CIP Cycle Development and Cleaning Validation

ISPE GLC Regional Meeting April 2012

Matt Wiencek P.E. Commissioning Agents, Inc.

Agenda

Predicate Rules, References Overview Cleaning Validation Basic CIP Cycle and Equipment Case study of CIP CD

Why is Cleaning Important?

It is the first step in the next batch not the
last step of the current batch

Residue remaining prior to SIP serves as

an insulator to bioburden

Sterile filth is no more desirable than nonsterile filth - Seiberling

Predicate Rules
21CFR Part 211.67 and 211.182 Equipment Cleaning
and Maintenance
Appropriate intervals, written procedure, protection from contamination prior to use, cleaning records

Eudralex Volume 4, Ch 3, Premise and Equipment

Premise cleaning, prevent cross contamination, procedures, equipment clean storage and dry, dedicated cleaning equipment

Eudralex Volume 4 - Annex 1- Sterile Products

Terminal sterilization, moist heat, dry heat, radiation, aseptic processing

Eudralex Volume 4 - Annex 2- Biological Products

Personnel training, equipment cleaning, equipment operating principles and quality control

Regulatory Guidance
ICH Q7 - GMPs for APIs
Procedures, segregation of equipment, cleaning schedules, cleaning agents, disassembly/assembly procedures, inspection prior to use, clean hold time, dirty hold time, equipment status, cleaning validation, shared vs dedicated equipment

ICH Q8 - Pharmaceutical Development

CQAs, risk assessments, design space, control strategy, life cycle approach

ICH Q9 - Quality Risk Management

QRM methods, FMEA, HACCP etc

FDA - Validation of Cleaning Processes Guide

SOPs, protocol requirements, sample plans, methods validation, acceptance criteria justification

FDA - Biotechnology Inspection Guide

How clean is clean?, residue level worst case locations

References
PDA Technical Report #49 - Points to Consider
for Biotechnology Cleaning Validation

Clean-In-Place for Biopharmaceutical

Processes, Seiberling, 2009
CIP technology, design issues, C&Q

Cleaning and Cleaning Validation: A

Biotechnology Perspective, PDA, 1996

Validation study design and acceptance criteria

Cleaning Validation
FDA : The purpose of cleaning validation is to demonstrate that a
particular cleaning process will consistently clean the equipment to a predetermined limit: the sampling and analytical test methods should be scientifically sound and provide adequate scientific rationale to support the validation.

Practically Speaking:
Data gathering exercise via samples, in-line trends, operating procedures and reports which demonstrate a compliant, robust and repeatable process that satisfies end user requirements and regulatory expectations. Not a time to trouble shoot, debug and investigate failures. If this happens most likely a process is not designed to be cleanable and/or the CIP cycle development effort was inadequate and/or change is not being managed properly.

Cleaning Validation
Regulatory(Guidance(and(Best(Prac.ces( Site(Valida.on(Master(Plan( Cleaning(Valida.on(SOP(or(Master(Plan( Cleaning(Valida.on(Project(Plan((and(Report(for(closeout)( Cleaning(Valida.on(Risk(Assessment( Cleaning(Valida.on(Protocol(Reports( Cleaning(Valida.on(Protocols(:(Comply(with(Plan( CIP(Cycle(Development(Report(:(What(Changed(and(Why,(Results( CIP(Cycle(Development(:(Adjust(Parameters,(Develop(SOPs,(Samples( Commissioning(and(Func.onal(Check3out(:(CIP(Skid(and(Equipment( Design(Review(:(Is(it(Cleanable?(Mechanical(and(Automa.on(

PDA Guidance

Technical Report No.49 Points to Consider for Biotechnology Cleaning Validation

Technical Report #49

Cleaning Process
Design and Development Acceptance Limits Sampling Methods Analytical Methods Cleaning Validation Protocols Maintenance of Validated State

Master Planning for

Cleaning Validation Risk Assessment and Management Special Considerations Regulatory Issues References MACO Calculation Examples

