Process Validation: Solid Dosage Forms

Part II
by Pramote Cholayudth GPO, BIOLAB & VALITECH Tel 0-1932-2374 Email: cpramote2000@yahoo.com
August 22, 2006
1

USP CU Distribution Curve

Conventional Lot RSD for USP CU = 10%

86.64%

Validation CU Distribution Curve

98.08%

97.79%

Criteria for Proposed Acceptance Criteria

As-is data limit is modified from US FDA Guide to 75 125% LA RSD limit is modified from Thai FDA Guide based on higher probability of meeting USP Content Uniformity test i.e. at least 50% First stages sample size of 30s is 50% of US FDA sampling plan and coincidentally 3 times the USP CU sampling plan

Products Using USP 28 Content Uniformity Test

USP 20-27 Content Uniformity Test Procedure

USP Content Uniformity Testing Procedure
Step 1, 10 tablets No
1 of 10 (85%,115%) All 10 (75%, 125%)

All 10 (85%, 115%) RSD 6%

Yes Step 2, additional 20 tablets

Yes No Accept Reject

At most 1 of 30 (85%,115%) All 30 (75%, 125%) RSD 7.8%

No Reject

Yes Accept

USP 28 Content Uniformity Test Procedure

USP 28 Content Uniformity Testing Procedure
Step 1, 10 units
AV 15

All 10 (0.75M, 1.25M) Yes Accept

No

AV = M X + ks 15
AV > 15

All 10 (0.75M, 1.25M) No Reject

Yes Step 2, additional 20 units

= Fall within

All 30 (0.75M, 1.25M) Yes Accept

AV 15

No Reject

Acceptance Criteria

Acceptance Criteria 1) AV 15 2) All (0.75M, 1.25M)

AV = Acceptance Value

AV = M X + ks 15
15

ks

CU Mean Curve CU Curve

Condition: M and AV (Acceptance Value)

Target (T) 101.5% LA > 101.5% LA Condition 98.5 X 101.5% LA X < 98.5% LA X > 101.5% LA 98.5 X T X < 98.5% M X> T M
X

98.5 101.5
X

98.5 T

AV ( 15) ks 98.5 X + ks 101.5 X + ks ks 98.5 X + ks X T + ks

QC Testing (USP) n = 10, k = 2.4 n = 30, k = 2.0

Validation Testing n = 30, k = 2.7 n = 70, k = 2.5

Establishing k Value Using Tolerance Interval (TI) Method

n 1 1 .s TI = x ks = x Z1 / 2 . 1 + . 2 n 0.9,n1 1 n 1 k = Z1 / 2 . 1 + . 2 n 0.9,n1
1 9 k = 1.555. 1 + . = 2.4( Z 0.94 = 1.555) 10 4.168 1 29 k = 1.645. 1 + . = 2.0( Z 0.95 = 1.645) 30 19.768 10

Explanation

For k = 2.4 (n = 10), with 90% confidence there is at least 88% (approx. 90%) of the lot falls between 15% of the reference value (M) For k = 2.0 (n = 30), with 90% confidence there is at least 90% of the lot falls between 15% of the reference value (M) For USP criterion, there is 86.64% of the lot falls between 15% of M e.g. 85-115% LA 11

Establishing Content Uniformity Test

(For Products Using USP 28 CU Test; Stage 1)
As-is Data (CU Data) Product Parameters Weight-Corrected Data (BU Data)

All 75 125% Content Uniformity of M; SD 4.5 (CU): n = 30

Means 90 110% TA; SD 2.7SD 15 M x (individuals) 4.5

Sampling Plan: 10 locations x 7 units; Test 10 x 3 units Meeting the criteria means there is a 95% confidence that at least 96.5% of the lot (USP = 86.64%) will fall between 15% of the reference value (M) How about registered limit? 12

Establishing Content Uniformity Test

(For Products Using USP 28 CU Test; Stage 2)
As-is Data (CU Data) Product Parameters Weight-Corrected Data (BU Data)

All 75 125% Content Uniformity of M; SD 5.4 (CU): n = 70

Means 90 110% TA; SD 2.5SD 15 M x (individuals) 5.4

Testing Plan: 10 x 4 units; Evaluate 70 units Meeting the criteria means there is a 95% confidence that at least 96.5% of the lot (USP = 86.64%) will fall between 15% of the reference value (M) 13

Establishing Content Uniformity Test

(For USP 28 CU Test, Summary; Stage 1 & 2)
As-is Data (CU Data) Product Parameters Weight-Corrected Data (BU Data)

All 75 125% Content Uniformity of M; SD s (CU)

k.SD 15 M x

Means 90 110% TA; SD (individuals) s

Stage 1: n=30, s=4.5, k=2.7; Stage 2: n=70, s=5.4, k=2.5 Meeting the criteria means there is a 95% confidence that at least 96.5% of the lot (USP = 86.64%) will fall between 15% of the reference value (M) 14

