Like-For-Like Changes: Is Validation Testing Needed? Validation Case Study #7

Paul L. Pluta] Like-For-Like Changes: Is Validation Testing Needed? Validation Case Study #7 Paul L. Pluta Validation Case Studies discusses validation situations useful to practitioners in validation and compliance. Each case presented deals with a specific validation problem, elements of which are described to demonstrate strategy to solve validation problems. We intend this column to be a useful resource for daily work applications. Reader comments, questions, and suggestions are needed to help us fulfill our objective for this column. Please send your comments and suggestions to managing editor Susan Haigney at shaigney@advanstar.com. KEY POINTS DISCUSSED The following key points are discussed: Change control is a critical activity in regulated pharmaceutical manufacturing. Changes to manufacturing processes, formulations, equipment, cleaning procedures, analytical methods, and other systems are evaluated based on risk or impact. Appropriate validation or qualification work is then prescribed. Like-for-like changes are usually considered to be minimal changes not requiring confirmatory validation testing. This discussion addresses situations in which likefor-like changes did not perform as expected due to incorrect installation of the replacement equipment. Several actual occurrences are described. Faulty installation of like-for-like equipment resulted in serious consequences for the manufacturing site. The site validation approval committee (VAC) should evaluate all changes, including like-for-like changes, to standardize evaluation and decision processes, and to carefully consider associated risks. Emergency changes may be approved as needed by maintenance or other management. However, these changes should ultimately be reviewed by the VAC for final disposition. Documentation attesting to correct installation of high-risk, like-for-like equipment can be accomplished by simple approved memo. This approach provides certainty of successful installation while reducing burdensome documentation requirements. Engineering and maintenance activities should have clear and defined procedures for like-for-like equipment replacement. Personnel should be cautioned against cutting corners due to business pressures. Validation and compliance personnel should be wary of supposed inconsequential like-for-like changes and ensure that such equipment in highrisk applications is properly installed including appropriate documentation. For more Author information, go to gxpandjvt.com/bios [ABOUT THE AUTHOR Paul L. Pluta, Ph.D., is a pharmaceutical scientist with extensive technical and management experience in the pharmaceutical industry. He is also adjunct assistant professor at the University of Illinois at Chicago (UIC) College of Pharmacy in Chicago, Illinois USA. He may be contacted by e-mail at paul.pluta@comcast.net. gxpandjvt.com Journal of Validation Technology [Spring 2011] 73

INTRODUCTION Change control is a critical component in regulated pharmaceutical manufacturing and quality systems. Changes to manufacturing processes, formulations, equipment, cleaning procedures, analytical methods, and other systems are evaluated based on risk or impact. Complicating these judgments are emergency situations when changes must be made to maintain operations without proactive thorough evaluation of risk or impact. Risk evaluation of change is a critical determination. At one extreme, changes may be significant representing a high risk to continuing critical processing or other operations. Such changes require full validation or qualification. At the other extreme, changes may be completely insignificant with minimal risk to patient, product, process, or equipment. Like-for-like changes are often judged to be changes in this latter category. Like-for-like changes are minimal changes made to processes, equipment, utilities, facilities, computers, or other systems. Like-for-like changes are usually judged to be equivalent replacements. Often these changes are identical replacements of the original item of interest. Some may not consider like-for-like changes to be an actual change. A replacement motor, replacement screen, replacement filter bag, replacement piping, and so on are often routine maintenance on validated or qualified equipment, and not really an actual change. Like-for-like changes are thought to not require any subsequent testing. Typical logic is that because the original equipment or system has already been validated, and because nothing has really changed, why the need to do new validation work? Why waste time or effort when nothing has changed? Isn t that the problem with validation doing too much unnecessary work? This discussion addresses situations in which like-forlike changes did not perform as expected. Several validation managers presented examples of such situations at international validation conferences. The occurrences described are actual incidents. Examples described demonstrate the broad scope and significant magnitude of potential problems with like-for-like changes. The following discussion includes: Background. The typical validation or qualification process is described. Compliance events. Descriptions of several actual like-for-like validation events. What are the issues? What happened to cause these problems? Corrective action and preventive action (CAPA). Recommended actions and improvements to prevent future problem occurrences. BACKGROUND The process of validation or qualification typically comprises the following sequence of activities: 1. Change desired. A new product or process, process change, or equipment change is needed or required. This may be a necessary change, a desirable improvement, emergency work, or routine maintenance. 2. Support pre-work. Appropriate pre-work is completed in advance and supporting the change. This work may range from highly complex and far-reaching (e.g., new process development, new equipment purchase, factory acceptance testing), to very minimal (e.g., selecting and ordering a minor replacement part). 3. Validation or change request. A formal request to initiate the validation process is submitted to the validation approval committee (VAC). Support work reports may be included in the request in support of the change. The change request may include a proposed level of work to confirm the acceptability of the change. The level of work is based on risk to the patient and to the organization. The VAC approves the validation request. 4. Validation plan. Depending on the scope and magnitude of the validation request, a validation plan may be submitted. This plan describes the validation work required in greater detail, appropriate testing and sampling proposed to demonstrate a successful change, and acceptance criteria for the recommended testing. The VAC approves the validation plan. 5. Validation protocol. A protocol is written specifying detailed sampling and testing to confirm the acceptability of the change. The VAC approves the validation protocol. 6. Validation work. Validation work is performed according to the protocol. Sampling and testing are completed. Data and other results are generated and recorded. 7. Validation report. A report containing all test results with discussion and conclusions is prepared and submitted to the VAC for approval. The report is approved, and the process or equipment change is implemented. An appropriate level of post-validation monitoring is proposed in the report. 8. Validation closure. If no other work is needed, the validation project initiated by the change request is closed. 74 Journal of Validation Technology [Spring 2011] ivthome.com

