dr dan egan (msd) ispe cleaning slide

8/9/2019 Dr Dan Egan (MSD) ISPE Cleaning Slide

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ISPE Seminar:

a sson u o e ,Cork

Ma 22nd 2014

Equipment Cleaning in a multipurpose API

facility and the development of a Risk Based

Approach to Cross Contamination Control

Dr. Daniel Egan

Technical Lead, API

MSD


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MSD Businesses across Ireland


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•

• Named API R&D Commercialisation site in 2005• ew ormu a on ac y opera ona n

• 430 employees + ~70 full time outside contractors

Site currently supportsworldwide revenues of

.

on new product R&D

commercialisation

25 international customers

~


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Cross Contamination Control – Using a Risk Based

Approach . Risk Identification Risk Analysis Risk Evaluation

Role of Cleaning Validation in Cross ContaminationControl Development of a new cleaning regime

ean ng pec ca ons Cleaning Validation Documentation Cleaning Execution

Using the Risk Based approach in Cleaning Validation

Key Take Aways/Challenges/Opportunities


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a y ne : qu pmen

53 vessels (reactors, extractors, tanks)

7 centrifuges (Tolhurst & Heinkel) & 2 Filter Driers 4 Rotar Dr ers

Factory 03: 25 vessels (reactors, extractors, tanks)

,

4 Conical Dryers

Both Facilities are modular: The outlet(s) of any vessel can be

Typically 25 campaigns (450 Modules cleaned per year)

including new process steps both Clinical and Commercial.

Cleaning is just one part of our overall strategy for crosscontamination control.


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ISPE Baseline Guide,

Volume 7 'Risk Based

Manufacture ofPharmaceutical Products'.


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Applying the Risk based Approach to

Cross Contamination

ep : s en ca on:

The Cross Contamination Hazards are

API’s/Intermediates/Raw Materials

Impurities

By-products Degradants

Deter ents

Solvents

Exposure) Limit.

.


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Step 2: Cross contamination Risk

ssessmen na ys s

Need to identify the quantity of the Hazard & the Failure mode Quantity

Carry over that will cause an adverse affect:

ADE*106= 0.1mg/day*106/100 = 1000mg/kg = 1.0g/Kg (0.1Kg/100kg)

Route to cross contamination Severity of the

effect

Severity ranking

based on Quanti ty

Quantity per 100Kg batch

Mix-Up Critical effect 9 > 1Kg

Retention Critical effect 9 0.05 - 1Kg

Mechanical Transfer Major effect 6 6 0.01-0.05Kg (10g-50g)

r orne rans er .


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Route for CrossDefinition Examples

Mix UpMix-up is defined as

contamination at unsafe levels ofone product with another

Charge of material to the wrongequipment

Charge of incorrect material toequipment

Retention

Carry-over on product contactsurfaces from one product to

another in the same equipmentused in a se uential or cam ai n

Inadequate cleaning of equipment

Inadequate cleaning specifications

Inadequate visual inspection of

manner.equipment post cleaning

Routes by which material can betransferred from contaminatednon-product contact surfaces,

Carry-over of product on operatorclothing

Carry-over of product on equipment

MechanicalTransfer

inadvertent or transient contactwith other contaminated non-

designated product contact areasand direct contact of the product

with such surfaces as operator

Carry-over of product onwalls/ceilings/ledges

Carry-over of product on wasteappare an g oves

Airborne Transfer

Routes by which a suspension offine solid/liquid particles in air

moves to another area where it

Carry-over of product in generalventilation

Carry-over of product in the specific

on another exposed product.ventilation


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ssessmen na ys s

Route to cross

contamination

Detection Detection Ranking How?

Mix-Up Very High probability 1

Detectable by procedural

controls, material balances,

analytical testing

Retention Good Probability 3Detectable by pre-

campaign checks, analytical

testing

Mechanical Transfer Low Probability 6Maybe detectable by

analytical testing

Unlikely to be caught by

low level

Occurrence is the determining factor .


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This step evaluates available data for each of the identified failure modes and determines either a

quan a ve es ma e e.g. numer ca or qua a ve escr p on e.g. g , me um or ow o

occurrence of the Failure Mode

Mix Up:

Defined as contamination at unsafe levels of one product with another.

Examples are charging of the desired material to the wrong equipment, charge of incorrect

material to desired e ui ment and accidental use of dirt e ui ment.

Review Controls Include:

Facility design (Single product rooms)

Identification procedures (both equipment and Materials)

Batch record Controls/Checks

Equipment Cleaning status

Site Audit programme

Deviation review


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.

Retention is defined as carry-over of material on product contact surfaces.

qu pmen ean ng a a on rogramme: Modular basis using pre-defined cleaning regime Solvent rinse where a ro riate swab and visual ins ection

specifications.

Detailed cleaning procedures are in place

used with the maximum carry-over using 'Health Based Calculation'.


