Regulation. Code of Federal Regulations in the United States. Chapter 1 Title 21 CFR is the title for pharmaceuticals.

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Ethelbert Fields
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ASME BPE 2014 The ASME BPE standard provides requirements for systems and components that are subject to cleaning and sanitization and/or sterilization

1 ASME BPE 2014 The ASME BPE standard provides requirements for systems and components that are subject to cleaning and sanitization and/or sterilization including systems that are cleaned in place (CIP) and/or steamed in place (SIP) and/or other suitable processes used in the manufacturing of biopharmaceuticals.

2 Industry criteria

3 Title 21 CFR Regulation Code of Federal Regulations in the United States. Chapter 1 Title 21 CFR is the title for pharmaceuticals. USP USP: United States Pharmacopeia, Classes V and VI In vivo animal biological reactive tests for polymeric materials FDA Food and Drug Administration

4 What is sterile manufacturing Aseptic processing area where product is formulated Direct impact systems (have affect on product quality) Indirect impact systems (do not have affect on product quality)

5 Where used Aseptic processing area

6 Where used Direct impact system

Where used Indirect impact system Process Support Systems Purified water and WFI (water for injection) Nitrogen and other Process Gases Clean steam

7 Where used Indirect impact system Process Support Systems Purified water and WFI (water for injection) Nitrogen and other Process Gases Clean steam (from steam generator) Compressed air Heating and cooling systems Steam and hot water systems Process vacuum systems Potable water Mechanical seal fluids

8 Why do we need cleaning? Multi-product Manufacturing Contaminants present in next batch manufactured: Precursors to the active pharmaceutical ingredient By-products and/or degradation products of the active pharmaceutical ingredient The previous product Solvents and other materials employed during the manufacturing process. Micro-organisms Cleaning agents and lubricants

9 How we do cleaning In-line sterilization of processing equipment Clean in place/steam in place (CIP/SIP) A way to clean processing equipment without moving them or taking them apart using a high-pressure rinsing treatment and is sometimes followed by SIP sanitization (tanks, piping, valves etc.)

10 Cleaning method Manual cleaning SIP (Steam in place) CIP (Clean in place) COP (Clean out of place)

11 CIP & SIP

12 CIP (cleaning in place) Cycle Phase 1 Pre-Rinse Phase 4 Water Rinse Phase 7 WFI Rinse and Drain Phase 2 Alkaline Wash Phase 5 Acid Wash Phase 8 Airblow and Drain Phase 3 Airblow and Drain Phase 6 Airblow and Drain CIP skid package

CIP capacity gains 4 factors that affect efficiency of CIP: Cleaning Solution Temperature Cleaning Solution concentration Cleaning Solution contact time

13 CIP capacity gains 4 factors that affect efficiency of CIP: Cleaning Solution Temperature Cleaning Solution concentration Cleaning Solution contact time Velocity and pressure (turbulence) Capacity Gains Reduce cycle time by 50% Increase production runs Reduction of water usage Cleaning agent usage Plant operating costs

Cleaning method SIP (steam in place) is a timed sterilization of the upstream & downstream biopharmaceutical production train with clean steam.

14 Cleaning method SIP (steam in place) is a timed sterilization of the upstream & downstream biopharmaceutical production train with clean steam. It is part of the 5 step sanitation routine that occurs after every production batch and follows the final rinse (CIP). Every square cm of all process piping & vessels that come in direct or indirect contact with process input, process & process output is sterilized to insure that there is no microbiological activity in the system. Clean steam is circulated through all the process tubing during this stage and enters large vessels through spray balls (engineering nozzle) imbedded in the vessel ceiling.

How we do cleaning Critical requirement of SIP (steam in place) Proper clean steam distribution Non condensable gas removal from the clean steam with

15 How we do cleaning Critical requirement of SIP (steam in place) Proper clean steam distribution Non condensable gas removal from the clean steam with separator Continuous condensate elimination with steam trap Note: SIP is done also for: Sterilization of sterilizer (autoclave) Sterilization of filters Etc.

16 Cleaning method Semi-automatic cleaning Automated cleaning systems Steam sterilization and sanitization Chemical sterilization & sanitization

17 Essentials to ensure CIP/SIP validation Good Engineering Practices Adequate piping design Steam traps Valves Monitoring instrumentation CIP validation

18 The level of cleaning The equipment usage (dedicated equipment or not) The stage of manufacture (early, intermediate, final stage) The nature of contaminants (toxicity, solubility etc.)

19 Valve related issues How do we reduce contamination? What can we do about sterility? What must we implement in our valves? What technologies can we use? What type valves are used? What designs are there? What are acceptable materials? What are the ball valve applications? What are acceptable criteria s?

