CIP Cleaning in the. The ASME Guide for Bioprocessing Equipment (BPE 2007) and CIP Design. Full TACCT functionality

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Blanche Montgomery
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1 CIP Cleaning in the Life Science Industry The ASME Guide for Bioprocessing Equipment (BPE 2007) and CIP Design Decentralized CIP System Design with Full TACCT functionality

2 Agenda Cleaning in the Life Science Industry ASME Guide for Bioprocessing Equipment 2007 Decentralized CIP System Design with full TACCT functionality Pump types Spray ball versus JetHead devices Pressure control versus Flow control Testing of performance

Bio-pharma production CIP Cleaning in the Life Science

stream API(B) Drug discovery Bench top equipment Pilot plants

Freezing Lyophilizing API (b) Sterile production API (b) API

systems Tank farms Filling process Disposable filling process

& Liquids Mixing process and formulation Fixed tanks and hard

3 Bio-pharma production CIP Cleaning in the Life Science Industry Life Science Industry Equipment R&D Up stream Down stream API(B) Drug discovery Bench top equipment Pilot plants Media preparation Cell culture Harvest Capture concentration Freezing Lyophilizing API (b) Sterile production API (b) API (c) Mixing process and Formulation Fixed tanks and hard piped systems Tank farms Filling process Disposable filling process Standard filling machines Sterile Liquid Drug Ointment, Creams & Liquids Mixing process and formulation Fixed tanks and hard piped systems Filling process Standard filling machines Non sterile GMP Product

4 Solid dosage Milling Mills Pre blending Blenders Granulatio n Granulator s Classificati on Agglomera tion Drying Fluid Beds Milling Mills Final blending Blenders Final milling Tableting Tablet coating Packaging Oral Drug API production IBC containers Reactors Mixers Collectors Condensers Filters Inline systems API (c)

5 Life Science Industry and cleaning Statement The cleaning in the life science industry is insufficient, lacks consistency and is still - mainly - based on manual methods. Core issue is that the automated CIP approach is based on the CIP process originally developed for the dairy industry in the 1950 s. This is especially true when efficient cleaning is needed most as e.g. where product residuals are difficult to remove, like non-water soluble residuals and with products residuals with sedimentation issues. CIP = Cleaning-in-Place

6 Life Science Industry and cleaning As a result the industry is facing: Cross-contamination issues Cleaning failures Cleaning validation struggles Sterility issues Solutions so far? Dedicated production lines Disposable equipment Manual cleaning, when possible Automated CIP however often insufficient

7 Life Science Industry and cleaning FDA enforcement and position: Equipment Cleaning and Maintenance is one of the most frequent Warning Letter citations ( ~ 18%) ECA (European Compliance Academy) analysing FDA warnings letters 21 CFR

8 Applied Cleaning Methods / Procedures within the Pharmaceutical Process Areas Market share Product Segment CIP 25% COP 25% Rev 3% Disp. 7% Manual 40% Biopharmaceuticals CIP 15% COP 25% Rev 2% Disp. 3% Manual 55% Sterile manufacturing CIP 5% COP 15% Manual 80% Solid dosage CIP 2% Reversing Process Fill, Boil & Dump 83% Manual 15% API c

9 Hygienic and Sanitary Design Standards DIN EN Hygienic requirements of food processing equipment. EHEDG (European Hygienic Equipment Design Group) ASME Guide for Bioprocessing Equipment 2007 ISO Hygienic requirements of equipment for processing of food, pharmaceutical and biotechnological products. USDA (US Department of Agriculture) NSF (National Sanitation Foundation) 3A (Sanitary standard and accepted practices (1950 ies) QHD (Qualified Hygienic Design) VDMA, Frankfurt, Certification)

