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Transcript of Change Implement a Risk-Based Cleaning Validation Program 3_El Azib_pres.pdf · Rationale for...
1/
Change Implement a Risk-Based
Cleaning Validation Program
Walid El Azab
Technical Service Manager
+32479790273
2/
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
3/
Copyright © 2014 STERIS Corporations. All Rights Reserved. CONFIDENTIAL and PROPRIETARY to STERIS Corporation
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….
5/
Copyright © 2014 STERIS Corporations. All Rights Reserved. CONFIDENTIAL and PROPRIETARY to STERIS Corporation
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
8/
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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)
11/
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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.
12/
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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
Current European change and impact on cleaning validation
1
Define CPP and CQA2
Develop a risk based assessment 3
Workshop exercise4
Conclusion5
16/
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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
18/
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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
21/
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
22/
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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
23/
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Steps
Risk assessment process
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
Define the team project I.
II.
III.
V.
Define the scope
Deep dive the process
Remediate the risk
IV. Rank the risk
VI. Implement the results
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:
Risk assessment process
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Steps
Define the team project I.
II.
III.
V.
Define the scope
Deep dive the process
Remediate the risk
IV. Rank the risk
VI. Implement the results
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
Define the team project I.
II.
III.
V.
Define the scope
Deep dive the process
Remediate the risk
IV. Rank the risk
VI. Implement the results
VII. Control
To identify the adequate cleaning and monitoring procedure the ranking assessment has to be done on:
1. the process steps (interactive exercise)
Risk assessment process EXAMPLE
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Steps
Define the team project I.
II.
III.
V.
Define the scope
Deep dive the process
Remediate the risk
IV. Rank the risk
VI. Implement the results
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
Risk assessment process EXAMPLE
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Steps
Define the team project I.
II.
III.
V.
Define the scope
Deep dive the process
Remediate the risk
IV. Rank the risk
VI. Implement the results
VII. Control
Put in place systems or procedure that would reduce the RPN value
Risk assessment process EXAMPLE
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Steps
Define the team project I.
II.
III.
V.
Define the scope
Deep dive the process
Remediate the risk
IV. Rank the risk
VI. Implement the results
VII. Control
preventive maintenance Equipment design Calibration
monitoring: in line or out line frequency
sampling location:
Risk assessment process
Implement the findings of the risk analysis:
EXAMPLE
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Steps
Define the team project I.
II.
III.
V.
Define the scope
Deep dive the process
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
Risk assessment process
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Agenda
Current European change and impact on cleaning validation
1
Define CPP and CQA2
Develop a risk based assessment 3
Workshop exercise4
Conclusion5
32/
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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
33/
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Washing machine
Source: image
34/
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CIP system
Source: image
35/
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Manual cleaning
Source: image
36/
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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
39/
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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
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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
PRC150 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
Cleaner Conc Time / TempVisual
Observat ion
Water
Break-Free
PRC100 Detergent 1% v/v 15 min / 60°C Visually Clean Yes
PRC150 Detergent 1% v/v 15 min / 60°C Light Part iculate Film Yes
PRC100 Detergent 2% v/v 15 min / 70°C Visually Clean Yes
Manual cleaning
Cleaner Conc Time / TempVisual
Observat ion
Water
Break-Free
PRC100 Detergent 1% v/v 5 min / 30°C Visually Clean Yes
PRC150 Detergent 1% v/v 5 min / 30°C Light Part iculate Film Yes
PRC100 Detergent 2% v/v 3 min / 25°C Visually Clean Yes
42/
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PACE results
Cleaner Conc Time / TempVisual
Observat ion
Water
Break-Free
PRC100 Detergent 1% v/v 40 min / 60°C Light Film Yes
PRC150 Detergent 1% v/v 40 min / 60°C Visually Clean Yes
PRC100 Detergent 2% v/v 30 min / 70°C Light Film Yes
Product tested P2 – P4 :
Agitated Immersion
Spray Wash at 11 psi
Cleaner Conc Time / TempVisual
Observat ion
Water
Break-Free
PRC100 Detergent 1% v/v 30 min / 60°C Light Part iculate Film Yes
PRC150 Detergent 1% v/v 30 min / 60°C Visually Clean Yes
PRC100 Detergent 2% v/v 30 min / 70°C Light Film Yes
Manual cleaning
Cleaner Conc Time / TempVisual
Observat ion
Water
Break-Free
PRC100 Detergent 1% v/v 5 min / 30°C Visually Clean Yes
PRC150 Detergent0.5%
v/v5 min / 30°C Visually Clean Yes
PRC100 Detergent 2% v/v 3 min / 25°C Light Film Yes
43/
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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)
44/
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Identify the worst case product and limit to be used
MACO Toxicological 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 toxicological dose
MACO= (L/D50*70kg)*MBS next)(2000*1000*TTD next)
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Identify the worst case product and limit to be used
MACO health based 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 health based dose
MACO= (PDE*MBS next)(TTD next)
46/
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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)
47/
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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
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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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.