Maintenance Qualification: Improving Compliance and Performance in Pharmaceutical Manufacturing

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1 Qualification: mproving Compliance and Performance in Pharmaceutical Manufacturing This article describes an approach to management that delivers enhanced compliance for direct GMP systems and improved effectiveness for indirect or low systems. A.D. Martin Brown is a principal consultant and Jim McCabe is a sector manager at ABB Engineering Services, UK. engineers are the unsung heroes of the pharmaceutical production process. Once the project engineers have left it is the engineers who manage and mitigate the risks associated with ongoing manufacturing operations.these include risks to product integrity due to contamination or malfunctioning equipment; risks to production through poor equipment availability; risks associated with health, safety and the environment; and inspection risks arising from an inability to demonstrate that adequate controls are in place. Yet in an environment where there is increased focus on cost of production, it is often the budget that faces cuts. Where can these cuts be made without compromising current good manufacturing practice (cgmp) compliance? qualification provides documentary evidence of the controls in place to maintain cgmp, and identifies the optimum policies required for cost-effective and efficient operations. The approach is a rapid methodology used to understand the risk of equipment failure to identify the critical equipment items, that is, those items that present the greatest business risk; and to identify measures to manage the risk. These measures include: policy and practices operations policy and practices fitness for purpose 2

2 predictive technical support spares cover protective systems. By eliminating unnecessary or nonvalue-adding routines and by focussing resources on those equipment items with the greatest on business performance can enhance compliance and reduce costs and unplanned downtime (Figure 1). Methodology A key requirement of the methodology is to channel effort only on critical equipment. This is determined by assessing whether the equipment or system is GMP-critical and by further assessing the business risk of failure. The controls in place to ensure the continued compliance of GMP-critical equipment are reviewed and documented. controls for other equipment items are assessed to identify opportunities to improve reliability and make efficiency savings (Figure 2). Prescreening. With a large number of equipment items to consider, a prescreening assessment is used to improve the overall efficiency of the process. Prescreening uses the concept of positive exclusion to identify noncritical items and, thereby, reduce the load on the subsequent criticality analysis. The assessment tests all equipment items against two criteria risk and consequence using a few (typically two) simple questions. A prescreening assessment can substantially reduce the numbers of items to be assessed during criticality analysis; in some cases by 80%. mpact assessment. Following prescreening, GMP criticality is determined by a system assessment. 1 Systems are divided into direct, indirect or non systems, which are defined as follows: Direct a system that is expected to have a direct on product quality, via product contact or direct influence on quality. ndirect system a system that is not expected to have a direct on product quality, but typically supports a direct system. Non system a system Figure 1 qualification. Current regime Extent and cost of Documented procedures/processes Fully trained and enabled people Prescreening System assessment that will not have any, either directly or indirectly, on product quality. The assessment process is divided into two main activities. The first identifies the system boundaries and evaluates the of the system on the product quality. The second evaluates the criticality of the components within each direct system with respect to their role in assuring product quality. qualification. For direct systems or those indirect systems with critical components, qualification will document and review the adequacy of the controls in place to ensure system/component integrity. The equipment should not adversely affect the safety, identity, strength, quality or purity of the manufactured product, either through its construction or through contamination from other manufacturing operations. 2 Maintaining a validated state requires a formal, documented periodic review of systems and processes. The qualification con- High Direct Medium ndirect Low Noning Systems Future regime Extent and cost of Equipment availability costs Cost of ongoing compliance Figure 2 The qualification and definition process. Noncritical Detailed FMECA frequency optimization No Direct ndirect Very high qualification Criticality analysis High Spares optimization Contingency planning Low High/medium GMP spares Generic policy Generic FMEA Medium policy setting Documented equipment strategy

3 Figure 3 Failure modes. Safety (mmediate Effect) Plant tem Number R111_A Agitator Shaft failure BC122_Z1 Double Batching Hopper Blockage F101_BK Health (long Term Effect) Environment Plant tem Description Catalyst Filter JC821 HTF Chiller Spurious trip Figure 4 Criticality criteria. HSE Criticality (HSE) Quality Criticality or mpact Customer mpact Customer Criticality (C) Production Loss Rate /hr Assumed Failure Mode Bottom shaft seal failure (lip seal) frequent & catastrophic Failure Downtime hour Production Loss Annual Budget Repair Cost Additional nformation Production Criticality (P) Criticality (M) GMP Criticality (GMP) cept can be dovetailed into a riskbased periodic review process. qualification procedures automatically generate evidence that equipment and processes are under full control in line with their GMP duties and intended use. This ordered information enables the periodic review to be a check box exercise and facilitates automation of the review. Only if this high level check uncovers abnormalities or nonconformance does the periodic review progress to a more detailed level. This can lead to substantial savings in the periodic review of GMP items. The qualification process itself will be conducted in accordance with a standard operating procedure (SOP) and will address the following elements: The validation status of all relevant systems. The availability and currentness of supporting information (e.g., operating and manuals, spare parts lists, as-built drawings and equipment log books). Whether documented and calibration policies and procedures, including schedules, are established. Whether instrumentation has a valid calibration status, and if this is clearly identified and any configurable parameters are appropriate and documented. Whether equipment has, and is clearly identified as having, a valid status. Whether equipment cleaning status and content are clearly identified. Whether the and calibration records are up to date. Whether change controls are in place. Whether appropriate training programmes are in place. Documenting existing controls is a necessary, but not sufficient, part of reviewing the adequacy of preventive of equipment. The failure modes of equipment and supporting systems must be assessed to determine whether any of these situations have the potential to adversely affect the identity, strength, quality or purity of the drug (Figure 3). This approach will consider equipment failure modes, 4