10 Life Science Industry and cleaning This presentation will focus on describing how to achieve efficient and reproducible CIP cleaning. Full TACCT functionality in CIP systems Changing the BPE guideline for utilizing full TACCT TACCT (H. Sinners circle describing the contribution factors for removing soil from a surface of processing equipment) BPE (ASME guideline for Biopharmaceutical i Equipment, 2007

11 ASME Guide for Bioprocessing Equipment 2007 The American Society of Mechanical Engineers (ASME) prepared p the Bioprocessing Equipment to set up guidelines for designing process equipment (herewith also CIP system) that is applied within the biotech and sterile segments of the pharmaceutical industry (life science). The guidelines are based upon the 3A standard and focus on mechanical design, such as component selection criteria, stainless steel grades, surface finish, welding procedures, sanitary (hygienic) requirements, etc. First version of the guideline was released in Has become the Bible for most engineering firms in North America. Differ on specifics from European Hygienic standards.

12 ASME Bioprocessing Equipment 2007 Problematic sections in guideline from a cleaning efficiency perspective: SD-4.5 SD (3) SD SD SD SD-5.1 Pumps CIP Systems and Design (CIP variables) CIP Design Concepts (a), (f), (h), Design Guidelines for Cleaning Process Vessels (a), (b) CIP Spray Devices (a), (e), (g) Spray Ball testing

13 Centrifugal pumps ASME BPE: SD-4.5 Hygienic Centrifugal Pumps BPE is only describing single stage centrifugal pumps and positive displacement pumps (rotary lube) as acceptable. These pump types can basically only be controlled by flow, and are low-pressure pumps (< 60 psi). This makes CIP processes difficult to validate, because of substantial pressure fluctuations in the cleaning media throughout the process equipment and therefore also flow fluctuations. From a validations point-of-view, you need to setup and maintain an overkill approach in order to ensure that each flow path and static spray ball ON AVERAGE* has been supplied with cleaning media at the right pressure/flow for a specified amount of time.

Single stage Centrifugal pumps The median

will create laminar flow in tubes as well

14 Single stage Centrifugal pumps The median lines indicate the optimal flow during the specified cleaning. Flow rates below the lower median line will create laminar flow in tubes as well as insufficient flow for the static spray balls to achieve coverage.

15 H. Sinner s Circle for Cleaning - TACCT Time to clean Temperaturep of cleaning liquid Flow of cleaning liquid Mechanical energy / Wall shear Factor Action (Impact) Coverage of surfaces to be cleaned Chemical concentration

16 SD (3) CIP Systems and Design (CIP variables) (3) The following CIP variables are important t to success with any cleaning process: (a) time of exposure to cleaning and rinsing solutions (b) temperature of wash and rinse solutions (c) chemical concentration of wash solutions (d) CIP solution flow rates (e) hygienic design of the equipment or system being cleaned In order to comply with Sinner s circle for cleaning (d), (e) should be changed to: (d) Physical impact or action of the cleaning media (e) Coverage of all parts of the equipment to be cleaned

17 SD Design Concepts (a) The centralized CIP system consists of a recirculation tank that is mounted on a common frame with all requisite valves, pumps, and controls. (b) - (c) - (d) - (e) - (f) The system will have flow control, either via pump speed/flow or by means of flow control valves. (g) - (h) CIP supply and return pumps shall meet guidelines for hygienic pumps as outlined in this Standard. (i) - (j) -

18 SD Design Guidelines for Cleaning Process Vessels (a), (b) (a) Dished-head vertical vessels are cleaned with the majority of flow directed toward the upper head and sidewall area at the knuckle radius. Gravity then provides for a continuous solution sheeting over the sidewall and bottom head. (b) The guideline for cleaning flow rates for vertical process vessels with dished heads provides sufficient coverage for typical cleaning loads. These guidelines apply for Spray balls cleaning only

19 Spray Ball Cleaning Static spray ball coverage is partial Hits one point Water cascades down in streams Leaves dry spots in even easy-to-clean equipment Cannot clean behind obstacles Static spray ball impingement is low Functions as shower head - i.e. a soft rinse of surfaces with low impact / impingement

