Change Implement a Risk-Based Cleaning Validation Program 3_El Azib_pres.pdf · Rationale for change: implement the scientific approach chap 3 and chap 5 of EU GMP, ... F4: A factor

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Change Implement a Risk-Based

Cleaning Validation Program

Walid El Azab

Technical Service Manager

+32479790273

[email protected]

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Copyright © 2014 STERIS Corporations. All Rights Reserved. CONFIDENTIAL and PROPRIETARY to STERIS Corporation

Agenda

Current European change and impact on cleaning validation

1

Define CPP and CQA2

Develop a risk based assessment 3

Workshop exercise4

Conclusion5

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EU GMP Annex 15 revision: introducing element of ICH, modern manufacturing technology and EU GMP guide changes

EC Annex 15

EMA concept paper (Nov. 2012) On the revision of the annex 15

EC GMP guide Part I

US FDA Guide on Process Validation

ASTM E2500-07

ICH Q8 – Q10Manufacturing Technologies

EMA draft on process validation

EC Annex 11

EMA guideline on process validation (PV)

PIC/S

ICH Q8: Design space ICH Q9: Risk-based approach ICH Q8 & Q10: Knowledge management ICH Q11: Life cycle validation & qualification

Computer System Validation software & hard ware back up

Alignment with the EMEA guidance on setting limits Modern manufacturing technologyAlignment with:

Chapter 3 Chapter 5

EMA settinghealth based limit and

Process Validation

Include modern aspect: ICH Q8 – Q10 PAT, RTRT QdB Harmonization with FDA guidance on process validation

Cleaning validation Process validation Transport validation Packaging validation Qualification Utilities Analytical method continuous process verification and On-going verification concept

LIST NON EXHAUSTIVE

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Manufacturer selling products into EMA regulated market should comply to these changes

Who is impacted by these changes?

EU GMP manufacturers producing :

Human drugs

Veterinary drugs

Biological and biotechnology products

Active pharmaceutical ingredient (API) manufacturers

Manufacturers in other non-EU but PIC/S regulated markets could be impact indirectly. Because, PIC/S has align partially its document to the EU GMP guide changes

Medical devices manufacturers are not directly affected….

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Changes in the annex 15 impact the industry validation process

Annex 152015

▪ Start a RM before cleaning validation ▪ Worst case approach is required for manual cleaning ▪ Grouping equipment in CV▪ Carry over of product based on Toxicological data – PDE (2014 – New)▪ Worst case definition should include PDE data ▪ CHT, DHT, campaign time▪ Rational for WC position choice using a risk assessment ▪Visual inspection alone is not sufficient ▪ Sampling methods swab, rinsing ▪ Number of validation run determine by RM – link to PDA TR 29 ▪ Cleaning verification for rarely manufactured product ▪ Qualification : DQ ->FAT/SAT->I/O/PQ combined step is possible▪Planning and documentation for qualification and validation ▪ Major revision for process validation: on going process verification,

countinous process verfication, hybrid approach ect…▪The chapter “re-validation” replaced by “re-qualification”

Rationale for change: adjustment with annex 11 – ICHQ8-11, PAT, EMEA PDE, EMA PV and process validation and part I of the EU GMP:

Clean

ing valid

ation

chan

geLIST NON EXHAUSTIVE

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Changes in the EMA PDE setting guidance impact the industry validation process

Guideline on setting healthbased exposurelimits (PDEs)2014

Rationale for change: implement the scientific approach chap 3 and chap 5 of EU GMP, scientific rationale for cytotoxic and antibiotic to be produced in dedicated equipment :

▪ NOEL is now NOAEL▪ 10ppm approach is enhance by the calculation of the PDE based on all

toxicological and pharmacological data NOAEL – present in the ICHQ3C (R4)

▪ Threshold of Toxicological Concern (TTC) or 1.5 µg/person/day – Ex. Genotoxic

▪ Dedicated equipment are needed for substance which lowest threshold is not known

▪ Not applicable on macromolecule since could be inactivate by chemically or thermally actions

▪ PDE animal < PDE human▪ VICH GL18 residual solvent and link with EU CMP chap 3 and Chap 5

LIST NON EXHAUSTIVE

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Changes in the EMA PDE setting guidance impact the industry validation programs

