( 配付用）高生理活性設備Part 1 - ph-s.com

1 #Pharma Solutions Co., Ltd. 2009 03 GMP GMP EMEA Conceptual Paper ICH Q9 Step Risk=Severity Probability EFPIA Resource Paper ispe White Paper Risk=Hazard Exposure RISK MAPP Steering Committee #PenicillinCephalos-porinsCarbaPenemsCar baCephemOther -LactamsCurrent GMP1. FDA/CGMP 2. EU-GMP 3. J-GMP 4. WHO-GMP 5. PIC/S GMP Guidelines6. FDA Proposed CGMP Changes (1996) 7. ICH API GMP Guide (ICHQ7) : Segregated Facility : Campaign with necessary validation can be accepted FDA CDER (Safety Officer) 2008 ispe Washington Conference #GMP/ GuidanceLive microorganismsCertainHormones(Certain Steroids)CytotoxicsubstancesHighly Active ProductsCurrent GMP1.

2 FDA CGMP 2. EU-MP 3. J-GMP 4. WHO-GMP 5. PIC/S GMP Guidance 6. FDA Proposed CGMP Changes (1996) 7. ICH API GMP (ICHQ7) : Segregated Facility : Campaign with necessary validation can be accepted FDA CDER (Safety Officer) 2008 ispe Washington Conference #FDA CDER (Safety Officer) 2008 ispe Washington Conference GMP ICH GMP Q7 # GMP GMP EMEA Conceptual Paper ICH Q9 Step

3 Risk=Severity Probability EFPIA Resource Paper ispe White Paper Risk=Hazard Exposure RISK MAPP Steering Committee EMEA Conceptual Paper 2005 5 Section Section ICH Q9 Step 2005 11 Risk=Severity Probability EFPIA Resource Paper 2005 11 # U-GMP 2008 2009 ICHQ9 U-GMP # ispe White Paper 2006 3 Risk=Hazard Exposure RISK MAPP Task Team Risk MaPPRiskBasedManufacturing of Pharmaceutical Products 2 ICH Harmonised Tripartite Guideline : Quality Risk Management (ICH Q9)ICH Q9.

4 Quality Risk Management#Risk-MaPP ICH Q9 Courtesy of Stephanie Wilkins ispe June 2007 ispe Baseline Guide Risk MaPP RiskBased Manufacture of Pharmaceutical Products ispe Baseline Guide Risk MaPP 1/1000 10 ADI PQ GMP GMP # NOAEL ADI Courtesy of Stephanie Wilkins ispe June 2007 Risk Based Approach ?

5 ICH Q9 QRM RiskCommunication Ri sk Management tools RiskCommunication Ri sk Management tools # = ( ) Case by Case Risk MaPP GMP Hazard Exposure Risk #Quality FirstSafe Working ConditionsCourtesy of Stephanie Wilkins ispe June 2007 Risk MaPP GMP ADI #

6 GMP GMP EMEA Conceptual Paper ICH Q9 Step Risk=Severity Probability EFPIA Resource Paper ispe White Paper Risk=Hazard Exposure RISK MAPP Steering Committee (ADI): ADI (ADI)#ADI (mg/day) = NOAEL (mg/kg/day) x BW (kg)UFcx MF x PKwhere:ADI = Acceptable Daily IntakeNOAEL = No-Observed-Adverse-Effect Level BW = Body Weight UFc= Uncertainty Factor(s) MF = Modifying Factor PK = Pharmacokinetic Adjustment(s) (ADI) API) (ADI) ADI #FDA CDER (Safety Officer)

7 2008 ispe Washington Conference 1/1000 LD50 10 ppm LD50 LD50 NOAEL Leyton (1987) 10-4 LD50 LD50 LD50 LD50 461 mg/kg ( 60kg) 5 10-4 14 mg ADI B LD50 # NOAEL( ) TDI( ) NOAEL( ) NOAEL>( )

8 10 1 B DNA EMEA( )(2006) Muller (2006) 100,000 1 1 mcg/ #RiskBased Manufacture of Pharmaceutical ProductsComparison of Other LimitsCytotoxic Antineoplastic AgentADI1/1000 LCDLD50/50,000 Result1 g/day70-960 g/day4800 g/day ( mg/day)

9 Rationale or BasisExcess cancer risk 1 x 10-5 Low Clinical DoseLethal Dose 50% test animalsCourtesy of Naumann/ Weideman ispe June 2007 Provides guidance for relatively unstudied compoundsthat fall into one of three categories:1) compounds that are likely to be carcinogenic (ADI = 1 ug/day)2) compounds that are likely to be potentor highly toxic(ADI = 10 ug/day)3) compounds that are notlikely to be potent, highly toxic, or genotoxic(ADI = 100 ug/day)Dolan DG, Naumann BD, Sargent EV, Maier A, Dourson M Application of the threshold of toxicological concern concept topharmaceutical manufacturing operations.

10 Regul. Tox. :1-9 (2005). ADI #Swab Limit(mg/swab)= ADI* x BS x TA x RFMDD x SSAwhere:ADI = Acceptable Daily Intake (mg/day)BS = Batch Size (mg)TA = Test Area (cm2)RF = Recovery FactorMDD = Maximum Daily Dose (mg)SSA = Shared Surface Area (cm2)*May require adjustment for route of exposure ICH Q9 ICH Q9 Risk Assessment ModelWhat might go wrong? What is the likelihood (probability) it will go wrong?( What are the consequences Severity)? # (Airborne) (Mechanical Transfer) (Retention) (Mix up)Courtesy of Stephanie Wilkins ispe June 2007 FDA CDER (Safety Officer) 2008 ispe Washington Conference #Table IV.