6 th Annual EU Validation Week David W. Vincent SESSION 10: Setting Acceptance Criteria for Cleaning Validation Amsterdam, Netherlands March 17 – 19,

6th Annual EU Validation Week

David W. Vincent

SESSION 10: Setting Acceptance Criteria for Cleaning Validation

Amsterdam, NetherlandsMarch 17 – 19, 2015

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CONTACT INFORMATION for Course Leaders:

David Vincent/CEO/COO

Validation Technologies, Inc.

San Diego, CA

Toll Office: 800-930-9222

Phone: 858-673-3606

Email: [email protected]

Website: www.validation.org

mailto:[email protected]

http://www.validation.org/

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Seminar Contents

• Regulatory Expectations• Cleaning Cycle

Development • Setting Acceptance

Criteria for Cleaning Validation

• Validation Cleaning Policy/Program

• Cleaning Considerations

Part 1

Regulatory Expectation For Cleaning Validation

International Regulatory Good Manufacturing Practice

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Possible types of limits

• Chemical• Visual• Microbiological• Endotoxins • Particulate

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Visual inspection

• Equipment should be visually clean• Why? GMPs require inspection for visual cleanliness prior

to manufacture• Key items to consider

– Surface usually must be dry– Angle/viewer– Location/Access– Distance– Lighting

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Chemical analytical limits

• Care in terminology• Avoid

– “No” residue– “None detected”

• Confusion in use of term “limit”– What is “10 ppm” --

• 10 ppm in swab desorption sample?

• 10 ppm in “rinse” sample?

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Possible uses of “limit”

– Concentration in next product (µg/mL)– Absolute amount in manufacturing vessel train (mg) [MAC-

maximum allowable carryover]– Amount per surface area (µg/cm2 or in2)– Amount in analytical sample (µg or µg/mL)– Concentration in “rinse” water (µg/mL)

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Other basis for limit

• Other options than clinical dose– Minimum pharmacological effect dose– NOEL (no observable effect level)

– Safety related factor (ADI, LD50, reproductive hazards)

• Other ppm levels based on– Effects on stability– Effects on efficacy of subsequent product

(diagnostics)

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Safety factors

• Some use staged factors:– Parenteral: 10,000 0.0001– Oral: 1,000 0.001– Topical: 100 0.01

• “Safety” factor is not a “pure” safety factor– Factor actually is combination of conversion factor &

safety factor– Practical matter: still called safety factors

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Limit depends on...

• First active – Minimum daily dose of active– Calculated asactive/unit X units/dose X minimum doses per day

• Second product– Maximum daily dose of product– Calculated asunit weight X units/dose X maximum doses per day

Part 2

Setting Limits for Use in Cleaning Validation – Case Study

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Does not depend on…

• Nature of active in next drug product• Level of active in next drug product• Exception: specific information available to suggest adverse

interaction

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But we aren’t just worried about product residues

• We have to set limits / acceptance criteria for product residues and cleaning residues – but the clear expectation is that we also set limits / acceptance criteria for bioburden and endotoxin – and other measures of general cleanliness (as appropriate for your soils/equipment (Company uses TOC and Conductivity) as well.

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Setting the non-product related limits

• Some – especially your Quality counterpart – may want you to set your limits at WFI spec.– The common statement is “the final rinse water coming

out of the equipment should meet the same specifications as the water being put into the system to do the rinse”

– This would mean (if you use WFI for your final rinse)• TOC - <500ppb• Conductivity < 2.1µcm/cm2

• Bioburden <10cfu/100ml• Endotoxin < 0.25EU/ml

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Setting the non-product related limits

• Setting the limits at WFI specs – pros and cons

• Pros– Your protocols go through your quality department without

“discussions” (i.e., arguments and heated debates) about how you chose the limits

– Your discussion with the auditors during audits is very easy and, in my experience, when you tell them you have set your limits at WFI specs they back off the topic and move on

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Setting the non-product related limits• Cons

– You will have to go to monumental efforts/have long wash and flush times/have very short clean hold times to meet these limits

– Translation – development and validation take 3x’s longer (so your project manager hates you)

– the cycle you validate in the end uses tons more WFI (so your utility manager hates you)

– the cycle you validate is very long to run (so your operations manager hates you)

– you get more “alert” hits during routine monitoring which puts product on hold (so your site vice president of operations hates you)

• Ultra Translation – you better look for a new job– In some cases with some equipment designs – you just

won’t be able to meet these limits• centrifuge example

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The Centrifuge

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Centrifuge Example

• The project was in response to a March FDA observation that stated that no studies had been performed to validate the cleaning and sanitization of the centrifuge utilizing the rotors used in the zonal centrifugation step.

• The response to FDA was that validation to support the cleaning and sanitization of the centrifuge was targeted for completion by Q4.

