QbD 적용을위한품질심사해설서 ( 예시 )

QbD 적용을위한품질심사해설서 ( 예시 )

목차 - 1 -

적용예시 1. FDA 사례요약 - 제네릭의약품 ( 속방성정제 ) - 2 -

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약동학적변수 Lot #2 Lot #3 Lot #4 (d 90 20 um) (d 90 30 um) (d 90 45 um) 대조약 - 8 -

90 max - 9 -

0-t max 10 50 90-10 -

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μ μ - 16 -

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μ μ - 27 -

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μ - 35 -

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ρπ ρ - 66 -

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θ θ θ θ - 72 -

μ μ μ μ - 73 -

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2. FDA 사례요약 - 제네릭의약품 ( 방출제어정제 ) - 76 -

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3. 일본 MHLW - 사쿠라정주요공정의디자인스페이스및관리전략수립요약 - 81 -

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4. 일본 MHLW - 사쿠라블룸정허가신청서중완제의약품의제조방법, 기준및시험방법 μ - 110 -

μ φ - 111 -

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5. 일본 MHLW - 사쿠라블룸정개발경위 (2.3.P.2.) 2.3.P.1 (, ) (Sakura Bloom Tablet) 2.3.9.1-1. 2.3.P.1-1 20mg JP e) JP e) a) 20mg JP e) 6mg JP e) 10mg 192mg JP e) 2mg 194mg JP e) b) 4.8mg JP e) 6000 0.6mg JP e) 0.6mg JPE f) 6mg 200mg PTP/Al c) 500 / d) a) 100~350, 7.0%, 0.10~0.46g/cm 3 b) : 2910, : 6 mpa s c), d) + e) (JP) f) (JPE) 2.3.PP.2 (, ) 2.3.P.2.1 2.3.P.2.1.1 (Sakura Bloom Tablet) (Prunus) 2.3.S.1.3. 450. ph, 37 C. 20 mg BSC(Biopharmaceutical Classification System). 1-/ (log D) 25 C 252.6. Cacco-2 BCSDP. - 124 -

, BCS 2 ( ). 2.3.P.2.1-1 ph 2.3.P.2.1.2,., D-,.,,.,,.,.,.,., 6000. (III). 2.3.P.2.2 1), (QbD )., (Design of Experiment, DoE). (Critical Quality Attributes, CQA) (Critical Process Parameters, CPP), (Real Time Release Testing, RTRT).,. - 125 -

1. (Quality Target Product Profile, QTPP) 2., (p-cma) - - - - - - - - - 3. (p-cpp) (CMA) - - - - - 4. 5. 6. PHA(Preliminary Hazard Analysis, ), FMEA(Failure Mode Effects Analysis, ).,,,,, (,, ). (CMA).,,. (NIR).,,, (PAT). (,, )., NIR,. (). 2) - 126 -

2.3.P.2.2-1 20mg (),,, (),,,, 3 (), a),, a : 2.3.P.2.2.1 2.3.P.2.1.1,, (fluid bed granulation process, ). 2.3.P.2.1.2.,, 3,. 5%, 3w/w%, 1w/w%. ( ). 3%. 5, 10, 20 mg (NDA) 20mg 2.3.P.2.2-2. 20 mg,. NDA. (NDA) 20mg () 3 20mg () (Guidelines for Bioequivalence Studies of Generic Drug Products), 3 (Guideline for Bioequivalence Studies for Formulation Changes of Oral Solid Dosage Forms) (2012.2.29. PFSB No. 0229-10), A. (12 ). 2.3.P.2.2-3, 20mg () 3 20mg. 1 2 3 NDA 1,2,3 5mg 10mg 20mg 20mg 50 50 50 100* 20XX 4 20XX 4 20XX 4 20XX 4 2.3.P.2.2-2 XX Prunus 5.0 10.0 20.0 20.0 / (mg/ ) 151.0 146.0 136.0 136.0 20.0 20.0 20.0 20.0 10.0 10.0 10.0 10.0-127 -

