Reprinted from PHARMACEUTICAL ENGINEERING® The Official Magazine of ISPE CIP Cycle Development September/October 2006, Vol. 26 No. 5 This article presents case Biotech CIP Cycle Development: study examples of CIP cycle Case Study Examples Utilizing QRM development activities and lessons learned by Matt Wiencek from several modern biotechnology facilities. The CIP Cycle Development Clean-In-Place (CIP) Cycle Develop- producing adulterated drug products. There- program ment (CD) program for a large scale fore, QRM principles can be applied to CIP CD biotech manufacturing facility was de- and CV to identify important risk factors to be incorporates scribed in the September/October 2004 eliminated or minimized to acceptable levels. aspects of Aissue of Pharmaceutical Engineering. A three How then might QRM be used to develop a Quality Risk stage program of water, chemical, and soiled CIP CD program and validated cleaning cycles? Management CIP CD and a project execution strategy utiliz- Annex I (Risk Management Tools and Meth- ing the ISPE Baseline® Commissioning and ods) describes several structured approaches to (QRM) to meet Qualification Guide were presented. The pur- QRM. Formal methodologies can be applied, the needs of the pose of the CIP CD program was to identify and including Failure Mode Effects Analysis biotechnology resolve cleaning challenges prior to beginning (FMEA), Failure Mode Effects and Criticality industry in the Cleaning Validation (CV) program. This Analysis (FMEAC), and Hazard Analysis and follow up article will present practical case Critical Control Points Analysis (HACCP). Case today’s study examples and describe the manufactur- study examples of these structured risk assess- regulatory ing efficiencies gained. Finally, some aspects of ment approaches to CV and equipment clean- environment. Quality Risk Management (QRM) will be ad- ing and hold strategies have been published.3 dressed as they apply to CIP CD. This article is However, Q9 also states the following: not intended to be a complete overview of QRM “The use of informal risk management concepts. processes (using empirical tools and/or QRM Applied to CIP CD internal procedures) can also be consid- ered acceptable.”4 QRM applied to the pharmaceutical industry is intended to protect the patient from adulter- A structured approach to CIP CD focusing on ated drug products. The ICH Harmonized Tri- the development of cleaning control param- partite Guideline Q9, Annex II, explains the eters, yields data which can be used to mitigate potential applications for QRM. Annex II.3 risk of product contamination. Defined as such, (QRM as Part of Development) and Annex II.4 CIP CD is an informal risk management tool. (QRM for Facilities, Equipment, and Utilities) The data gathered during a CIP CD program can be interpreted in part to promote the use of can be used to determine control and alarm CIP CD as a risk management tool based on the setpoints and ensure cleaning cycles are ro- examples cited. Annex II.3 lists one purpose of bust, repeatable, and efficient. Practically QRM to be: speaking, operational knowledge gained by the end users results in improved cleaning proce- “To establish appropriate specifications, dures and enhanced personnel training. identify critical process parameters, and Finally, the FDA’s Guide to the Inspection of establish manufacturing controls.”1 Cleaning Validation Processes states the fol- Annex II.4 provides another example: lowing: “To determine acceptable cleaning vali- “It is not unusual to see manufacturers dation limits.”2 use extensive sampling and testing pro- grams following the cleaning process with- The cleaning of equipment through the use of out ever really evaluating the effectiveness validated procedures may mitigate the risk of of the steps used to clean the equipment.”5 ©Copyright ISPE 2006 SEPTEMBER/OCTOBER 2006 PHARMACEUTICAL ENGINEERING 1 CIP Cycle Development This guidance document does not explicitly recommend a checklist which defines the acceptance criteria that all structured approach to CIP CD. However, a CIP CD program stake holders pre-approve does facilitate the methodical evaluation of steps used to 7. good project management skills used to execute the work clean the equipment when the program includes all the with available resources based on a schedule and budget manufacturing and quality stakeholders. 