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CIP Cycle Development SEPTEMBER/OCTOBER 2004 PHARMACEUTICAL ENGINEERING 1 ©Copy

CIP Cycle Development SEPTEMBER/OCTOBER 2004 PHARMACEUTICAL ENGINEERING 1 ©Copyright ISPE 2004 Biotech CIP Cycle Development by Timothy Howard and Matt Wiencek This article demonstrates how the principles of ISPE's C&Q Baseline® Guide can be applied to a cycle development program at a modern biotech manufacturing facility. Figure 1. Overview of CD testing program and cleaning validation prerequisites. Introduction C IP Cycle Development (CD) is a sys- tematic approach of setting CIP sys- tems to work in a manner that pro- motes rapid and successful execution of Cleaning Validation (CV) activities. The Cycle Development program is an integral part of the overall commissioning of a facility and its processes. It is not enough to merely confirm tubing, valves, pumps, controllers, and instru- mentation are installed as designed, function- ing as specified, and within acceptable toler- ances. The act of running a cleaning cycle, and confirming the software and associated control elements respond as expected (or functional testing) does not constitute Cycle Development. All of these activities are elements that must take place prior to Cycle Development, but do not provide for development of a cleaning cycle. Cycle Development employs CIP skids that have been commissioned, and through a three step process, optimizes the cycle parameters for each cleaning circuit in the plant. A formal Cycle Development program will lead to robust CIP cleaning cycles, which in turn minimizes cleaning validation deviations, retests, and lengthy investigations of failures. The purpose of this article is to demonstrate how the prin- ciples of the ISPE Commissioning and Qualifi- cation (C&Q) Baseline® Guide can be applied to a Cycle Development program at a modern biotech manufacturing facility.1 Background Cycle Development (CD) typically occurs after CIP and support systems are mechanically complete and prior to Cleaning Validation (CV) execution. CD is one subset of activities within the overall commissioning effort. The ISPE Baseline® Guide on Commissioning and Quali- fication (C&Q) can be applied to plan and ex- ecute an organized and efficient CD program. Reprinted from The Official Journal of ISPE PHARMACEUTICAL ENGINEERING® September/October 2004, Vol. 24 No. 5 CIP Cycle Development 2 PHARMACEUTICAL ENGINEERING SEPTEMBER/OCTOBER 2004 ©Copyright ISPE 2004 This article will examine the planning of a CD program for a modern biotechnology manufacturing facility and present two case studies for execution of the plan. The case studies will examine development of a process vessel cleaning circuit and a Tangential Flow Filter (TFF) skid cleaning circuit. For the purposes of this case study, the CIP system is deemed to be a “direct impact” system as defined in the C&Q Guide.2 The CIP system includes the CIP skid, supply and return piping, process equipment, and the instrumentation used to monitor critical parameters of the cycle. Direct Im- pact systems require full commissioning prior to or inte- grated with qualification activities. The Baseline® Guide defines commissioning as: A well planned, documented, and managed engineering approach to the start-up and turnover of facilities, systems, and equipment to the End-User that results in safe and functional environment that meets established design requirements and stakeholder expectations.3 The Commissioning Program is defined by a formal Commis- sioning Plan which lists a set of deliverables. The C&Q Guide defines these as follows:4 • Commissioning Schedule • Budget, Pre-Delivery Inspection Plan, and Report • Factory Acceptance Plan and Report • On-Site Inspection Plan and Report • Functional Test Plan and Report • Commissioning Plan Summary Report. The C&Q Guide describes the activities contained in the Functional Test Plan as follows:5 • setting equipment to work • regulation and adjustment • performance testing CIP Cycle Development activities fall into the category of Performance Testing, and therefore should be defined within the Functional Test Plan of the Commissioning Program. CD requires a fully functional, integrated control system/physi- cal installation. CD may result in changes to either the physical configuration of a system or to the cleaning sequence of operations. Therefore, it should occur after the functional testing phase of commissioning, but prior to formal opera- tional qualification. Performing at least some CD before operational qualification (although perhaps not the soiled phase) will reduce the necessity for strict change control and the number of qualification deviations that may need to be processed as a result of changes to operational sequences or physical configuration – Figure 1. Developing