1PHARMACEUTICAL ENGINEERING NOVEMBER/DECEMBER 2013regulatory complianceRisk-MaPPRisk Assessment for Cross-Contamination in Solid Dosage Form Manufacturing Facilitiesby Mock FMEA Special Interest Group (SIG), Containment COP, and ISPE Japan AfliateThis article presents a risk evaluation method and case studies using Failure Mode and Effects Analysis (FMEA) introduced in ICH Q9 to establish cost-effective countermeasures for cross-contamination in solid dosage form manufacturing facilities.I SPE developed a Baseline Guide, Risk-Based Manufac-ture of Pharmaceutical Products (Risk-MaPP),1 using a scientifc risk-based approach to maintain product qual-ity and worker safety in order to refect the importance of quality risk management as defned by ICH Q9.2 Pro-fessionals with varied experience representing a number of pharmaceutical companies in the US, EU and Japan collaborated on the development of the Risk-MaPP Guide. The content of the Guide was reviewed by the US Food and Drug Administration (FDA) and acknowledged in the forward section of the guide.The Containment Community of Practice (COP) of ISPE Japan Affliate has been committed to the development and the implementation of Risk-MaPP from the beginning.In this article, some examples of the risk assessment based on Risk-MaPP are provided for the prevention of cross-contamination in solid dosage form manufacturing facilities and summarized in the Appendices.The four routes of cross-contamination indicated in Risk-MaPP are listed below in order of importance:Mix-Up: mix-up of API, process, potency, labeling, etc.Retention: carry over on product contact parts, failure to clean to limits of product to another product on gowning and equipment Airborne Transfer3: sedimentation of aerosols from one product into anotherWhen executing a risk assessment, it may be reasonable to leave issues related to mix-up and retention to the existing GMP and cleaning validation activities since GMP guidelines provide recommendations for prevention of cross-contam-ination. In most existing manufacturing, countermeasures for cross-contamination attributed to mechanical and airborne transfers have been based on visual inspection on non-product contact surfaces, such as containers, foors, walls, corridors and fttings. When highly potent products (as opposed to general products) are manufactured, judg-ing by visual inspection is inappropriate because visible amounts that are transferable by mechanical and airborne pathways would exceed acceptable limits for non-product surfaces. Accordingly, a risk assessment here is conducted focusing mainly on mechanical transfer and airborne trans-fer on non-product contact surfaces for highly potent prod-ucts on the assumption that there are plausible pathways by which this material could be transferred to a product being manufactured in the same area.Risk Management Tools Among the tools introduced in ICH Q9, Failure Mode and Effect Analysis (FMEA) is employed herein. As introduced in ICH Q9, FMEA enables one to establish cost-effective coun-termeasures against risks by prioritizing risks and counter-measures by relative scores.Reprinted fromPHARMACEUTICAL ENGINEERINGTHE OFFICIAL TECHNICAL MAGAZINE OF ISPENOVEMBER/DECEMBER 2013, VOL 33, NO 6Copyright ISPE 2013www.PharmaceuticalEngineering.org2NOVEMBER/DECEMBER 2013 PHARMACEUTICAL ENGINEERINGregulatory complianceRisk-MaPPRisk Evaluation using FMEA for ProcessA rule for scoring needs to be established prior to the risk assessment using FMEA and for this example as follows:1.Unit of Evaluation: a typical part of a manufacturing sys-tem including process equipment, a building and HVAC system. 2.Potential Failure Mode: mechanical transfer and airborne transfer are taken as potential failure mode herein that could lead to exposure among the four routes of cross-contamination. (The others are mix-up and retention as discussed above).3.Potential Effect(s) of Failure: patients exposure and pre-sumed adverse effects.4.Severity: scoring for the degree of the impact of exposure to patients and/or workers that is determined by the matrix of Acceptable Daily Exposure (ADE) and exposure route (Table A).5.Potential Cause(s) of Failure: lack of control, ineffective control technique, human error and equipment malfunc-tion are considered as the major factors among major causes.6.Occurrence for Process: scoring for the degree of con-tamination occurrence which is attributable to process unit operations. That is defned by the matrix of amount of airborne/residue and degree of process. The example of scoring of occurrence is shown in Table B.7. Current Controls (Detection): scoring is based on char-acters of failures (e.g., carry over, upset, and leakage) and its detection devise as shown in Table C. Failures are classifed into 1. failure that is foreseeable and avoided beforehand by detecting its root cause, 2. failure that can be detected when it happens, and 3. failure that cannot be detected when it happens. Detection devices (automatic