Challenges with Implementing Cleaning Validation

By Miguel Montalvo

Though published well over 25 years ago, FDA’s guidance surrounding cleaning validation continues to cause industry confusion. While everyone agrees that cleaning validation is critical, the application of incorrect or ineffective approaches whether by misunderstanding the purpose of validating cleaning procedures or taking an extremely conservative approach create impractical demands on resources.

Planning is the root of all successful and compliant cleaning validation programs to ensure the assessment will accurately test the desired points. These plans will include a process flow to determine the activities to be conducted starting with the development of matrices for equipment/cleaning procedure combinations for all manufactured products. The next step is to select a worst-case product for each equipment/cleaning procedure combination. It is acceptable to use product family grouping if applicable. Once the worst-case product(s) is(are) chosen, analytical methods that quantify residue levels of target components of these product must be established, including acceptable limits for the residues (also called Maximum Carryover or MACO). The CV protocol can also be prepared at this point. Also, as part of the planning stage, a review of all training programs and process for the cleaning procedures will help to ensure adequate levels of challenges and qualifications are incorporated.

Prerequisites within each protocol execution must be established before initiating cleaning validations. This includes equipment design, analytical methods, adequate cleaning procedures, employee training and calibration of equipment. Cleaning procedures appropriate to each piece of equipment must be documented in appropriate detail. It is not always necessary for the analytical methods to be specific to the chemical entity under examination. If a non-specific method that appropriately measures and quantifies residues of interest under the sampling conditions applied, it’s use may be appropriate. Non-specific analytical methods save time by a considerable factor.

It should be noted that cleaning and sanitizing are often incorrectly combined into one step. The reason these should not be combined is the differences in the purposes. Cleaning is concerned with removing the residues from the previous product (and the cleaning agent if applicable) using a worst-case dirty hold time. Sanitization is concerned with the condition of the equipment before it is used next, particularly from a microbial consideration. As a good option, many companies are establishing a sanitization process/step before using the equipment again and this step is validated separately from the cleaning validation. Or, separately they may test for the microbial bioburden in the equipment surface after the worst-case clean hold time has elapsed to see whether a sanitization step is necessary. If the test fails, the option will be to apply a sanitization step which could be as simple as a high purity water rinse or other more sophisticated processes such as a hydrogen peroxide rinse/application. Of course, these considerations will be affected by the type of product/process being manufactured – from a topical drug, oral solid dosage to the more critical sterile products, specifically those aseptically filled.

There are many considerations when designing and implementing a cleaning validation approach. Ensuring due diligence is paid to assessing and determining which factors best suit each situation will pay dividends in the long run with a thorough and well documented program.

For more information on cleaning validation, including critical missteps, you may wish to view Miguel’s full length article recently published by the International Society of Pharmaceutical Engineers blog (ISPE iSpeak). EAS offers assessment and development of cleaning validation protocols. Contact us to learn more.

Posted in 2019, 2019 June, EASeNews, Issue of the Month.