Towards Process Understanding:

Transcription

1 Towards Process Understanding: sta2s2cal analysis applied to the manufacturing process of tablets Drug Product Development: A QbD Approach Nadia Bou-Chacra Faculty of Pharmaceutical Sciences University of Sao Paulo, Brazil

2 OUTLINES FDA s New Process Valida2on Guidance; Measurement system variability: precision to tolerance ra2o; Understanding the Cause of Process Variability; Control charts: Is your process out of control? Nested ANOVA model applied to evaluate variability; Es2ma2ng process capability indices.

3 Case Study Applica2on of PAT in Captopril (25 mg) tablet process evalua2on using NIR spectroscopy.

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5 FDA s New Process Valida2on Guidance strongly emphasizes that the pharmaceu2cal industry has to understand process varia2on including all sources and degrees of varia2on and ul2mately the impact of varia2on on any product asributes.

6 FDA s New Process Valida2on Guidance Process valida2on is defined as the collec2on and evalua2on of data, from the process design stage through commercial produc2on, which establishes scien2fic evidence that a process is capable of consistently delivering quality product..develop the data collec2on plan and sta2s2cal methods used in measuring and evalua2ng process stability and process capability.

7 MEASUREMENT SYSTEM VARIABILITY: PRECISION TO TOLERANCE RATIO

8 a σ 2 Real (Process) + σ2 Measurement System = σ2 Total b

9 Precision/Tolerance ratio: %P/T = 6σ MS 00 USL LSL Precision/Total Variation ratio: %RR = (σ MS /σ total ) 00 (R&R) is the estimate of the combined variation from repeatability and reproducibility.

10 If %P/T < 0% and %RR < 0% Good! If 0% < %P/T < 30% and/or 0% < %RR < 30% Ok If %P/T > 30% or %RR > 30% Bad!!!!

11 Histogram of Dosage-unit uniformity Lamivudine (%w/w) Normal Mean 00,0 StDev 0,4746 N 00 Frequency ,0 97,5 99,0 00,5 02,0 03,5 05,0

12 Histogram of Dosage-unit uniformity Lamivudine (%w/w) Normal Mean 99,84 StDev,800 N 00 Frequency

13 Histogram of Dosage-unit uniformity Lamivudine (%w/w) Normal Mean 99,84 StDev,800 N 00 Frequency

14 UNDERSTANDING THE CAUSE OF PROCESS VARIABILITY

15 Two causes of varia2on: common and special Common (random) cause varia2on is inherent in the manufacturing process as result of the process design, machinery and ac2vi2es; Special (assignable) cause varia2on is created by a nonrandom event leading to an unexpected change in the process output. The effects are intermisent and unpredictable. It is caused by factors that can be clearly iden2fied and possibly managed.

16 CONTROL CHARTS: IS YOUR PROCESS OUT OF CONTROL?

17 Control chart: Control limits versus Spec limits Spec limits or tolerances ensure safety, efficacy and quality of medicines. Control limits: Characteris2c of the process in ques2on; Dependent on sampling parameters, sample size, alpha-risk (Type I error); Used to iden2fy presence/absence of special-cause varia2on; Based on the process mean and varia2on.

18 Special causes I Chart of Dosage-unit Uniformity of Captopril tablets 25 mg 5 5 USL Individual Value UCL=09,7 _ X=0,2 LCL=93, LSL Observation

19 Capability indices: Cp and Cpk Normal Cp < Cp 0,9 0,8 0,7 0,6 0,5 0,4 0,3 0,2 0, ,0 96,0 97,5 99,0 00,5 02,0 03,5 05,0 +3σ

20 Process Capability Indices: Cp and CpK

21 Normal Distribu2on

22 Anderson-Darling Normality Test The Anderson-Darling test for normality is one of three general normality tests designed to detect all departures from normality. The test rejects the hypothesis of normality when the p-value is less than or equal to 0.05.

