Clean-In-Place for Biopharmaceutical Processes Seiberling_9697_TP.ind1 1 9/11/07 3:39:20 PM Clean-In-Place for Biopharmaceutical Processes edited by Dale A. Seiberling Vice President - Electrol Specialties Company South Beloit, Illinois, USA Seiberling_9697_TP.ind2 2 9/11/07 3:39:37 PM Informa Healthcare USA, Inc. 52 Vanderbilt Avenue New York, NY 10017 q 2008 by Informa Healthcare USA, Inc.

Informa Healthcare is an Informa business No claim to original U.S. Government works Printed in the United States of America on acid-free paper 10 9 8 7 6 5 4 3 2 1 International Standard Book Number-10: 0-8493-8089-8 (Hardcover) International Standard Book Number-13: 978-0-8493-8089-1 (Hardcover) This book contains information obtained from authentic and highly regarded sources. Reprinted material is quoted with permission, and sources are indicated. A wide variety of references are listed. Reasonable efforts have been made to publish reliable data and information, but the author and the publisher cannot assume responsibility for the validity of all materials or for the consequence of their use. No part of this book may be reprinted, reproduced, transmitted, or utilized in any form by any electronic, mechanical, or other means, now known or hereafter invented, including photocopying, microfilming, and recording, or in any information storage or retrieval system, without written permission from the publishers. For permission to photocopy or use material electronically from this work, please access www.copyright.com (or contact the Copyright Clearance Center, Inc. Infinity Land Biffy Clyro Rarity.

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Trademark Notice: Product or corporate names may be trademarks or registered trademarks, and are used only for identification and explanation without intent to infringe. Library of Congress Cataloging-in-Publication Data Clean-in-place for biopharmaceutical processes / edited by Dale A. – (Drugs and the pharmaceutical sciences; v. 173) Includes bibliographical references. ISBN-13: 978-0-8493-4069-7 (hardcover: alk.

Paper) ISBN-10: 0-8493-4069-1 (hardcover: alk. Pharmaceutical technology–Equipment and supplies–Cleaning.

Pharmaceutical technology–Quality control. Pharmaceutical technology–Standards. Seiberling, Dale A. Technology, Pharmaceutical–methods. Drug Contamination–prevention & control.

Equipment Contamination–prevention & control. Technology, Pharmaceutical– standards. W1 DR893B v.173 2007 / QV 778 C623 2007] RS199.S 615’.7–dc22 Visit the Informa Web site at www.informa.com and the Informa Healthcare Web site at www.informahealthcare.com Preface Clean-in-Place for Biopharmaceutical Processes is intended to be a source of information for personnel from all disciplines who are involved in the manufacture of a pharmaceutical product—from the scientist who creates the drug to those responsible for the design, construction, validation, and operation and maintenance of a facility, as well as for those responsible for regulation. The objective of this book is to combine the experience and knowledge of experts familiar with the many items of equipment required for the pharmaceutical process with the knowledge of people who have had long experience in the successful application of clean-in-place technology to a variety of non-biopharmaceutical and biopharmaceutical processes. The unit operations of the process are analyzed with respect to whether or not clean-in-place is a possible or preferred method of cleaning, and examples of successful applications are included. While each new user of clean-in-place has a tendency to “reinvent the wheel,” this book is an attempt to show that, for the most part, there are no new problems; rather there are problems solved previously, in a different application.

However, considerable effort has been made to recognize and define innovative and emerging technology. The established criteria for successful clean-in-place is well defined, explained, and illustrated.

A major goal of this book is to guide all readers to the development of the need for clean-in-place rather than clean-in-part. Clean-in-place technology has been developing constantly for more than 50 years in dairy, beverage, and food applications for cleaning processes that produce fluid, semi-fluid, and dry granular products. Early development in these industries was generally guided by a small group of user personnel with intimate knowledge of the chemistry, bacteriology, and cleaning needs of the product, who were willing and able to seek outside support regarding the application of developing clean-inplace technology, sometimes referred to as “in-place cleaning” or “recirculation cleaning” in early literature. Much of the technical know-how was acquired during the early period of retrofitting clean-in-place to existing processes, primarily in dairy and brewing applications. A few well-qualified vendors of clean-in-place systems, sprays, and associated components served the needs of the entire market with “off-the-shelf” components and systems that were quite similar in the operating characteristics of flow and pressure. The regulatory agencies concerned with the application of this new technology were participants in the projects and members of the 3-A Sanitary Standards committee that quickly recognized the need for standards and practices to guide the application of the developing technology. As the biopharmaceutical industry became clean-in-place users, the major application was to new projects.

Most of the manufacturing companies lacked architects, engineers, and construction managers, and the overall design responsibility was necessarily delegated to large engineering companies. The selected firm often determined how clean-in-place would be applied, developing voluminous documentation describing its design, fabrication, and operation. Each new project was treated as a unique, different, and demanding application. During this same iii iv Preface period, the industry recognized the need for “validatable cleaning” and clean-inplace was quickly recognized as a useful tool in meeting that need. The validation requirements for biopharmaceutical processes quickly spread to include all components of the clean-in-place system, and this has exacerbated the cost and complexity of clean-in-place in today’s industry. Clean-in-place technology is a powerful cleaning process when applied to a well-engineered “CIPable” process, and properly controlled and monitored to achieve the required combination of time, temperature, and concentration for the specific circuit and soil load encountered.

The desired results are best assured by a combination of engineering design and end point control. A focus on program performance alone rather than the intricate details of how that program is made to occur has been demonstrated to be effective in dairy, food, and beverage applications for four decades. A change in the criteria for assuring validated cleaning—to apply what is necessary, rather than what is possible—could have great impact on the cost of the hardware and software required.

Seiberling Acknowledgments During the final years of our life together, my first wife Jean often suggested that I give up the excitement of travel, new projects, and new problems and stay at home and write a book. She supported and encouraged my second love through fiftyfour years of continuous activity in a variety of industries.

Her ability and willingness to manage the family and home, combined with my use of personal aircraft for expedited travel, enabled my active participation in many phases of the development and commercialization of a technology that has fascinated me since I first wrote a term paper on the subject in 1949. I dedicate this book to Jean F. I also want to thank Informa Healthcare for the opportunity to share a lifetime of wonderfully satisfying experiences. My life’s work has touched all peoples in the developed nations of the world in a manner they will never know, let alone comprehend.

It is a privilege to help expand the successful application of clean-inplace to biopharmaceutical processes. V Contents Preface iii Acknowledgments Contributors v ix 1. Introduction and Historical Development Dale A. Seiberling 1 2.

Project Planning for the CIPable Pharmaceutical or Biopharmaceutical Facility 21 Johannes R. Roebers and Dale A. Seiberling 3. Water for the CIP System Jay C. The Composition of Cleaning Agents for the Pharmaceutical Industries Dietmar Rosner 5. Cleaning Cycle Sequences Sally J. CIP System Components and Configurations 93 Dale A.

Seiberling 7. CIP System Instrumentation and Controls Barry J. Cleaning Agent Injection Systems Samuel F. Lebowitz 145 9. CIP Spray Device Design and Application John W.

Franks and Dale A. Seiberling 10. CIP Distribution Piping Systems Samuel F.

