Compliance Case Study #3 Manual Processes, Performance, Responsibilities, and Training

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1 Compliance Case Study #3 Manual Processes, Performance, Responsibilities, and Training Paul L. Pluta, Timothy J. Fields, and Alan J. Smith IMAGEZOO/GETTY IMAGES Compliance Case Studies discusses compliance situations useful to practitioners in compliance and validation. Each case presented deals with a specific compliance problem, elements of which are described to demonstrate strategy to solve compliance problems. We intend this column to be a useful resource for daily work applications. The main objective of this column: Useful and practical information. Reader comments, questions, and suggestions are needed to help us fulfill our objective for this column. Case studies illustrating compliance issues submitted by readers are also most welcome. Please send your comments and suggestions to journal coordinating editor Susan Haigney at shaigney@advanstar.com. KEY POINTS DISCUSSED The following key points are discussed in this case study: A compliance case study involving manual cleaning, performance and responsibilities of manufacturing personnel, supervisors and quality control (QC) personnel, and training supporting all involved is discussed. The event comprised cleaning of manufacturing equipment per procedure. After cleaning and inspection by multiple personnel affirming successful cleaning, product residue was observed. Multiple issues were investigated including technical cleaning and cleaning procedures, clean equipment inspection procedures, responsibilities of supervision, QC responsibilities, documentation practices, adequacy of cleaning parameters, and the attitude of the organization toward cleaning and other quality activities. Investigation and root cause determination involved personnel interviews and cleaning procedure technical evaluation. Root cause was determined to be inadequate job performance by several individuals. Corrective action and preventive action (CAPA) addressed the specific root cause as well as implementing multiple improvements to the site cleaning procedures, equip- Winter 2010 Volume 14 Number 1 37

2 ment inspection procedure, and the site-training program including multiple training initiatives. Post CAPA activities verified and maintained the continuing success of CAPA initiatives. Other activities prompted by this event were very significant for cleaning and associated activities. These demonstrated upper management concern and commitment to maintain quality standards. INTRODUCTION This case study was provided to the Journal of GXP Compliance by a reader who requested anonymity. The circumstances describe an actual occurrence. This discussion provides the following: Background. A description of the event, the key issues to be addressed, and applicable current good manufacturing practice (CGMP) requirements. Investigation. Interviews and actions conducted to investigate the event. Discussion. Key information and analysis. CAPA. Actions and improvements implemented. These included the cleaning procedure change, equipment inspection procedure change, training on new procedures, cleaning validation, and associated activities. Post CAPA. Verifying and maintaining validation and performance. Other activities. Management involvement including policy changes. Comments and recommendations from the authors are included. BACKGROUND The circumstances of the event were as follows: Pharmaceutical manufacturing plant, end of the second shift, weekday night. Operator Jones, a recently hired, fully trained and qualified, but relatively inexperienced operator working the PM shift, hurriedly cleaned manufacturing equipment he used during his shift. Equipment included a particle size reduction mill, wet granulation equipment, and associated small parts. This equipment was used in part of the manufacturing process for a tablet product. The cleaning performed was a manual cleaning process including equipment disassembly, scrubbing with alkaline cleaning agent, rinsing with tap water, rinsing with distilled water, and drying with compressed air. After completion of the cleaning process and associated documentation per site procedure, Operator Jones requested his manufacturing supervisor to sign the cleaning record to affirm completion of the cleaning procedure and that the equipment was clean. The supervisor signed the cleaning record. Per procedure, the supervisor then requested the QC supervisor to check the equipment for cleanliness and to approve the cleaning record. The QC supervisor inspected the equipment and signed the cleaning record. When the plant re-opened the following morning for manufacturing, Operator Brown, working the AM shift, noted that multiple areas of the equipment were not clean. There were visible areas with white powder on the equipment. Manufacturing could not be initiated without re-cleaning the equipment. A representative sample of the visible residue was obtained for analysis. The AM manufacturing supervisor confirmed that the equipment was not clean. What Are The Issues? There were several critical issues involving performance that needed to be investigated in the event as follows: Equipment cleanliness. The equipment had been cleaned per procedure, but was found to have residue from previous manufacturing. Cleaning validation. The equipment was supposedly cleaned by the validated cleaning procedure. There should have not been any residue. Equipment cleanliness evaluation. The cleaned equipment was evaluated as clean by multiple individuals after cleaning (all end of PM shift), but was subsequently (next morning, 8 hours later) observed to be dirty with multiple occurrences of product residue from previous manufacturing. Supervision and management responsibility. The manufacturing supervisor affirmed that all cleaning steps were performed and evaluated the equipment as clean. QC responsibility. The QC supervisor also evaluated the equipment as clean. Training. Was the operator who originally cleaned the equipment adequately trained? 38 Journal of GXP Compliance