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28 APPLICATION OF PROCESS ANALYTICAL TECHNOLOGY (PAT) AT IN CAPTOPRIL (25 MG) TABLET PROCESS EVALUATION USING NEAR INFRA RED (NIR) SPECTROSCOPY

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30 Table. Sample plan for the process validation of Captopril tablets 25 mg Assays Sample PosiEon Number of samples Total Blending uniformity Tablet weight* 20 units each 2 minutes Uniformity of dosage unit 0 3 samples for each loca2on 30 ( batch) 90 (3 batches) 6 units each 2 minutes % (w/v) release Beginning Middle End 600 units for each side (lei and right) 98 units for each side (lei and right) 6 units for each posi2on (3 for each side: lei and right),200 ( batch) 3,600 (3 batches) 396 ( batch),88 (3 batches) 8 ( batch) 54 (3 batches) Batch size: kg; aprox.: 2, units (34 mg); cycle time: 360 min.

31 The content homogeneity of the powder mixture (blend uniformity) in the process manufacturing of Captopril tablets 25 mg

32 Sampling locations

33 I-MR-R/S (Between/Within) Chart of Blend Uniformity Captopril tablets 25 mg Subgroup Mean 00,2 99,9 99,6 UCL=00,287 _ X=99,937 LC L=99, MR of Subgroup Mean 0,4 0,2 0,0 UCL=0,4299 MR=0,36 LC L=0 2 3 Sample StDev,2 0,9 UCL=,3777 _ S=0,9872 0,6 2 Sample 3 LC L=0,5967

34 Table a. Nested ANOVA: Es2mated Variance Component for Blending Uniformity Captopril 25 mg. Source Variance Component % of Total Standard DeviaEon Batch Posi2on Error Total ** Value is negative, and is estimated by zero

35 Normality test: blend uniformity Histogram of Blend Uniformity Captopril tablets 25mg Normal Probability Plot of Blend Uniformity Normal Frequency Mean 99,94 StDev 0,9843 N 90 Percent 99, Mean 99,94 StDev 0,9843 N 90 AD 0,98 P-Value 0, ,0 97,5 99,0 00,5 02,0 Blend Uniformity 03,5 05,0 0, Blend Uniformity Table b. Descriptive statistics: blend uniformity Variable N N* Mean StDev Median Minimum Maximum Blend Uniformity

36 Process Capability of Blend Uniformity Captopril tablets 25 mg (using 95,0% confidence) Process Data LSL 95 Target * USL 05 Sample Mean 99,937 Sample N 90 StDev(Within),04923 StDev(Overall) 0,98434 LSL USL Within Overall Potential (Within) Capability Cp,59 Lower CL,36 Upper CL,82 CPL,57 CPU,6 Cpk,57 Lower CL,33 Upper CL,8 Overall Capability Observed Performance PPM < LSL 0,00 PPM > USL 0,00 PPM Total 0,00 96,0 97,5 Exp. Within Performance PPM < LSL,27 PPM > USL 0,70 PPM Total,97 99,0 00,5 02,0 Exp. Overall Performance PPM < LSL 0,26 PPM > USL 0,3 PPM Total 0,40 03,5 05,0 Pp,69 Lower CL,44 Upper CL,94 PPL,67 PPU,7 Ppk,67 Lower CL,42 Upper CL,93 Cpm * Lower CL *

37 Evaluation of the individual tablet weight (mg) in the process manufacturing of Captopril tablet 25 mg Double sided rotary press 3200i 700,000 tablets/hour

38 Observation Individual Value _ X=33,95 UCL=43,75 LCL=24,4 A B C Observation Moving Range MR=3,69 UCL=2,04 LCL=0 A B C I-MR Chart of Captopril Tablet Weight (mg)

39 I-MR-R/S (Between/Within) Chart of Tablet Weight by batch 35,0 UCL=35,26 Subgroup Mean 33,5 32,0 _ X=33,464 LC L=3, MR of Subgroup Mean 2 0 UCL=2,208 MR=0,676 LC L=0 2 3 UCL=3,6839 Sample StDev 3,6 3,4 3,2 2 Sample 3 _ S=3,472 LC L=3,2585