• With a monumental effort – we were passing cleaning validation for TOC, endotoxin, and conductivity

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Centrifuge Example

• The cleaning that was developed consisted of a manual clean along with an in-place clean– We were cleaning first manually (tearing apart the

centrifuge) and • scrubbing the rotar in the sink with CP310• Sonicating all of the greasy parts in a sonicator with

micro 90• Hand wiping the inside of the centrifuge

– We then put the centrifuge back together and attached a bottle of hypochlorite/hydroxide mix to the centrifuge and, using a peristaltic pump, pumped the flow around for approx 1 hr (with the rotar spinning slowly)

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Centrifuge Example

• The cleaning that was developed consisted of a manual clean along with an in-place clean (con’t) – Then we put cooled WFI in a bottle attached that and let

that flow around for about 30 min– We then replaced the bottle with a new bottle of cooled

WFI and again let that flow around for 30 min– We repeated the cooled WFI for a third time and took

samples• Bioburden still was NOT passing 10cfu/100ml.

– We were getting hits of 20cfu/100ml to 120 cfu/100ml during our validation attempts

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Centrifuge Example

• So we were getting way more than a 3 log reduction in bioburden during our cleaning…..but we weren’t meeting the WFI bioburden spec that the site had set as the acceptance criteria

• The centrifuge can not handle high heat – the rotar is made of Noryl which expands quickly at high temperatures and binds up the centrifuge

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Centrifuge Example

• The centrifuge has threaded fittings and small bore openings; there is a deadleg on the top of the centrifuge where the rotary seals are located

• The project was already years late in completing the work we had committed to for the FDA.

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Centrifuge Example

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Centrifuge Example

• In the end – our site acceptance criteria for bioburden during cleaning validation was modified site-wide to– 10cfu/ml (1000cfu/100ml) for equipment that is NOT post

cleaning sterilized– 100cfu/ml (10000cfu/100ml) for equipment that is post

cleaning sterilized

• FDA accepted the response to the 483 for the cleaning of the centrifuge’s. The bioburden acceptance criteria has not been challenged by the FDA since the criteria was modified.

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What about TOC? Is <500ppb realistic

• NO – the processing equipment is just not capable of maintaining the same WFI specs as the piping system designed specifically for maintaining WFI specs.

• How do I set the limits for TOC then?– TOC is coming from: the water, the equipment, my

product (we will talk about product specific limits a little later), the detergent

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TOC

• At Company we set the TOC limits at– 10ppm rinse or swab in “stage 1” equipment– 5ppm rinse or swab in “stage 2” equipment– 2.5ppm rinse or swab in “stage 3” equipment

• These numbers are based upon cleaning capability and the risk to the next batch from leaving this level of soil behind

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Endotoxin

• At Company we set the Endotoxin limits at– 8EU/ml for stage 1 Harvest – 4EU/ml for stage 2 Purification – 0.25UE/ml for stage 3 Formulation and filling

• These numbers are based upon cleaning capability and the risk to the next batch from leaving this level of soil behind

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Conductivity

• This one gives us the most problems during routine monitoring– Easy to contaminate sample– Conductivity level in the WFI has some variability (it may have run

around 1.2 during validation but is now running closer to 1.6– In-line conductivity probe may be solidly passing but we still get a

barely failing results from our grab sample• So – WHY do I have to rinse to 2.1µsm/cm2?

– Detergent carryover MAC calcs correlated to conductivity tell me I can be closer to 5µsm/cm2 with no impact

– BUT – just because you are below the MAC does NOT mean the residual will have no impact on the process

• EDTA example – ppt residual levels are impacting the process reaction

• At Company we plan to do more work to set limits for conductivity that are correlated with MAC calculations and process impact assessments

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Product Specific Residues

• MAC (Maximum allowable Carryover) calculation or 10ppm calculation– At Company – we need to perform MAC calculations and

10ppm calculation for (where applicable):• Product markers• Aluminum• Mercury• Detergents• Other Impurities

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Setting Limits for Use in Cleaning Validation

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Part 3

Development Acceptance Criteria

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Cleaning Selection Process

• Manual cleaning is labor intensive, depends on operators, and not reproducible. (varies from operator to operator)

• Clean-Out-Place (COP) requires dirty parts and/or component to be removed (disassembled) from the system and transported to location where they can be cleaned. i.e. Parts Washer, Ultrasonic Bath

• Clean-In-Place (CIP) automated, all dirty (soiled) surfaces are cleaned in place. (large surface area i.e. process piping, vessels, valves, gaskets, etc.)