Nov 2014

Final Published

Jun 2015

Effective date

Dec 2015

Effective for new product

Jun 2016

Effective for existing product

Impacted: Annex 15 EUGMP (October 2015) Chapter 3 EUGMP (March 2015) Chapter 5 EUGMP (March 2015)WHO guidance on cleaning validation

Time line for implementation:

March 2015

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MACO calculation: European guideline

EMA: setting health based limit (2014)

EC guide:

Annex 15 (2015) Before: Visually cleanAfter : Cleaning validation

Chapter 3 and 5 Part II

PIC/S: Guidance - cleaning validation in active pharmaceutical ingredient plants (2014)

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International guidelines: harmonization on MACO

Canadian HPFB: cleaning validation guideline (2008)

ICH: ICHQ7 : GMP ICHQ3 : impurities

VICH: GL18 impurities - veterinary medicinal product (2011)

Australia: Align with ICH,EC, EMA, USFDA

WHO: Annex 4, WHO Technical Report Series 937, 2006

PIC/S 2014

LIST IS NOT EXHAUSTIVE

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Integrating MACO data

US FDA: 21CFR211.42 21CFR211.167 Cross contamination management

ISPE : Risk MaPP (2010) First document on ADE, TTC,

pharmacological and toxicological data calculation for MACO.

ADE (mg/day) = NOAEL (or LOAEL) x BW /

(UFC × MF × PK)

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Equivalency between the ADE and the PDE can be demonstrated by a toxicologist

PDE = (NOAEL* BW)/(SF1xSF2xSF3xSF4xSF5) ADE = NOAEL (or LOAEL) x BW / (UFC × MF × PK)

NOAEL: No Observed Adversible Effect Level

BW: weight adjustment - 50kg for human medicinal products 1Kg for veterinary medicinal products

F1: A factor (values between 2 and 12) to account for extrapolation between species

F2: A factor of 10 to account for variability between individuals

F3: A factor 10 to account for repeat-dose toxicity studies of short duration, i.e., less than 4-weeks

F4: A factor (1-10) that may be applied in cases of severe toxicity, e.g. non-genotoxic carcinogenicity, neurotoxicity or teratogenicity

F5: A variable factor that may be applied if the no-effect level was not established. When only an LOEL is available, a factor of up to 10 could be used depending on the severity of the toxicity.

NOAEL: No Observed Adversible Effect Level

LOAEL: Lowest Observable Adversible Effect Level

BW: weight adjustment - 50kg for human medicinal products

UFC: composite Uncertainty factor:

UFH: Intra species differences

UFA : Inter species differences

UFS: Subchronic to chronic extrapolation

UFD: database completeness – toxicity database

UFL: LOAEL to NOAEL extrapolation

MF: Modifying factor – to adress residual uncertainty

PK: pharmacocinetic adjustment

The determination of the ADE and equivalent PDE involves hazard identification by reviewing : all relevant data, identification of critical effects or effects, determination of the NOAEL of the findings that are considered to be critical effects and use several adjustments to account for various uncertainties.

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Cleaning strategy

Active residue proprietary

Identify active residue

Portfolio management

Visually clean

+

Lowest MACO

Worst case active residue

=

Lowest MACO

Therapeutic

daily dose

Extrinsic source of active residues:

Active and/or cleaner residue, material degradation, leachable/extractible

Intrinsic source of active residues:

Product intrinsic impurity

Minimum therapeutic

dose that give a

pharmacological effect

1/1000th

Setting acceptance criteria (MACO)

MACO= TDD*MBS

TDDN * SF

1/1000th

Toxicological

based

Minimum dose with kill

of 50% population

(LD50)

NOAEL limit

MACO= NOAEL *MBS

TDDN*SF

LD50* BW

SF

Health

based

MACO= PDE *MBS

TDDN

NOAEL * BW

F1*F2*F3*F4*F5

Minimum dose with

toxicological and

pharmacokinetic

(NOAEL) PDE/ADE

limit

Cleaning program strategy for acceptance criteria setting

Source: Impact of the changes to the European Good Manufacturing Practice on Cleaning Validation: Part I , Walid El Azab, April 2016, GMP Journal

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Health based limit is consider as the scientific methods