Lebowitz 119 159 175 11. Materials of Construction and Surface Finishes David M. Cleanable In-Line Components Lyle W. Clem 195 211 13. Cleanable Liquids Processing Equipment and Systems Dale A.

Seiberling vii 235 53 viii Contents 14. Cleanable Solids Processing Equipment and Systems Simon E.J. Cleanable API Processing Equipment and Systems Gerald J. CIP System Troubleshooting Guide 297 17. Waste Treatment for the CIP System 315 Sally J.

Rush Linda Rauch and Jay C. Commissioning and Qualification 327 James P. Cleaning Validation Strategies Charles Lankford 20.

International Regulations 361 Albrecht Killinger and Joachim Ho¨ller Index 379 347 257 275 Contributors Barry J. Andersen Seiberling Associates, Inc., Beloit, Wisconsin, U.S.A. Ankers LifeTek Solutions, Inc., Blue Bell, Pennsylvania, U.S.A. Cerulli Lyle W. Clem Integrated Project Services, Somerset, New Jersey, U.S.A. Electrol Specialties Company (ESC), South Beloit, Illinois, U.S.A.

Forder John W. Franks JM Hyde Consulting, Inc., San Francisco, California, U.S.A. Electrol Specialties Company (ESC), South Beloit, Illinois, U.S.A. Greene Paulus, Sokolowski & Sartor (PS&S), LLC, Warren, New Jersey, U.S.A. Joachim Ho¨ller Boehringer Ingelheim Austria GmbH, Vienna, Austria Albrecht Killinger Uhde GmbH, Biotechnology Division, Leipzig, Germany Charles Lankford PharmaSys, Inc., Cary, North Carolina, U.S.A. Lebowitz Electrol Specialties Company (ESC), South Beloit, Illinois, U.S.A. Norton Linda Rauch Eli Lilly and Company, Indianapolis, Indiana, U.S.A.

CH2M Hill, Boston, Massachusetts, U.S.A. Roebers West Coast Engineering Biogen-idec, Inc., Oceanside, California, U.S.A. Dietmar Rosner Ecolab GmbH & Co. OHG, Du¨esseldorf, Germany Sally J. Rush Seiberling Associates, Inc., Beloit, Wisconsin, U.S.A.

Seiberling Illinois, U.S.A. Electrol Specialties Company (ESC), South Beloit, ix 1 Introduction and Historical Development Dale A.

Seiberling Electrol Specialties Company (ESC), South Beloit, Illinois, U.S.A. INTRODUCTION Many technical reference books begin with a review of the development of the subject material.

Your editor, and the author of this chapter, has followed that practice in many prior publications. However, clean-in-place (CIP) did not start and was not initially developed in the pharmaceutical or biotechnology industries. It began more than 55 years ago, on the dairy farm, as the means of cleaning the newly introduced Pyrexw (Corning Incorporated, Corning, New York) glass milking system pipelines. During the subsequent 15 years, it was adopted by the dairy, beverage, brewery, winery, and food processing users. Only during the past two decades, has CIP been widely adopted by the biopharmaceutical industries. My recent teaching experience has suggested that the technical personnel of the industries to which this book is directed are more interested in the current CIP technology than its historical development and application. Therefore, clean-inplace for biopharma ceutical processes will start with a question, “What is CIP?” in the biopharmaceutical industry at this time?

A generic two-tank process and transfer line will be discussed in depth to provide the reader with an overview of the technology and some direction to those chapters in which the full detail can be found. But first, it is necessary to consider the broad subject of “cleaning.” Batch manufacturing processes require cleaning as one of many manufacturing steps. Whereas cleaning has long been recognized to be an important procedure, until recent years it was performed manually, typically by the least experienced and least trained employees under little, if any, supervision. The equipment and supplies provided to accomplish cleaning were also, in many cases, substandard. Cleaning in the biopharmaceutical process, however, is as important as the production of the active ingredients, the formulation and filling of those ingredients, and the sterilizein-place (SIP) of the process equipment.

Effective cleaning is the most important precedent to SIP as sanitization/sterilization requires contact between steam and microorganisms that will not achieve the desired time-temperature conditions if product residue insulates and/or protects the microorganisms. And it is well understood that chemical residue contaminants must be removed as well. It is also well understood that sterile filth in a pharmaceutical product is no more desirable than unsterile filth. Cleaning can be accomplished by disassembly of the equipment followed by manually washing and rinsing, or transfer of the parts to a cleaned-out-of-place (COP) system. Or, it can be accomplished “in-place,” by the CIP procedure.

Tunner (1), when writing about validation of manual cleaning, states, “The most important difference between manual and automated cleaning can be summarized as the human factor, with the inherent variability of personal training and commitment to quality.” He cites DeBlanc and coworkers’ (2) observation that “cleaning is not 1 2 Seiberling the last step of a batch manufacturing process and has no impact on the quality of the batch for which the cleaning is performed.” Rather, it is the first step in the manufacture of the next product batch and can greatly impact the safety and efficacy. If the process owner, validation department, and, above all, the cleaning operators view cleaning as the first step of manufacturing, the importance of a properly designed, validated, and followed cleaning procedure is obvious. By comparison, Tunner recognizes that “The effectiveness of an automated cleaning process depends primarily on the equipment and program design, which is confirmed by proper validation and maintained by an effective maintenance program. Operator training, while important, is secondary to the process and equipment design.” In today’s manufacturing processes, Roebers (3) suggests that there is a mandate to apply automated CIP, noting that “If you cannot clean your process equipment and piping in a robust, reproducible way, don’t even think about making a biopharmaceutical product!” WHAT IS CIP?

The acronym CIP refers to a complex technology that embraces: (i) processing equipment designed and fabricated to be CIPable, i.e., capable of being cleaned in place, (ii) permanently installed spray devices to the maximum extent possible, (iii) CIP supply (CIPS)/return piping (CIPR), (iv) a CIP skid with chemical feed equipment, and (v) a control system to run the CIP skid and deliver the cleaning solutions in the correct sequences at the required composition, temperature, pressure, and flow rate. The process control system must operate process equipment pumps, valves, and other appurtenances to ensure the efficacy of the CIP process. When applied to biopharmaceutical processes the general application is to clean the process equipment and piping, generally in sequence, following each period of use. The train may be comprised of individual tanks or equipment items, or groups of different sized tanks of similar function in series, the common element of the CIP process being the transfer line from the first tank to the next.

SIP logically follows CIP, and the design of a CIPable process fulfills the major needs for SIP also, via the addition of clean steam (CS) and condensate drain connections. Components of a Generic CIPable Process Figure 1 illustrates a typical two-tank train supported by the requisite CIP equipment and piping. The train could extend to include multiple systems to the maximum extent possible in the applicable CIP circuits. The train may be individual vessels in sequence, per this example, or several in parallel in sequence with others in parallel via multiport transfer panels (TPs).