Basic CIP Cycle and Equipment

CIPS Valve Manifold Vessel 1 Valve Manifold Vessel 2 Valve Manifold

CIP Skid

Vessel 1 CIPR Valve Manifold Vessel 2 Valve Manifold

Vessel 2

Vessel 2 Valve Manifold

Basic CIP Cycle and Equipment

From CIP Circuit / CIPR Header TC V PID To CIP Circuit / CIPS Header FC V TE/ TIT HX TE/ TT LIT FSL Water Inlet Vessel SB AE/ AIT CIPS Pum p Chemical Injection May use VFD instead of FCV Vent Filter FE/ FIT PIT PID

AE/ AIT

Steam and Tempered Water

Basic CIP Cycle and Equipment

Dissolving
Mass transfer - diffusion of residue into solution

Saponifying
Degradation of lipids into fatty acids and glycerol

Peptizing
Cleavage of complex proteins into peptides

Wetting
Surfacants used to reduce surface tension

Emulsifying
Prevents precipitation, keeps residue in suspension

Sequestering
Chelants prevent minerals from precipitating Chlorine should never be used with acid!

Basic CIP Cycle and Equipment

Pre-rinse, caustic wash, rough rinse, acid wash, pre-final rinse,
final rinse
Pre-rinse-removes bulk soil to drain, single pass, can be based on time, RO, PW, WFI, cool or hot Caustic wash (CIP-310TM) solubilizes carbonaceous material, recirculated, hot Rough rinse removes detergent and soil, based on time, hot, single pass Acid wash (CIP-200TM) demineralizes inorganic salts, mild derouge and passivation, time based, recirculated Pre-final rinse removes acid solution, time based, single pass Final rinse, time based to a conductivity limit with time-out limit

Basic CIP Cycle and Equipment

90
Flow (gpm) Temp (C) CIPS Cond (mS) CIPR Cond (uS)

80

70

60

50

40

30

20

10

0 0 20 40 60 Time (min) 80 100 120 140

Basic CIP Cycle and Equipment

Sequence Definition Matrix

Charge Wash Tank

Chemical Feed

Heat Solution

Recirculate
X

Pump Out

Drain #1

Temp reqd Level reqd Timer reqd Caustic feed Acid Feed X X X X X X X

Rinse #1

X X

CIP Sequence advances to the next step when the condition is met

Drain #2

Basic CIP Cycle and Equipment

Recipe Matrix Chart

Rinse #1 Drain #1 Pump Out Charge Wash Tank Chemical Feed Recirculate Wash Drain #2 Rinse #2 Drain #3

Recipe 1 (time)

30 20 60 120 20 30 20 30 20

Time parameters listed for each CIP recipe

Recipe 2 (time)
20 10 40 100 10 20 10 20 10

Basic CIP Cycle and Equipment

Device Sequence Matrix
Charge Wash Tank Chemical Feed Heat Solution Pump Out Recirculate Drain #1 Drain #2 Rinse #1 Rinse #2

Valve 1 Valve 2 Valve 3 Valve 4 Valve 5

O C P C C

C C O C C

C C C O C

O O C C C

C C C C O

O C O C C

O C P C C

C C O C C

O C P C C

Each recipe step includes definition of which devices are energized.

Case Study
100 individual CIP circuits cleaned with 35 procedures. Procedures are
customized via configurable parameters - recipes - using ISA-S88 batch control standard Delta V Control Platform for all process and CIP skids (no PLCs) Total number of CIP CD runs for all departments ~ 410 Total number of CIP parameters managed ~ 3,000 Total number of samples taken during CIP CD ~ 2,500 Dry Run valve sequencing was tested during commissioning Developed a CD protocol per area that required a water only hydraulic balancing run followed by a chemical only CIP cycle to demonstrate cleaning solution removal. Objective was an alarm/stop/abort free cycle, efficient use of water, chemical and time, robustness Following successful chemical cycle, soiled runs were conducted with rinse samples, swabs and visual inspections Dont soil equipment until a verified chemical cycle is in-place Parameters locked down after soiled run success for CV Conducted some preliminary SHT and CHT testing when possible - risk

