Whitepaper Design for Cleaning

Transcription

1 Whitepaper Design for Cleaning FOR PHARMACEUTICAL MANUFACTURING SYSTEMS I N D U S T R Y I N S I G H T S Stephen Hall, PE Sr. Process Engineer

2 I N D U S T R Y I N S I G H T S Genesis periodically publishes white papers and reports about topics of special interest to the industries we serve. As veteran advisors for major corporate infrastructure, energy management, facilities, technology, manufacturing and building systems of every type, our leaders share their perspectives to help both clients and the public at large make high value decisions by having the best available information. All information contained herein is copyrighted and cannot be reproduced without permission. For academic uses, please contact us.

3 Whitepaper Design for Cleaning FOR PHARMACEUTICAL MANUFACTURING SYSTEMS Introduction This whitepaper outlines some important design considerations for Clean-in-Place (CIP) systems, which are ubiquitous in the pharmaceutical industry. The goal for every CIP system is to remove residues from product contact surfaces. The residues must be reduced to pre-established criteria. Typically, critical process parameters for cleaning include the chemistry of the cleaning and rinsing agents, temperature, and flow rate. Certain design practices ensure that the critical parameters are met, help achieve the cleaning goal, and preserve the cleanliness of the process system, especially if it is not immediately returned to service. Above all, the cleaning and rinsing agents must wet all of the product contact surfaces. Therefore, many good design practices address wetting by consideration of: Appropriate definition of system boundaries, Avoidance of shadows, lengthy branch connections and crevices, Removal of air from piping and components, Proper spray-ball configuration, and Flow assessment (hydraulic calculations) Cleaning efficacy is also affected by design specifications such as valve and component selections, materials of construction, surface finish, slopes to drain, and automated sequences. System Boundaries System boundaries should be established in specifications and drawings to fully define the pipes, components, and equipment that must be cleaned. Classify surfaces within the boundaries as process contact or product contact. BPE defines these terms as follows 1 : Process contact surface: a surface under design operating conditions that is in contact with, or has the potential to be in contact with, raw materials, in-process materials, APIs, clean utilities (e.g., WFI, CIP, pure steam, process gases), or components (e.g., stoppers) and where there is a potential for the surface to affect product safety, quality, identity, strength, or purity. 1 ASME BPE, Bioprocess Equipment Standard, Copyright Genesis Engineers 2015 All rights reserved Do not reproduce without written permission 3

4 Product contact surface: a process contact surface that is in contact with, or has the potential to be in contact with, a product where product is defined by the owner/user. Examples of product contact surfaces may include the interior surfaces of bioreactors, transfer tubing, chromatography columns, vessels, and recirculating segments of CIP systems. Acceptance criteria for cleaning should be applied throughout a system. Pay particular attention to the underlined phrase. Shadows, Branch Connections, and Crevices Shadows occur in vessels when a spray pattern is blocked by an internal component such as an agitator shaft, baffle, vortex breaker, sparger, or dip pipe. The undersides of internal components may be of particular concern as they are often difficult to reach with spray from the tank head. During the design phase, systems should be assessed for potential shadows. Strategies for overcoming them include: Redesign the shadowed component to remove the shadow Remove the offending component during CIP to eliminate the shadow. This requires an SOP for removal and reinstallation of the component, and a Clean Out of Place procedure for cleaning the component. Redesign the spray balls to cover the shadow. This may involve temporary installation (for CIP) of spray devices low in the vessel, special drilling of the spray balls, or a different type of spray ball (i.e., rotary vs. stationary). Branch connections which present a challenge during cleaning include valved flow branches, instrument connections, vessel nozzles and any other place where the otherwise smooth interior of a system is interrupted by a TEE or nozzle. Consult BPE for specific recommendations for many specific types of equipment. A primary consideration is the length of a branch through which there is no flow under normal conditions (e.g., an instrument connection). BPE defines a characteristic length for these branches, so-called dead legs, with the term L/D. L is the leg extension from the inside wall of the main pipe, and D is the inside diameter of the extension or the nominal dimension of a valve or instrument (see Figure 1). For valves, L is measured to the seal point of the valve to the nearest tangent of the main pipe (see Figure 1). The current best practice is to design branch connections for L/D <= 2. According to the BPE Subcommittee for System Design, there is no scientific basis for this value other than the fact that it is achievable with modern components 2. The study reported in the next section was undertaken to address this deficiency. The primary intent for the L/D rule is to ensure that all air is removed from a piping system during CIP, and that spray balls reach into vessel nozzles. The study provides important data that underscores the importance for proper orientation of branch connections and orientation of TEEs with respect to direction of flow. If practicable, place branches in vertical segments. Branches in horizontal lines should be in the horizontal plane. If they are angled upward then an air pocket can form, if angled down then they won t drain fully. 2 ASME BPE Subcommittee for System Design, Meeting to Discuss Potential Changes to the BPE Standard, May 20, 2015 Copyright Genesis Engineers 2015 All rights reserved Do not reproduce without written permission 4