[

Source: Cleaning Limits—Why the 10-ppm Criterion should be Abandoned The 10-ppm criterion for the acceptable concentration of potential API in cleaning validation is no longer necessary and a risk-based approach should be universally adopted. Jan 01, 2016 By Michel Crevoisier [1], Ester Lovsin Barle [2], Andreas Flueckiger [3], David G. Dolan [4], Allan Ader [5], Andrew Walsh [6] Pharmaceutical Technology Volume 40, Issue 1

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The worst case soil have to be confirmed based on toxicological data (PDE)

Equipments

Equipments group

Cleaning SOP 1

Cleaning SOP 2

Cleaning SOP 3

Equipments groupCleaning SOP 1

Product 1

Product 2

Product 3

Determine MACO worst case – MDD

Determine worst case product to clean

3 runs

Equipments

Equipments group

Cleaning SOP 1

Cleaning SOP 2

Cleaning SOP 3

Equipments groupCleaning SOP 1

Product 1

Product 2

Product 3

Determine MACO worst case

Determine worst case product to clean

3 runs

“Current” approach: MACO was determine using therapeutic daily dose or the 10 ppm

New guideline: MACO should be determine using therapeutic daily dose, health and/or toxicological based

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Conference agenda


1

Define CPP and CQA2


Workshop exercise4

Conclusion5

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Different cleaning methods

Automated or Semi-automated Manual

Washing machine Cleaning in place Tunnel washers Static immersion Agitated immersion Ultrasonic High pressure spray jet Solvent reflux

Scrub / brush ImmersionWipe / mop Foamer High pressure spray jet

Cleaning in place (CIP)

Cleaning out of place (COP)

Manual cleaning

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Understand critical cleaning parameters

Time

• Assess optimal time

• Volume or flow totalizer achieved

Action

• High: clog, remove of big block

• Low: poor residual removal

Temperature

• Cloud point for detergent

• Depending on the cleaning steps

Concentration/chemistry

• Optimal : remove soils

• High: difficulty to remove cleaning residue

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Parameters affecting cleaning performance

Surface

Soil residue

Surface & equipment design: Surface propriety Material of constructionEquipment design

A

Soil categorization and removal:

Amount Acceptable carry-over Nature Tenacity (adherence)Mixing & dispersion of the soil in the cleaning agentToxicological data

B

Cleaning parameters:Coverage TACCTWater quality DHT impact Toxicological data driven for cleaning agent / product residue

C

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How to define cleaning critical parameters?

* Carry over / cross over for each batch calculation ** one question is yes = critical sub-function

Theory

▪ The scope of the study should include existing systems and related utilities

Define boundaries equipments

Definitionprocess study

DefinitionCQA

DefinitionCPP

Definitionsub-functionequip/process

AnalysisSubfunction criticity

Control CPP

▪ Ensure MFG product/cleaning agent sand microorganisms are removed to safe level / each batches

▪ 6 CQA identified: 1) Conductivity 2) drainability 3) VI 4) Cleaning 5) product 6) micro residue

▪ Time, Action, Concentration/Chemistry, Temperature

▪ 2 categories : manual / automated ▪ From disassembling to storage

▪ Sub-function impact CQA/CPP? **▪ Sub-function impact regulatory? **▪ Sub-function related to CPP? **

▪ Clear SOP ▪ Operators training and/or qualification ▪ Optimal cleaning cycle for automated

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Worst case active residue identification process

• Explain the cleaning evaluation results:

• Time • Action • Concentration/chemistry• Temperature

• Test in field (pre-PQ)

• Physico-chemical proprieties

• Cleaning propriety

• Residue profileand carryover

• Product category

• Physical or chemical removal

• Factors affecting soil removal : • Soil Type and quantity • Soil time contact (DHT…) • Equipment surface

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Agenda


1

Define CPP and CQA2


Workshop exercise4

Conclusion5

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Risk assessment process

Identify the topic to be address –

Collect topics or potential arguments for / against the issue

Use brainstorming / process mapping techniques to provide exhaustive coverage of the issues

Select proposed RiskMAPP tool to record decisions / data

Gather supporting evidence pro / con for the expected arguments

Explore all arguments exhaustively pro / con

Record results and provide pertinent written explanation of conclusions – link to protocol / CVMP

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Steps


II.

