I’m in the middle of preparing SOP’s/Validation/Qualification for cleaning. One potential issue that has cropped up, is the composition of any detergents used, and how they are a potential contaminant that must be proven removed before production can occur.
This is for a natural health production plant, with the aim of attaining a DEL.
My question is what do people typically use as a cleaning agent? I had read in some supporting documentation that indicated commercial cleansers are not viable because the composition is unknown, and any change in formulation is not readily available. Also, how would one verify that the cleaning agent is not present?
Thanks in advance, any help would be greatly appreciated.
I’ve worked at 3 pharma companies. For normal cleaning, we’ve always used commercial detergent. For more stuborn stains, we have used either strong acid combination, or 30% sodium hydroxide (for different type of products mind you).
It really depends on your products. Normally, alkaline detergent, i.e. the one containing certain percentage of sodium or potassium hydroxide will be adequate. You can use pharmaceutical grade detergent, e.g. CIP 100 (by Steris), but they are quite pricey. Otherwise you can use “food grade” detergent. Then you can be more sure they don’t have any harmful ingredient in there.
To determine the cleanliness from detergent, I would think for your purpose conductivity and pH tests are adequate, as most detergents are ionic and can be easily detected. For stricter product, I would use TOC.
There is no single cleaning agent (&/or cleaning parameters) which could be used for each and every type of contaminant (i.e. “typical” cleaning agents don’t exist). People in industry develop and customize cleaning agents based on their needs. Whatever cleaning agent I use for my products, may or may not work for you. There are many factors which dictate the choice and selection of cleaning agents. As a guide I am including few factors (as given below) for your understanding.
Factors affecting selection of cleaning agents:
[LIST=1]
[b]Chemistry and characteristics of the soil contaminant[/b]: The properties of the soil (i.e. solubility, concentration, dry/wet, stability etc.) are important factors, which plays an important role in selecting appropriate cleaning agent (and cleaning parameters) for soil’s removal. To study, if the selected cleaning agent could efficiently remove the soil contaminant from the equipment (& its surfaces), you may conduct laboratory studies using spiked coupons and subjecting them to simulated cleaning conditions (such as pipetting out given volume of cleaning solution on to coupons or agitating coupons immersed in beakers etc.)
[b]Toxicity[/b] of the cleaning agent: The cleaning agent should not be toxic to humans (this is to ensure ease in handling and to reduce risk of contamination arising due to use of cleaning agent). For this purpose make sure the cleaning agent manufacturer has provided you with necessary Toxicity Data (i.e. LD50/NOEL/Exposure Limit/Acceptable Daily Intake value) for the cleaning agent, as it (toxicity) would be required for determining acceptance criteria/limit for cleaning agent residues.
[b]Compatibility[/b]: The cleaning agent should be compatible with the equipment (surfaces) and the drug product(s) under set cleaning parameters (i.e. factors such as temperature, pressure etc. should not cause the cleaning agent to react with the drug product and/or equipments surfaces thereby leading to formation of unknown contaminants). If possible, tackle this compatibility issue at the development phase itself by performing laboratory studies.
[b]Stability[/b]: The cleaning agent should not degrade to form any toxic residues (as per PIC/S PI 006 - Section 7.9 Detergents: “The possibility of detergent breakdown should be considered when validating cleaning procedures.”)
[b]Composition[/b]: Make sure the composition of cleaning agent is available (as per PIC/S PI 006 - Section 7.9 Detergents: “The composition of detergents should be known to the manufacturer. If such information is not available, alternative detergents should be selected whose composition can be defined. As a guide, food regulations may be consulted.”). Now, the question arises why do we need to know the composition of cleaning agents? Well, this is because of following reasons:
to establish acceptance limits for residues (which would not be possible when the composition is not known).
to develop analytical methods. Obviously, developing a specific analytical method (as required by PIC/S) would not be possible until you know what you are looking for.
Availability of [b]analytical methods [/b]for cleaning agents, which is required:
to demonstrate the removal of cleaning agent(s). This is only possible when you have a validated analytical method, which could detect cleaning agent residues in the samples (collected) to show that the residues are well below acceptance limits. Obviously, developing a specific analytical method (as required by PIC/S) would not be possible until you know what you are looking for.
to determine lot to lot variability of the cleaning agent (as per PIC/S PI 006 - Section 7.9 Detergents, 7.9.2: The manufacturer should ensure, either by a written commitment or by a contract that he is notified by the detergent supplier of any critical changes in the formulation of the detergent.)
The issue is also stated in FDA’s Guide to Inspections of Validation of Cleaning Processes (under section VI. Other Issues, b. Detergents) . . “If a detergent or soap is used for cleaning, determine and consider the difficulty that may arise when attempting to test for residues. A common problem associated with detergent use is its composition. Many detergent suppliers will not provide specific composition, which makes it difficult for the user to evaluate residues. As with product residues, it is important and it is expected that the manufacturer evaluate the efficiency of the cleaning process for the removal of residues. However, unlike product residues, it is expected that no (or for ultra sensitive analytical test methods - very low) detergent levels remain after cleaning. Detergents are not part of the manufacturing process and are only added to facilitate cleaning during the cleaning process. Thus, they should be easily removable. Otherwise, a different detergent should be selected.”
[b]Environmental impact[/b]: This cover possible difficulty a manufacturer may face in removing the residues of the cleaning agents from the waste-water.
Use this guide to select appropriate cleaning agent for your requirement. You may develop cleaning agents in-house or may try contacting few cleaning agent suppliers and discuss the issue faced by you. As some of the suppliers are aware of the regulatory issues and may provide necessary support (such as analytical method etc.)