20 Spray Ball Cleaning Main part of tank area is dependant on gravity-driven cascading flow

21 Spray Ball Cleaning Clear lack of coverage and dimpingementi

22 Spray Ball Cleaning Cascading Flow Dry spots Rivers Force Technology Purified water vessel

23 Spray Ball Cleaning Questionable self-cleanability unpredictable blockage of holes

24 Spray Ball Cleaning The rule of thumb is to apply static spray balls, to comply with the BPE recommendation. The FDA, however, does not dictate sanitary view points on CIP cleaning. In contrary, the FDA continues with more and more emphasis to focus on the poor cleaning efficiency of the spray ball cleaning.

25 SD CIP Spray Devices (a), (e), (g) (a) Spray devices shall produce a uniform spray coverage over a particular defined area of the equipment. (b) - (c) - (d) - (e) The performance of the spray device should not be affected by variations of ±20% in flow rate or ±20% in delivered pressure, at the design conditions. (f) The spray device shall be designed in such a manner as to be easily removable if required. If removable, then a positioning device or mark shall be incorporated into the design to allow for proper location and cleaning of the equipment. (g) For optimum cleanability, fixed ball-type sprays operating in the range of 15 psi to 30 psi are suggested. Dynamic spraying/cleaning devices may be used with the approval of the owner/user. (h) -

centrifugal pumps (refer to pump flow curve) Partly or completely insoluble

26 Spray Ball Cleaning + 20% variations in operating pressure and flow will lead to coverage failures wording is, however, necessary to justify use of single stage centrifugal pumps (refer to pump flow curve) Partly or completely insoluble residues will not be removed due to the spray characteristics of the static spray ball.

27 Spray Ball Cleaning In short, static spray balls can be applied successfully in many applications - provided that the production design is simple with No built-in devices, sensors, and agitators that create shadow areas No hard-to-reach areas, such as dead-leg type top nozzles, etc. The static spray ball is not capable of overcoming design challenges. The only possible solution from a BPE point-of-view is to install more static spray balls.

28 Jet Heads Jet head coverage is full Water jets built up pattern Combination of direct attack of soil through water jets and cascading flow Can clean behind obstacles Can clean through indirect impingement and water splashing back Jet head impingement is High Functions as power washer - i.e. a targeted jet that rotates to cover all surfaces with force -

29 Jet Heads P 1. Pressure is the driving force - Pressure is converted to water jet velocity 2. The flow turns the tank cleaning machine 3. Cea Clean-ability ab by Wall Shear Stress 4. Machine gearing makes an indexed pattern Water Jet t d d Wall Shear Stress under Turbulent Flow Conditions

30 Jet Heads Rotating Jet Heads Indexed pattern Impingement, Attack of residue

31 Dead-Legs ASME BPE: DT Dimensions and Tolerances for Stainless Steel Automatic Welding and Hygienic Clamp Tube Fittings and Process Components Problems Low velocity in dead leg Unused areas where water (product residues) can accumulate Accumulation (stagnation) can lead to various types of contamination Slow cleaning Et Extended ddcleaning periods id No clear rules Existing recommendations are not always applicable Small or no dead legs are expensive to design/manufacture Solutions High flow rate turbulence Co-ordination between process and design Risk assessment analysis Small or no dead d legs only where it is necessary

32 Dead leg Definition Process pipe in use D L L L3 d L2 L1 L "FDA guide to inspection of High Purity Water systems" defines "dead leg" as >6*d of the branching pipe measured from the center of the circulation pipe (L1). This represents a constraint. In worst case it is impossible to observe if a sampling tap is wanted on a large circulation pipe. Therefore, the aim is to make the dead leg distance" as small as possible and maximum 3*d of the branching pipe measured from the inner periphery of the main pipe to the valve center (L2).