III.

V.

Define the scope

Deep dive the process

Remediate the risk

IV. Rank the risk

VI. Implement the results

VII. Control

Define the team project I.

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Steps


II.

III.

V.

Define the scope


Remediate the risk

IV. Rank the risk


VII. Control

E. Assembly

F. Wrapping and

dirty hold time

(DHT) A. Assembly

B. Wrapping

C. Clean Hold time

(CHT)

D. Cleaning

cycle

The CQA and CPP involved will depend on the process step:


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Steps


II.

III.

V.

Define the scope


Remediate the risk

IV. Rank the risk


VII. Control

Assembly Clean Hold time Cleaning cycle

Drying process Storagecondition

Loading respect

Ambient air Time respect Equipment design

Filtered air Cleaning process

Manual assembly Routine check

Operators with gloves Visually check

Operators with Masks Alarm systems

Assembly time Routine maintenance on critical equipment

End of cleaning:

Grade area

Drying process

Transfer process

Details all parameters entering in the cleaning process:

Risk assessment process EXAMPLE

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Steps


II.

III.

V.

Define the scope


Remediate the risk

IV. Rank the risk


VII. Control

To identify the adequate cleaning and monitoring procedure the ranking assessment has to be done on:

1. the process steps (interactive exercise)


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Steps


II.

III.

V.

Define the scope


Remediate the risk

IV. Rank the risk


VII. Control

To identify the adequate cleaning and monitoring procedure the ranking assessment has to be done on:

1. the process steps (interactive exercise)2. the critical equipmentExample of Forced Ranking - Bioreactor

Sampling

Location

Critical Site:

Potential large

contaminant

area

Hot Spot

(historically

hard to clean)

Affinity to

MOC or

Surface

Finish

Role in

process

likely to

lead to

difficult

residue

Cleanability of

location/

coverage and

access

Ranking

Sidewall 1 1 1 1 1 5

Bottom

Outlet

Valve

5 3 3 1 1 13

Dome Lid 1 1 1 1 5 9

Instrument

Port

1 5 3 1 5 15

Sampling

Port

5 5 3 1 1 15

Agitator 1 1 1 1 3 7

Other Options – Combine Categories (e.g. critical area / hot spot Weight categories (cleanability)

– Add Notes Category: like instrument ports are hand cleaned bottom valves are disassembled and cleaned

- Draw equivalence for like ranking (instrument & sample port)

- If ranking locations keep in mind that some of the “simple locations” may also need to be assessed to confirm that these

locations are “in fact” clean

1 = Low Risk

3 = Moderate Risk

5 = High Risk


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Steps


II.

III.

V.

Define the scope


Remediate the risk

IV. Rank the risk


VII. Control

Put in place systems or procedure that would reduce the RPN value


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Steps


II.

III.

V.

Define the scope


Remediate the risk

IV. Rank the risk


VII. Control

preventive maintenance Equipment design Calibration

monitoring: in line or out line frequency

sampling location:


Implement the findings of the risk analysis:

EXAMPLE

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Steps


II.

III.

V.

Define the scope


Remediate the risk

IV. Rank the risk

Risk Review

Ris

kC

om

mu

nic

at i

on

Risk Assessment

Risk Evaluationunacceptable

Risk Control

Risk Analysis

Risk Reduction

Risk Identification

Review Events

Risk Acceptance

InitiateQuality Risk Management Process

Output / Result of theQuality Risk Management Process

Risk

Ma

nag

em

en

tto

olsVI. Implement the results

VII. Control


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Agenda


1

Define CPP and CQA2


Workshop exercise4

Conclusion5

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Workshop on cleaning validation

Company multiproduct facility

Introduction of a new product P5 and P6

The current cleaning method has been validated 5 years ago

The production process flow is the following :

• Weighing

• Granulation

• Compressing

• Packaging

Their cleaning methods are manual and/or automated

Their current cleaner is Detergent PRC100 and Detergent PRC150

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Washing machine

Source: image

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CIP system

Source: image

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Manual cleaning

Source: image

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Questions – Part I

Define your cleaning validation strategy

Define your grouping (bracketing) concepts for the validation studies and routine productions

Define the worst case product

Define the detergent to be used for automated and manual cleaning

Define the limit you will use – justify your choices

Define the cleaning procedure

Define the sampling methods and location – justify your choices.

