Applying a Quality Risk Management Approach to a Cleaning Validation System Jesús M. Medina Master of Engineering in Manufacturing Engineering Edgar Torres, Ph.D. Industrial Engineering Department Polytechnic University of Puerto Rico Abstract Cleaning Validation is a crucial step quality of the medicine across the product life cycle on assuring product effectiveness and safety by [5]. Therefore QRM could be a powerful tool in assuring that the equipment to be used has the order to identify, mitigate a minimize occurrence of appropriate condition to manufacture a new any risk associate to final product which start when product without any foreign substances that could the equipment to be use is clean and release for use. endanger the patient to ingest this product. A quality risk management approach was used to see PROJECT DESCRIPTION possible risks on a cleaning validation system and give recommendations in order to mitigate and This project will consist in the design and control those the risks by seeking options to development of a quality risk management access does risks in an effective and reliable approach to identify, reduce and control possible manner. FDA 21 CFR 210-211 was used as a risk that could compromise the outcome of a guide for regulations regards cleaning validation cleaning process during a cleaning validation. systems. Key Terms  Cleaning Validation, FMEA, PROJECT OBJECTIVES PAT, Quality Risk Management. The project objective is to design, develop and document a quality risk management assessment on PROBLEM STATEMENT a cleaning validation system. Project Contribution In order to meet the quality expectations in the Quality – As part of the continuous search for pharmaceutical industry is crucial, the guaranteed complying and business improvement to achieve a that the equipment used in the manufacturing product that meet the requirement and regulation process, is clean and free of any undesired residue from the accreditation agencies by assuring that the that could put on risk the manufactured product. final product will be one safe and effective for the To achieve this is important to have a cleaning patients, is crucial to assure a cleaning program that validation system that validates all cleaning process compliance with regulation in a concise and within any pharmaceutical manufacturing plant. In effective manner. the last two (2) decades the cleaning process have achieved an major emphasis by both, regulatory LITERATURE REVIEW agencies and also the industrial pharmaceutical in order to have a consistent, validated manufacturing This section summarizes the most relevant process; this new emphasis has been caused by topic that will be key for the understanding of this several developments in the pasts decades for article. examples, new generation of products with a higher Cleaning Validation concentration doses, series of tragic contaminations that have as a result some serious personal injuries Andrew Walsh describe in his article among others. “Cleaning Validation for the 21ST Century: Quality Risk Management (QRM) is defined Overview of New ISPE Cleaning Guide” as a by the ICH Q9 as a systematic process assessment required activity within the pharmaceutical, in control communication and review of risk to the biological, nutritional supplement and medical device industries. The objective for any robust Ingredient (API): The main danger with this cleaning validation process is, to assure that the method of contamination is based that the product cleaning process meet the specification and becomes a multiple ingredient product and not a regulation to protect the patient safety [7]. The single active ingredient as it should be on the first basic reason to have a capable and consistent- place. The second mechanism of contamination is cleaning program is to prevent contamination final Microbiological Contamination: this contamination product produce consequently using the same has the peculiarity of develop at any time that equipment. Although cleaning validation has includes a product that was cleaned effectively. boomed in the past two decades the Food Drug This contamination involves effects on the stability Administration (FDA) has maintained the approach of the finished product. Storage of equipment in to ensure the cleanliness of the equipment used in wet condition provides a natural medium for any manufacturing process before being performed, bacteria to grown. The third mechanism of as the 1963 GMP Regulations (Part 133.4) stated contamination is Contamination by Cleaning or “Equipment shall be maintained in a clean and Sanitizing Agent: In some manufacturing cleaning orderly manner” (FDA, First USA GMP process a detergent may be need in order to clean Regulation, 1963). Today in the FDA Code of the equipment. It