5 D L Figure 1: Branch connection in a horizontal pipeline should be level. When a branch occurs at a change in direction (i.e., the main flow turns at a TEE), then the direction of flow should be into the branch. FLOW THERMOWELL Figure 2: The direction of flow should be into a branch Crevices may exist wherever two parts are joined. Crevices are very difficult to clean and can lead to corrosion or accumulation of contaminants, including biofilm. BPE details many acceptable (and unacceptable) practices for hygienic service. BPE defines Hygienic as: Pertaining to equipment and piping systems that by design, materials of construction, and operation provide for the maintenance of cleanliness so that products produced by these systems will not adversely affect human or animal health. Air Removal CIP solutions must reach surfaces to clean them. The BPE Committee undertook a study 3 to, Provide information on the flow conditions required to displace air from piping branches in a timely manner. The report goes on to say: When air is displaced from the branched fitting, the cleaning solution comes in contact with the branched piping components being cleaned-in-place (CIP d) and effective cleaning can occur. Without contact of CIP solutions, there is no cleaning. The key finding from the study is that very high velocities may be necessary to completely remove air from branch connections. The lowest velocity found to be effective for air removal was 5 ft/s; some configurations required more than 14 ft/s. The criterion used in the study was that all air pockets be removed (with some bubbles allowed to remain) within 1 minute. For the worst configuration, an upward facing 3 ASME BPE Committee, Branch Leg Study, June 1, 2013 Copyright Genesis Engineers 2015 All rights reserved Do not reproduce without written permission 5

6 branch with L/D = 2, 10 ft/s was required to reach an acceptable level of air removal within 1 minute. The study proves that Reynolds number alone is not an appropriate criterion for CIP flow rate. The Reynolds number for 10 ft/s in 2-inch tubing for water flowing at 80 F is approximately 150,000. If a criterion of Re = 10,000 were applied (the Reynolds number corresponding to fully turbulent flow), the velocity in the pipe would be 0.6 ft/s and the flow rate 5.4 gpm. The study very clearly shows that this is far from the flow needed to clear air out of branch connections. These design features should be considered to enhance contact with CIP solutions and ensure full air removal: Use zero static valves for take-offs from a system Use flush-mounted instrument fittings where possible. Thermowells and pressure sensors are available in flush-mounted designs. Use short-outlet TEEs Flow through branches during CIP Orient branches so the flow of liquid entering the TEE is directed toward the blocked branch (Figure 2) Include branches that have a risk of incomplete air removal in the cleaning confirmation and validation studies. These should be listed along with other worst-case soil locations in the system. Existing Systems Legacy systems might not meet the design goals instituted for new installations. The scope of BPE is specifically for new systems so its requirements don t strictly apply to existing ones. That does not change the fact that the performance of CIP depends in part on design factors that might not be optimal in an older system. When evaluating an existing system for air removal and cleanability, consider these mitigating factors: Operate CIP at a higher flow rate than process fluids. The CIP solutions are more likely to wet those surfaces that were soiled by the process flow. This factor needs to be carefully evaluated since the CIP flow could simply move the soiled boundary deeper into a branch without removing it (the bathtub ring effect). And if the process fluid is prone to foaming, process foam might reach all portions of a branch making it imperative to completely remove air during CIP. Use care when making dynamic flow adjustments during CIP transitions to use pulsations and water hammer effects to help push fluids into branches and displace air. Dynamic flow adjustments may help with air removal, but potential stresses in the piping should be evaluated to avoid damaging the system. Assess the geometry of instruments in suspect branch connections. The shape of the instrument might provide additional local turbulence that helps CIP solutions wet the entire branch. Copyright Genesis Engineers 2015 All rights reserved Do not reproduce without written permission 6