Define the critical part of the equipment

Calculate the Swab limit for a shared surface 120000cm2

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Questions – Part II

Define the equipment that need calibration frequency:

• Washing machine

• CIP system

Define if the following changes do have an impact on your validate status (CIP system):

• Change of the spray ball position

• Change of the pump

• Add a new CIP skid in the CIP systems

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Questions – Part III

Define if the following changes do have an impact on your validate status (washing machine):

• Add few equipment in the load – the risk assessment shows no impact

• The company has several washer from the same supplier. They decide to use the racks for any washing machine

• Replace the pump by the same supplier

• Change the washer arm for a like for like

• Replace the heater

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Product info

Product PDE (mg) Daily dosage (mg)

L/D50 (mg) Batch size (Kg)

P1 2,5 50 n.a. 80

P2 0,5 5 n.a. 30

P3 3 30 n.a. 50

P4 0,7 400 n.a. 50

P5 4 400 n.a. 150

P6 0,010 0,01 n.a. 50

PRC100 7 n.a. 1000 n.a.

PRC150 6 n.a. 800 n.a.

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PACE laboratory study – Coupon studies

7.6 cm x 15.2 cm SS coupons coated with samples

Emulate soil conditions incustomer’s equipment to represent the worst case

Develop cleaning parameters Visually clean?

Water break-free?

Weight change?

PACE report issued

PACE booklet submitted at [email protected] or with samples

mailto:[email protected]

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PACE results

Cleaner Conc Time / TempVisual

Observat ion

Water

Break-Free

PRC100 Detergent 1% v/v 30 min / 60°C Light Part iculate Film Yes


PRC100 Detergent 2% v/v 25 min / 70°C Visually Clean Yes

Product tested P1 – P3 – P5 –P6:

Agitated Immersion

Spray Wash at 11 psi


Observat ion

Water

Break-Free




Manual cleaning


Observat ion

Water

Break-Free




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PACE results


Observat ion

Water

Break-Free

PRC100 Detergent 1% v/v 40 min / 60°C Light Film Yes



Product tested P2 – P4 :

Agitated Immersion

Spray Wash at 11 psi


Observat ion

Water

Break-Free




Manual cleaning


Observat ion

Water

Break-Free


PRC150 Detergent0.5%

v/v5 min / 30°C Visually Clean Yes


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Identify the worst case product and limit to be used

MACO Therapeutic dose

Product PDE (mg) Daily dosage (mg/day)

L/D50 (mg)

Batch size (Kg)

P1 2,5 50 n.a. 80

P2 0,5 5 n.a. 30

P3 3 30 n.a. 50

P4 0,7 400 n.a. 50

P5 4 400 n.a. 150

P6 0,010 0,01 n.a. 50

PRC100 7 n.a. 1000 n.a.

PRC150 6 n.a. 800 n.a.

Calculate the MACO using the therapeutic based

MACO= (TDD previous*MBS next)(1000*TTD next)

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MACO Toxicological dose


L/D50 (mg)

Batch size (Kg)

P1 2,5 50 n.a. 80

P2 0,5 5 n.a. 30

P3 3 30 n.a. 50

P4 0,7 400 n.a. 50

P5 4 400 n.a. 150

P6 0,010 0,01 n.a. 50

PRC100 7 n.a. 1000 n.a.

PRC150 6 n.a. 800 n.a.

Calculate the MACO using the toxicological dose

MACO= (L/D50*70kg)*MBS next)(2000*1000*TTD next)

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MACO health based dose


L/D50 (mg)

Batch size (Kg)

P1 2,5 50 n.a. 80

P2 0,5 5 n.a. 30

P3 3 30 n.a. 50

P4 0,7 400 n.a. 50

P5 4 400 n.a. 150

P6 0,010 0,01 n.a. 50

PRC100 7 n.a. 1000 n.a.

PRC150 6 n.a. 800 n.a.