The major components are identified by number in Figure 1 and include the following. Vessels Tanks T1 and T2, (1) each fitted with permanently installed fixed spray devices, a vent filter, manway, agitator, and (not shown) a rupture disk or equivalent overpressure protection device for the American Society of Mechanical Engineers (ASME) code vessel. The vessel may include heat transfer surface in one or more zones, and is commonly insulated for process and sterilize-in-place (SIP) reasons. Drain 4 CIP Skid T1 1 2 TP1 T1V1 AWFI T1V3 T1V2 CA 9 CIP return CS CIPS1 CIP return pump 7 3 Vent filter CIP return 1 2 TP2 T2V1 T2V4 AWFI T2V3 9 T2V2 CA T2 Vent Transfer line CS CIPS2 8 FIGURE 1 This generic two-tank process train illustrates a CIPable and SIPable design, with major components identified by number for reference in the narrative. AWFI Vent filter Vent 6 CIPS3 Next tank CIP flush line 5 CIP supply Introduction and Historical Development 3 4 Seiberling The vessel capacity may range from 30 L to 16 m3 or more.

A majority of CIP-cleaned processes are automatically controlled and the vessel and its dedicated piping will include air-operated valves to fill (T1V1 and T2V1), empty (T1V2 and T2V2), supply flush, wash and rinse solutions to the circuit (T1V3 and T2V3), and to subcircuits such as dip tubes and sample connections. Valves for the vent filter, sampling, etc., may be manually operated or automated, this decision being made on the basis of process automation requirements.

An outlet valve of adequate size to accommodate CIP flush, wash and rinse solution flow rates is mandatory and a flat plate vortex breaker above the outlet opening is highly recommended to minimize air entrainment and prevent cavitation of any required return pumps. Additional criteria for CIPable design will follow later in this chapter. Figure 2 is a photo of typical tank top piping as shown schematically in Figure 1 including a vent filter with a manual valve and a rupture disk. The two airoperated valves upper left control flow from a common line originating at a TP to either the inlet, or the spray, or both (for CIP) and are equivalent to T1V1 and T1V3 on T1 in the figure.

Figure 3 shows the spray balls to either side behind the manway rim, and a magnetically driven agitator and permanently installed flat plate vortex breaker on the bottom. The selection and application of spray devices is described in chapter 9. U-Bend Transfer Panels Multi-port TPs (TP1 and TP2) shown as (3) are generally used to organize installation and support of product and CIPS/CIPR piping, and facilitate connections for required production, CIP and SIP operations. The design and application of TPs is described in depth in chapter 12. TPs require manual operations to FIGURE 2 This view of a media prep vessel illustrates the high manway collar and also the rupture disc, vent filter, and level indicator nozzles that create clean-in-place spray coverage problems.

5 Introduction and Historical Development FIGURE 3 A view through the open manway shows the two sprayballs near the top, and the permanently installed vortex breaker and magnetically driven agitator on the bottom. Configure the equipment for process, CIP or SIP functions, and may be replaced or supplemented with additional air-operated valves for a higher degree of automation in large production processes. The TPs in Figure 1 would be considered to be “low-level” panels, as they are located so that the vessels drain to port 4 (Fig. This figure illustrates the port arrangement for this “generic” panel, and the associated isometric view illustrates how a “standard” U-Bend would fit between From source To next vessel To this vessel 4 From tank 2 1 3 6 To CIPR 3-Leg 7 5 CS CIPS Standard FIGURE 4 This detail of the low-level transfer panel shown on schematics in this chapter identifies the ports by number.

Note the 3-Leg U-Bend. All U-Bends are of the same length, to permit full interchangeability.

Abbreviations: CIPR, clean-in-place return; CIPS, clean-in-place supply. 6 Seiberling any two ports. For purposes of this discussion, the 3-Leg U-Bend shown at the left side of the isometric view would connect any three ports, which is sometimes necessary for greater flexibility. The position of both types of U-Bends could be monitored by proximity sensors. Later references will be made to this figure for explanation of the use of the various ports. TPs may be installed, supported, and accessed in many different ways. Alternatives include “through-the-wall” mounting as shown in Figure 5.

The vessels in “gray space” behind the wall are accessed only from the clean room side, in this instance a high-level TP above the vessel head for the vent and product filters, and a low-level TP only partially visible behind the large filter housing. The design and application of TPs will be further discussed in chapter 13. Transfer Line Most early CIP systems in dairy, food, and beverage processes cleaned vessels and piping (lines) in separate circuits, as the vessels were often filled with product when the lines were cleaned on a daily or more frequent basis and the line circuits were generally large and complex, often including several arrays of air-operated valves. However, in many biopharmaceutical processes, the vessel and the associated transfer line (3) to the next vessel are available for cleaning at the same time following each sequential batch operation. Substantial savings in water, time, and chemicals can be made by cleaning a vessel in combination with the transfer line to the next process vessel. Since this line may be smaller than required for CIP flow, to reduce holdup volume, and because there is often no adequate CIP motivation in the process path beyond the vessel outlet, a preferred method is to FIGURE 5 This view of a 1982 vintage sterile process shows U-Bend TPs installed through the wall between the clean room and the gray space in which the vessels and piping are located.

Note use of TPs to mount filter housings. Abbreviation: TP, transfer panel. Introduction and Historical Development 7 clean the transfer line, in reverse flow, by sequencing flush, wash, and rinse solution from the spray CIP source to the transfer line on a repetitive, but intermittent, basis, i.e., 15 to 30 seconds of each minute. As the CIPS valve opens to the transfer line, the flow to the sprays is diminished, but continues at a reduced pressure and flow. The back pressure created by the sprays creates the driving force to cause flow through the transfer line and the supply flow will divide to create equal pressure drop through the two parallel paths for the periods of parallel flow. The flow rate and hence cleaning velocity in the transfer line can be easily estimated or calculated and/or measured.

Though flow through this path is not continuous chemical cleaning action, continues during periods of no flow. Automated CIP Skid To ensure validatable CIP a fully automated CIP skid (4) is essential, including also the requisite chemical feed equipment, program control equipment, and instrumentation. Figure 1 provides a simple block diagram of one of several applicable CIP system configurations described in chapter 6, and supported by controls and instrumentation and chemical dosing equipment as described in chapters 7 and 8. CIP Supply Piping The CIP skid shown is interfaced to the two vessels via installation of permanently installed CIPS piping (5) to the TPs.

CIPS piping is most commonly installed above the process vessels and TPs, and is commonly sloped to drain away from the spray. CIPR Piping Low-level return piping (6), preferably 15 to 18 in. (0.5 m) below the outlet of the largest vessel to improve return pump net positive suction head (NPSH) conditions with minimum vessel puddle will be installed from the TPs to a CIPR pump, or directly to the CIP skid if located below the process equipment. CIPR Pump Return pumps (7) may be used when the return flow must be elevated to high-level piping runs back to the CIP skid. Gravity return may also be used, and other methods of return flow motivation, will also be discussed in detail in chapter 10.

Return pumps are generally fitted with casing drain valves and become the lowpoint drain for much of the circuit. CIPR Flush Valve and Bypass Line To eliminate dead legs in the CIPS and CIPR piping headers a small diameter CIPR flush line (8) is shown installed between the most distant ends of the CIPS and CIPR headers. This line also facilitates operation of the CIP Skid for test and maintenance purposes. Automatic control of valve CIPS3 enables brief repetitive pulses of flush, wash, and rinse solutions to partially bypass the spray devices and flush the full CIPS/R piping system.