7 Sprayballs Spray CIP solutions at high velocity onto surfaces that cannot be flooded. Vessels are always CIP d using spray balls. Other equipment with chambers, such as lyophilizers, may also utilize spray balls only when employing a Clean-In-Place system. Ductwork, if cleaned, may also incorporate spraying devices. Users often use the term spray balls generically to include fixed spray balls or rotary spray heads. Figure 3: Fixed Spray Ball and Rotary Spray Head Table 1: Comparison of Spray Balls to Spray Heads Fixed Spray Ball Rotary Spray Head Advantages May require less water to cover interior Simple design surfaces Custom drilling to optimize spray pattern Slot less likely to trap particulates Flow pattern can be adjusted by drilling new holes, enlarging existing ones, or Dynamic flow during rotation blocking existing holes Disadvantages Small holes can trap particulates which Requires sensors to detect rotation disrupts spray pattern stoppage If custom-drilled, orientation and location in Must be installed vertically to ensure full the tank may be critical parameters that drainage and minimize lateral stress on the must be controlled (with guide pins, for rotating mechanism example) The chemistry of the solution being distributed works with the spray patterns to effect cleaning. Spray patterns do not work alone. Vessel cleaning usually depends on the chemistry of the cleaning solutions to remove soils. The solutions must wet the entire surface, but impingement from the spray ball onto the wall is not relied upon for cleaning. The reason for discounting the effect of impingement is that the force from the water stream differs throughout the vessel; if impingement is considered a critical factor then Acceptance Criteria are needed along with verification. Copyright Genesis Engineers 2015 All rights reserved Do not reproduce without written permission 7

8 Vessels need 2.5 to 3 gpm per ft of circumference to ensure complete wetting of the sidewalls. This is an empirically determined rule-of-thumb that is accepted throughout the industry. The height of the vessel does not change the flow requirement. A critical mass of water forms a sheet, around the entire perimeter of the tank; the sheet propagates down the tank wall. Lower flows may succeed in wetting the entire perimeter near the top of the tank, but as it flows down the sidewall the surface tension causes the sheet to break apart resulting in rivulets rather than a cascading sheet. If the spray balls are drilled to direct water at internal components, such as an agitator shaft and impeller, then the water so directed is added to the 2.5 to 3 gpm to obtain the total flow requirement. Rotating spray heads might require less flow than fixed heads, if it can be shown that their pattern successfully washes over the vessel walls. Essentially, the rotating head directs its total flow toward a fraction of the wall but moves the flow around to progressively sheet the solution down all sides. Spray balls are usually specified to flow a certain amount of water at a certain pressure drop (e.g., psi). They have a limited reach (the distance the spray travels horizontally without simply dropping to the bottom of the vessel) which is partially determined by the pressure. Therefore, although the spray device follows standard fluid flow rules, with the flow rate being proportional to the square-root of the pressure drop, the velocity through the holes is correlated linearly with flow and it s the velocity that determines how far the spray will reach. Spray reach is especially important in larger tanks (diameter greater than about 6 ft). These tanks are likely to use multiple spray devices. If the devices spray equally in all directions, then it s likely that some of the solution will not reach the tank sidewall. Custom-drilled spray balls mitigate the problem of flow being directed toward the tank center-line and falling to the bottom before reaching the opposite side. Flow Hydraulics Exercise extreme caution when applying rules-of-thumb for CIP flow rates. Engineers often characterize CIP flow rates in terms of velocity. A typical goal is to size a system to provide a minimum velocity of 5 ft/s (1.5 m/s). If that rate cannot be achieved in portions of the system then a lower rate of 3 ft/s or a flow that results in turbulence may be accepted. As already discussed, the BPE Subcommittee for System Design performed experiments that show the difficulty of removing air from piping systems and that in some cases the velocity must exceed 10 ft/s to achieve acceptable results. This data, and BPE s focus on air removal, make it difficult to justify the case for a low (< 5 ft/s) flow. Where there are no air pockets (upward-facing cavities, branches, etc.) then air will not accumulate and the cleanability of the soils (verified with testing) can be used as the criteria. Consider these factors to establish flow rates, recognizing that different sections of a system might respond differently due to geometry and orientation: Branch connections size and orientation. Horizontal branches are recommended to provide a balance between ease of air removal and drainability. Branches facing down do not accumulate air, but they need drain valves to fully empty. Branches facing up are extremely difficult to remove air from unless they have vents. Larger branches are less prone to accumulate air. Copyright Genesis Engineers 2015 All rights reserved Do not reproduce without written permission 8