Paul L. Pluta. 9. Emergency changes. In cases of emergency changes, management may authorize changes to be completed as needed apart from the abovedescribed process. Emergency changes should be evaluated by the VAC as soon as possible. Supporting documentation is then completed to confirm the acceptability of the change and submitted to the VAC for approval. 10. Documentation. All relevant documentation described (activities 2-9) including supporting pre-work should be stored in the validation library or readily accessible through a knowledge management system. 11. Continued verification. Post-validation monitoring confirming acceptability of the change continues throughout the lifecycle. The issue addressed in this case study occurred in step number three, the validation or change request, which initiates the formal documented validation process. Emergency changes may also have application in this discussion. Specifically, changes requested were judged to be like-for-like changes that should have had no impact on the process or equipment. Because no impact was expected, no testing or other work was recommended by the VAC (or by management) as part of the change. Like-for-like replacement work was authorized and completed. Work was documented on equipment history logs, maintenance records, or other systems in accordance with site procedures. VALIDATION EVENTS A discussion with several validation managers regarding problems with validation activities indicated that like-for-like changes were a recurring problem. In general, changes are defined as like-for-like to eliminate additional validation work. The definition of like-forlike may be broadly interpreted in these cases and in some cases, too broadly interpreted. Occasionally, these judgments and ensuing problems had significant consequences. Several actual examples described by managers demonstrated such events. Personnel responsible for these like-for-like judgments did not realize the potential problems caused by their judgments. Laminar Air Flow in Aseptic Processing Facility One manager described an incident in which routine revalidation of an aseptic filling line was being performed. All activities and tests were performed according to procedure, including sterilizer revalidation, media runs, interventions, and so on. All results were acceptable and as expected until the filling line smoke test was conducted. The smoke test confirms the laminar airflow direction in the aseptic suite. All involved were shocked when the airflow was shown to be upward toward the HEPA filter instead of downward through the filter toward open product. Room and equipment history records were checked. The only activity performed in the area that could have caused this event was the installation of a like-for-like replacement blower motor by the site maintenance shop several months prior. HEPA filtration of room air had thus been compromised for several months, during which time multiple product lots were manufactured. These lots had passed all product testing and were released to commercial distribution. The US Food and Drug Administration was notified. All lots manufactured during the time period when the blower motor was operating incorrectly were recalled. Aside from this incident being highly embarrassing to the organization, the recall costs involved were significant. Milling Solids for Tablet Products Another manager described an incident in which major processing problems with several tablet products occurred. This event occurred in a large manufacturing facility that produced multiple solid dosage forms (e.g., tablets, capsules, granules, powders). Occasional product processing problems were observed with several products. As these individual incidents became more frequent, investigations were initiated. The problem was eventually associated with particle size distribution changes. Blended granulations had smaller particle size distributions than expected when compared to historical data. Eventually these problems were associated with processing using a specific impact mill. When operation of the mill was investigated, it was found that the mill was running in the reverse direction compared to other mills at the site. This caused incorrect milling of solids and improper particle size distributions. Equipment history records were reviewed. The only activity performed that could have caused this event was the installation of a like-for-like replacement motor. The motor change was correlated to the first report of process problems at the site. Problems were associated with milling of large quantities of drug and inactive ingredients for respective lots. gxpandjvt.com Journal of Validation Technology [Spring 2011] 75