Deadlegs, their impact on CIP, and methods of elimination by piping design, will be further defined in chapters 10 and 13. This line and valve may also be used to bypass part of the CIPS/R flow required for proper line velocity when small outlet valves exist by intent, or more commonly, improper design and require vessels to be spray washed at a flow rate below that required for desired CIPS/R velocity. 8 Seiberling AWFI (or Any Water) Supply If the process requires the addition of product quality water to the process vessel, for product makeup, or perhaps through the sprays for rinsing following completion of the transfer, an ambient water for injection (AWFI) supply loop (9) may be connected to the vessel spray supply manifold. Two-ported diaphragm valves applied as shown in Figure 1 will isolate the AWFI loop from CIPS, and provide an AWFI sample port. The AWFI connection for initial batch makeup may alternatively be through the transfer panel TP1 to the first vessel (commonly used for mixing), and via a valve to the spray supply manifold on subsequent vessels in the train. Operation of the Generic Two-Tank Process Train Figure 6 will serve as the reference for description of the typical process required in the operation involving two tanks in a train connected by a transfer line. Mixing and Transfer As an example of mixing and transfer operations, consider T1 to be the initial mixing tank.

TP1 would have a U-Bend between ports 1 and 2 for supply of AWFI from the facility loop via the isolation and sample valves shown. A U-Bend will also be required between ports 3 and 4 for the subsequent transfer and TP2 would requires a U-Bend between ports 1 and 2 for transfer to T2. AWFI would be supplied to fill the tank via path (F) under final control of valve T1V1, the quantity being controlled by a meter, load cells, or a probe (none shown). The vent filter vent valve would be open for the fill.

The product ingredients (P) would then be added via the manway or by alternative means, and following agitation, transfer to T2 would be accomplished by first closing the vent filter vent valve and then applying pressure to T1 using compressed air (CA) (or other gas) through the vent filter. Valves T1V2 CIP supply CIPS3 CIPS1 Vent Vent filter AWFI CIP skid Transfer line CA P Vent F T1V3 F T AWFI T CA T2V3 Vent filter T2V4 T1V1 T2V1 T T2 T1 F CS CS T Drain Next tank AWFI CIPS2 T1V2 TP1 T2V2 CIP flush line CIP return TP2 CIP return CIP return pump FIGURE 6 This schematic has been heavy-lined to define the movement of gases and the product during filling with AWFI, the addition of product (P) through the manway, and a top pressure motivated transfer from T1 to T2 (T). Abbreviation: AWFI, ambient water for injection. 9 Introduction and Historical Development and T2 V1 would be opened, and also the vent filter vent valve, to allow flow to commence from T1 to T2 in accordance with transfer path (T) arrow heads. Product Rinse Forward With the inlet line and sprays still connected to the AWFI supply, the loop valves and T1V3 would be opened briefly to flush the vessel via the spray device, thus recovering product from the vessel surfaces. If this step is necessary, the initial water volume will be reduced to allow for the dilution by this rinse volume.

CIP Cleaning of the Generic Two-Tank Process Train Tank CIP Following the transfer and AWFI rinse of T1 and the line, the TP1 U-Bend on port 2 would be relocated to the CIPS port 5 and the outlet line U-Bend on port 3 would be repositioned to port 6. The CIP system would then deliver flush, wash, and rinse solutions at the required conditions of time, temperature, and concentration, through the sprays, at a flow rate equivalent to 2.5 to 3.0 gpm/ft (30–35 lpm/m) of vessel circumference or 5 ft/sec (1.5 m/sec) in the CIPS/R piping, whichever is greatest. CIPS1 would direct solutions to TP1 and T1V3 would be open to the sprays for the full program, whereas T1V1 would be “pulsed” open for perhaps two to three seconds of each minute to clean the fill connection.

The CIPR flush valve CIPS3 would also be “pulsed” a few seconds each minute to flush the CIPS header downstream of CIPS1 and the CIPR header upstream of TP1, thus assuring no “deadlegs” in the circuit. The flush, wash, and rinse solutions would follow the flow path designated by the (T) arrow heads in Figure 7 for the full duration of the CIP CIPS1 CIP return L AWFI Vent T,L CIP skid T CA T1 L T2V3 Vent filter T1V1 (Pulse) T,L T2V4 T2V1 T,L T,L T2 T L CS CS T Drain T1V2 L AWFI Vent T1V3 CIPS2 (Intermittent) Transfer line T CA Vent filter AWFI (Pulse) CIPS3 L Next tank T,L TP1 T2V2 TP2 CIP flush line CIP supply L CIP return T,L CIP return pump FIGURE 7 This schematic has been heavy lined to define the tank circuit flow path by arrow heads (T) and the line circuit flow path by arrow heads (L). The CIPR flush valve CIPS3 would be pulsed during both programs to clean the deadlegs of the CIPS/R headers. Abbreviations: AWFI, ambient water for injection; CA, compressed air; CIPR, CIP return; CIPS, CIP supply. 10 Seiberling program, and through the “pulsed” paths by the arrow heads for brief intermittent periods. An air blow of the CIPS line will generally follow each program phase, after which, time will be provided for the return pump to evacuate the vessel. On completion of the program, low-point drain valves will open to assure drainage of the entire circuit.

Transfer Line CIP Following completion of the tank CIP program, the TP2 U-Bend on port 1 would be relocated to the CIPS port 5 and the TP1 U-Bend on port 6 would be repositioned to port 4. The CIP system would deliver flush, wash, and rinse solutions at the required conditions of time, temperature, and concentration, through the piping path defined by arrow heads (L) in Figure 7, at a flow rate equivalent to or greater than 5 ft/sec through the largest diameter tubing in the circuit. CIPS2 would direct solutions to TP2 and the CIPR flush valve CIPS3 would also be “pulsed” a few seconds each minute to flush the CIPR header upstream of TP1, thus assuring no “deadlegs” in the circuit. The flush, wash, and rinse solutions would follow the flow path designated by the circuit arrow heads (L). When cleaning circuits with no vessel that accumulates a “holdup” volume, there is no need for an air blow of the CIPS line between each program phase, but the CIPS and CIPR lines will generally be evacuated by an air blow at the end of the program. On completion of the program, the low-point drain valves will open to assure drainage of the entire circuit.

Typical Cleaning Programs and Water Requirements The effectiveness of mechanical/chemical cleaning is related to a number of variables including time, temperature, concentration, and physical action. Physical action is dependent on proper design and engineering, i.e., the selection and application of the correct sprays, supply and return pumps, and the sizing of CIPS/R and product piping to achieve the required flow velocity.

There is no single “best way” to handle any particular cleaning program as the first objective must be to “do what is necessary to get the equipment clean” after which further adjustments giving consideration to limitations of temperature, time, or cleaning chemical cost may be completed. Dependency on exact or specific numbers (as part of the recommendation) is of no value if the equipment is still dirty upon completion of a cleaning cycle. Four decades of experience have demonstrated that fat-, protein-, and carbohydrate-based soils encountered in most dairy, food, pharmaceutical, and biotechnology processes can be removed by one or a combination of several of the following treatments.

Prewash Rinse Following completion of the batch operation and transfer, subsequent rinse forward, and reconfiguration of the process piping for CIP, any available cold water may be used to flush the remaining product from the equipment and piping surfaces. CIP skids are generally supplied with two different qualities or type of water [i.e., wash and rinse, soft and purified, reverse osmosis (RO) water, deionized water, AWFI, or hot water for injection (HWFI)].

