannot be introduced and tested in the production equipment. In this case, the cleaning process should be developed in the laboratory and scaled up before cleaning validation.
However, as F&D scientists are not expected to be experts in cleaning agents and science of cleaning, they should work together with cleaning agent manufacturing companies to determine the right cleaner as well as the optimal cleaning conditions. Dober’s Chematic division provides support for cleaning procedure development by replicating the residue & cleaning conditions, that are available in the production site, in the Chematic lab and testing the cleaning agents. This decreases the time and effort of the pharmaceutical company and helps them get the starting guideline from which they can proceed with optimization in the laboratory before moving to scale-up.
The question that arises quite frequently during testing and optimization is ‘How to start?’.
Listed below are a few guidelines to perform laboratory scale cleaning trials by considering scale-up, equipment and parameters. Based on the equipment, residue and the method of cleaning, the laboratory trials have to be modified to suit individual cleaning processes.
It is always recommended to work with cleaning agent manufacturing companies to develop the most efficient cleaning procedure, cleaning scale-up and troubleshooting.
Note: If the practice of intermittent cleaning with water/solvents between campaign batches is followed, it should be replicated on the coupons by coating/ residue application, water/solvent wash and drying as per the cleaning SOP (& repeating the process) to check for impact of this step on the final detergent cleaning.
a. Beaker study:
This method of cleaning trial can be used to replicate cleaning for the following equipment and conditions:
If a pre-rinse step is used, the temperature of the pre-rinse step should be based on recommendation and equipment capability. If no instructions are available, impact of pre-rinse temperature on cleanability should be observed and noted. Temperature of the pre-rinse can be varied during testing to check for its impact (residue swelling, pigment retention, toughning of residue, etc) on the residue.
For the detergent step, heat pre-decided volume of water (if required) in a beaker. Add the amount of cleaning agent calculated to prepare the recommended concentration once the recommended temperature is attained. The volume of detergent solution in the beaker must be such that the entire coupon is dipped into the solution. Stir/agitate by means of the magnetic stirrer to circulate the solution and improve dissolution and/or suspension of the residue, also replicating the movement of the solution in production scale.
Dip the coupon into the detergent solution for a recommended time period (or ~15 – 60 minutes). Based on the mechanism of cleaning of the detergent, it should dissolve or disintegrate the residue and hold it in solution/suspension when in motion.
The coupon can be observed at set time intervals by pulling it out of the detergent solution but while doing so, it should be ensured that the coupon doesn’t dry as this could hamper the cleaning.
The time taken to chemically remove the residue or any other observations (if the residue is dissolving or coming out in flakes and if the flakes dissolve, whether the residue is chemically removed or not, whether the residue softens) must be noted down.
Post rinse should be done immediately after the detergent step by placing the coupon under running water. Post rinse in a beaker must be avoided to prevent redeposition of cleaning agent and residue on the coupon.
Note: For certain residues like multi-layer coating or multi-polymer residue, it may be necessary to use more than one cleaning agent. This can be confirmed by CCE studies performed at Dober.
To replicate manual cleaning, mild scrubbing with a toothbrush can be employed if slight residues remain on the coupon or if you want to decrease the soaking time.
The temperature of the pre-rinse, detergent step and post rinse should be determined by the capability of the production site, equipment, and cleaning recommendation.
If the CIP skid in the scale-up equipment is capable of maintaining temperature, the beaker study must be carried out at the optimum temperature maintained by the use of a magnetic stirrer with heating.
If the temperature cannot be maintained in production scale, then the beaker study could be conducted at a temperature higher than the optimum but within the recommended temperature range, which is also available in the production setup.
Magnetic stirrer speed cannot be directly correlated to scale-up equipment as there are many variables involved. However, 400-700 RPM would be representative of the motion in a CIP or WIP system.
If coupons are not available, the insides of a stainless steel beaker (or similar material as of the equipment to be cleaned) can be soiled and cleaned in a similar manner.
b. Trigger Spray Cleaning
This method can be used to replicate cleaning of equipment like Fluid bed processors, fermentation tanks or any other equipment that can use spray balls, automated CIP/WIP systems or high-pressure hoses for cleaning.
Pre-rinse should be done based on the requirement by fill, soak and agitate method or by placing the coupon under running water for 5-10 minutes.
For the detergent step, heat pre-decided volume of water (if required) in a beaker to recommended temperature and add the amount of cleaning agent calculated to prepare the recommended concentration. Place the coupon vertically and spray the detergent solution on it to cover the entire coupon. If this is performed in a beaker, pooling of the detergent solution will occur in the bottom, hence, the coupon should be raised slightly to be above the level of the detergent pooling.
Post rinse should be done immediately after the detergent step by similar spray method.
To replicate fill, soak, spray system of an automated cleaning system, the trigger spray method can be performed after a beaker soaking for ~10-30 minutes.
c. Manual Cleaning
This method of cleaning trial can be used to replicate manual cleaning with minimum effort or scrubbing, in equipment where soaking and agitation is not possible.
Pre-rinse should be done based on the requirement by placing the coupon under running water for 5-10 minutes.
For the detergent step, use trigger spray for soaking the residue for ~10-30 minutes (Soaking time could be longer for tougher residues) at the highest temperature safe for manual cleaning. Ensure that the residue is continually soaked and not left to dry at any given point. Once the residue is softened or starts to dissolved, use mild scrubbing with toothbrush and repeat soaking/scrubbing as required.
The cleaning step must be immediately followed by the post-rinse step.
7. Optimization and Troubleshooting
If the cleaning trial is not successful in the first attempt, vary the T.A.C.T parameters (Contact Time, manual or mechanical Action, concentration Chemistry and process Temperature) and if improvement is observed, optimize accordingly. It is important to understand which parameter impacts the residue in what manner.
If haze is observed, determine the root cause (hidden residue, insoluble pigments, adverse impact of temperature, etc.) based on the evaluation, vary T.A.C.T parameters after discussion with the cleaning agent manufacturer.