6.0 6.0 6.0 6.0 2.0 2.0 2.0 2.0 (mg) 194.0 194.0 194.0 194.0 / (mg/ ) 4.8 4.8 4.8 4.8 6000 0.6 0.6 0.6 0.6 0.6 0.6 0.6 0.6 - - - 0.01 (mg) 200.0 200.0 200.0 200.0 3 A B C A,B,C * 1/10 2.3.P.2.2-3 3 20mg 20mg : ph 4.0, 50 rpm ( ) 3 NDA 1 (%) (%) (%) 5 15-30 85% 59.9 61.2 1.3 15 83.4 84.0 0.6 2.3.P.2.2 2.3.P.2.2.3 20mg (: NAD 1) (JP) 1 (JP-1), McIlvaine (ph 4.0), (JP) 2 (JP-2) 50 rpm. 2.3.P.2.2-1,, ph. 2.3.P.2.2-1 3 20 mg, McIlvaine (ph 4.0) ( 85% ). - 128 -

2.3.P.2.3. 1():, 2():, 3():, 4(), 5(), 6()... 2.3.P.2.3-1 (QbD).,, (,,,,, ), (,, ) ( 2.3.P.2.3-2). (Material Attributes, MA).,. (Process Parameters, PP).,. ( PAT ).,..,.,. (Process Analytical Technology, PAT), (ongoing process verification) *.. - 129 -

2.3.P.2.3-1 (QbD) * (ongoing process verification). GMP 3) -.,,, ( ),.,,.. FDA Guidance for Industry Process Validation : General Principles and Practices (Continued Process Verification), PAT ( ) (Continuous Process Verification)(ICH Q8), CPV. (ongoing process verification)., (ongoing process verification). 2.3.P.2.3.1 2.3.S.1.3,,,,,. PHA. 2.3.P.2.3-2, PHA 3.2.P.2.3.,,, /,,.., - 130 -

,,, /,...,...,.,,.. (,, ) 2.3.P.5.4 2.3.P.5.4, 2.3.P.8.,.,.,, /,,.,.,,,, /,,.,. *,. - - 2.3.P.2.3-2 2.3.P.2.3.2 2.3.P.2.3.2.1 2.3.P.2.3-1. 3 (,, ) ( 3.2.P.2.3 ).,,, - 131 -

,,,,,..,, Ishikawa 2.3.P.2.3-3. FMEA. FMEA 3.2.P.2.3. RPN(risk priority number, ) 40 (40 ), 20 ( 20) 40 (<40), 20 (<20)., 2.3.P.2.3-4 2.3.P.2.3-2,. 2.3.P.2.3-1,,,,,,,, (,, ),,, (),,,, ( : ),,,,,,,,,, (,, ), (, ),,,,,, ( ),,,,, (), (,, ),,, (),,,,,,,,,,,,,,,,,,,,,, //,, /,,, ( ),,, (,, ),,, /, //, 2.3.P.2.3-3,, - 132 -

2.3.P.2.3-4 FMEA 2.3.P.2.3-2 FMEA ( 3.2.P.2.3 ) RPN a) 3 4 4 48 4 4 4 64 4 4 4 64 4 3 4 48 4 4 4 64 4 4 4 64 4 4 4 64 3 3 4 36 3 4 4 48 3 4 4 48 4 5 4 80 a) RPN( ). RPN 40 (40 ), 20 ( 20) 40 (<40), 20 (<20). 2.3.P.2.3.2.2. ( /) 2.3.P.2.3-5(a),. ( ), FMEA. 2.3.P.2.3-5(b). ( ) - 133 -

. RPN FMEA. (a) (b) (ph 4.0, 50 rpm) 2.3.P.2.3-5 (, ) : FMEA (severity). (significance).,... ///, ( ) A, ( 2.3.P.2.3-6 [a] ). 2.3.P.2.3-6(b), A 10%.., 2.3.P.2.3-7. FMEA. (a) (b) - 134 -

2.3.P.2.3-6 2.3.P.2.3-7, FMEA. 2.3.P.2.3-8,, FMEA. 2.3.P.2.3-8(a), A., 2.3.P.2.3-6 2, 50 rpm., A.,. (a) ( A) (b) 50 rpm (3 ) 2.3.P.2.3-8 ( ) ( ).. 2.3.P.2.3-9, 6 3 3-135 -