Calculate the MACO using the health based dose

MACO= (PDE*MBS next)(TTD next)

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Sampling surface calculation

Swab sampling:

(1) SAL (Surface area limit)= MAC (mg)/ Shared area surface (cm2) = mg/cm2

(2) Swab limit = SAL (mg/cm2) * Sampling area (cm2)= mg/Swab or ppm

Rinse sampling:

(1)

(2)

Quantity of residue on the equipment (mg)

= Vol. of final rinse (ml)

x

Conc. of the residue in a sample of final rinse (mg/l)

-Blank of the rinse sampling(mg/l)

Conc. Of residue in the final rinse sample (mg/ml)

=

Quantity of residue in equipment (mg)

Vol. of final rinse (ml)

+Blank of the rinsing solvent (mg/ml)

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47

Bonus – Tank vessel CIP cleaning issue

The manufacturer change the tank vessel volume from 500L to 1000L vessels tank. The PACE evaluation for the cleaning of your worst case residue/soil is the following:

• Cleaner : PRC100 at 1%

• Temperature : 60°C

• Time: 30 min.

You took these information and develop a cleaning cycle for the CIP system. In the meantime,

After the testing, the results were failed for the 1000L. The manufacturer call you and tell you that your product is not working.

The manufacturer send you the drawing of the CIP and Tank:

spray device

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Agenda


1

Define CPP and CQA2


Workshop exercise4

Conclusion5

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Cleaning and process validation is on the TOP 10 deficiencies observed

Validation deficiencies observed in FY 2012

Source: http://webarchive.nationalarchives.gov.uk/20141205150130/http://www.mhra.gov.uk/home/groups/pl-a/documents/websiteresources/con464241.pdf

Most deficiencies observed 2007 -2014

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Conclusion

The recent changes in the GMPs have triggered the review of manufacturer’s cleaning validation programs and cleaning procedures.

Risk-assed the gap with the current cleaning requirements, the new regulatory requirements must be understood and integrated into cleaning life cycle programs.

Regulators are expecting that the cleaning limit used by the manufacturer should be justified using a risk-based approach to demonstrate safety to the product and patient.

Limits should be risk-based on understanding the process capability of the equipment, sampling method, analytical method, visual residue limit and the pharmacological/toxicological residue limit.

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Questions?

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References

European Medicine Agency (EMA), Guideline on setting health based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities, November 2014

[4] Lai Yeo Lian, M. Ovais. (2008) Setting Cleaning Validation Acceptance Limits for Topical Formulations Pharmaceutical Technology, Volume 32, Issue 1

European Commission, Good Manufacturing Practice Medicinal Products for Human and Veterinary Use - Annex 15, Qualification and Validation, 2015.

European Commission, Good Manufacturing Practice Medicinal Products for Human and Veterinary Use - chapter 3, Premises and equipment, 2015.

European Commission, Good Manufacturing Practice Medicinal Products for Human and Veterinary Use - chapter 5, Production, 2015. Fourman, G., and Mullen, M., “Determining Cleaning Validation Acceptance Limits for Pharmaceutical Manufacturing Operations,”

Pharmaceutical Technology, April 1993 Active Pharmaceutical Ingredients committee (APIC), Guidance on Aspect of Cleaning Validation in Active Pharmaceutical Ingredient

Plants, May 2014. International Society for Pharmaceutical Engineering (ISPE), Risk-Based Manufacture of Pharmaceutical Products, September 2010 Impact of the changes to the European Good Manufacturing Practice on Cleaning Validation: Part I , Walid El Azab, April 2016, GMP

Journal Cleaning Limits—Why the 10-ppm Criterion should be Abandoned The 10-ppm criterion for the acceptable concentration of potential API

in cleaning validation is no longer necessary and a risk-based approach should be universally adopted. Jan 01, 2016 By Michel Crevoisier[1], Ester Lovsin Barle [2], Andreas Flueckiger [3], David G. Dolan [4], Allan Ader [5], Andrew Walsh [6] Pharmaceutical Technology Volume 40, Issue 1

*Note: This is not a complete listing, just a guidance to literature the speaker has found to be interesting/beneficial.

Documents

Change Implement a Risk-Based Cleaning Validation Program 3_El Azib_pres.pdf · Rationale for change: implement the scientific approach chap 3 and chap 5 of EU GMP, ... F4: A factor