High potent OSD multi-production plant Concept, Containment & Cleaning

2015 Vogel Pharmaceutical Engineering International ForumJun . 2015, Taizhou, China

Horch Guo, Hongxing.guo@yahoo.comShanghai 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

25 VOGELVOGELStatic Air Sampling Swab Sampling

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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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