3 Paul L. Pluta, Timothy J. Fields, and Alan J. Smith CGMP Requirements Relevant GMP requirements applicable to the event are as follows: Subpart B Organization and Personnel Responsibilities of Quality Control Unit Personnel Qualifications Subpart D Equipment Equipment Cleaning and Maintenance Subpart F Production and Process Controls Written Procedures; Deviations Subpart J Records and Reports General Requirements Equipment Cleaning and Use Log Batch Production and Control Records Production Record Review. INVESTIGATION Investigation and ultimate resolution of this event required involvement of several groups including personnel involved in the incident (operations and QA) and technical personnel responsible for the cleaning procedure. The following details needed to be investigated: Why was the equipment dirty after cleaning? Was the equipment unusually soiled after processing causing the cleaning procedure to be ineffective? Was cleaning performed as directed in the cleaning procedure? Is the cleaning procedure adequate? Is there a technical reason for residue on the equipment? Was this a validated cleaning process? Was the cleaning procedure used in manufacturing identical to the procedure that was validated? Was the equipment actually observed to be clean after the cleaning procedure was completed? Was the equipment dry when the cleaned equipment was evaluated? When the residue was discovered, was the residue from PM manufacturing or was it contaminated with other material? What was the nature of the soil? Could the equipment have become contaminated overnight due to improper storage? What parts of the equipment were not clean? Was the equipment uniformly dirty? Were the dirty areas localized? Personnel Interviews Personnel involved in the incidence included Operator Jones (PM operator), the PM manufacturing supervisor, the PM QC supervisor, Operator Brown (AM operator), and the AM manufacturing supervisor. Operator Jones confirmed that nothing unusual had occurred associated with equipment cleaning. The equipment was not unusually or heavily soiled. All cleaning procedure steps were performed as required. Because it was late in the shift, minimum scrubbing and rinsing as specified in the procedure was performed. Jones examined the equipment after cleaning and it was clean enough for future manufacturing not perfectly clean but clean enough. There might have been some small patches of residue. Operator Jones stated that it was the responsibility of the next manufacturing group to do a final cleanup if any residue was noticed. The PM supervisor confirmed that all cleaning procedure steps were performed. He did not have time to thoroughly examine the equipment after cleaning because the work shift was already past time, and overtime pay was not allowed by management. He was sure that the equipment was clean because Jones was a good worker, so he signed the cleaning record. The PM QC supervisor did not have enough time to thoroughly examine the equipment after cleaning due to the lateness of the shift. He was sure that the equipment was clean because Jones and his supervisor already inspected the equipment, so he signed the cleaning record. The AM operator and his supervisor confirmed that the equipment was not clean when they initially examined the equipment prior to starting manufacturing in the morning. There were multiple obvious and distinct patches of white residue in various locations on the equipment. Residue was clearly visible on the granulator, particle size reduction mill, and associated parts. Technical Evaluation Technical personnel reviewed the cleaning procedure and supporting cleaning validation documentation. The Winter 2010 Volume 14 Number 1 39

4 process was almost entirely manual and dependent on performance of manufacturing personnel who clean the equipment. The procedure used in manufacturing was identical to the process that had been validated. There had been no previous occurrences of deviations, non-conformances, or other problems with this cleaning procedure. The procedure had been in use for several years without any problem occurrences. When the morning personnel noticed the presence of residue, technical people obtained a swab sample of the residue for analysis. The sample was analyzed to determine if the residue was product or another substance. The results of the analysis indicated that the residue contained product residue. DISCUSSION The interviews described were key to determining the root causes of the event. This case study demonstrates the inherent