Cell Culture Agitation Another validation manager described an event in which the cell growth in a biotechnology process was significantly lower than the historical average when cultures were grown in a specific manufacturing tank. Because this product was a high volume product that was made in multiple tanks, the lower growth was not immediately obvious. As more low growth batches were manufactured, it became apparent that low yields were being consistently produced in a single tank. Equipment history records for the suspect tank were reviewed. The only work performed on the tank as documented in the equipment history log was the installation of a replacement motor on the mixer. The motor change was correlated to the first report of lowered growth and subsequent batches thereafter. When operation of the tank was thoroughly investigated, it was found that the impeller was running in the reverse direction compared to the original installation and compared to other tanks at the site. This effect significantly altered the mixing profile of the cell culture, resulting in reduced cell growth and active pharmaceutical ingredient yield. WHAT ARE THE ISSUES? In each of the events presented, a like-for-like change was performed without need for any confirmatory testing. Identical replacement equipment was available for each of the changes. All personnel involved believed that installation of replacement equipment was inconsequential and would be done correctly. The problems observed were completely unexpected. In each case, the like-for-like change was considered to be insignificant. Additional testing to verify acceptable equipment installation was not prescribed. Although the like-for-like equipment selection was accurate and acceptable, installation of the equipment was not. Faulty installation resulted in serious consequences for the manufacturing site and the organization. In the aseptic HEPA filter incident, a significant recall of product released to the marketplace was required. CORRECTIVE AND PREVENTIVE ACTIONS The incidents presented herein caused each validation manager to make changes in the change control review process at their respective manufacturing sites. Some of their comments and suggested approaches are described as follows. Validation Approval Committee Review of All Changes Validation managers agreed that all changes, including like-for-like changes, should ultimately be evaluated by the site VAC. Having all changes reviewed by a single responsible group (VAC) standardizes evaluation and decision processes. Consideration for risk to patient and organization and ensuing judgments should be uniformly conducted by the VAC. Appropriate confirmation that like-for-like equipment is properly installed would then be based on VAC judgment. In many cases, additional confirmatory work would not be required. For example, verification of a correctly-installed replacement conveyor belt motor is not necessary; if the motor was installed incorrectly and the conveyor is going backwards, the problem would be easily observed. The only like-for-like changes requiring verification are those in which installation errors would not be obvious during operation (e.g., reversed laminar air flow). In some organizations, maintenance management has the final and complete authority to judge whether or not validation of a change under their auspices is required. This practice should be limited to initiation of emergency changes only. If a change is like-for-like in the judgment of maintenance management, the emergency work should be initiated as soon as possible. Work should then be documented in equipment history logs or other site documentation systems. Completed emergency changes should then be evaluated by the site VAC. Completed changes are then evaluated based on work done and risk to patient and organization. Appropriate confirmatory work would then be prescribed. Maintenance management should be permitted to authorize emergency changes. All changes ultimately should be reviewed, evaluated, and judged by the site VAC. The VAC judgments are documented in the usual manner. Acceptability of changes is the ultimate responsibility of the VAC. Validation Documentation Requirements Protocols should not always be required to confirm acceptability of a like-for-like installation. A simple written memo with appropriate review and approval attesting to correct installation of replacement equipment should be sufficient to complete the work. The memo should include a statement that correct equipment operation had been confirmed by a second individual. Management of the responsible group (e.g., maintenance, engineering, others) and the site quality assurance (QA) department should approve 76 Journal of Validation Technology [Spring 2011] ivthome.com

Paul L. Pluta. the memo. The approved memo would then be filed with the validation request to close the like-for-like activity. This documentation approach accomplishes the need to verify high-risk installation without the encumbrance of validation protocols, excessive approvals, and other burdens. Some managers have successfully implemented this approach for certain high-risk changes. No additional verification documentation (other than equipment history, etc.) was required for insignificant like-for-like changes or for changes in which correct installation was apparent by obvious faulty equipment operation. Procedures and Training The above approaches to decision-making and documentation should be specified in approved procedure. Specifying the acceptability of such confirmatory documentation provides flexibility to accomplish verification without the burden of excessive protocol requirements. All associated individuals in technical functions, validation personnel, maintenance management, VAC members, and QA personnel should be trained on the new procedure. Equipment Installation and Maintenance Procedures Validation managers commented that engineering and maintenance areas must have clear procedures for like-for-like equipment replacement. Procedures must be maintained and strengthened as needed when incidents occur. New personnel should be made aware of events such as those presented herein and be cautioned about cutting corners. Business and operation pressures often demand rapid work from these groups. Personnel must understand that proper equipment installation must never be potentially compromised. Senior Management Support Validation managers reported that their respective site senior management was supportive of the above approaches. Validation managers reported no similar faulty installation incidents after implementation of the new verification procedure. CONCLUSIONS This case study describes several examples of improper installation of like-for-like equipment that caused significant problems for the manufacturing site. Likefor-like changes are generally assumed to be of no consequence. However, improper installation of such equipment can have serious ramifications including product recalls. Validation managers agreed that all changes, including like-for-like changes, should be evaluated by the site VAC to standardize evaluation and decision processes. Documentation requirements attesting to correct installation of high-risk, like-for-like equipment can be accomplished by a simple approved memo that is filed with the documentation request. This approach provides certainty of successful installation without undue documentation burden. Engineering and maintenance procedures for like-for-like equipment replacement must be clear. Validation and compliance personnel should be wary of supposed inconsequential like-for-like changes and ensure that such equipment in high-risk applications is properly installed. JVT gxpandjvt.com Journal of Validation Technology [Spring 2011] 77