20 Where valves are used

21 Valve design concept Cleaning and maintaining sterility Minimize dead legs Material conformity No entrapment Flushing of internal cavities Proper drainage Valve manifold assemblies Proper slope (1 or 2 %, 0.6 to 1.2, 10 to 20 mm per meter) Minimize distance between valves

22 Valve design features Design to ASME/BPE S.St. 316L Body, Ends, Ball and Stem Matched ID Minimum Dead Leg Encapsulated Body seals Non exposed body bolts ISO 5211 mounting pad Live Loading Stem

23 48 series ball valve Tubore feature True bore flow Bubble tight Shut-off Non-exposed body bolts Cast or forged made body and ends HermetiX stem seal TFM seats FDA approved 25 Ra max standard surface finish ISO 5211 for cast valves Locking Device (LD), Fugitive Emission (FE) and spring return handle (SRH) mountable

Body material Castings A351 CF3M (316L) Forged Stainless steel 316L/1.4435 Ferrite level < 5% (< 1% optional) Controlled Sulfur 0.005 0.

24 Body material Castings A351 CF3M (316L) Forged Stainless steel 316L/ Ferrite level < 5% (< 1% optional) Controlled Sulfur % FDA approved soft materials PTFE, TFM or virgin PEEK Stainless steel bolts, nuts and handle Optional Alloy C22 castings, AL6XN, Alloy 20, Other exotic alloys

25 Seat design No slots or chamfers Low torque Bubble tight TFM material

26 Seat material

29 Cavity filler seat

30 What is rouging What is it? Result of the formation of iron oxide, hydroxide or carbonate either from external sources or from destruction of the passive layer Rouging can take place in: pure water ultra pure water Steam treated potable water untreated process water

31 Class I Rouge originating from external sources, usually by erosion or cavitation of pump surfaces concentration is heaviest near the source and decreases with distance Color change with distance from the source, being orange to redorange near the source and changing to magenta some distance away Class II Rouge originating from chloride induced corrosion of the stainless steel surfaces Class III Rouge Rouging class either blue or black, found in high temperature steam systems

It does not remove all chromium depleted material from the surface Leaves microscopic crevices.

32 How do we avoid rouging SURFACE TREATMENT Passivation A process to remove free iron contamination Mechanical polish Often used to prepare stainless steel surfaces before pickling. It does not remove all chromium depleted material from the surface Leaves microscopic crevices. These create concentration cells where the acid chloride solutions may be retained and continue to react Electro polish Removes microscopic crevices Produces a passive layer with a higher Cr/Fe ratio

33 SURFACE TREATMENT

34 SURFACE TREATMENT

35 SURFACE TREATMENT

36 Mechanical polishing & electro polishing Standard 25 Ra max 15 Ra max for special applications Improve Cleanability Enhance corrosion resistance Removes inclusions

37 Tubore design feature Fully drainable valve FDA approved materials High Cv Excellent Shutoff Unexposed seats and ball Blowout proof Stem Simple to Maintain Easy to Actuate

38 End connections IMPERIAL Clamp ends (TC) Extended tube OD (ETO) ASME BPE METRIC DIN Clamp ends (TCD) DIN DIN Extended tube (ETD) DIN Extended tube (ETI) ISO 1127 ISO Clamp ends (TCI) ISO 2852

39 End connections

40 Tubore valve option True bore Diverter D and S 4 Way 64 series Cavity filler Flush Tank Fire Safe Manifolds Self Flush Ball options

Fire safe design Fire safe to API 607 Double

Antistatic Alignment of body to end Tongue &

41 Fire safe design Fire safe to API 607 Double containment sealing Graphite sealing of Body and Stem Primary PTFE seals in body HermetiX fire safe stem seal Secondary graphite seals Antistatic Alignment of body to end Tongue & Groove Shorts bolts tapped to body One size up bolts Metal sealing in line

42 Cleaning testing & packaging In House assembly Oil free assembly area DI Water Vacuum oven dry 100% testing Helium leak test Nitrogen bagged Marking & MTR s

43 Locking device Locked In last position In Line assembly Spring loaded 6 mm pad lock (not included) Sizes ½ to 1½ Stainless steel

44 Flush bottom valve Manual or actuated Extended mounting kits Special balls for draining Cavity or Flush ports

45 CIP valve s ball design

46 Valve s design for biotech industry Existence of Dead Leg in pipe lines may cause contamination and rejection of valuable process batch Habonim introduced to the market a complete line of Zero pocket valves which eliminates bacteria colonies development

We Offer Both Cast Ball Valves & Forged Ball Valves.

We Offer Both Cast Ball Valves & Forged Ball Valves. 11 GENEL SCREWED END BALL VALVES / FORGED BALL VALVES V-155 THREE PIECES BALL VALVES V-255 Full port : 1/4 2-1/2 (DN8-DN65) : 3/8 2-1/2 (DN10-DN65), Anti-static design ASTM A351 Gr.CF8M (1.4408) Full port