difficulty of validating and maintaining performance of a manual cleaning process in a facility with multiple manufacturing personnel. The more people involved, the more difficult it is to standardize performance. It further demonstrates the necessity of heightened vigilance by supervisory and QC personnel when performance of manual processes is involved. When manual processes are involved, adequacy of performance must not be assumed. The incident and subsequent interviews indicated fundamental failures in performance at this facility including technical cleaning and cleaning procedures, clean equipment inspection procedures, documentation procedures, responsibilities of supervision, and QC responsibilities. The number and seriousness of the deficiencies observed in this event indicated that site-specific training modules and general approach and management of training should also be reviewed. Because Operator Jones stated that he performed all steps in the cleaning procedure at a minimum level due to a lack of time, the minimum cleaning process parameters were reviewed to be sure that minimum cleaning parameters were able to adequately clean the equipment. Management s no overtime policy was implicated in these problems. Finally, the events of this case study demonstrated that an unacceptable attitude might be present in parts of the organization. Technical Cleaning And The Cleaning Procedure The discussion with Operator Jones clearly indicated that he did not understand that the objective of cleaning was to remove all residue. His statement that the equipment was clean enough for future manufacturing demonstrated his lack of understanding. He did not acknowledge that it was his responsibility to thoroughly and completely remove all residue to a level of visual cleanliness. His statement that manufacturing personnel for the next batch would clean any remaining residue before future manufacturing was initiated was contrary to basic understanding of the objective of cleaning and his responsibility to complete same. His understanding of cleaning and performance suggested a lack of oversight by his supervisor. Also, his statements suggested a possible lack of effectiveness of the site s training program regarding basics of cleaning. Clean Equipment Inspection Procedures Operator Jones, his supervisor, and the QC supervisor all affirmed that the equipment was clean when it was not. Jones did not understand the definition of clean. The others mistakenly trusted that Jones did a good job and did not carefully inspect equipment due to the lateness of the shift. Both the manufacturing supervisor and the QC supervisor blamed management policy of no overtime for rushing with their inspections. All three should have known that equipment must be thoroughly inspected, paying special attention to most difficult to clean locations in the equipment. Supervisory Responsibilities The PM manufacturing supervisor failed to adequately monitor his employee. Because Operator Jones was relatively inexperienced, the supervisor should have been especially vigilant. It was his responsibility to reinforce training, provide counsel, recommend re-training if needed whatever was necessary to maintain manufacturing and quality standards. Operator Jones, his direct responsibility, did not understand his fundamental responsibility to completely clean the equipment. QC Responsibilities The PM QC supervisor did not understand his GMP oversight responsibility in pharmaceutical manufac- 40 Journal of GXP Compliance

5 Paul L. Pluta, Timothy J. Fields, and Alan J. Smith turing. This responsibility is clearly stated in CGMP regulations. Documentation Procedures Operator Jones, his supervisor, and the QC supervisor all affirmed that the equipment was clean by their respective signatures on cleaning documentation, when the equipment was obviously not clean. All three did not understand the seriousness of fraudulently signing manufacturing documents. Training Site General Approach To Training The number of problems noted in this event and seriousness of the observations indicates a need for review and evaluation of the site general approach to training. While training is the specific responsibility of the training functional group, upper management restrictions on time, resources, personnel availability, policies, etc. may significantly contribute to these problems. Was all training read and sign or another approach? Was risk analysis applied to training? Was more intensive training applied to more critical activities? What was the frequency of re-training? Cleaning Procedure There had been no other occurrences of inadequate cleaning when using this procedure when performed by several other operators in the facility. Operator Jones stated that he performed all steps of the cleaning procedure as stated, but at a minimum level due to a lack of time. The minimum cleaning process parameters (i.e., time, rinse water volume, etc.) were evaluated by technical personnel and found to be effective. Their analysis indicated that Operator Jones did not thoroughly and completely clean the equipment (i.e., certain areas of equipment were not scrubbed) resulting in the presence of residue. All areas of the equipment must be scrubbed and rinsed in order to clean the equipment. Organizational Attitude And Culture This event