Case Study
Lessons Learned
It is impossible to over communicate with manufacturing and maintenance staff regarding schedule. CV is not the only activity on the schedule Semi-automated CIP cycles are high risk for failure. Fully automate if possible. UF membrane final rinsing requirements require extra attention and robustness Run all possible operation combinations in parallel to ensure no conflicts in equipment/valve acquisition. Very helpful have QA buy-in to separate CV event failures between those critical to TACT versus operational issues. Have a Critical Conversation before you approve the protocols. Efficiency CD step cut short due to schedule pressure

CIP CD Considerations
Manual.Automated Cleaning COP..CIP DedicatedNon-Dedicated Product ContactNon-Product Contact Non-Critical SiteCritical Site Simple Equipment...Complex Equipment Low Risk.High Risk Drug Highly Characterized Soil..Poorly Characterized Sterile..Non-Sterile Solid Formulations..Liquid Formulations SolubleInsoluble Single Product FacilityMultiple Product Campaigned Production.Non-Campaigned Single Equipment Train..Multiple Train Equipment

From PDA TR#26 (retired)

CIP CD Considerations
Before you start, analyze the process
PID CIP circuit review for overlap and gap analysis How is the equipment integrated with the overall circuit Parallel paths cleaning is tricky Pipe diameters of circuit should be similar size Slopes 1/16 - 1/8 per foot and low point drain availability SB flow of 2.5 - 3.0 gpm / ft of tank circumference 5 ft sec or 30,000-40,000 Re will sweep out air pockets Passive layer must be maintained, 25Ra EP Filter cleaning dictated by materialscheck with vendor T style filter housings versus flow through housings Dead leg(s) and low points w/o drains. Portable equipment may be difficult to clean What is the plan for cleaning and tracking hoses? What are the target CHT and SHT for the process? Have coupon studies been conducted to determine target concentrations and temperatures?

CIP CD Considerations
Grouping Strategies
Purpose - Make a complex project simpler Family or Matrix Approach

Similar or same equipment type Holdup volume Cleaning method and agent Soil types

Worst case
Concentrate CD on worst case and leverage data

CIP CD Program : Scope

CD starts ideally after commissioning Typically run before OQ - flexible Needs to be complete prior to PV/CV CD Program comprised of 3 Phases
Water only cycle - parameter verification Configure to meet cleaning user requirements Chemical only cycle - remove detergent Verify no dead legs in the system Soiled study prior to CV - remove product Establish that CV will be successful, limit NCEs during
CV

CIP CD Program : Scope

Benefits
The cleaning process is not fully understood until equipment soiled. Project cost pays for itself if OOS batches are minimized. Control Systems and equipment engineering projects resolved prior to cGMP state (change management). CD Study results for non-GMP investigative purpose. Not subject to audit. CV team walks through CV program logistics prior to CV (QC, CHT, SHT)

CIP CD Program : Scope

CIP CD is a method to address and minimize risks associated
with cleaning processes and develop process understanding.

SME knowledge should not leave the site when the project is
complete.

What risks?
Carryover over product from batch to batch - high TOC Residual detergents - high conductivity Soiled and Clean Hold Time Qualification - bioburden CIP cycle performance and repeatability - HOLD events Maintenance of surface finish - visual inspection CFR requirement Well developed SOPs and trained operators