The lowest cost water, or perhaps the lowest temperature water will be most often used for the prerinse, alkaline solution wash, and postrinse. Introduction and Historical Development 11 Alkaline Solution Wash In its simplest form, this chemical solution may be nothing more than a mild solution of sodium hydroxide or potassium hydroxide, or a blended product which combines the base ingredient with other chemicals to enhance performance. Chemical concentrations may vary from as low as 800 to 1200 ppm of alkali for lightly soiled equipment to a maximum of 1% to 2% for heavily soiled equipment. Cleaning temperatures are normally in the range of 708F to 1408F (57–718C), and exposure time (recirculation time at temperature) may vary from as little as 5 minutes to as much as 20 minutes, or more.

Heavily soiled heat exchange equipment may require concentrations of 1.5% to 2% alkali and times of 45 to 60 minutes for effective results under all operating conditions. Lightly soiled equipment such as buffer prep tanks, or vessels used for highly soluble drugs may respond to rinsing alone. Postwash Rinse Following the solution wash, a minimum of softened water will be used to flush the soil and alkaline solution from the equipment surfaces. Neither sodium hydroxide nor potassium hydroxide is free rinsing, however, and whereas the simple check of conductivity at the discharge to drain may suggest that the alkaline material has been removed early in the rinse, sampling of the equipment surface may reveal a considerable alkali residual. Acidified Rinse The postwash rinse may be followed with a recirculated solution of soft or pure water lightly acidified with food grade phosphoric acid (or equivalent mild acid) to produce a pH of 5.5 to 6.0 (just slightly on the acid side of neutral).

This solution, recirculated at the water supply temperature (no additional heating), will neutralize all traces of alkali residual on the equipment surfaces. Some users of CIP prefer to apply this step as an acid wash, at higher than suggested concentrations, and with the addition of heat for an increased period of time. Detailed discussion of chemical cleaning materials and programs is provided in chapters 4 and 5. Post-Acid Rinse The acidified rinse (or wash) will be followed with a rinse as described for the postalkali wash. Final Rinse Pharmaceutical and biotechnology processes require removal of all traces of cleaning solutions from the equipment surface.

This may be accomplished in one or two steps of rinsing straight through to drain with either purified water alone or soft water followed by purified water, to achieve the desired rinse test. Typical Water Requirements The volume of water required to prerinse a piping circuit is normally found to be 1.5 to 2 times the volume contained in that piping. To establish an understanding of water needs for CIP, consider the fact that 100 ft (30 m) of 1 in. (25 mm) diameter tubing will contain approximately 7 gal (26.5 L) and 100 ft (30 m) of 2 in.

(50 mm) diameter tubing will contain approximately 14 gal (53 L). If the volume of the complete process piping circuit is, for example, 100 gal (380 L), then the total water requirement will be approximately 200 gal (760 L) for a pre-rinse plus 100 gal 12 Seiberling (380 L) for the solution wash, plus 200 gal (760 L) for the post-rinse, plus 100 gal (380 L) for an acidified rinse, plus 200 gal (760 L) (perhaps more) for the final pure water rinse. The total water requirement for a spray cleaning program for a vessel is related to (i) the spray delivery rate, (ii) the volume of the CIPS/CIPR, and (iii) the volume of the recirculation tank, plus (iv) the holdup volume required in the vessel being cleaned to achieve reliable recirculation. Prerinse and post-rinse times of 40 to 60 seconds are generally adequate. A final pure water rinse once through to the drain may require delivery at the spray design rate for two to three minutes, or more. A conservative estimate for the total water requirement for cleaning a tank at 80 gpm (300 lpm) in a system containing 200 ft (61 m) of 2 in. (50 mm) supply/return piping would include 80 gal (300 L) for the prerinse, 40 gal (150 L) for the solution wash, 80 gal (300 L) for the post-rinse, 40 gal (150 L) for the acidified rinse, and 240 to 360 gal (900–1350 L) for the final pure water rinse, for a single tank CIP unit which operates with no solution in the recirculation unit tank.

Alternative multi-tank recirculating units may add an additional 100 to 150 gal (380–570 L) total in the solution tank and in the vessel being cleaned to achieve stable recirculation with pumped return. Deadlegs in the CIPS/R piping and excessive holdup in the vessel will dramatically increase the rinse volume required to achieve set-point resistivity. Tank and Line CIP in Combination Whereas vessels and lines are traditionally cleaned in separate circuits because of the different CIPS flow and pressure requirements, the careful consideration of the above numbers will reveal that the major amount of water used for the total program is to fill the CIPS/R piping to and from the circuit. For a CIPS/R length of 100 ft of 2 in. Tubing, this will be 28 gal minimum. A very large vessel fitted with a vortex breaker may need only 3 to 5 gal more for reliable recirculation.

A 50 ft transfer line of 1.5 in. Diameter will contain only 3.5 gal of solution. The addition of the transfer line to the vessel circuit will increase the volume contained in the circuit by only 10% to 15% and washing the vessel and line in combination will effectively reduce total water for both circuits by 40% to 45%, as compared to washing them individually. There is generally no scheduling problem to wash the transfer line with the vessel as both are soiled and available for CIP at the same time following the transfer.

The two individual tank and line circuits shown in Figure 6 can be combined by installing the 3-Leg U-Bend illustrated in Figure 4 on TP1, thus combining CIPR flow from the vessel (port 3) and the transfer line (port 4) to the CIPR pump (port 6). Tank T1 would be sprayed and the inlet line “pulsed” as described above for tank CIP, and CIPS2 would open for perhaps 20 to 30 seconds of each minute, allowing flush, wash and rinse solutions to pass through the transfer line in a reverse direction, with motivation being the back pressure caused by the sprays, commonly operated at 25 psi. Addition of a Process Component to a Transfer Line Seldom will a simple length of unobstructed tubing be installed between the two tanks of a train. The transfer path may include a pump, filter, heat exchanger, another process component, or a combination of several such devices. Figure 8 illustrates a relatively simple product filter through which the transfer could be accomplished via head pressure as previously described. Following completion of the transfer, the filter housing would be opened to 13 Introduction and Historical Development CIPS1 T,L CIP skid Drain CA Vent T1V3 Vent filter T T,L T T1 T,L CS T1V2 L T2V3 T2V4 T2V1 T2 F1V4 L F1V3 T TP1 CA Vent filter Vent CA T1V1 (Pulse) L T,L AWFI Air AWFI L Transfer line T AWFI Vent (Pulse) CIPS3 CIPS2 (Intermittent) L Next tank CIP return T,L F1V1 CS L F1V2 (Pulse) T,L T2V2 TP2 CIP flush line CIP supply CA (pulse) CIP return T,L CIP return pump FIGURE 8 This version of the schematic includes a product filter housing in the transfer line. CIP of T1, transfer line and filter housing is described in the narrative.

Remove the cartridge after which the housing would be replaced after manually cleaning the base joint and gasket area. The TP U-Bends would be installed as described for the more simple circuit shown in Figure 7. Filter valves F1V1 and F1V4 would be open full time for CIP. Tank T1 would be sprayed and the fill line “pulsed” as described above for tank CIP. However, when CIPS2 would open for perhaps 20 to 30 seconds of each minute, allowing flush, wash and rinse solutions to pass through the transfer line and filter housing in a reverse direction, F1V2 would be pulsed for two to three of the 20 to 30 seconds, allowing solution passage through the filter inlet line and valve.