3. 2.3.P.2.3-9 (3 ) / (CQA) 3 ( ). 2.3.P.2.3-10(a), () ( ).. ( 2.3.P.2.3-6 ) 2.3.P.2.3-10(b).,.,. (a) / (b) / 2.3.P.2.3-10 / // FMEA RPN 2.3.P.2.3-11 2.3.P.3-3. (MA).. - 136 -

: : :,,,, 2.3.P.2.3-11 FMEA : FMEA. 2.3.P.2.3-3 FMEA (3.2.P.2.3 ) RPN a) 1 4 4 16 4 1 4 16 4 3 4 48 4 2 4 32 4 3 4 48 4 2 4 32 4 4 4 64 1 3 4 12 3 4 4 48 1 4 4 16 4 4 4 64 a) RPN 40 (40 ), 20( 20) 40(<40), 20 (<20). : t. 2.3.P.2.3.3 2.3.P.2.3.3.1 (p-cpp) 2.3.P.2.3-4 2.3.P.2.3.2. ( ),. - 137 -

,. 3 ( 3.2.P.2.3 ).,,,,. FMEA. FMEA 3.2.P.2.3. RPN, 40 (40 ), 20 ( 20) 40 (< 40), 20 (< 20)., 2.3.P.2.3-12 2.3.P.2.3-5,.,,, Ishikawa 2.3.P.2.3-13. 2.3.P.2.3-4,,,,,,, (, ),,, (, ),, (, ),,, 2.3.P.2.3-12 FMEA 2.3.P.2.3-5 FMEA (3.2.P.2.3 ) RPN a) 4 4 4 64 4 3 4 48 4 3 4 48 4 4 4 64 4 4 4 64-138 -

5 4 4 80 4 2 4 32 5 4 4 80 a) RPN 40 ( 40), 20 ( 20) 40 (< 40), 20 (< 20). 2.3.P.2.3-13,,, 2.3.P.2.3.3.2. ( ) ( ), //.,. ( // ),. 2.3.P.2.3-6 L4(2 3 ),. 2.3.P.2.3-14, Run-1,.. (Run-2 ~ Run-4). 2.3.P.2.3-6 L4(2 3 ) Run (m 3 /min) ( C) (g/min) 1 50 90 800 2 35 90 1200 3 50 70 1200 4 35 70 800-139 -

(a) (b) 2.3.P.2.3-14 ( ).,. 2.3.P.2.3-15, 50 rpm (Run-1). ( ). 2.3.P.2.3-15 2.3.P.2.3-14,., 2.3.P.2.3-16.. /. 2.3.P.2.3-16 - 140 -

/ / / /. 2.3.P.2.3-6 L4(2 3 ),.,. 2.3.P.2.3-17 2.3.P.2.3-18, 3,. /. 2.3.P.2.3-17 2.3.P.2.3-18 / 2.3.P.2.3-14 Run-2 /., 2.3.P.2.3-19,.,.. - 141 -

2.3.P.2.3-19 /, FMEA RPN 2.3.P.2.3-20 2.3.P.2.3-7... : ( ) () : :,, 2.3.P.2.3-20 FMEA : FMEA. 2.3.P.2.3-7 FMEA (3.2.P.2.3 ) RPN a) 4 3 4 48 1 3 4 12-142 -

1 3 4 12 4 3 4 48 4 3 4 48 5 4 4 80 2 2 4 16 5 4 4 80 a) RPN 40 ( 40), 20 ( 20) 40 (< 40), 20 (< 20). :. 2.3.P.2.3.4 2.3.P.2.3.2 2.3.P.2.3.3 /,, Ishikawa 2.3.P.2.3-21. 2.3.P.2.3-21,,,. 2.3.P.2.3.4.1 ( ) ( ) 3,, NIR., ( ) PAT. 200. 2.3.P.2.3.4.2 ( ) ( ).,. (). - 143 -

