Whitepaper Design for Cleaning - Genesis Engineers

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 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. Copyright Genesis Engineers 2015 All rights reserved Do not reproduce without written permission 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.

2 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.

3 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 follows1: 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 ( , WFI, CIP, pure steam, process gases), or components ( , 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, 2014. Copyright Genesis Engineers 2015 All rights reserved Do not reproduce without written permission 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.

4 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.

5 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 ( , 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 ( , an instrument connection). BPE defines a characteristic length for these branches, so-called dead legs, with the term L/D.

6 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 components2. 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.

7 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 5 Figure 1: Branch connection in a horizontal pipeline should be level. When a branch occurs at a change in direction ( , the main flow turns at a TEE), then the direction of flow should be into the branch. 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.

8 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 study3 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.

9 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 DLFLOWTHERMOWELLC opyright Genesis Engineers 2015 All rights reserved Do not reproduce without written permission 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 ft/s and the flow rate gpm.

10 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.