vs. manual) provide easiness and reliability on detections of failure and its root cause.8. Risk Priority Number (RPN): RPN is a number obtained by multiplying scores of severity, occurrence and detec-tion. Limits or zones need to be established for RPN by which acceptability and correction priority can be as-sessed.FMEA Evaluation (Examples)In this article, the following two case studies for risk assess-ment based upon Risk-MaPP are discussed:Case Study 1: Weighing ProcessWeighing of materials for an anti-neoplastic agent is con-ducted in a weighing isolator as seen in Figure 1. The inside of the isolator is kept under negative pressure. Air is sup-plied to the isolator from the process room through HEPA flters and double HEPA flters are located at the exhaust port. All of the necessary equipment and sealed material containers are transported into the isolator through the Pass Table A. Scoring of severity (example).Hazard Level Exposure RouteAcceptable Daily Exposure (ADE)Mechanical TransferAirborne Transfer>10 mg/day 1 11 - 10 mg/day 3 10.01 - 1 mg/day 5 3< 10 g/day 7 5The values of severity are dened:10: Injury to a patient or employee7: Cause extreme customer dissatisfaction5: Something likely to result in a complaint3: Minor nuisance resulting in no loss1: Unnoticed and does not affect performanceTable C. Scoring of detection (sample).Failure Classication Automatic DetectionManual DetectionForeseeable failure with its detectable root cause1 3Detectable failure (Not foreseeable)5 7Undetectable failure 10 10Table B. Scoring of occurrence for process (example).Property ofOperationAmount ofAirborne/ResidueOpen Process Closed ProcessLong TermShort Term1Product Contact Parts MT (More Than) ADE or Cleaning Limit10 7 1Product Contact PartsNMT ADE or Cleaning Limit1 1 1Non-product Contact Parts2 NMT ADE or Cleaning Limit1 1 1Notes:1.Short term means less than a few seconds. The scoring table is based on the risk assessment table proposed in Baseline Guide Bulk Pharmaceutical Chemicals (Second Edition).2.In Table B, the scoring in case of MT cleaning limit at non-product contact parts is not dened. When containment system do function well, the above case could not be considered.3PHARMACEUTICAL ENGINEERING NOVEMBER/DECEMBER 2013regulatory complianceRisk-MaPPBox (PB) prior to weighing. After conducting predetermined weighing procedures in the isolator, the weighed materials are charged into a weighing container via the Split Butterfy Valves (SBV). Containers with leftover materials are put into a container via the Rapid Transfer Port (RTP) and kept in storage. Any wastes in the isolator are contained in a plastic bag through the bag-out port, removed using a safe-change system, and incinerated. When a series of process operations is completed, the inside of the isolator is manually cleaned with water by glove operation using spray guns. Case Study 2: Compression ProcessA typical rotary tablet press machine is used as an example in the second case study - Figure 2. The reason for this is be-cause such tablet press machine is suitable for mass-production and can be easily automated. Also, the weight variation of each product manu-factured by this machine tends to be small. Moreover, this machine contains generated dust and is easy to handle. These are many benefts for using this machine. A tablet press machine with rotary system is formed by several metallic punches and dies (upper punch, lower punch, and die) attached to a horizontal turntable. The turntable is rotated by a motor and while it rotates through 360 degrees, the fol-lowing series of procedures is conducted continuously: 1. powder flling a raw material powder is flled quantitatively into a cavity, 2. compression molding - compression and molding are conducted as the upper punches and lower punches rotate through the compression roll, and 3. product discharge.Materials are charged from the top of a device using supply containers and the tablet product is contained in a product container. Prior to implementation of any risk reduction measures, these contain-ers had a split butterfy valve installed to enable containment. In this scenario, the tablet press machine itself has no device to predict risks, such as device to monitor the pressure inside a machine.For the manufacturing of the anti-neoplastic products, the risk reduction measures for cross-contamination from a GMP standpoint was considered to ensure the safety of patients who take the pharmaceuticals.Figure 1. Diagram of a weighing isolator.Figure 2. Diagram of a tablet press machine.4NOVEMBER/DECEMBER 2013 PHARMACEUTICAL ENGINEERINGregulatory complianceRisk-MaPPThe FMEA evaluation examples in the risk tables could occur in the pharmaceutical manufacturing process (Tables D and E).RecommendationsIn this article, the risk assessment methodology for GMP (quality) concerns regarding cross-contamination, especially airborne and mechanical transfer mode exclusively, was Table E. FMEA (compression process, in case of ADE