high potent osd multi-production plant -3c [????]cleaning-validation phase- cleaning...
TRANSCRIPT
High potent OSD multi-production plant Concept, Containment & Cleaning
2015 Vogel Pharmaceutical Engineering International ForumJun . 2015, Taizhou, China
Horch Guo, [email protected] Roche Pharmaceutical Ltd.
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Content
PART I: CONCEPT & REGULATION
PART II: CONTAINMENT
PART III: CLEANING
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PART I: CONCEPT & REGULATION
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API Harzard ClassificationOEB, OEL, ADE
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WW
Mar
ket-S
harin
g (%
)
%Sales growth: CAGR 2013-2020
12%8 %4 %0 %-4 %
0 %
4 %
8 %
12 %
16 %
Oncology
Anti-diabetics
Anti-VirusVaccines
Sensory Organs
DermatologicalMS therapies
Anti-rheumatic
Anti-hypertensive
Bronchodilators
Source: Evaluatepharm 《World Preview 2014, Outlook to 2020》
TOP10 Therapy area in Y2020–Market share & Sales Growth for hipo
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World Tier
State Tier
Organization Tier
Company & Peers Tier
Regulations & Guideline–Hierarchy
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Regulations & Guideline–Cross-contaminationAuthorities Chapters/Guidelines Key pointsSFDA Chapter 4, Premises & Facilities,
Article 46, Article 53Cross-contamination and dedicated facilities requirements on layout, premises , Penicillins and other beta lactam antibiotics
Chapter 9, Production Management, Article 197, 198
Measures to avoid the cross-contaminations
WHO TRS 961, 2011,Annex 5 Non-Sterile HVAC
TRS 957, 2010, Annex 3 GMP for hazard products
EMA V4, Chapter 3, Premises & Equipment, Mar, 2015
Section 6
V4,Chapter 5, Production, Mar 2015 Section 17~21
FDA ICH Q7 4.4, 21 CFR 211.42 Penicillins and other beta lactam antibiotics
Guidance for Industry - Non-penicillin Beta-Lactam drugs, April 2013
Framework for Preventing Cross-Contamination
ICH Q7 4.4, 21 CFR 211.42 high pharmacologic activity or toxicity products
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GMP Inspection Statistics–PIC/S top most severe GMP deficiencies
• Design and maintenance of premises
• Contamination, potential for (chemical, physical, microbial)
• Design and maintenance of equipment
• Sterility assurance
• Batch release procedure
• Process Validation
• Cleaning Validation
• Investigation of anomalies
• Documentation-QS elements/procedure
• Regulatory issues
• Documentation-manufacturing
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Poor Quality& incompliance results
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PART II: CONTAINMENT
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High potent OSD plant Containment -Containment Levels
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Secondary Containment-HVAC 100% fresh air-PAL, MAL, De-con AL
Primary Containment
Product Personnel
-Equipment tightness-Negative Pressure-Transfer Container-Cleaning procedure-Dust collection
-PPE-Half Suit-Full Suit-Breathing Air《制药业》
High potent OSD plant Containment -Product containment Risk -Classical
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High potent OSD plant Containment -Improvement based on the Risk –State-of-art
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High potent OSD plant Containment Example:Tablet Press System
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High potent OSD plant Containment -Briefly Comparision Hipo vs. Lopo OSD plant in MNC
Process Equipments
High Potent Low Potent
Facilities/Utilities
Operation expense
CAPEX
OPEXMaintenance
Engineering
Facilities/ Utilities
Quality cost
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EHS
Startup
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Primary Containment-Design Phase -Encapsulation
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Primary Containment -FAT ,SAT phase/ Surrogate Testing
Surrogate Positives Negatives Typical ApplicationsLactose -Low toxicity
-Low cost-Water soluble-Non API
-Agglomeration-Relatively difficult analysis
-Not as effective for comparison to extremely dusty materials.-Widely used in FAT
Naproxen-Na -Extremely dusty-Low toxicity-Simple analytical method-Highly water soluble-For all process
-GMP cleaning issues after testing-Relatively expensive
-Very useful for testing of systems with highly hazardous-Widely used in SAT/OQ
Paracetamol -Reasonably dusty-Multiple analytical methods-Water soluble
-GMP cleaning issues after testing
-Easier to analyze than lactose-Used also in SAT/OQ
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Source:ISPE Good Practice Guide: -Assessing the Particulate Containment Performance of Pharmaceutical Equipment, 2nd version.