9 Nature of the soil see Table 2. Flow rates for CIP should always be equal or greater than the flow rates for process fluids. If soils are difficult to solubilize then greater flow rates may be required. For soils containing sediments, consider the flow needed to keep solids in suspension and be vigilant for solids accumulations. Temperature. Reynolds number (i.e., turbulence) decreases with increasing temperature. Pulsating flow. Whenever the flow rate changes, by starting/stopping a pump or opening/closing a valve, the momentum of fluid in the pipe can create pressure waves that may help clear air from branches. Taken to an extreme, rapid flow rate changes result in potentially damaging water hammer. Changes in pipe diameter. CIP systems that clean several different process systems might be sized for varying flow rates and the CIP supply and return lines could be larger than some of the process systems being cleaned. The larger pipes must be carefully evaluated; it can be difficult to maintain sufficient flow in larger pipes when cleaning smaller ones. Table 2: Minimum Velocity to Avoid Settling During Slurry Transport 4 Type of Solid Fjine, over 200 mesh Sand, 200 to 20 mesh Coarse, 20 4 mesh Sludge, less than 4 mesh Flow Velocity 3 5 ft/s (1 1.5 m/s) 5 7 ft/s (1.5 2 m/s) 7 11 ft/s (2 3.2 m/s) ft/s ( m/s) Table 3: The Reynolds Number at 5 ft/s Velocity is Well into the Turbulent Region Pipe Size (Sanitary Tubing) Flow to Achieve 5 ft/s 1 inch , inch ,200 2 inch , inch ,100 3 inch ,100 4 inch ,400 Reynolds Number (Water, 25 C) Ring Distribution Engineers often use a ring distribution concept for mix-proof valve arrays and flow panels. With a ring, the CIP supply or return flow flushes through all of the piping to the distribution point without creating a deadleg. See Figures 4 and 5. Without the ring, in Figure 5 the valve to the right of the open valve would see no flow and would be a potential deadleg during operation. Hydraulic calculations show that the velocities in both directions around the ring satisfy the design goals. The specific calculations will be presented in a separate paper. 4 The Engineering Toolbox, accessed June Copyright Genesis Engineers 2015 All rights reserved Do not reproduce without written permission 9

10 Figure 4: Mix-Proof Valves in a Distribution Array. CIP Supply on the top tier fills the entire length of pipe. One valve opens which connects the CIP Supply to one destination. Ring CIP Supply To Process Equipment Figure 5: This schematic depicts an array of five mix-proof valves with the top tier in blue and the bottom tier in gold. If the green valve is open, the CIP Supply travels through the three valves at left and also through the ring and the valve at right, rejoining at the open valve to supply one user. Flow Paths The quantity and complexity of CIP piping often exceeds the process piping. Flow paths include the CIP piping (supply and return), process piping and process equipment. Paths define the route that CIP solutions take through the system, and they must include every portion of the system. There is an art to good flow path design; here are a few tips to help when designing CIP piping: Plan the entry and exit points to maximize the amount of process in-line equipment and piping that is cleaned in a path The required flow rates to clean vessels may be vastly different than the rate needed for piping, so they are often on different paths Try to coordinate the paths with process system boundaries to minimize the number of paths per system. Each path requires a certain amount of time for cleaning, and Copyright Genesis Engineers 2015 All rights reserved Do not reproduce without written permission 10