is important to be aware of the Federal of Regulation (CFR) has regarding cleaning composition of the detergent to be used. The four programs the following requirements [4]. mechanism of contamination is Contamination by • 21 CFR 211.65 “Equipment shall be Miscellaneous Other Material: Excipient, bristles constructed so that surfaces that contact from brushes, paper filters, micron filter among components, in-process materials, or drug other can be a possible source of contamination products shall not be reactive, additive, or depending of the nature of the product being absorptive so as to alter the safety, identity, manufacture [2]. quality, or purity of the drug product beyond The Cleaning Validation process consists of 4 the official or other established requirements.” stages [8]. In the first stage the first step is to • 21 CFR 211.67 (a) “Equipment and utensil determine the most appropriate cleaning procedure shall be cleaned, maintained, and, as for the equipment. During this step the acceptance appropriate for the nature of the drug, sanitized criteria data for the contaminant will be generated. and/or sterilized at appropriate intervals to Then the process, equipment the cleaning agents prevent malfunctions or contamination that and the cleaning techniques available, will would alter the safety, identity, strength, determine the cleaning method. Finally all aspects quality, or purity of the drug product beyond of the cleaning procedure should be clearly defined the official or other established requirements.” in de the Standard Operation Procedure (SOP) • 21 CFR 211.167 (b) “Written procedure shall Cleaning In Place (CIP) or Cleaning out of Place be established and followed for cleaning and (COP) equipment. The second step is to develop maintenance of equipment, including utensils, and validate the sampling and chosen analytical used in the manufacture, processing, packing, methods for the compounds(s) being cleaned. or holding of a drug product.” During this step is important to decide is the • 21 CFR 211.180-182 “Records shall be kept of sampling will be gather by swabbing the surface or maintenance, cleaning, sanitizing and by a sampling of the rinse during cleaning, this inspection.” depend of the kind of product and the equipment to be cleaned. Also is important to determine the There is four (4) mechanisms of contamination percent of recovery, the limit of detection limits of that can be found of products with a poor cleaning quantitation, accuracy of method, the process that could affect the patient (Hall, 2003): reproducibility, and the stability over time among First is Cross – Contamination with Active other process. The third step of stage one is to Risk assessment consists of the identification evaluate equipment surfaces and determine the of hazards and the analysis and evaluation of risks worst-case location to sample (swab sampling), the associated with the exposure to those hazards. volume and type of rinse solvent to be employed Risk identification is a systematic use of (rinse sampling) and the equipment surface area, information to identify hazards referring to the risk which is necessary to calculate carryover into question or problem description. subsequent batches. Risk Analysis is the estimation of the risk The second stage of the cleaning validation associated with the identified hazards. It is the process consists in developing a cleaning validation qualitative or quantitative process linking the protocol for the product and the equipment being likelihood of occurrence and severity of harms. cleaned. This protocol should include: an Risk Evaluation compared identified and introduction, the scope of the validation to be analyzed risk, against given risk criteria. It performed, the equipment that will be cleaned, the considers the strength of evidence for all three of cleaning procedure to be validated, the sampling the fundamental questions. procedures, the analytical testing procedure, the Risk control purpose is to reduce the risk to an Acceptance limits, and the acceptance criteria for acceptable level. The final decision might be the validation to be performed. obtained by the use of different processes, which The third stage of the cleaning validation includes benefit-cost analysis, for understanding the process is the development of the interim report. In optimal level of risk control. this report the goal is to generate an interim Risk reduction focuses on process for cleaning validation report on a clean by clean basis mitigation or avoidance of quality risk when it detailing the acceptability of the cleaning procedure exceeds a specified level. It might include actions for the equipment and the product. This stage is taken to mitigate the severity and probability of required is there is a long