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. 

Industry criteria

Title 21 CFR– 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 VIIn vivo animal biological reactive tests for polymeric materials

FDA– Food and Drug Administration

Regulation

• 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)

What is sterile manufacturing

Where used

Aseptic processing area

Direct impact system

Where used

• 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

Where used

Indirect impact system

• Multi-product ManufacturingContaminants 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

Why do we need 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.)

How we do cleaning

• Manual cleaning• SIP (Steam in place)• CIP (Clean in place)• COP (Clean out of place)

Cleaning method

CIP & SIP

Phase 1

Pre-Rinse

Phase 2

Alkaline Wash

Phase 3

Airblow and Drain

Phase 4

Water Rinse

Phase 5

Acid Wash

Phase 6

Airblow and Drain

Phase 7

WFI Rinse

and Drain

Phase 8

Airblow and Drain

CIP (cleaning in place) Cycle

CIP skid package

• 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

CIP capacity gains

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.

Cleaning method

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.

• Semi-automatic cleaning• Automated cleaning systems• Steam sterilization and sanitization• Chemical sterilization & sanitization

Cleaning method

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

CIP validation

• The equipment usage – (dedicated equipment or

not)

• The stage of manufacture – (early, intermediate, final

stage)

• The nature of contaminants– (toxicity, solubility etc.)

The level of cleaning

• 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?

Valve related issues

Where valves are used

• 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

Valve design concept

• 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

Valve design features

• 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

48 series ball valve Tubore feature

• Castings A351 CF3M (316L)

• Forged Stainless steel 316L/1.4435 

• Ferrite level < 5% (< 1% optional)

• Controlled Sulfur 0.005 – 0.017%

• 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

Body material

• No slots or chamfers• Low torque• Bubble tight• TFM material

Seat design

Seat material

Cavity filler seat

• 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

What is rouging

• 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 red‐

orange 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– either blue or black, found in high temperature steam systems

Rouging class

• 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

How do we avoid rouging  SURFACE TREATMENT

SURFACE TREATMENT

SURFACE TREATMENT

SURFACE TREATMENT

• Standard 25 Ra max• 15 Ra max for special applications • Improve Cleanability• Enhance corrosion resistance• Removes inclusions

Mechanical polishing & electro‐polishing

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

Tubore design feature

• IMPERIAL– Clamp ends (TC)– Extended tube OD (ETO)– ASME BPE

• METRIC– DIN Clamp ends (TCD)

• DIN 32676

– DIN Extended tube (ETD)• DIN 11850

– Extended tube (ETI)• ISO 1127

– ISO Clamp ends (TCI)• ISO 2852

End connections

End connections

• True bore• Diverter D and S• 4‐Way 64 series• Cavity filler• Flush Tank• Fire Safe • Manifolds• Self Flush• Ball options 

Tubore valve option

• 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

Fire safe design

• In‐House assembly• Oil free assembly area• DI Water• Vacuum oven dry• 100% testing• Helium leak test• Nitrogen bagged• Marking & MTR’s

Cleaning testing & packaging

• Locked In last position• In‐Line assembly• Spring loaded• 6 mm pad lock (not included)• Sizes ½” to 1½”• Stainless steel

Locking device

• Manual or actuated• Extended mounting kits• Special balls for draining• Cavity or Flush ports

Flush bottom valve

CIP valve’s ball design

• 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 

Valve’s design for biotech industry