Then, when F1V2 closes, the reverse flow will spray the filter housing via the permanently installed ball or disc-type distributor (see chap. 9), the flow being caused by the back pressure created by the T1 sprays.

The filter housing may be evacuated by the CIPR pump only, or may be assisted by the introduction of a controlled flow of CA to the CIPS line at the CIP Skid. The intentional injection of air to the CIPS flow will require a return system and CIP Skid that can handle retained air, and these will be discussed in chapter 6. SIP of the Transfer Line with Filter Housing and Destination Vessel Figure 9 illustrates one method of steaming the assembled components of the combination vessel and line CIP circuit (Fig. 8) for sterilizing purposes. Following CIP, the filter cartridges would be installed in the product filter and vent filter and the appropriate U-Bends would be installed on T1TP1 and T2TP2, with steam traps as shown.

CS supplied to T2 via use of the 3-Leg U-Bend would then be cycled in sequence through the transfer line and process filter with the vent open to remove air, after which the vent valve would be closed and steam admitted at the top and bottom would continue to the trap on T1TP1. Then, with the T2 vent valve open, T2V2 would be opened to admit steam to the bottom of T2, driving air out the top. 14 Seiberling CIP supply CIPS3 CIP return CIPS2 CIPS1 Transfer line AWFI Vent T1V1 CIP skid T1 CA F1V4 T2V3 Vent filter T2V4 T2V1 T2 CS CS F1V3 Drain Next tank Vent filter AWFI Vent T1V3 CA T1V2 TP1 F1V1 F1V2 T T2V2 CIP return TP2 CIP flush line Vent AWFI CA T CIP return pump FIGURE 9 This version of the schematic illustrates the flow path for SIP sanitizing of T2 with the filter housing and transfer line prior to the T1 T2 transfer. The design would also permit hot water sanitizing.

A full sterile process would require several added valves to maintain sterility during removal of the 3-Leg U-Bend after sterilize-in-place. When steam appears at the vent valve, it would be closed and steam would be admitted to all of the remaining tank top piping to bring the entire system to temperatures and pressures required. The selection, arrangement, and installation of the above-described generic CIPcleaned process may vary in many ways, for example: & & & & & & & Vessels may vary in capacity from 30 L to 16 m3, or larger.

Vessels may be fixed or portable, or a combination of both. Vessels may be simple in design and function (e.g., media prep or buffer prep), or complex (e.g., a bioreactor with multiple legs to be cleaned with the vessel). CIPS/R and product piping may be fixed, or fixed in combination with flexible hose final connections to portable equipment. Individual TPs may be replaced with larger top and bottom located multitank TPs. For the production facility, all TPs may be replaced with valve arrays of diaphragm, rising stem mixproof, or diaphragm mixproof type, to enhance control and minimize labor requirements for conversion from production to CIP and back. Transfer lines may be smaller (generally) than CIPS/R piping, and may include other equipment in the transfer path. Some components which permit flow in only one direction, i.e., a diaphragm pump, may require a bypass for CIP in reverse flow.

Introduction and Historical Development 15 CIP and SIP Again Defined As described above and practiced today, the CIP process is essentially chemical in nature, and generally requires recirculation to minimize water and chemical costs. Flushing, washing, rinsing, and (optional) sanitizing solutions are brought into immediate contact with all product contact surfaces under controlled conditions of time, temperature, and concentration, and continuously replenished. Vessels and filter housings are sprayed and piping is pressure washed. Steam-in-place (SIP) is the next logical step following CIP.

The objective is to reduce the microbiological content in the equipment. Depending on the process requirements, SIP means to “sanitize” or “sterilize” the equipment. Both CIP and SIP can be applied to fixed or portable process vessels and holding vessels and process piping systems consisting of pumps, interconnecting piping, and valves. In addition to the basic tanks and piping, CIP circuits may include filter housings, membrane filters, homogenizers, centrifugal machines, heat exchangers, evaporators, dryers, congealing towers, screw and belt conveyors, process ductwork, and a variety of packaging machines.

The successful application of CIP requires that the technology be understood and accepted by all disciplines involved in design, fabrication, installation, commissioning, and validation of a project. DeLucia (4) suggested that “cleaning is (too often) an afterthought in the design of pharmaceutical facilities.” Process development groups, design firms, and equipment vendors focus on their own process expertise and everyone assumes that “cleanability belongs to the CIP system and the validation department.” The above-described equipment can be cleaned thoroughly and efficiently only if the cleaning requirements are integrated into the complete design process.

3-A Practice Revision As this is being written, the 3-A Standards Committee is in the process of developing new definitions to be included in the next revision of the 3-A Practice. B1.1 CIP cleaning. The removal of soil from product contact surfaces in their process position by circulating, spraying, or flowing chemical detergent solutions and water rinses onto and over the surfaces to be cleaned.

Components of the equipment which were not designed to be cleaned in place are removed from the equipment to be manually cleaned. (CIP was previously referred to as mechanical cleaning.) B1.2 Manual (COP) cleaning.

Removal of soil when the equipment is partially or totally disassembled. Soil removal is effected with chemical solutions and water rinses with the assistance of one or a combination of brushes, nonmetallic scouring pads and scrapers, and high- or low-pressure hoses, with cleaning aids manipulated by hand, or wash tank(s) which may be fitted with recirculating pump(s). The design principles on which the CIP and SIP procedures for the generic twotank train have been described above constitute a “template” that has been successfully applied in many of this nation’s newest biopharmaceutical facilities during the past 15 years.

The projects have varied in size from as few as five fixed vessels, to as many as 65 vessels ranging in capacity from 30 L to 15,000 L (15 m3). The process facilities have included pilot plant R&D and clinical trials production, blood fractionation, respiratory care products, the production of multiple biological 16 Seiberling products in a single facility, active pharmaceutical ingredient (API) processes, and even liquid creams and ointments. The physical arrangements have varied from single floor to five floors with CIP in a basement, maximizing the use of gravity CIPR. The degree of process automation has varied but all CIP functions have been fully automated, and the CIP programs successfully validated. There is virtue in considering the avoidance of all line CIP circuits by designing to clean every vessel in combination with its downstream transfer line and SIPing every vessel with its upstream transfer line, to achieve uniformity of design and operation, minimize the circuits required, and reduce water, time, and chemicals required for cleaning the total process. CIP Cleanable Equipment and Process Design Criteria Process equipment and piping that have been designed to be totally disassembled for manual cleaning, as used in the pharmaceutical industry until the recent past, is not suitable for application of automated CIP cleaning.

The general design criteria for processes that handle fluid or semi-fluid products that must be maintained in a very clean or sterile condition include: 1. All equipment that will be contacted by cleaning solutions must be made of stainless steel, glass-lined, or equally corrosion resistant construction, and CIPcleanable materials, sealed and closed with elastomers which are validated for the intended application. The equipment must be designed to confine the solutions used for flushing, washing, and rinsing. The entire process, consisting of the equipment and interconnecting piping, must be drainable. A minimum radius of 1 in. (25.4 mm) is desirable at all corners, whether vertical or horizontal. Mechanical seals must be used for agitators.