()., 200. 2.3.P.2.3.4.3 ( ). 1) ( ), 2) ( ), 3) FBRM (Focused Beam Reflectance Measurement), 4) PAT.. 2, (upstrem)(downstream) (feedforward control). 3, 3. 2.3.P.2.3-22,. (central composite design). 2.3.P.2.3-22,,..,. ( ) = A-B - C - D - E, (20 kg) (200 kg) (,,, 2.3.P.2.3-8 ) - 144 -

., 2.3.P.2.3-23,, RMSEP(Root Mean Square Error of Prediction, ) 1.6%.,. 2.3.P.2.3-7 (μm) (μm) (kn) 3.9 9.8 102 7.1 (20 kg) (200 kg) 20.2 147 38.9 202 10.1 99 19.3 151 19.3 148 40.2 197 11.2 3.8 7.2 11.1 4.0 7.2 11.3 3.7 7.1 11.1 3.6 7.0 11.0 3.9 7.2 11.4 3.8 7.1 11.2 2.3.P.2.3-23 - 145 -

, (response surface) 2.3.P.2.3-23. () 80%. 90% (feedforward control).,, ( ) ( ). 2.3.p.2.3-25. 2.3.P.2.3-24 () 2.3.P.2.3-25 2.3.P.2.3.4.4 NIR,. - 146 -

(). 2.3.P.2.3.5, ( 2.3.P.2.3-26, 2.3.P-2.3-9) ( 2.3.P.2.3-27, 2.3.P-2.3-10), /. 2.3.P.2.3.5.1 ( ) NIR, FMEA. /. /,, FMEA. 2.3.S.2, (milling) FMEA. ( ),,, FMEA. ( ),, FMEA. - 147 -

2.3.P.2.3-26 FMEA : FMEA. 2.3.P.2.3-7 FMEA (3.2.P.2.3 ) RPN a) 1 4 4 16 4 1 4 16 4 2 2 16 4 1 3 12 4 2 2 16 4 1 3 12 4 2 2 16 1 3 4 12 3 2 2 12 1 4 4 16 4 2 2 16 a) RPN 40 ( 40), 20 ( 20) 40 (< 40), 20 (< 20). :. 2.3.P.2.3.5.2, NIR,, FMEA.,,, FMEA.,,, FMEA.,,, FMEA.,, FMEA. - 148 -

2.3.P.2.3-27 FMEA : FMEA. 2.3.P.2.3-9 FMEA (3.2.P.2.3 ) RPN a) 4 2 2 16 1 2 2 4 1 2 2 4 4 2 2 16 4 2 2 16 5 2 1 10 2 1 2 4 5 2 1 10 a) RPN 40 ( 40), 20 ( 20) 40 (< 40), 20 (< 20). :. 2.3.P.2.3.5.3 ( 2.3.P.2.3-2). 2.3.P.5 2.3.P.8, NDA ( ),,, ().. - 149 -

2.3.P.5 2.3.P.8, ( ).. 2.3.P.2.3-2. ü, 2.3.P.2.3-5.,. ü,.,. NDA,. ü. 2.3.P.2.3.2.2 2.3.P.2.3.3.2,. 2.3.P.2.3.4,. ü 2.3.P.2.3,. ü... 2.3.P.2.4 75% RH 3%. / 3%., 36. 2.3.P.2.5,.. (JP). 10 JP. 2.3.P.2.6. - 150 -

2.3.P.3 2.3.P.3.3 2.3.P.3.3-1.. 2.3.P.2.3.4,, 1( ) 3(). 2.3.P.3.3-1 2.3.P.3.3.1 / 2.3.P.3.3-1. (performance qualification, PQ).. 2.3.P.3.3-1 - 151 -

( ) () () (Proven Acceptable Range, PAR) / - 40 ~ 45 m 3 /min 35 ~ 50 m 3 /min ( ),,,.. < 1> * - 75 ~ 85 75 ~ 90 ( ),,,.. 900 ~ 1100 g/min 900 ~ 1100 g/min 800 ~ 1200 g/min ( ),,,.. < 2> - 10-20 rpm 5 ~ 20 ( ) 5 ~ 30 ( ) 20 rpm ( ) /.. /. /. < 3> * - 20 ~ 30 rpm 5 ~ 50 rpm ( ),,, NIR ( ).. 6 ~ 14 kn 6 ~ 14 kn 5 ~ 15 kn ( ),, ( - 152 -