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.Mechanical Transfer

Mechanical Transfer is the process by which material can be transferred from

• Contaminated non-product contact surfaces

• inadvertent or transient contact with other contaminated non-designated

product contact areas

•

gloves.

Procedural Controls around open product handling

Gowning/PPE (Personnel Protective Equipment)

- ,

Room cleaning Procedures

Site Audit programme

ranng

Deviation review


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.

Airborne Transfer is the process by which a suspension of

fine solid/liquid particles in air moves to another areaexposed product.

Review Controls Include: Air flows/differential pressures design and Monitoring

y : . .

Provision of HEPA filtered air (no recycling).

Air Changes per Hour (ACPH)


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.Overall FMEA Scorin Overall a Risk Priority Number (RPN) can be calculated as follows for each

failure mode.

RPN= Severity x Detection x Occurrence

Retention for non-dedicated equipment was the highest riskwith Airborne Transfer and Retention on dedicatedequipment the lowest RPN.

We understand the materials we are handling & our facility isdesigned to handle such materials

Next…..Cleaning of Multipurpose Equipment


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For a new product: Developed based on technical evaluation.

Identifying the main contaminants in each module

Solubility in water and other possible cleaning solvents (taking,

Forced degradation studies/cleaning interactions as required.

Laborator cleanin simulation.

Documented in a ‘Cleaning Technical Assessment Memo’.

Critical cleaning parameters are identified

Analytical development is completed (UV Rinse + Universal HPLCSwab Method).

solvent through all the vessel loops (out bottom, in top).

Cleaning ex Clinical Manufacture - Cleaning Verification

Cleaning ex Commercial Manufacture - Cleaning Validation


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Pre-defined justified cleaning specifications.

Set based on the ‘Health Based Cleaning’ methodology. Rinse tested to meet pre-determined specification

Swab testing to meet pre-determined specification 100mcg/25cm2

swab

Vessel visually clean (inspected when dry)

.

• Suitability of the cleaning specifications going into the process step.

• Calculation of the total carry-over for each contaminant going into thecampaign.

• The worst case carr -over is calculated based on the maximum swabspecification .


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Prior to cleaning:

Cleaning Technical assessment memo.

Cleaning Sample Keys (summary of testing requirements for the Laboratory)

Cleaning validation protocol – This documents the validation plan for the campaign. For new products: Cleaning Specification Justification including Genotoxic

assessment.

Post Campaign Flush (typically with the process solvent or Methanol) Modular approach - Each equipment module associated with a process equipment

train is cleaned se aratel to an other module in that train.

Validation status is applied to each module which is uniquely associated with the

process from which the module is being cleaned

Three successful cleanouts of a module are required for a clean-out to be deemedvalidated.

Post execution of cleaning

ean ng va a on comp e on ocumen e as pos execu on sec on o pro oco .

Includes all Laboratory cleaning Results


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Using the Risk based Approach in Cleaning

Validation

► Risk based approach to swabbing as part of cleaning validation

programme► Equipment which is not shared product contact (e.g. insides of glove-

boxes).

Question

What is the

equipment

classification?

What is the

surface area ofproduct

contact part?

What is the

potential toabsorb/adhere

product?

Is it easilyCleaned?

Is it easily

Visually

Inspected?

FinalRating

Score/Multiplier 40 20 20 15 5 100

3Direct Product

Contact>50% High potential Difficult Difficult 300

2 Auxiliary

Component10-50%

Medium

potentialModerate Moderate 200

1Proximity

Area


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Using the Risk based Approach in

ean ng a a on

► Swab Locations: Worse case assessment of hard to cleanlocations (Cannot swab all the vessel!)

► r y o me an ampa gn eng w ere s a pro emand not for all equipment.

is to be used for immuno suppressed populations,parenterals, products which are non-inhibitory to microbialgrowth.


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re- ampa gn ec s

Equipment status check (electronic tracking system) is

completed which confirms that the equipment is cleannsure con am na on rom mec an ca se -up wor oes

not impact on product quality

, .

Before Processing, Water Dummy Runs, Solvent

steps) are completed.

Not part of formal cleaning and confirm ‘equipmentreadiness’ for processing.


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ey a eaways Cross Contamination Control is not just equipment Cleaning.

Apply a Risk Based Approach and formally document the Risk

Assessmenta a e qu pmen ean ng – omp ex ys em or non-

dedicated Equipment (Multiple Modules, Multiple products all with

different processes).

Understanding of Process Contaminants and Cleaning Regimesis paramount – Should not be underestimated…

Process Understanding

Robust business systems

People with Expertise and Experience


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Challenges/Opportunities

Cleaning Verification only?

Reduced Verification Post Cleaning Validation

Turnaround: Time spent in cleaning and set up.

Science of Cleaning – Solubility only, Detergents?

–where does cleaning fit in?


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Thank You

ues ons

dr dan egan (msd) ispe cleaning slide

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