CIP CD Program : Scope

How much is this going to cost?
Circuit Circuit Type M-1 Inlet line M-2 Inlet line M-3 Inlet line M-4 Outlet line M-5 Outlet line M-6 Outlet line M-7 Vessel M-8 Vessel M-9 Vessel M-10 Vessel Total Field Work Total to write studies Total to write final reports Total for rework associated with problems identified, tested Total for Project Days/ Days/ Water Chemical Days/Soile Unique/Clone Test Test d Test U 1 0.5 0.5 U 1 0.5 0.5 C 0.25 0 0 U 0.5 0.25 0.25 U 0.5 0.25 0.25 C 0.25 0 0 U 2 1 1 C 0.5 0 0 U 2 1 1 C 0.5 0 0 8.5 3.5 3.5 Total Days 2 2 0.25 1 1 0.25 4 0.5 4 0.5 15.5 20 15 5 40

CIP CD Program : Scope

Scope of water/chemical study
Definition of WHAT.not HOW

Temperature - ambient, intermediate or hot Cleaning concentration - supply conductivity Target flow rates
Vessels use FAT coverage results Lines use turbulent flow (5 ft / sec) UF skids use required shear rate per manufacturer

Develop full caustic/acid cycles in all departments? Return conductivity - final rinse limits Target rinse and wash time calculations - optimal Drain and air blow-down targets Control limits for critical parameters Chemical batch dosing curves WFI minimum flush volume requirements

CIP CD Program : Scope Questions

Scope of water/chemical study
Configurable Parameters - Standard vs Unique?

Wash Time example for Vessels

[(Sprayball wash time) + (diptube wash time) + (sample port time) + (additional path time)] x 120% Sprayball wash time will be >= the greater of two values: 2X FAT sprayball burst time 3 minutes Diptube, sample port and additional path time will be >= 1 minute per branch. Ensure that the last valve in the branch is cycled ON/OFF Valve cycling during the wash should be divided to achieve >= 2 complete cycles between sprayballs and all branches and minimize pooling < 1/3 dish volume

Chemical bulk dose example

The amount of time to achieve 90% of setpoint for specified volume

Mix wash example

The amount of time to turnover the average wash volume one time

CIP CD Program : Scope Questions

Scope of water/chemical study
Configurable Parameters - Standard vs Unique? Wash Time example for Lines UF skid flow rate example Centrifuge wash time
Ensure the wash time is long enough to accommodate manufacturers recommended number of discharges and minimal discharge volume Time to achieve 2-3X volume turnover of hold-up at 5 ft /sec Ensure each cartridge is cleaned using specified shear rate with valve cycling composite

CIPR flow time-out limit CIPR pump ON time

Amount of time to fill CIP circuit as detected by CIPR flow switch Amount of time to flood CIPR pump casing drain

CIP CD Program : Scope Questions

Scope of soiled study
Is this an Investigative Study or Validation Study?

IS is potentially more flexible. VS may permit leverage into CV Align the grouping analysis with CV Equipment size, configuration, material, soils
Define soils by unit operation. Is there a worst case (buffer)? Does equipment of the same size use the same procedure? How similar in configuration do they need to be to be the same

What is the equipment/CIP circuit grouping strategy to be used in CV?

What is the sample plan per unit operation

Rinse samples and swab samples Where do we swab? Where are the worst case locations? How do you decide what is worst case? Are the methods we will need for CV currently validated? How to prevent rinse sample contamination?

CIP CD Program : Scope Questions

Scope of soiled study
How many samples are required?

# of unit operations x # samples/unit operation x # of runs = #

samples Is QC ready for this sample load? Is the team trained in all appropriate methods to obtain samples? Are rinse sample valves available at all CIPR sample points? How are the final results tracked? Submission - testing - authorize results - reporting Are systems in-place to handle meta-data associated with samples? Most importantly, how many samples guarantee successful CV? When are you done? How much risk is permitted to carry into CV?

CIP CD Program : Scope Questions

Scope of soiled study
Execution of soiled study logistical considerations

Will production stop when we identify a problem to be fixed?

Is engineering and PCS support available? Are IOPQ activities competing for same equipment and engineering resources?

Does production have capability to schedule SHT and CHT? Does management understand impact of inadequate SHT and
CHT?
Exceed SHT - equipment release at risk Exceed CHT - re-clean, extra time and water

CIP CD Program : Scope Questions

Scope of soiled study
How to manage configurable parameters?