demonstrated the possibility of unacceptable underlying attitude or culture in the organization. This may occur in second and third shift workers who are separated from the first shift personnel and somewhat distant from the first-shift activity and communication in the organization. Jones stated a clean enough approach to cleaning, rather than demonstrating responsibility of complete equipment cleaning. Jones, his supervisor, and the QC supervisor compromised their responsibilities because of lack of time; they were unwilling to fulfill the responsibilities when it was inconvenient (i.e., beyond their hourly shift) to do so. CORRECTIVE AND PREVENTIVE ACTIONS CAPA and associated activities were conducted on the following: Training on cleaning procedures, clean equipment inspection procedures, documentation practices, supervision responsibilities, QC responsibilities, and the site strategy and approach to training Cleaning procedure review Impact on past manufacturing. Training Cleaning Procedures Operator Jones was re-trained on fundamentals of cleaning and the specific cleaning procedure of this event. This included read-and-sign understanding of the specific procedure as well as hands-on training on the manufacturing floor. A new classroom training module was developed to educate the staff on basic cleaning requirements. The new classroom training addressed misunderstanding such as equipment was clean enough, and that it was the responsibility of future manufacturing to finish cleaning the equipment. Training Clean Equipment Inspection Procedures Operator Jones, his supervisor, and the QC supervisor were re-trained on cleaning equipment inspection procedures. Additionally, the clean equipment inspection procedure was enhanced to use additional lighting and a hand-held mirror to aid in the inspection of areas that may be difficult to access. Training Supervision Responsibilities The PM supervisor was re-trained on responsibilities of supervisory personnel. Training QC Responsibilities The QC supervisor was re-trained on the responsibilities of QC. Winter 2010 Volume 14 Number 1 41

6 Training Documentation Practices Operator Jones, the PM supervisor, and the QC supervisor were re-trained on documentation practices. This training specifically addressed signing activities that were performed and not assuming that certain activities were performed when they were not. The seriousness of fraudulently signing manufacturing records was emphasized. Training General Site management and the training group evaluated the site strategy and approach to training. Specific areas of training were prioritized by a risk management approach. Training on critical activities was enhanced. Enhancements included on-the-job training in addition to read-and-sign training. Training evaluation included consideration of training effectiveness as measured by ongoing CAPA requirements for training (i.e., the incidence of re-training as a CAPA potentially indicated that the initial training was not effective). Cleaning Procedure Review The specific cleaning procedure used in the event was reviewed. Minimum requirements were found to successfully clean equipment as long as the operator did not overlook any areas of equipment. Their analysis indicated that Operator Jones did not thoroughly and completely clean the equipment (i.e., certain areas of equipment were not scrubbed) resulting in the presence of residue. The cleaning procedure was enhanced to identify areas most difficult to clean and to emphasize thorough scrubbing and rinsing of these areas. There had been no other occurrences of inadequate cleaning when using this procedure when performed by several other operators in the facility. Impact On Past Manufacturing Past manufacturing history was reviewed. There had been no other occurrences of inadequate cleaning when using this procedure when performed by several other operators in the facility. This event had no impact on previously released product. OTHER ACTIONS Operator Jones was placed on disciplinary probation. He had completed training and was qualified to perform the cleaning procedure. However, he was a recent hire and a relatively inexperienced operator. The PM supervisor and PM QC supervisor were placed on disciplinary probation and also received additional punitive suspensions. Both PM supervisor and QC supervisor were derelict in their stated responsibilities and also falsified manufacturing documents. The PM manufacturing supervisor did not adequately monitor and supervise his inexperienced operator. The severity of these actions demonstrated management s view of the seriousness of the event. The management policy of no overtime was cited by all involved as causing them to not adequately complete their responsibilities. This policy was clarified; the no overtime policy was never intended to supersede CGMP performance. Management then approved selected exceptions to the no overtime policy. Shift supervisors were allowed to approve unplanned overtime as needed for critical tasks. Shift supervisors clearly understood that CGMP activities were paramount relative to work shift timing. This change was communicated to all employees. Management also supported recommended changes in the strategy and approach to training in the facility. This incident in which three levels of personnel