33 Dead leg s impact on temperature DL-FACTORS 2 = 9,4 3 = 5,6 4 = 4,0 5 = 1,5 1,6 =

34 Temperature Distribution Downstream Position of Dead leg TEMP. ( C C) ,4 m/s 1,2 m/s 2,0 m/s TIME (min) DL-FACTORS TEMP 2 = 9,4 TEMP 3 = 56 5,6 TEMP 4 = 4,0 TEMP 5 = 1,5 TEMP 1,6 = 0 TEMP 1, 5, 6 TEMP 2 TEMP 3 TEMP 4

35 CIP Cleaning in the Life Science Industry

36 Other design factors relevant for efficient CIP Cleaning Sterility concept sterile filter, sterile air blanket Type of valves zero-dead leg radial diaphragm Surface roughness Orbital versus manual welding methods Heat exchanger design One or two tank CIP system Turbulent flow in pipes (Reynold s number) go beyond 5 ft/sec

37 Summary of mismatch between BPE and H. Sinner s Circle for Cleaning - TACCT CIP Cleaning in the Life Science Industry Time to clean Temperaturep of cleaning liquid Flow of cleaning liquid Mechanical energy / Wall Stress Factor Action (Impact) Coverage of surfaces to be cleaned Chemical concentration

38 Summary of mismatch between BPE and H. Sinner s Circle for Cleaning - TACCT CIP Cleaning in the Life Science Industry Temperaturep of cleaning liquid Make it possible to CIP at temperatures above 90 o C. - Use multi-stage centrifugal pump to avoid cavitation.

39 Summary of mismatch. Achieve coverage through JetHead technology in stead of spray ball. Obtain full coverage of all parts Do it faster Use less water Reproducible process Coverage of surfaces to be cleaned

40 Summary of mismatch Use pressure as controlling parameter to meet a +/- 3% requirement in stead of +/- 20% Coverage of surfaces to be cleaned Therefore use pumps with pressure control in stead of flow control

41 Summary of mismatch Use impact through JetHeads and higher pressure (>100 psi) Action (Impact) Increase efficiency Lower water usage Mechanical energy / Wall Stress Factor CIP process can be monitored (PAT) Therefore use sanitary multi-stage li pumps to deliver enough pressure (Hilge, Fristam, ITT, GEA, Grundfos)

42 Summary of mismatch. Flow of cleaning liquid Action (Impact) Increase velocity of flow and have enough pressure available control performance accurately through h pressure in stead of flow.

43 TACCT Cleaning to its full extent Efficient CIP cleaning is achieved when the following factors and their underlying parameters can be adjusted and controlled as part of the CIP recipe: Mechanical Forces; powerful flows of fluid in combination with physical effects through nozzles. Chemical Reaction; dissolves residues. 90% of chemical cleaning agents are based on a alkaline formulation, using a acid to remove the alkaline film Temperature Reaction; (Heat), kills micro organisms and increases solubility and thereby the removal of residues. Time / Duration; the period of time in which the above points are in effect.

44 Testing of Coverage and Impact Performance BPE SD-5.1 Spray Ball Test Riboflavin is sprayed on internal surfaces, and coverage is verified by visually by ultraviolet lamp Test / verify coverage but not cleanability. As riboflavin is 100% soluble in water it is easily removed. Add other substances like protein and chemicals to detect and verify coverage and cleanability.

45 Testing of Coverage and Impact Performance Newer methods available for verifying reproducibility of cleaning performance are besides conductivity: Monitor frequency and amperage on multi-stage centrifugal pumps Acoustic monitoring of: Rotation Spray Loss Spray Pressure Variations Rotational Frequency Variations TOC monitoring

The Green, Clean and Lean Approach to Cleaning API Equipment

The Green, Clean and Lean Approach to Cleaning API Equipment By: Albin J. Friedrich Project Manager - Mork Process Inc. Traditional Clean-in-Place (CIP) technology has its shortcomings: its labor intensive,