# of CIP circuits x # of parameters / circuit = # of parameters in study

100 CIP circuits x 30 parameters / circuit = 3,000

How is the audit trail handled for all parameters? Is it needed?

Is there a Gating mechanism that permits CV to start?

Does QA need to post-approve study final report prior to initiating CV?

Configurable parameters from study used in CV

How are investigations closed during the study?

CV will have formal investigations. Study may not.

CIP Cycle Time

Demonstrated we can clean the circuit. Is the time optimal? What risks associated with non-optimal cycle times? Is it a processing bottleneck? What is impact on water consumption? Where is it easiest to optimize? Washing, rinsing

Case Study Challenges

Sample Logistic Challenges
Engineering needs to install rinse sample ports Vessels may not have manways

Not reasonable to disassemble Access through ports using swab pole Confined space entry logistics
Aseptic technique for bioburden samples 2nd and 3rd shift coverage Some samples need to be on-test within 24 hrs Scheduling maintenance help for disassembly

Batching Chemical Solution Challenges

Volume vs Time based algorithms

Rinse Time Constraint Challenges

Single pass rinse capacity issues

Case Study Challenges

Vessel Cleaning
ASME BPE Cleanability SD-3.1 System Design SD-3.11
L/D, pipe velocity, Sprayball Test - SD-5.1

Identify Dead Legs

Chemical only cycle will highlight deadlegs

Transfer Line Cleaning Issues

Turnover volumes Velocity Limitations due to restrictions

TFF Cleaning Issues

Permeate backpressure inhibit flow to CIPR? Shear rates Temperature and chemistry unique requirements from 316L SS equipment

Case Study Challenges

Centrifuge Cleaning
ASME BPE 2001 Centrifuges SD-4.2 Product contact area definition when bowl is
disassembled

Bioreactor Issues
Multiple parallel paths increase cycle time Complex swab sampling plan

Valve and Diaphragm Issues

Valve fault due to hydraulic lock - line is full Failed diaphragms - how to locate

Case Study Challenges

Dirty Hold Time
Qualifies the CIP procedure Bioburden load while wet versus dry soil?

Clean Hold Time

Qualifies the method of holding equipment clean Measure the bioburden load with surface sample If a circuit is held under pressure dry, do you need to sample it?

Derouge and Passivation Concerns

Surfaces cannot be passivated while rouge is present Once rouge is removed, self catalyzed process with exposure to oxygen Nitric acid and citric acid good passivator CIP 200 (for example) good derouger

Case Study Optimization Examples

Optimize wash volumes
Use the minimal hold-up volume x safety factor 50L saved per wash x 2 wash / cycle x 50 cycle / month=5,000L/month = 60,000L/yr 5000L x 1% by volume = 50L chemicals / month = 600L / year

Optimize cycle times

Wash times = 2x FAT burst time vs arbitrary we clean everything here for 30min Reduce gravity drains and air blows to actual time by inspection, stethoscope Optimize valve cycling composites sequence based on flow Minimize water usage by using in-line trends or developing rinse out curves Selectively enable acid wash vs PM acid cycle 50 cycle month x (2.5 hr - 2.0hr) / cycle = 25 hrs / month = 275 hr / year

Full CIP Cycle vs WFI only Cycle

Non-carbonaceous soils (buffers) may not require regular chemical cycle Two WFI rinses vs Pre rinse, caustic, rough rinse, acid, pre-final and final rinse 10 cycles / month x ( 2.0 hr - 0.5 hr) / cycle = 20 hr / month = 240 hrs / year

Wrap-Up
Start as early as possible by establishing
scientific cleaning requirements Develop a structured approach to CD by the use of test protocols Establish a multi-disciplinary team that carries through to CV completion Dont fix a poor mechanical design with software Before a change is made, understand the root cause of the problem

 Questions? Contact Info

Matt.Wiencek@cagents.com