40 Table 2a. Nested ANOVA: Es2mated Variance Component for Tablet Weight Captopril 25 mg. Source Variance component % of Total Standard DeviaEon Batch Side (Lei and Right) -0.63** Time* Error Total *B: beginning; M: middle; E: end ** Value is negative, and is estimated by zero

41 Normality test: tablet weight Table 2b. Descriptive statistics: tablet weight Variable N N* Mean StDev Median Min Max Tablet weight

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43 Process Capability of Tablet Weight Captopril 25 mg (using 95,0% confidence) Process Data LSL 26 Target * USL 42 Sample Mean 33,464 Sample N 3600 StDev(Within) 3,707 StDev(Overall) 3,5249 LSL USL Within Overall Potential (Within) Capability Cp 0,84 Lower CL 0,82 Upper CL 0,86 CPL 0,78 CPU 0,90 Cpk 0,78 Lower CL 0,76 Upper CL 0,8 Overall Capability Observed Performance PPM < LSL 8055,56 PPM > USL 7777,78 PPM Total 5833, Exp. Within Performance PPM < LSL 9285,82 PPM > USL 3549,27 PPM Total 2835, Exp. Overall Performance PPM < LSL 709,78 PPM > USL 7724,90 PPM Total 24834, Pp 0,76 Lower CL 0,74 Upper CL 0,77 PPL 0,7 PPU 0,8 Ppk 0,7 Lower CL 0,69 Upper CL 0,73 Cpm * Lower CL *

44 EvaluaEon of the uniformity of dosage unit in the process manufacturing of Captopril tablets 25 mg

45 I-MR Chart of Dosage-unit Uniformity Captopril tablets 25 mg Individual Value USL UCL=09,36 _ X=0,4 LCL=92,92 85 LSL Observation ,0 UCL=0,09 Moving Range 7,5 5,0 2,5 MR=3,09 0,0 LCL= Observation

46 I-MR Chart of Dosage-unit Uniformity by Batch Captopril tablets 25 mg 204L 207L 24L 5 USL Individual Value UCL=09,22 _ X=0,0 LCL=92,98 85 LSL Observation ,0 204L 207L 24L UCL=9,97 Moving Range 7,5 5,0 2,5 0,0 MR=3,05 LCL= Observation

47 I-MR-R/S (Between/Within) Chart of Dosage-unit Uniformity Captopril tablets 25 mg Subgroup Mean UCL=06,03 _ X=0,4 LC L=96,25 MR of Subgroup Mean 5,0 2,5 0,0 UCL=6,0 MR=,840 LC L=0 2 3 Sample StDev 3,3 3,0 UCL=3,3938 _ S=3,0664 2,7 LC L=2, Sample 3

48 Table 3a. Nested ANOVA: Es2mated Variance Component for uniformity of dosage unit (%w/w) Captopril 25 mg. Source Variance Component % of Total Standard DeviaEon Batch Side -0.06** Posi2on* Error Total *B: beginning; M: middle; E: end ** Value is negative, and is estimated by zero

49 Normality test: uniformity of dosage unit Frequency Histogram of Dosage-unit Uniformity Captopril tablets 25 mg Normal Mean 0, StDev 3,230 N 88 Percent Probability Plot of Dosage-unit Uniformity Captopril tablets 25 mg Normal 99, Mean 0, StDev 3,230 N 88 AD 5,686 P-Value <0, , Dosage-unit Uniformity 0 5 Table 3b. Descriptive statistics: uniformity of dosage unit Variable N N* Mean StDev Median Min Max Uniformity of Dosage unit

50 Process Capability of Dosage-unit Uniformity Captopril tablets 25 mg (using 95,0% confidence) Process Data LSL 85 Target * USL 5 Sample Mean 0,4 Sample N 88 StDev(Within) 2,7386 StDev(Overall) 3,22992 LSL USL Within Overall Potential (Within) Capability Cp,83 Lower CL,75 Upper CL,90 CPL,96 CPU,69 Cpk,69 Lower CL,62 Upper CL,76 Overall Capability Observed Performance PPM < LSL 0,00 PPM > USL 0,00 PPM Total 0, Exp. Within Performance PPM < LSL 0,00 PPM > USL 0,2 PPM Total 0, Exp. Overall Performance PPM < LSL 0,29 PPM > USL 8,89 PPM Total 9, Pp,55 Lower CL,49 Upper CL,6 PPL,67 PPU,43 Ppk,43 Lower CL,37 Upper CL,49 Cpm * Lower CL *