Projectile-type thermometer sensors are acceptable for use with filled tube or resistance temperature detector (RTD)-based temperature indicating and recording systems. Thermocouple(s) or RTD(s) installed so as to sense only the temperature of the tank surface provide an even more satisfactory installation from the standpoint of cleanability. Automatic orbital welded joints are the most suitable for all permanent connections in transfer systems constructed of stainless steel. Clamp-type joints of CIP design are acceptable for semi-permanent connections.

An acceptable CIP design infers (i) a joint and gasket assembly which will maintain the alignment of the interconnecting fittings, (ii) a gasket positioned so as to maintain a flush interior surface, and (iii) assurance of pressure on each side of the gasket at the interior surface to avoid product build-up in crevices that might exist in joints which are otherwise “water-tight.” 9. Dead ends and branches are prohibited, and all mandatory branches or tees should be located in a horizontal position and limited to a L/D (length/diameter) ratio of 2, or the branches shall be cleaned-through during CIP. Vertical dead ends are undesirable in fluid processes because entrapped air prevents cleaning solution from reaching the upper portion of the fitting. All parts of the piping or ductwork should be continually sloped at 1/16 in.

(5 mm/m) to 1/8 in. (10 mm/m) per feet to drain points. Introduction and Historical Development 17 11. The support system provided for the piping and ductwork should be of rigid construction to maintain pitch and alignment under all operating and cleaning conditions.

The process and interconnecting piping design should provide for inclusion of the maximum amount of the system in the CIP circuit(s). It is better to install one or two small jumpers than to remove and manually clean five or six short lengths of piping.

Mechanical/chemical cleaning is much more rigorous and is subject to better control than manual cleaning. The Goals of Automated CIP The goals of an automated CIP system include: 1.

Elimination of human error and assurance of uniformity and reproducibility of cleaning, rinsing, and sanitizing not possible with manual procedures. Prevention of accidental product contamination through operator error (by system design). Improvement of the safety of production and cleaning personnel. Improvement of productivity by reducing the production operation down time for cleaning. CIP-cleaned equipment generally requires less maintenance, thus also reducing maintenance downtime. The automated CIP procedure enables modern computer-based technology to be applied to document the performance of the cleaning process when compared with the requirement.

The properly engineered CIP-cleaned process will generally contribute to substantial reduction of product losses. The most effective and repeatable CIP operations are achieved by a high level of automation. Therefore, the highly automated process is generally more easily designed as a CIP-cleanable process when compared with processes which utilize manually operated pumps and valves, or considerable manually assembled product piping.

To achieve the most effective results, it is necessary to design the process and the CIP components and circuits simultaneously, giving equal consideration to the process requirement and the method of cleaning the process. CIP is seldom efficient as an after-thought. Historical Development and Overview of CIP Technology In-place cleaning was first applied in the dairy industry in the late 1940s, both at the farm level (pipeline milking systems) and in the early 1950s, in processing facilities.

An early publication about CIP in the pharmaceutical industry by Grimes described “An Automated System for Cleaning Tanks and Parts Used in the Processing of Pharmaceuticals” (5). The biopharmaceutical industry interest in CIP was confirmed in the late 1980s and early 1990s when the major professional societies began to develop educational programs. The first ISPE CIP seminar was presented in Chicago, Illinois in 1986. In 1990, the ASME bioprocess equipment design course included a two-hour session on CIP. This program developed rapidly and was soon an annual three-day and then a four-day CIP course.

The Parenteral Drug Association (PDA) presented its first CIP seminar in St. Louis, Missouri, in 1992, and this program continued once or twice a year until the first aseptic process course was conducted in 1999. 18 Seiberling The literature began to address CIP in the pharmaceutical environment as Seiberling (6) described a 1978 vintage large-scale parenteral solutions system that was fully designed and engineered for CIP but cleaned by rinsing with distilled water (rinse-in-place) and sterilized by steaming (SIP). In 1987, a book written for the pharmaceutical industry (7) reported a summary of the development of CIP in the dairy, brewery, wine, and food processing industries prior to 1976 as background leading to the application of this technology by pharmaceutical users. The 1987 book provided more detail about the large IV Solution process of 1978 vintage designed to CIP standards, but only rinsed and SIP.

Attention was also given to a sterile albumin process and a blood fractionation process, both of early 1980s vintage, installed to 3-A (dairy) standards and cleaned with full CIP programs. These projects involved the first efforts to apply an integrated approach to piping design for the pharmaceutical process. A comparison of dairy and pharmaceutical piping processes and the unique problems involved with installation of CIP/SP systems in clean rooms were also discussed in this book. Adams and Agarwal (8) contributed concepts in “CIP System Design and Installation” based on current experiences in 1990, and added information about integrated piping design was further described in “Alternatives to Conventional Process/CIP Design—for Improved Cleanability” by Seiberling (9) in 1992.

A comprehensive review of current technology was offered by Seiberling and Ratz (10) in the chapter “Engineering Considerations for CIP/SIP,” in Sterile Pharmaceutical Products—Process Engineering Applications edited by Avis in 1995, and this was perhaps the first major effort to use pharmaceutical and biotech design examples and installation photographs. This book gave attention to the large U-Bend TPs and mixproof valves than being placed into current projects, and also addressed the dry drug segment of the industry. In 1996, Stewart and Seiberling (11) reported a project which applied CIP very successfully to an agricultural herbicide process and provided all of the challenges of the current API processes.

This project applied fully automated CIP via a CIP Skid to clean a solvent-based process with alkali and acid in essentially the conventional manner. Engineering design approaches and validation were jointly described by Seiberling and Hyde (12) in (1997) in an article titled “Pharmaceutical Process Design Criteria for Validatable CIP Cleaning,” an early effort to address the design of a validatable CIPable process in an exclusive publication by the Institute of Cleaning Validation Technology. Marks (13) further explored and explained “An Integrated Approach to CIP/SIP Design for Bioprocess Equipment” in 1999, and in 2002 Cerulli and Franks (14) compared the cleaning regimen currently employed in much of the API segment of the industry to the alternative CIP procedures now being applied, but generally under manual control. Greene (15), writing about “Practical CIP System Design” in 2003, has addressed in a scholarly manner the subjects of flow rate and pressure, and the kinetics of CIP. He observed that even with 15 years of industry experience, “Proper implementation of CIP appears to be a mixture of art and science,” a valid observation from the editor/author’s viewpoint also.

Forder and Hyde (16) elaborate on everything taught in the early pages of this chapter under process system design for CIP, noting that “For the most effective use of CIP, circuits must be designed into the facility from the beginning” and not developed as an afterthought. This article mentions the use of potable water in some newer biopharmaceutical facilities for all Introduction and Historical Development 19 phases of the CIP program except the final rinse and this cost reduction approach is noteworthy. Substantial experience has shown that the effective application of CIP procedures requires some combination of the components described previously under section What is CIP? Seldom are two processes similar, and during the decades of the 1980s and 1990s and into 2005 many different types of pharmaceutical and biotech processes have been designed to be CIPable and successfully validated. Though applied at first to primarily processes which handled liquid products, the technology is equally applicable (via different procedures and components) to dry drug processes (chap. And whereas it was first applied to the final products which required the highest degree of process cleanliness and/or sterility, the technology is now being used in the API segment of the industry (chap.

