Defined and consistent particle sizing and distribution is mandatory during the production of Active Pharmaceutical Ingredients (APIs) and Oral Solid Dosage (OSD) drugs. The production techniques most used to achieve this are milling, delumping, fine grinding and security screening. These techniques are used globally by pharmaceutical producers and contract manufacturers and have become the industry standard.
In adhering to today’s tight regulation and validation requirements, manufacturers have no option but to clearly define their production workflows and then follow them very closely. A key factor in these workflows is ensuring equipment is clean, reducing the risk of cross contamination. With the massive investment needed to develop and produce new products, manufacturers cannot afford to waste product ingredients that have become contaminated from dirty equipment.
More importantly, production facilities can receive severe warnings from the FDA or even be shutdown completely, due to cleaning and sterilizing validation failures.
Cleaning process development
Cleaning processes need to be developed systematically by adopting the optimum cleaning parameters for both the product and the equipment to be cleaned. Manufacturers can’t afford to base their processes purely on techniques used previously. They need to choose, adopt and optimize processes using the most appropriate parameters and cleaning agents that reduce risk to the lowest levels possible and provide a high assurance of safety to end users of the pharmaceutical products.
In addition, many pharmaceutical manufacturers produce dozens of products and can have as many as 100 pieces of equipment that all need to be cleaned and validated as clean.
Clean in place (CIP) methodology
Clean-in-place (CIP) is widely used in pharmaceutical manufacturing and is used to clean larger systems and components that are either difficult to remove from the production line, or would take too much time to fully disassemble. CIP often reduces downtime and operators use a variety of methods including the use of automated systems, spray systems and immersion.
Clean-out-of-place (COP) is often used for smaller equipment or components from larger systems that can be disassembled easily and removed for cleaning. COP is facilitated by washing manually or use of machine washers. Equipment is re-assembled after cleaning by using very specific instructions.
Sterilization-in-place (SIP), also known as Steam-in-place, is an extension of the SIP process. The sterilization of hygiene-critical processes takes place using steam at the end of the actual CIP process. SIP is completed in almost all cases by using saturated steam at a pressure of 2 bar or less for a predetermined amount of time. After sterilization, systems are cooled down by means of blowing out the system with sterile air and—in case of process vessels and other sensitive equipment—a cooling jacket is activated. After the SIP process, the functionality of sensitive components has to be carefully checked. This is most important for components like filters used in sterile filtration.
Firms manufacturing pharmaceutical products must validate their cleaning process to ensure compliance with Good Manufacturing Practice (GMP).
Cleaning validation proves the effectiveness and consistent methodology of a cleaning process. It reduces the risk of cross contamination and adulteration of drug products with other active ingredients (including microbiological contamination and unintended compounds), preventing serious issues.
Sampling techniques for cleaning validation
The most common sampling methods employed in cleaning validation are direct surface sampling, swab sampling and rinse sampling.
Sampling sites are chosen based on their accessibility, and the difficulty of cleaning them. Equipment is often characterized into hot spots, and critical sites. Hot spots are locations deemed to be most likely to become dirty or collect (trap) product and that are difficult to clean. Critical sites are those locations that if they become dirty, they will certainly show a disproportionate level of contamination to the next exhibit batch.
Direct surface sampling
Direct sampling allows for areas that are the hardest to clean but reasonably accessible, to be evaluated enabling the operator to establish a level of contamination or residue on a surface area. In addition, residues that are dried out or are insoluble can be removed and sampled.
It’s important that the type of sampling material used is determined based on its impact on the test data because in some cases the sampling material may interfere with the test. For example, the adhesive used in swabs has been found to interfere with the analysis of certain samples. Because of this, early in the validation program the sampling medium and solvent (used for extraction from the sampling medium) can be chosen based on satisfactory testing.
Swab sampling usually requires materials which are absorptive. Operators physically wipe the surface and recover the analyte. The swabs used need to be compatible with the active ingredients and not interfere with the assay.
Although it’s more difficult to evaluate larger areas, or areas that are complex in design or harder to reach, swab sampling is easily adaptable to a variety of surfaces. Operators dissolve and physically remove samples and the technique allows for sampling of a defined area.
Rinse samples allow for a larger surface area to be sampled, and inaccessible systems—or ones that cannot be routinely disassembled—can be sampled and evaluated. The sampling and testing of rinse samples for residual active ingredients is a commonly adopted method to evaluate cleanliness.
One disadvantage of using rinse samples is that the residue or contaminant is sometimes not soluble or may be physically occluded in the equipment. To further explain this, think of the analogy of a dirty saucepan in a kitchen. When a saucepan is hand washed, particularly cleaning dried out residues, the cleaner doesn’t think to look at the soapy water to see that it’s clean, they look to see how clean the saucepan is.
Therefore, operators need to check that a direct measurement of the residue or contaminant has been made for the rinse water when it is used to validate the cleaning process. For example, it’s not acceptable to simply test rinse water for water quality (does it meet the compendia tests) rather than test it for potential contaminates.
The global support team at Quadro hope that you have found this article useful. For additional information, please see: ‘Cleaning validation for pharmaceuticals, biopharmaceuticals, cosmetic and nutraceutical industries,’.
If you are a pharmaceutical manufacturer and you are looking at Quadro Engineering’s options for Particle size reduction mills and equipment (for particle milling, fine grinding, screening and delumping) please get in touch to learn more about how our products will fit into your workflow. Contact us for a free consultation today.