period of time between harm. Process to improve the detectability of risks manufacture and validation runs. might be used as part of the risk control strategy. Risk reduction implementation reduction measures Quality Risk Management could introduce new risk into the system or increase Quality Risk Management (QRM) is defined the significance of existing risks. by ICH as a systematic process for the assessment, Risk Acceptance is a decision to accept risk It control, communication and review of risk to the is important to understand that for some types of quality of the drug product across the product harm, even the best QRM practices might not lifecycle [5]. eliminate risk entirely [5]. The basic steps used to initiate and plan a Risk Communication is the sharing of QRM process includes the following (ICH, Quality information about risk and risk management Risk Management Q9, 2005): between the decision makers and others. • Define the problem and/or risk question. Some tools that could be uses as part of a QRM are • Assemble background information and/or data [5]. on potential hazard, harm or human health • Basic risk Management facilitation methods impact relevant to the risk assessment. (flowchart, check sheets, etc.); • Identify a leader and critical resources. • Failure Mode Effect Analysis (FMEA); • Specify a timeline deliverables and appropriate • Fault Tree Analysis (FTA); level of decision making for the risk Process Analytical Technologies management process. FDA considers Process Analytical Technologies (PAT) to be a system for designing, analyzing and controlling manufacturing through historical data or in time data from the timely measurements of critical quality and organization. performance attributes of raw and in-process • Analyze: On the analyze phase the goal is to materials and process, with a goal of ensuring final identify the root causes in the process that are product quality. It includes chemical, causing the process to not meet the desire microbiological, mathematical, and risk analysis in output. an integrated manner. The main purpose or goal of • Improve: On the improve phase the goal is to PAT is to enhance understanding and control of look for innovative initiatives to eliminate or manufacturing processes that is consistent with the minimized the root causes that are causing the current quality system: quality cannot be tested process not to meet the desire output and intro products; it should be by design [3]. measure that improvement. • Control: On the control phase the goal is to Lean Six Sigma develop a control plan that assure the Lean and Six Sigma are a combination of the continuity of the improvements made on the methodology of Lean Manufacturing and Six process and to help identify future problem that Sigma that looks for elimination activities that add could occur on process as part of the no value and reducing the variation of any process. continuous improvement mentality. Lean manufacturing is as a systematic identification and elimination of wastes; the METHODOLOGY implementation of the concepts of continuous flow; The Methodology to be used during this and customer pull. Waste or activities that add no project will be the DMAIC methodology. This value in a process that lean manufacturing defined methodology is define in 5 phases as previously in seven (7) major areas: overproduction, inventory, discussed in the literature review and consist on the waiting, motion, transportation, rework, and over define phase, the measure phase, the analyze phase processing [6]. the improve phase and the control phase. Six Sigma is a highly disciplined process that During the Define phase a CTQ diagram will focuses on developing and delivering near-perfect be develop to focus on the most critical areas in products and service consistently. Six Sigma is which the QRM needs to assess risk with the bigger also a management strategy to use statistical tools impact in the achievement of compliance on the and project work to achieve breakthrough cleaning validation system. Finally this phase will profitability and quantum gains in quality. The end with a SIPOC Diagram to help us have a high- main purpose of Sig Sigma is the variation level understanding of the scope of the process and reduction of process in other to have a consistent to give us the key outputs of the process. quality final product [6]. During the measure phase it will be decided the Six Sigma and Lean Six Sigma phases on most possible risks and its ranking system to be used for organizations is describes as DMAIC. DMAIC is the QRM of the cleaning validation system. an acronym for define, measure, analyze, improve During the analyze phase 3 FMEA will be and control These 5 phases can be described as performed in order to analyze the most critical risks