were deficient in their responsibilities supported this change. A risk-based approached to training was implemented. The increased time and resources for acceptable training was acknowledged and supported by management. The incident and CAPA activities were discussed with all manufacturing and QC individuals at a plant meeting to emphasize the seriousness of the event, reinforce the responsibilities of all personnel, reinforce corrective actions, reinforce the importance of training, and demonstrate management commitment to quality principles involved. POST CAPA VERIFYING AND MAINTAINING VALIDATION AND PERFORMANCE The described actions enabled closure of the CAPA associated with this case study event. However, post event monitoring was implemented to verify success of the CAPA and maintain performance. Training for all concerned on the equipment cleaning procedures and cleaned equipment inspection procedures was required for all new personnel. Annual re-training on 42 Journal of GXP Compliance

7 Paul L. Pluta, Timothy J. Fields, and Alan J. Smith most critical procedures was implemented. The annual re-training requirement provided repeated emphasis on the importance of the cleaning procedure and inspection procedure, especially when in cases where cleaning is a manual process. Training evaluation was changed from an attendance-based evaluation (i.e., if you are present you are trained) to an effectiveness evaluation. Training evaluation included consideration of training effectiveness measured by ongoing CAPA requirements for training (i.e., the incidence of re-training as a CAPA potentially indicated that the initial training was not effective). CONCLUSIONS This case study illustrated several important points, including solution to the specific problem of the event, application to associated procedures and processes at the site, and continued verification and maintenance of corrective and preventive actions. The involvement and importance of site management was also demonstrated. The following improvements were implemented: Investigations. Investigations must be thoroughly conducted. In the presented example, a thorough investigation resulted in a defined root cause for the cleaning event, a specific solution to the identified root cause, a comprehensive solution addressing associated and contributing elements to the problem, subsequent improvements in processes and procedures, and site policy changes implemented by senior management. Correction of the identified root cause ultimately was a minor outcome of the total changes caused by the event. Cleaning procedure. Cleaning procedures that are manual or mostly manual are very difficult to validate and continually maintain, especially in large facilities with multiple workers. The improvements developed for the cleaning procedure of the specific event were then applied to other cleaning procedures at the site. Equipment inspection. This event prompted evaluation of the cleaned equipment inspection procedure, again resulting in several improvements that were applied to all equipment inspections at the site. CAPA. It was decided that all CAPA activities associated with the event must be carefully and thoroughly completed. These included training activities, cleaning inspection changes, and the impact of the problem procedure on previously manufactured lots and possible application to other cleaning. Post CAPA. Activities to verify and maintain operator performance and maintain the validated state of the cleaning program were implemented. These included enhancements to the cleaning monitoring program, cleaned equipment inspection program, and training program. These enhancements also provided timely maintenance and review of the cleaning program. Improvements. The events of this case study also resulted in a number of improvements to existing site policies and procedures. These included the specific cleaning procedure, other related cleaning procedures, and the clean equipment inspection procedure. The site strategy and approach to cleaning was modified to a risk analysis approach, in which training activities were adjusted and made appropriate to focus on most critical activities. Management. The non-capa activities associated with this event demonstrated upper management concern for the seriousness of the event and commitment to correct and support job performance and training activities as necessary to maintain quality standards. Management clarified the no overtime policy to allow exceptions for CGMP requirements. Management also supported revision of training to a risk-based approach with enhanced training on most critical activities. GXP ARTICLE ACRONYM LISTING CAPA Corrective Action and Preventive Action CGMP Current Good Manufacturing Practice GMP Good Manufacturing Practice QC Quality Control ABOUT THE AUTHORS Paul L. Pluta, Ph.D., has extensive pharmaceutical industry and university academic experience. He may be reached by at paul. pluta@comcast.net Timothy J. Fields is a validation and compliance consultant with more than 25 years of experience in the pharmaceutical industry. He may be reached by at timfields213@comcast.net. Alan Smith, Ph.D., is an independent consultant specializing in quality management and the application of CGMPs. He can be reached by at ajsconsri@aol.com. Winter 2010 Volume 14 Number 1 43