51 EvaluaEon of % (w/v) release of Captopril in the process manufacturing of Captopril tablets 25 mg

52 I-MR Chart of %(w/v) Captopril Release Individual Value UCL=2,7 _ X=0,69 LCL=90, LSL (Q) Observation UCL=3,54 Moving Range 0 5 MR=4,4 0 LCL= Observation

53 I-MR Chart of %(w/v) Captopril Release by Batch 204L 207L 24L Individual Value UCL=3,78 _ X=02,84 90 LCL=9, Observation L 207L 24L Moving Range UCL=3,44 MR=4, 0 LCL= Observation

54 I-MR-R/S (Between/Within) Chart of %(w/v) Captopril Release UCL=06,9 Subgroup Mean _ X=0,69 LC L=96,46 MR of Subgroup Mean 5,0 2,5 0,0 UCL=6,49 MR=,965 LC L= UCL=8,2 Sample StDev 6 4 _ S=5,408 LC L=2,606 2 Sample 3

55 Table 4. Nested ANOVA: Es2mated Variance Component for % (w/v) Captopril Release. Source Variance component % of Total Standard DeviaEon Batch -3.92** Posi2on* Error Total *B: beginning; M: middle; E: end ** Value is negative, and is estimated by zero

56 Normality test: %(w/v) release Histogram of Captopril %(v/w) Release Normal Probability Plot of Captopril %(v/w) Release Normal Frequency Mean 0,7 StDev 5,639 N 54 Percent Mean 0,7 StDev 5,639 N 54 AD 0,787 P-Value 0, %(v/w) Release Table 4b. Descriptive statistics: % (w/w) Captopril Release Variable N N* Mean StDev Median Min Max % (w/w) Release

57 Process Capability of %(w/v) Captopril Release (using 95,0% confidence) Process Data LSL 80 Target * USL 20 Sample Mean 0,686 Sample N 54 StDev(Within) 3,67373 StDev(Overall) 5,63923 LSL USL Within Overall Potential (Within) Capability Cp,8 Lower CL,47 Upper CL 2,6 CPL,97 CPU,66 Cpk,66 Lower CL,33 Upper CL,99 Overall Capability Observed Performance PPM < LSL 0,00 PPM > USL 0,00 PPM Total 0, Exp. Within Performance PPM < LSL 0,00 PPM > USL 0,3 PPM Total 0, Exp. Overall Performance PPM < LSL 60,5 PPM > USL 58,8 PPM Total 64, Pp,8 Lower CL 0,96 Upper CL,4 PPL,28 PPU,08 Ppk,08 Lower CL 0,86 Upper CL,3 Cpm * Lower CL *

58 Conclusion The sta2s2cal approach used in the process evalua2on of blending, table2ng, dosage-unit uniformity, weight varia2on and dissolu2on behavior led to beser understanding of the manufacturing process. Although a limited number of batches were inves2gated, the sta2s2cal methods iden2fied possible approaches for process improvement in the manufacturing of Captopril tablets.

59 References FDA, Current Good Manufacturing Prac4ces for Drugs: Reports, Guidance and Addi4onal Informa4on. Pharmaceu4cal (cgmp) for the 2 st century: a risk based approach. (Rockville, MD, 2002). FDA, Guidance for Industry: Process valida2on: General Principles and Prac2ces, Jan. 25, 20. ICH, Q8(R) Pharmaceu4cal development, ich.org/lob/media/media4986.pdf, accessed Dec., ICH, Q0 Pharmaceu4cal Quality System, ich.org/lob/media/media397.pdf, accessed Dec., ICH, Q9 Quality Risk Management, ich.org/lob/media/media957.pdf, accessed Dec., 2009.