follows: and would it be their impact to the cleaning • Define: On the define phase the goal to seek is validation. The first FMEA will be using as an to define in a way that can be measure the example a 100% manual process; the second one problem (Y’s) to be improve. will be for a CIP process; and the last one will be • Measure: On the measure phase the goal is to for a COP Process. measure the current state of the process in an The improve and control phase will focus on objective and well-planned manner using even PAT strategies recommendation that could be implemented in a cleaning validation system focusing more on CIP and COP to increase efficiency a reliability of the process. Also another recommendation to mitigate the risks defined in the FMEA’s. This is the key on controlling the process and assures the reliability of the process going forward. RESULTS Define Phase A CTQ was used to assess the critical attributes needed to be address during a cleaning validation system in order to assure compliance with the regulator agency to assure the elimination of Figure 2 residues for API, Excipients, detergent or any SIPOC Diagram for Cleaning Validation System. miscellaneous that could affect the security, Measure integrity, potency purity and quality of the product Risk Assessment/Control Acceptability: as specified on cGMP’s CFR 21 part 210 and 211 Risk Assessment: for pharmaceutical products. Refer to Figure 1 for Based on the Critical to Quality Diagram, Cleaning Validation CTQ diagram. potential risks are asses to meet these regulatory requirements necessity to comply in order to achieve an effective cleaning validation system. Risk Control: The risk associated will be evaluated based on the FMEA assessment of severity, occurrence and detectability. Failure mode and effect analysis (FMEA) is a risk management tool that provides an evaluation for potential risk in a process/product. Risk Acceptability: Risk priority number (RPN) will be used to Figure 1 characterize risk. CTQ Diagram for Cleaning Validation System  RPN= Severity X Occurrence X Detection. A SIPOC diagram was used in order of  ALARP= “As Low As Reasonable Possible”. develop a better understanding of a cleaning A pharmaceutical consultant company program and identify key output crucial for the quantitative and qualitative ranking/risk indexing to compliance and efficiency of the cleaning rank severity occurrence and detection will be used validation system process that help us in the to rank the 3 FMEA of cleaning validation system identify the best strategy to used and what is needed for the 3 cleaning process to be addressed. This to apply this strategy. Refer to Figure 2 for three (3) process are: a 100 % manual cleaning Cleaning Validation SIPOC diagram. process; a CIP cleaning process; and a COP cleaning process. Refer to table 1, table 2, and table 3 for information regarding severity, occurrence and detection respectively. Table 4 is the risk acceptability table that will determine the risk is Table 4 Risk Accessibility Table tolerated or not. Table 1 Severity Classifications Analyze Three (3) FMEA were performed to asses, characterize and evaluate the risk on the following cleaning systems: a 100% manual cleaning process, a CIP process and a COP process. Refer to Tables 5, 6 and 7 for the FMEA results. To ascertain the ranking process of a cleaning validation system the help of the same pharmaceutical consulting company was used during the FMEA’s developing and analysis. Note: To refer to Severity, Occurrence and Detection on the following tables the letters S, O and S was used. Table 5 100% Manual Cleaning Process FMEA [1] RISK S O D RPN Incomplete 9 4 6 216 SOP Wrong Acceptance Table 2 Criteria (API 60 Occurrence Classifications Residue, 10 3 2 Temperature, Toxicity) Untrained 8 4 3 96 Personnel Wrong Water 9 2 1 18 Quality Wrong 10 2 1 20 Retention Time Lack of 8 5 1 40 Equipment Calibration 9 3 1 27 Problems Table 3 Failed Cleaning 7 6 1 42 Detection Classification Prolonged 5 7 3 105 Downtime Personnel 10 1 1 10 Injury Table 6 CIP Cleaning Process FMEA [1] RISK S O D RPN Incomplete 9 4 6 216 SOP Wrong The results decision of the FMEA’s performed are Acceptance showed in the following tables: Criteria (API 10 3 2 60 Residue, Table 8 Temperature, 100% Manual Cleaning Process Risk Accessibility Toxicity) Risk Accessibility Untrained 8 4 3 96 Incomplete SOP Intolerable Personnel Wrong Acceptance ALARP Wrong Water 9 2 1 18 Criteria (API Residue, Quality Temperature, Toxicity) Wrong 10 2 1 20 Untrained Personnel ALARP Retention Time Wrong Water Quality ALARP Lack of 8 5 1 40 Wrong Retention Time ALARP Equipment Lack of Equipment ALARP Calibration 9 3 1 27 Calibration Problems ALARP Problem Failed Cleaning Broadly Equipment 9 5 1 45 Acceptable Malfunction Prolonged