).. - 70 ~ 80 70 ~ 80 ( ) /. < 4> < 5> < 6> - -: - 40 ~ 45 m 3 /min 280 ~ 420 g/min - 2.0 ~ 6.0 rpm 40 ~ 45 m 3 /min ( ) 280 ~ 420 g/min ( ) 2.0 ~6.0 rpm ( ) /. /. /. 2.3.P.3.3.2 2.3.P.2.3.3,, 2.3.P.3.3-2. 2.3.P.3.3-2 () 194 mg ± 3%. (NIR ) 90.0 ~ 110.0%.. () () 90% 3 25 μm *. (FBRM, 90 ~ 210 μm* ) 3 ~ 11.5 kp* () - () NIR - 194 mg ± 3%. 95 ~ 105%,. 90 ~ 110%. 85.0-153 -

~ 115.0% 6, 85.0 ~ 115.0% 90.0 ~ 110.0%.,. * 2.3.P.2.3.4.3 ( ),,,. = A B C D E 2.3.P.3.3-2. 80%. 90%.,. 2.3.P.3.3-2 2.3.P.3.3.3 2.3.P.3.3.2, NIR Large-N.,,. 2.3.P.3.3.3-1 FBRM. FBRM,. 2.3.P.3.3-3. : FBRM: C35 : - 154 -

: φ35mm :5 2.3.P.3.3-3. FBRM,. 90%.. 2.3.P.3.3.3.2,.. (). 2.3.P.3.3-4., 194 mg ± 3%,. 2.3.P.3.3-4, NIR, ( ) PAT. - 155 -

NIR. 90 ~ 110%. : : : InGaAs : 12,500 ~ 3,600 cm -1 : 64 : 8 cm -1 : PLS., 90%,. 2.3.P.3.3.3.3 2.3.P.3.3-3 10 (). 3 At-line NIR. 2.3.P.3.3-3 (). 10 At-line NIR : : NIR : InGaAs : 12,500 ~ 3,600 cm -1 : 64 : 8 cm -1 : (PCA) : 3 2.3.P.3.4 (),,,.. 2.3.P.3.4.1-156 -

2.3.P.2.3 (),,,. 2.3.P.3.4.1.1 () ( ) (), 10 2.3.P.3.3-3. 2.3.P.3.4.1.2 ( ), 2.3.P.5.2 () < > ( ) At-line NIR 3. 2.3.P.3.4.1.3, NIR,. 200 (10 20 ). 2.3.P.3.3.3.2 2.3.P.5.6.3.1 ( ). 2.3.P.3.4.1.4 -.. ( ) FBRM. 2.3.P.3.4.1.3, 200 (10 20 ). 2.3.P.2.3.4.3 ( ),,, (). = A B C D E,.. 2.3.P.3.4.1.5 2.3.P.3.4.1.3 NIR, 200. 2.3.P.3.5 /,. 21 ( 2.3.P.2.3-7 ), 3. - 157 -

( ) ()..,...,..., (PQS).. 2.3.P.5,,. 2.3.P.5.1,,,,.,.. 2.3.P.5.1-1 20mg (JP) NIR HPLC HPLC NIR.. 200, 85.0 ~ 115.0% 6, 75.0 ~ 125.0% 1-158 -

HPLC : : FBRM : () NIR. (JP). 30 80%. 30 Q 80%. HPLC 95.0 ~ 105.0% ( ), 95.0 ~ 105.0%. * Decision Tree.. 2.3.P.5.2 (), (JP),,. ( ) 2.3.P.5.2.1 2.3.P.5.2.1.1 2.3.P.3.4.1.1 2.3.P.5.2.1.2 <> 2.3.9.5.2.2 2.3.P.5.2.2.1 At-line NIR. 2.3.P.5.2-1, (discriminating model) NIR.. At-line NIR HPLC. NIR. - 159 -