8. assurance that the goals of the CIP CD program align with the requirements of the Cleaning Validation program Practical Examples of CIP CD Issues 9. definition of CIP CD and CV completion based on accept- Having established that CIP CD is an informal risk manage- able analytical results, repeatability, and cycle time. What ment tool and can be used for cleaning process data analysis, constitutes “done?” two questions remain: The CIP CD approach utilized a three step process of optimiz- 1. What are some practical lessons learned from a CIP CD ing a CIP cycle: functional check-out with water, chemical program? CIP cycle testing (no soil) to confirm circuits can be rinsed of 2. What efficiencies can be gained which demonstrate a detergent residue, and finally, some degree of a soiled chal- Return On Investment (ROI), in a CIP CD program? lenge. An assessment of risk tolerance determined the level of soiled CIP circuit sampling required prior to proceeding to The first question will be addressed in a general manner that cleaning validation. describes case study examples that could be applied to any The following points outline practical lessons learned biotechnology manufacturing facility that utilizes automated applicable to any biotech process which utilizes automated CIP cycles. The second question cannot be answered com- CIP cycles and identifies potential risk mitigation areas. pletely. How can one quantify the cost savings to a project of problems resolved during CIP CD that otherwise would have Define Cleaning User Requirements been encountered during validation lots or at some point in In general, User Requirement Specifications (URS) should be the life cycle of the facility? The best way might be to profile developed prior to beginning the design and construction of two similar projects, one which included a CIP CD program any biotech facility. If this has not occurred, the first step of and another which did not, and to somehow quantify the the CIP CD program should be to assemble all the stakehold- project and product life cycle costs incurred by both resulting ers (manufacturing, engineering, quality, and validation) from cleaning problems. This type of analysis is beyond the and agree on cleaning user requirements for each CIP circuit scope of this article so “order of magnitude” estimate methods type. The user requirements should specify “what” the CIP will be used. However, the benefit of manufacturing improve- cycle process should accomplish to meet chemistry, tempera- ment projects has become so obvious to some big-pharma ture, time, flow, and cleaning action specifications. The CIP companies that they have stated a policy of: CD team will then utilize the equipment, automation, and configurable parameters to establish “how” the user require- “...treating projects to improve manufacturing as a re- ments are implemented. It is important to understand the search investment: anyone who proposes such a project distinction between “what” and “how.” does not have to submit a return-on-investment analy- The vendor should be included in the user requirement sis.”6 development process for specialty equipment such as centri- QRM is a “new” development in the pharmaceutical industry. fuges, Tangential-Flow-Filtration (TFF) skids, and homog- CIP CD is not new and there is no single correct method to enizers. Examples of user requirements to define for TFF plan and execute a CIP CD program. Each project must skids are: required shear rate, rinse/wash volumes, and account for limitations imposed by cleanability studies, equip- temperature ranges, chemical concentrations, dirty and clean ment availability, procedures, resources, objectives, time, wet hold strategies, post CIP membrane storage require- and money. However, all well executed CIP CD programs ments, and steam or chemical sanitization requirements. have the following common characteristics: Centrifuge user requirement definition includes: product contact surface area boundaries, volumetric flowrate/through- 1. a clear definition of system boundaries and mechanical put and backpressure specifications, discharge frequency configuration and interval length, and valve composite cycle timing for 2. detailed knowledge of the automation specifications parallel paths. ASME BPE 2001, Section SD-4.15 CIP Sys- 3. definition of an engineering/science rationale for the val- tems and Design also should be referenced when defining a ues of configurable parameters associated with the CIP URS for vessel and piping circuits. The URS should be pre- cycle approved by all stakeholders prior to starting the CIP CD 4. understanding of equipment, CIP circuit, and residue program. grouping strategies 5. understanding of the critical cleaning process control CIP CD Equipment Issues parameters: time, temperature, flow, chemistry, and clean- Identify the Appropriate CIP Chemistry and ing action Temperature 6. definition of a scope of work via a protocol, study, or An assessment of the proper cleaning chemistry and tem- 2 PHARMACEUTICAL ENGINEERING SEPTEMBER/OCTOBER 2006 ©Copyright ISPE 2006 CIP Cycle Development perature is a critical aspect of the development