11 multiple paths usually result longer cleaning times due to the time for each path being additive Consider flowing CIP solutions in the opposite direction of the process flows. Diaphragm valves are usually cleaned through, not up to. This means opening them and having the CIP path route through block valves located on branches. Remember that portions of the CIP piping used for recirculating solutions are included in the definition of product contact. Vessels need to be kept as empty as possible during cleaning to avoid a bathtub ring effect. This is difficult to accomplish with standard centrifugal return pumps due to their NPSH requirement and the high likelihood that air will be entrained in the tank outlet. Consider using eductors or liquid-ring pumps to mitigate the pumping problems that result from entrained air. Regulatory and Industry Guidance Regulatory bodies require that equipment be clean before use. However, they do not regulate how to accomplish the cleaning. What they expect is verification that cleaning meets pre-established acceptance criteria, that the cleaning procedures are reproducible, and that critical process parameters are defined and monitored. FDA enforces the Good Manufacturing Practices law, as outlined in 21 CFR 210 and 211. These GMP regulations don t provide much in the way of specifics on how to performcleaning: Equipment used in the manufacture, processing, packing, or holding of a drug product shall be of appropriate design, adequate size, and suitably located to facilitate operations for its intended use and for its cleaning and maintenance. (21 CFR ) FDA interprets the law to give further detail about its expectations. Warning Letters bring voice to the interpretations. For example, There should be written procedures for cleaning of equipment. Cleaning procedures should contain sufficient details to enable operators to clean each type of equipment in a reproducible and effective manner. Acceptance criteria should be established and cleaning procedures should be defined and evaluated. (Warning Letter, Changzhou SPL Company, April 21, 2008) They also publish Guidance documents that articulate expectations. Most guidance documents are intended for a certain sector, but the information can often be interpreted for use in other sectors. For example, this guidance for cleaning tanker cars used for transporting juices mostly applies to cleaning any type of raw material tank where the stored material may support microbial growth, The temperature, pressure, and potability of the water used in cleaning, sanitizing, and rinsing should be sufficient to ensure that the equipment is adequately sanitized. (FDA, Guidance for Industry: Guidance on Bulk Transport of Juice Concentrates and Certain Shelf-Stable Juices, April 24, 2003) The most stringent requirements apply to processes that suffer if unwanted bioburden exists. Bioprocesses, where the products are derived from biological sources through cell culture or fermentation, are a leading example. Sterile drug products, typically formulated for injection, are another (the drugs in a sterile injectable may or may not be created using a biological process). These stringent requirements are benchmarks against which other applications may be measured. The standards (e.g., ASME BPE, Bioprocess Equipment Standard, published every two years) and guidance (e.g., FDA, Guidance for Copyright Genesis Engineers 2015 All rights reserved Do not reproduce without written permission 11

12 Industry: Sterile Drug Products Produced by Aseptic Processing Current Good Manufacturing Practice, September 2004) apply directly to the bioprocess and aseptic processes that they are written for. They also apply, in whole or part, to other segments such as orally ingested liquid products or topical creams with scientifically justified extrapolations. Adequate cleaning, drying, and storage of equipment will control bioburden and prevent contribution of endotoxin load. Equipment should be designed to be easily assembled and disassembled, cleaned, sanitized, and/or sterilized. Some clean-in-place procedures employ initial rinses with appropriate high purity water and/or a cleaning agent (e.g., acid, base, surfactant), followed by final rinses with heated WFI. Equipment should be dried following cleaning, unless the equipment proceeds immediately to the sterilization step. (FDA, Guidance for Industry: Sterile Drug Products Produced by Aseptic Processing Current Good Manufacturing Practice, September 2004) Conclusions Engineering a CIP system is a daunting undertaking that should be performed at the same time that the process systems are being designed. Design shortcomings can cause lengthy delays in a project s timeline to diagnose and correct problems including retesting and requalification. Poor designs can also result in regulatory citations (e.g., 483s). But with effort and diligence, the CIP system can be a key component in a manufacturer s strategy to assure product Strength, Identity, Safety, Purity, and Quality (SISPQ) attributes. Copyright Genesis Engineers 2015 All rights reserved Do not reproduce without written permission 12

13 About the Author Stephen M. Hall, PE Sr. Process Engineer Genesis Engineers, Inc. Stephen Hall brings proven and trusted expertise to drive engineered capital projects for pharmaceutical manufacturers. He leverages his technical know-how with his management background and broad regulatory compliance experience to benefit the engineers, scientists, and operators who are tasked with executing the design, construction, start-up and qualification of new or renovated manufacturing facilities. His book, Rules of Thumb for Chemical Engineers, gives practical advice, information and mathematical formulas that are used by process and project engineers throughout industry (Butterworth-Heinemann, 2012). He is an expert in the evaluation, design and operation of facilities and equipment that create or formulate active pharmaceutical ingredients. His projects portfolio includes risk assessments (both leading and participating in GMP Risk Assessments and Process Hazard Analyses), area classifications, equipment specifications, ventilation (local and room) criteria and process containment (for highly potent and hazardous materials). He has a working knowledge of NFPA-30, OSHA (Process Safety Management) and other applicable Codes and Standards. Steve earned his B.S., Chemical Engineering, from the University of Pennsylvania and his MBA from Drexel University. He authored numerous articles for Pharmaceutical Engineering, Chemical Engineering, Chemical Engineering Progress and others, and presented at various professional meetings. For more information, please contact Stephen Hall at shall@geieng.com or x253 Copyright Genesis Engineers 2015 All rights reserved Do not reproduce without written permission 13