Downtime ALARP Failed Cleaning 7 6 1 42 Personnel Injury ALARP Prolong 5 7 3 105 Downtime Table 9 Personnel 10 1 1 10 CIP Cleaning Process Risk Accessibility Injury Risk Accessibility Incomplete SOP Intolerable Table 7 Wrong Acceptance ALARP COP Cleaning Process FMEA [1] Criteria (API Residue, Temperature, Toxicity) RISK S O D RPN Untrained Personnel ALARP Wrong Water Quality ALARP Incomplete Wrong Retention Time ALARP 9 4 6 216 SOP Lack of Equipment ALARP Wrong Calibration Problems ALARP Acceptance Equipment Malfunction Broadly Criteria (API Acceptable 10 3 2 60 Residue, Failed Cleaning Broadly Temperature, Acceptable Toxicity) Prolonged Downtime ALARP Untrained Personnel Injury ALARP 8 4 3 96 Personnel Wrong Water Table 10 9 2 1 18 Quality COP Process Risk Accessibility Wrong Risk Accessibility 10 2 1 20 Retention Time Incomplete SOP Intolerable Lack of Wrong Acceptance ALARP 8 5 1 40 Equipment Criteria (API Residue, Calibration Temperature, Toxicity) 9 3 1 27 Problems Untrained Personnel ALARP Equipment Wrong Water Quality ALARP 9 5 1 45 Malfunction Wrong Retention Time ALARP Failed Cleaning 7 6 1 42 Lack of Equipment ALARP Prolonged Calibration Problems ALARP 5 7 3 105 Downtime Equipment Malfunction Broadly Personnel Acceptable 10 1 1 10 Injury Failed Cleaning Broadly Acceptable technique based on the size and shape of molecular Prolonged Downtime ALARP ions. Personnel Injury ALARP Both techniques has showed success on detecting API, Detergent and Excipient residues as Improve and Control Recommendation shown in the Excellims article “Electrospray The FMEA’s showed that an incomplete Ionization- High Performance Ion Mobility standard operation procedure (SOP) is the only Spectrometry for Rapid On-site Cleaning intolerable risk following the acceptance criteria Validation in Pharmaceutical Manufacturing” and used for this analysis. It important to understand the Patrick J. Cullen, Ph.D., Ian Jones, Laura that an SOP is critical for any process because is Alvares-Jubete, Ph.D., Jaya Mishra and Carl the document that will be followed on the execution Sullivan, Ph.D article “Cleaning Validation Using of any process. As a recommendation to minimize Direct NIR Imaging”. the occurrence of this risk it will be helpful to apply Excellims results showed a robust way to the following steps: analyze 14 API’s drug molecules using HPIMS.  Assure that all the important process step will Cullen, Jones, Alvares-Jubete, Mishra and showed be including on the document. a lineal model with a R2 of 96% and 99% of  Use visual aids to ease the understanding of the detection for 2 different API. execution. A PAT constraint is in Microbiology analysis  Develop a checklist with all the information because of the bacterial grown time needed in order that an SOP needed in order to execute the to obtain an effective analysis of any microbial process successfully. activity.  Use a Video showing how the process needs to be executed for training and analysis purposes. CONCLUSION  Review at least every 6 months and ask the QRM approach is an effective systematic personnel executing the procedure their approach that allows us to manage risks and seeks feedback and recommendation for for way to mitigate, eliminate and control them. improvement if needed. QRM on a cleaning validation system helped us In addition is important to assure an effective understand risk and how critical their effect could sampling method that help to assure the cleaning be on compliance, effectiveness and reliability of process. PAT is a useful approach to develop a the cleaning process in order to obtain a cleaning robust analytical process for times to come. As process that meet regulatory agencies and safety previously discussed PAT stands for Process requirements while being profitable for the Analytical Technologies and is define as a system company. PAT is helpful in order to obtain a for designing, analyzing and controlling robust analytical method to assure the effectiveness manufacturing through timely measurements of of a cleaning process by giving the ability of critical quality and performance attributes of raw sample the hall cleaning area and giving us if and in-process materials and process, with a goal of implemented correctly a useful tool to obtain ensuring final product quality. analytical on time data that help on the assurance Examples of PAT used today to help assures an and compliance of a cleaning validation process. effective cleaning process are NIR and HPIMS. NIR spectroscopy is defined as a measurement REFERENCES system of the wavelength intensity of the [1] Leblanc, D,A. ”Validated Cleaning Technologies for absorption of near-infrared light by a specific Pharmaceutical Manufacturing”, Interpharm/CRC, Boca sample. 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