The individual or project design team member becoming involved with CIP for the first time can derive much benefit from a careful review of the most recent articles listed above, and in the References, specifically references 12 through 16 as these articles have been developed and contributed during the more mature stage of the application of CIP technology to the biopharmaceutical industry. REFERENCES 1. Manual cleaning procedure design and validation. Cleaning Validation. Royal Palm Beach, Florida: Institute of Validation Technology, 1997:21. LeBlanc DA, Danforth DD, Smith JM. Cleaning technologies for pharmaceutical manufacturing.

Pharm Technol 1993; 17(10):118–24. Project planning for the CIPable pharmaceutical or biotechnology facility.

In: CIP for Bioprocessing Systems Proceedings. San Francisco, CA: SBP Institute, May 23–27, 2005. Cleaning and cleaning validation: the biotechnology perspective. Personal Correspondence, 1994. Grimes TL, Fonner DE, Griffin JC, Pauli WA, Schadewald FH. An automated system for cleaning tanks and parts used in the processing of pharmaceuticals. Bull Parenter Drug Assoc 1977; 31(4):179–86.

Seiberling DA. Clean-in-place and sterilize-in-place applications in the parenteral solutions process.

Pharm Eng 1986; 6(6):30–5. Seiberling DA. Clean-in-place/sterilize-in-place (CIP/SIP).

In: Olson WP, Groves MJ, eds. Aseptic Pharmaceutical Manufacturing. Prairie View, IL: Interpharm Press Inc., 1987:247–314.

Adams DG, Agaarwal D. CIP system design and installation. Pharm Eng 1992; 10(6):9–15. Seiberling DA. Alternatives to conventional process/CIP design—for improved cleanability. Pharm Eng 1992; 12(2):16–26. Seiberling DA, Ratz AJ.

Engineering considerations for CIP/SIP. In: Avis KE, ed. Sterile Pharmaceutical Products—Process Engineering Applications. Buffalo Grove, IL: Interpharm Press Inc., 1995:135–219. Stewart JC, Seiberling DA. Clean-in-place—the secret’s out. Download Themes Hp Sony Ericsson W200i there. Chem Eng 1996; 103(1):72–9.

Seiberling DA, Hyde JM. Pharmaceutical process design criteria for validatable CIP cleaning. Cleaning Validation. Royal Palm Beach, FL: Institute of Validation Technology, 1997.

An integrated approach to CIP/SIP design for bioprocess equipment. Pharm Eng 1999; 19(2):34–40. Cerulli GJ, Franks JW. Making the case for clean-in-place. Chem Eng 2002; 109(2):78–82. Practical CIP system design. Pharm Eng 2003; 23(2):120–30.

Forder S, Hyde JM. Increasing plant efficiency through CIP. Biopharm Int 2005; 18(2):28–37. 2 Project Planning for the CIPable Pharmaceutical or Biopharmaceutical Facility Johannes R.

Roebers West Coast Engineering Biogen-idec, Inc., Oceanside, California, U.S.A. Seiberling Electrol Specialties Company (ESC), South Beloit, Illinois, U.S.A. INTRODUCTION The focus of this chapter is not to cover the vast subject of project planning, but rather the many considerations that must be given to planning a project that will include clean-in-place (CIP) as the major method of cleaning the process equipment.

Successful integrating of CIP into process and facility design, and hence a “CIPable” facility, includes far more than adding CIP skids to the equipment and installing spray devices in process vessels. For CIP to be successful, it must be considered and integrated into all project phases of process and facility design. The current production of many active pharmaceutical ingredients and most protein-based biopharmaceutical drug products is essentially accomplished in liquid handling processes that require the cleaning of complex and costly equipment and interconnecting piping. The process steps involving solids or liquid/solid separation steps also involve complex equipment, which is not easily disassembled for manual cleaning, but susceptible, through appropriate redesign, to CIP on production scale. Manual cleaning of equipment is also considered inefficient and difficult to validate. In addition, regulatory agencies have increasingly scrutinized manual, nonautomated cleaning of process equipment. Hence, the need for robust, validated, and efficient cleaning drives the need for CIP.

If you cannot clean the process equipment and piping in a robust, validated manner, do not even think about making a pharmaceutical or biological product! Why Focus on CIP During the Initial Part of the Life Cycle of a Facility Project? The process and required-process engineering is typically well defined and gets a lot of attention from the very beginning of a process facility project. Essential process scale-up experiments will be planned and executed by process development departments. The critical process parameters from the process development work will be incorporated in the knowledge base developed for the project process design. Often material first produced in small-scale equipment is used in clinical trials and therefore the process needs definition. The scale-up to the large-scale production facility must be well understood and should be well documented.

Regulatory agencies expect a well-documented technical transfer process as outlined, for 21 22 Roebers and Seiberling example, by ISPE (1). Finally, there are many “process experts” available to provide the required assistance in completing all phases of the process development and scale-up activity. Many other aspects of facility and facility design must comply with the many applicable codes and standards [Canadian Standards Association (CSA), Factory mutual (FM), electrical, and mechanical] and therefore receive considerable attention. However, CIP engineering and design in many instances receives little or no attention during scale-up and process development. Typically, no experiments are done for CIP-related design challenges.

In addition, CIP is not often even considered in conceptual facility and process engineering. Then, as the project planning moves forward, especially for smaller scale production, clean-out-of-place (COP) is often considered good enough. COP procedures, however, fail to match the efficacy and reliability of CIP, and manual COP has been under increased scrutiny of regulatory agencies. The application of full automation to the COP process can easily assure compliance with the time, temperature, and concentration requirements for effective CIP, but the COP procedure seldom assures the effective application of uniform physical energy to all equipment surfaces. And, COP is applicable only to those smaller components that can be moved from the point of use to the cleaning equipment area, a labor intensive operation. However, the removal, handling, and reinstalling operations contribute to physical damage of equipment and equipment surfaces.

In other instances, CIP is an “after thought” to those lacking a full understanding of the intricacy of validated CIP cleaning. CIP may be attempted by use of portable equipment that can be “rolled in,” or accomplished with a couple of portable tanks, a pump, and perhaps a few flexible hoses. The writer’s personal experience suggests that even the common understanding of CIP may vary, based on the knowledge and experience of those involved. Some may consider the CIP design requirement as the addition of the components, specifically the spray devices for vessels, the CIP skids, CIP supply and return (S/R) piping, and CIP return pumps superimposed on an otherwise traditional smaller scale process design. The Need for Integrated CIPable Design The successful large-scale project requires the design of a CIPable process; i.e., a process which gives equal consideration to the process requirement and the means of cleaning all product contact surfaces via validatable CIP following each period of use. The definition will preferably be expanded to describe an integrated CIPable process design, one which gives equal attention to the process design as to the CIP design with the ultimate goal of achieving process excellence with efficient, robust, and validated CIP operation with minimal additions of valves, pumps, and piping.

Potential Causes for Failure to Achieve Best Possible Design for CIP The Project Management Concern The available literature on the subject of large-scale project facility design suggests that those involved in the supervision of this activity give little, if any, consideration to CIP as a significant, identifiable part of the overall task.