2.3.P.5.2-1 2.3.P.5.2.2 <> 2.3.P.5.2.3 2.3.P.5.2.3.1 2.3.P.3.3.3.2 2.3.P.3.4.1.3. 2.3.P.3.3.3.2,. (%) = (%) (mg) / 194(, mg) 2.3.P.5.2.3.2 <> decision tree. decision tree. - 160 -

2.3.P.5.2.4 2.3.P.5.2.4.1 2.3.P.3.4.1.4 2.3.P.5.2.4.2 <> decision tree. - 161 -

2.3.P.5.2.5 2.3.P.5.2.5.1 2.3.P.3.4.1.5. 2.3.P.5.2.3.1 NIR 200. 2.3.P.5.2.5.2 <> 2.3.P.5.2.3 decision tree. 2.3.P.5.3 () 2.3.P.5.3.1 () NIR At-line NIR. 2.3.P.5.3.1.1 ( NIR ) (1) () 60, 80, 100, 120, 140%. 5 NIR (HPLC),. NIR A B X Y.. NIR. 6100 5500 cm -1 1 + PLS 3 0.985 0.67% - 162 -

(2) (5 3 ) NIR (HPLC). NIR (1),.,. 5 n = 3, 0.97. : 0.981 HPLC NIR 70, 100, 130% ± 5%, ±2%. RMSEP () 1.5%. RMSEP : 0.75%. 70 ~ 130% 70% : 5%, 4%, - 3%,, : 2% 100% : 3%, - 4%, - 1%, : -1% 130% : 1%, 2%, - 3%, : 0% (xx, yy, zz, ). (3) NIR, NIR, HPLC. NIR HPLC 1.0%,. 2.3.P.5.3.1.2 (At-line NIR ) (1) () 3 5. NIR A B X Y.. NIR. 10000 7500 cm -1, 6500 5500 cm -1 2 PLS 2 (2) ( ) NIR, 3.,. 2.3.P.5.3.2 () (1995.7.20. - 163 -

(PAB) 755 ) (1997.10.28. 338 ). <> 2.3.P.5.6 2.3.P.5.6.3 2.3.P.5.6.3.1 ( ) : 200, 85.0 ~ 115.0% 6 75.0 ~ 125.0% 1. < > 2.3.P.5.6.4 2.3.P.5.6.4.1 () : 30 Q 80%. < > 2.3.P.5.6.4.2 ( ) : 30 80%.,.,, 30 Q 80% 30 80%..,,, (central composite design). xx%. S2.,,. 2.3.P.5.6.5 <> - 164 -

(Health and Labour Sciences Research Group) (JP), (USP), (EP) ICH 2., 16 (JP 16) 6.02 1 10, 2 30. ((AV = M - + ks). (AV ) ( ).. 10 30, (PAT),. 1 (OC).. 5 ~ 10%.,.. 1. OC PhRMA Large-N Modified Large-N( ). Large-N Modified Large-N OC 2. JP16 OC (), Large-N JP16, Modified Large-N JP16.,, JP16. 1 EP (Ph.Eur.2.9.47). EP 1 JP 16 ( k ) - 165 -

(C1 ). 2 (C1 C2 ) 2. OC ( 3) 1( 3 1), 2( 3 2), JP16( 3 ICH ).. Large-N.,. Large-N PhRMA Modified Large-N EU, EP. EP 1 2,, 2. EP 2.,. : Large-N : Modified Large-N 2. Large-N Modified Large-N OC 3. Large-N Modified Large-N OC - 166 -

1. EP (n) 1 2 50 (k) C2(±25.0%) C1(±15.0%) C2(±25.0%) 50 - - - - 75 - - - - 100 2.15 0 3 0 150 2.19 0 4 0 200 2.21 1 6 1 300 2.23 2 8 2 500 2.25 4 13 4 1000 2.27 8 25 8 2000 2.29 18 47 18 5000 2.30 47 112 47 10000 2.31 94 217 94-167 -

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