4 common failure modes within systems and failure modes of supporting business processes. For example, the use of incorrect spare parts can be a source of contamination if these are in product contact applications. Such failures can occur when GMP spares are not sufficiently controlled or when suppliers provide in good faith a similar part to replace an item that is out of stock. A vulnerability analysis reviews the management of these risks for critical systems by evaluating factors such as policy and practices, predictive and protective systems to assess the adequacy of controls. The best results are achieved by using a team of operators and personnel facilitated by an experienced moderator to provide objective guidance on failure modes, guide the discussion, and maintain pace and momentum. The controls in place can be reviewed to assess their effectiveness and any recommendations for corrective actions identified. The qualification report will summarize the results of the review, comment on any deviations observed and identify any changes necessary to correct deficiencies. Criticality analysis. Business criticality analysis is applied to indirect and nondirect systems. The technique uses a range of criteria to address the areas of business risk that are considered relevant to the particular operation. A typical set is: product quality and customer criticality health, safety and environment (HSE) criticality business criticality GMP criticality. The effects of potential equipment failure modes are rated using established word models against each of the criteria enabling the overall criticality to be established (Figure 4). The criteria used to evaluate the consequences of the failures are tailored to suit the client operations; for example, what is a significant production loss or on costs? n addition to ranking the equipment according to criticality, the process also highlights the underlying issues. This information is recorded for subsequent use. An additional option for our criticality assessor is to review, for the critical items, the management of the risk, by evaluating such factors as: policy and practices operating policy and practices change control predictive technical support vulnerability protective systems. This evaluation can be completed with very little additive study time, using proven and simple word Figure 5 Management of risk. per Year Annual Failure Rate (1/MTBF) Policy & Practices Likelihood or Vulnerability Operating Policy & Practices Change Control Predictive Technical Support Weighting Vulnerability Protective Systems Care Factor Score Care Factor Likelihood (L) per Year

5 models (Figure 5). This allows critical items to be ranked, not only in terms of on operations and so on, but also in terms of how well the risk is managed. This approach identifies items where the high relative criticality comes from weaknesses in practices or hardware, rather than simply on basic potential. Following completion, the data can be rapidly sorted in a number of ways for further assessment, depending on the issues to be addressed, such as on GMP, costs or HSE. Analysis of this ranked data enables decisions to be made regarding criticality-cut points. nance instructions; and specific areas of training). At this stage, the activities, frequencies and timing are reviewed to agree and confirm that these are beneficial, cost-effective and can be resourced. Schedule mplementation Prior to implementing the agreed policies, it is beneficial to identify the readiness of the organization and the implications/requirements for implementation. The implementation itself will include the following elements: establish detailed implementation plan and milestones systems preparations (computerized management system [CMMS] and other documentation) resource preparation including contracted out service (original equipment manufacturer [OEM] or facilities management) implementation of routines identify appropriate effectiveness measures. Conclusions Manufacturing equipment must be regularly maintained to ensure that the equipment does not adversely affect the integrity of the drug substance or product; equipment is available when required for production; and to ensure safe and environmentally sustainable operations. Documentary evidence is required to demonstrate that adequate controls are in place to achieve this. qualification provides a review of the adequacy of procedures in place for direct systems as well as documenting critical factors relating to calibration, and cleaning of the equipment. For systems with indirect or no, it is possible that efficiencies may be made in the function. Business criticality analysis and definition provides a rapid methodology to establish equipment criticality, vulnerability and strategy. This targeted approach allows quick wins to be identified with the minimum input of time and resources and Definition Process The completed criticality analysis is used to guide the development of focussed and effective routines. Equipment items are identified as: High criticality failure mode and effect analysis (FMEA) studies, with and without failure mode criticality assessment (FMECA) is a well-established technique. 3,4 FMECA studies are applied to specific duty requirements to identify appropriate actions and frequencies. The technique can be timeconsuming if not done in a focussed and efficient way. Medium criticality FMEA studies can be done rapidly using existing generic studies for different equipment types. This speeds up the process considerably and avoids re-invention. Low criticality application of generic policies only or no action required. Best results are achieved by getting the right team in place, with an experienced facilitator leading the process to improve the efficiency of the study and reduce reliance on key operating and personnel. The studies will identify the following: key failure modes and the effects of the failure appropriate type appropriate activities and frequencies other required actions (e.g., operational checks operating/mainteavoiding the sticky depths of complex reliability studies. References 1. Pharmaceutical Engineering Guides for New Facilities, Volume 5: Guide on Commissioning and Qualification First Edition, March US Food and Drug Administration, Code of Federal Regulations, Title 21, Part 211, Subpart D (2004). 3. British Standards nstitution, BS5760 Reliability, Availability, Maintainability and Failure Modes and Effects Analysis (1988). 4. US Department of Defense, Military Standard Procedures for Performing FMEA (Mil-Std-1629), Washington DC (1980). 6