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Cleaning Cycle Development Steps

• Cleaning Cycle Development Plan− Process and Cleaner Evaluation (PACE) Studies (Lab

scale cycle development and cleaning agent selection) i.e. Coupon Soiling

− Worst Case Soling Material Assessment− Swab / Rinse Design of Equipment (DOE) Recovery− Material of Product Contact (MOPC) Assessment− Cleaning Characterization Studies

• Engineering Studies− CIP Skid: Wash Out Curve − Cleaning Cycle Development Shake Down Runs− Cleaning Cycle Optimization

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Cleaning Cycle Development Strategy (Step by Step)

• Performed prior to process validation• Spray Coverage – FAT or SAT• Perform Surface Area Calculation for Equipment Train• Lab Scale Cleaning Characterization

• PACE Studies• Characteristic of residuals• Cleaning agent select and concentration

• Analytical Methods to Be Developed and Validated• Cleaning cycle development procedures

• Perform Wash Out Curve to Meet TACT• Rinse cycle time and volume• Cleaning agent temperature• CIP-Pressure (Turbulence)

• Cleaning-SOP change or improvement• Operator training and training report

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Cleaning Cycle Development Strategy, Cont.

• Performed Wash Out Curve (WOC) – Determine at which stage conductivity readings becomes normal for final rinse cycle.

• WOC – Cost effective method of developing cleaning operating parameters

• Establish TACT

T

A

C

T

ime

ction

oncentration / Chemistry

emperature

Critical Process Parameters for Cleaning

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Spray Ball Coverage Study (CIP)

• Milk powder visual • Riboflavin (0.2 gm./L)

UV detection i.e. coat on surface i.e. top side walls, man way, blades, probes, etc..

• Pressure (established at standard flow rate)

• Visual detection• Photo documentation

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Part 4

Selection of Sample Location

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Worst Case Selection

• Develop a selection procedure for the worst case using a combination of the following areas and the information gathered on the matrices developed:– Minimum Pharmacological or Therapeutic Level

Evaluation – Toxicity Levels Evaluation– Hardest to Clean Component– Components Solubility Analysis– Equipment Considerations

• May result in several combinations selected as “worst case”

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Sampling Site Selection

• Best case Assumptions– Even distribution of contaminant– Sampling of any site satisfactory

• Worst case– Non-uniform distribution of contaminant– Careful selection of sampling sites required

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Considerations in Sampling Site Selection

• Types of sites selected may be based upon:– Equipment geometry

• Difficult to clean locations• Potential for non-homogeneous contamination

– Different materials of construction• Number of sites to be selected may be based upon:

– The considerations, above– The overall dimensions of the equipment

Part 7

Setting Acceptance Criteria and Calculating Residue Limits – Work Shop

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Absolute amount limit

• Absolute amount in manufacturing vessels [MAC]• Calculate by multiplying concentration limit times batch size

of subsequent product• Absolute Amount Sample:

– Concentration limit of active in A in product B is

2.0 µg/g– Batch size of B is 200 kg – Absolute amount of active in A allowed in batch of B is 2.0

µg/g X 200 kg = 400,000 µg– This is same amount allowed in shared product surface

area in vessels

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Limit per surface area

• Calculated by dividing absolute amount limit by shared surface area

• Example:– Absolute amount = 400,000 µg– Shared surface area is 200,000 cm2

– Limit per surface is

400,000 µg/200,000 cm2 = 2.0 µg/cm2

• Assumes uniform distribution (worst case)

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Analytical sample example

• Assumes uniform distribution (worst case)−Limit per surface area = 2.0 µg/cm2

−Surface sampled is 25 cm2

−Limit per swab = limit per surface X surface area − 2.0 µg/cm2 X 25 cm2 = 50 µg −If desorbed into 30 ml solvent,− 50 µg/30 ml = 1.7 µg/ml

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“Rinse” solution limits

• Meaning of “rinse” solution limits?– How relate to conc. in next product?– Is 5 ppm in “rinse” solution same as 5 ppm in next

product?• Key is to identify volume of rinse solution and area

sampled

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Sampling rinse example

• Limit per surface area = 2.5 µg/cm2

• Surface sampled = 200,000 cm2

• Sampling volume = 100 liters• Limit per analytical sample is… 2.5 µg/cm2 X 200,000 cm2 = 5.0 µg /mL 100,000 mLThis is same as: MAC amount rinse solution

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Summary

• WHEN TO VALIDATE– Initial Validation– Change In Cleaning Procedures– Change In Equipment– Change In Formulation– Change In Process– New Product Line– Operator Qualification

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Things to avoid

• Limit unrelated to target residue• Limits based on assay limits• Limits based on compendial water specs• Limits selected arbitrarily• No documentation of how selected

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Thank You!!

Documents

6 th Annual EU Validation Week David W. Vincent SESSION 10: Setting Acceptance Criteria for Cleaning Validation Amsterdam, Netherlands March 17 – 19,