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Primary Containment -FAT phase/ Surrogate Testing-Lactose
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Secondary Containment –Process Room Mode l Non high potent API
-Negative Pressure
-System closure control
-High risk for multi-production if primary containment failed
-Low reliable for the cleaning corridor
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Secondary Containment-Process Room Model /Non hipo API improvements
-Cascade Negative Pressure control with MAL & PAL
- System closure control
-Higher risk if the primary & seconday containment failed
-Mild reliable for the cleaning corridor
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Secondary Containment-Process Room Model /High potent API
-Cascade Negative Pressure control with MAL & PAL
-De-contamination locker for clean Person Flow even with contamination
- System closure control
-High reliable Clean corridor
-Low risk for the multi-production
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Secondary Containment-HVAC-100% fresh air
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HiPo OSD Plant- Layout Model -Horizontal Layout for integrated systems
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Process
Utilities
-Hipo multi-production plant
-Process Room Modular design with PAL, MAL and De-com AL.
-Seperated Process & utilities rooms
-Seperated dust disposal flow
-Compact design and higher space utilization
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HiPo OSD Plant- Layout Model -Vertical Layout for integrated systems
Utilities
Utilities
Process
-Hipo multi-production plant
-Process Room Modular design with PAL, MAL and De-com AL
-Seperated Process & utilities rooms
-Suitable for the process transfer by gravity
-Seperated dust collection contaimnent and disposal
-Compact design
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Containment Verification-Primary-Campaign production/IOEL testing-Granulation Room
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ICH Q9- Quality Risk Assessment ModelICH Q8/9/10- Patient linked risk assessment
Containment Verification–Quality based Risk Assessment Model
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Containment Verification-Integrated plant OEL Testing & FEMA Risk assessement
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Potential Cause Current Prevention Controls Occ PRN*Process/System Categories Req/Char/Spec Potential Failure Mode
PotentialEffect(s) of
FailureSev Current Detection Controls Det RPN
Failure ModeSeverity
Detection control Detectability
Prevention controlsOccurrence
Risk Low RPN 8~64 Acceptable.
Risk Medium RPN 72~160 Further risk reduction actions is to be investigated.
Risk High RPN 192~1000 Risk control actions are required.
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PART II: CLEANING
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Cleaning-Design Phase/Cleaning Process Diagram
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Cleaning-FAT, Qualification phase –Spray Coverage -Riboflavin
-Basic cleaning testing with water soluble simulator-Riboflavin
-FAT is a must for testing
-Identify the locations in equipment without adequately cleaned
-Actions needs to be executed for the cleaning effective improvement in FAT
-Spray coverage testing should be performed as part of qualification
-Riboflavin cleaning efficiency is critical and basis for insoluble products
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Cleaning-Validation phase- Cleaning Validation
-Cleaning Validation team with early involvement is most important for cleaning & cross-contamination!
Evaluation on the critical points for the equipment selection and design
Identify Product & Process contacted surface area and risk evaluation
Cleaning Validation Master Plan
Develop and validate the analysis method (API residual and recovery testing)
Develop the equipment based cleaning recipe and CVP
3 continuous CV for campaign production CV Sampling
QC analysis
Cleaning Validation Report
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Cleaning-Dedicated Parts for multi-production
-Dedicated Parts is to avoid the cross-containment and especially for the parts with high risk on cleaning
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Authorities:
• www.sda.gov.cn
• www.who.int
• www.ich.org
• www.fda.gov
• www.ema.europa.eu
• www.pda.org
• www.pics.org
More information....
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Q & A
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Thanks for your attention!
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