the Plan The first step in developing a CD test plan is to define the functional boundaries. The functional boundaries can easily be defined as the individual CIP cleaning circuits. Today’s biotechnology facilities have multiple CIP skids with each one typically dedicated to a manufacturing department or subset of similar equipment. In the example discussed below, one CIP skid services each of the following areas: Buffer Prep, Media Prep, Fermentation, and Purification. Each of these CIP skids will serve multiple cleaning circuits in its respec- tive area. The exact number of circuits should be defined in a Functional Specification (FS). The number of cleaning cir- cuits is based on the amount and type of unit operations in the plant. A CIP Cycle Development Test Plan for the Buffer Prep area is defined in Table A. Similar plans should be generated for the Media Prep, Fermentation, and Purification areas. The process P&IDs will define the major equipment sys- tems (column 1 of Table A). The FS will define the CIP circuit type and the unique circuit name (column 2 and 3 of Table A). Each circuit can be designated as “unique” or “clone” (column 4 of Table A). This designation is a necessary element of the test plan for accurate resource planning purposes. For ex- ample, two identical vessels located next to one another in the manufacturing area, and served by the same CIP Skid, may be considered the same for CD purposes. The 500L Buffer Prep Vessels in Table A meet these criteria. The “unique” or “clone” designation can only be made after a careful analysis of the equipment, size, location, configuration, soil type, and cleaning chemistry. The “clone” circuits will require less CD field work because programmable recipe parameters will be copied from the unique circuit. It is important to note that a circuit considered to be a clone during CD may or may not be considered a clone when performing cleaning validation stud- ies. Generating a Schedule A facility test matrix can then be developed to aid in the calculation of manpower requirements - Table B. This is necessary for generating a realistic Commissioning Schedule as required by the C&Q Guide. Equipment CIP Circuit Circuit Unique/ Name Clone 500L Buffer Prep Vessel #1 Tank B-C01 Unique Inlet Line B-C02 Unique Outlet Line B-C03 Unique 500L Buffer Prep Vessel #2 Tank B-C04 Clone (Vessel identical to #1) Inlet Line B-C05 Clone Outlet Line B-C06 Clone 2000L Buffer Prep Vessel #3 Tank B-C07 Unique Inlet Line B-C08 Unique Outlet Line B-C09 Unique 1000L Buffer Hold Vessel #4 Tank B-C10 Unique Outlet Line B-C11 Unique 2000L Buffer Hold Vessel #5 Tank B-C12 Unique Outlet Line B-C13 Unique 2000L Buffer Hold Vessel #6 Tank B-C14 Clone (Vessel identical to #5) Outlet Line B-C15 Clone 3000L Buffer Hold Vessel #7 Tank B-C16 Unique Outlet Line B-C17 Unique Table A. Functional test plan - buffer prep. CIP Cycle Development SEPTEMBER/OCTOBER 2004 PHARMACEUTICAL ENGINEERING 3 ©Copyright ISPE 2004 CD consists of three distinct phases: water cycle testing, chemical (or cleaning agent) cycle testing, and soiled equip- ment testing. This incremental approach assures that chemi- cals are introduced into the systems only when it is safe to do so. The effectiveness of the pre-qualification soiled test runs can be measured by collecting rinse samples. The rinse sample data can be used to establish a cleaning data bank prior to starting the Cleaning Validation program. The man- power estimates per task (shown in man-days in Table B) represent the amount of time one member of the CD team will spend in the field running the CIP skid and process equip- ment. Each facility should use estimates that are particular to their site. The manpower requirements shown in Table B are estimates. The Buffer Department estimates are shown in full detail. Again, similar tables should be developed for the Media Prep, Fermentation and Purification Departments. We will assume that the overall Commissioning Plan desig- nates a three month window in which the CD must be completed. Therefore, the following staffing estimates can be developed: 205 work-days / 20 work-days/month = 10 work-months 10 work-months / 3 months permitted by schedule ~ 4 team members full time to satisfy the schedule. The initial reaction to the required field execution time for Cycle Development is typically a surprise to those not famil- iar with the CD test procedures. The amount of time neces- sary for this effort often leads to multiple shift or around the clock testing. When scheduling the CD activities, it is critical to understand resource limitations that may negatively im- pact the effort. These limitations may include the capacity of water systems to meet demand and availability of QC labora- tory coverage for testing. Most water uploads/Ingenierie_Lourd/ cip-cycle-development-sep04.pdf