Establishing Acceptance Value at 95% CI and 100(1-)% TI

AV = M x + ks 15
AV = CI0.95 + TI0.95,1
CI = Confidence Interval TI = Tolerance Interval

x Z n 1 Z= , CI = x = Z. = . 2 .s / n n n n1

CI0.95 =

Z1(10.95^ 0.5) / 2 n

n 1
2 0.95^ 0.5,n1

.s
15

Joint CI = 95%

Establishing Acceptance Value at 95% CI and 100(1-)% TI

CI0.95 = CI0.95 CI0.95 Z1(10.95^ 0.5) / 2 n . n 1
2 0.95^ 0.5,n1

.s

2.236 29 = . .s = 0.55s(n = 30) 30 16.075 2.236 69 = . .s = 0.32s(n = 70) 70 47.974

16

Establishing Acceptance Value at 95% CI and 96.5% TI

TI0.95,1 1 n 1 = Z1 / 2 . 1 + . 2 .s n 0.95,n1

1 29 .s = 2.74s(n = 30) TI0.95,0.965 = 2.108. 1 + . 30 17.708 1 69 .s = 2.47s(n = 70) TI0.95,0.965 = 2.108. 1 + . 70 50.879
17

Establishing Acceptance Value at 95% CI and 96.5% TI

AV = CI0.95 + TI0.95,0.965

AV = 0.55s + 2.74s = 3.3s, s 4.5(n = 30) AV = 0.32s + 2.47s = 2.8s, s 5.4(n = 70)

Meeting the criteria means there is a 95% confidence that at least 96.5% of the lot will fall between 15% of the reference value (M)
18

New CU Distribution Curve

98.84%

97.97%

19

Acceptance Criteria: Assay

Acceptance CQA Sampling Plan Criteria LPL 90% LA, Take at least 40s from Assay UPL 110% LA beginning, middle & end of tableting cycle 95%LPL = x 5SD (total = 3x40s). Test 95%UPL = x + 5SD separately. LPL & UPL = Lower & Upper Prediction Limits; Product Specs: 90 110% LA
20

Acceptance Criteria: Dissolution

CQA Acceptance Criteria Meet Specs Sampling Plan

Take at least 48s LPL for results from beginning, Dissolution (stage 1) Q + 5 middle & end of tableting cycle (total = Rate (DR) LCL for result 3x48s). Test means (stage 2 separately. & 3) Q value LPL & LCL = Lower Prediction & Confidence Limits 21

Statistical Evaluation

22

Statistical Evaluation
Test results according to QC sampling and testing plan are statistically evaluated prior to meeting the acceptance criteria that are based on product specifications For the established acceptance criteria, no need for statistical evaluation

23

Statistical Evaluation: Assay

Data from multiple samples e.g. 3 samples from 3 segments (beginning, middle & end) Assay results: 98.7, 100.57, and 101.08% LA
Mean = 100.12% LA, SD = 1.25% LA 95% LPL & UPL = 93.89 & 106.34% LA

There is at least 95% confidence that 93.87 & 106.37 are within 90 110% LA
Why at least?
24

Statistical Evaluation: Dissolution

First stage dissolution test result has a mean = 91.5 %LA, SD = 2.15 %LA, n = 6, Limit: all results Q+5 (Q = 80 %LA) Lower 95% Prediction Limit = x t 0.05,n1SD 1 + 1/ n 91.52.01505x2.15/(1+1/6)0.5 = 86.82 %LA Conclusion: There is at least 95% confidence that the lots lowest DR data is above the specification
25

Statistical Evaluation: Dissolution

Second stage dissolution test result has a mean = 88.7 %LA, SD = 3.5 %LA, n = 12, Limit: Mean Q (Q = 80 %LA) Lower 95% Confidence Limit = x t 0.05,n1SD / n 88.71.79588x3.5/(12)0.5 = 86.89 %LA Conclusion: There is at least 95% confidence that the lot DR mean is above the specification
26

Statistical Evaluation: Dissolution

Third stage dissolution test result has a mean = 87.14 %LA, SD = 3.7 %LA, n = 24, Limit: Mean Q (Q = 80 %LA) Lower 95% Confidence Limit = x t 0.05,n1SD / n 87.141.71387x3.7/(24)0.5 = 85.85 %LA Conclusion: There is at least 95% confidence that the lot DR mean is above the specification
27

Statistical Evaluation: Dissolution

Statistical evaluation of composite data from the 3 segments (same stage) are also taken into account to demonstrate the overall lot dissolution performance Calculation for Lower 95% Prediction Limit can be made using the same formula with n = 18 for stage 1
95%LPL = x t 0.05,17SD 1 + 1/ 18 = x 1.79SD
28

Composite Data: Dissolution

Stage 2: n = 36
95%LCL = x t 0.05,35SD / 36 = x 0.28SD

Stage 3: n = 72
95%LCL = x t 0.05,71SD / 72 = x 0.20SD
29

Statistical Evaluation:
Probability of Meeting Content Uniformity & Dissolution Test

30

Exact Probability

Meeting the protocol acceptance criteria for content uniformity and dissolution test will provide a high probability of meeting their corresponding specifications for future QC samples The exact probability can be computed using the CU & DR validation data by means of Bergum method
31

James S. Bergum, PhD

Published in 1990 a paper entitled Constructing Acceptance Limits for Multiple Stage Tests Introduced how to compute the probability of passing the multiple stage tests for a sample e.g. USP Content Uniformity (USP 20-27) and Dissolution Tests Bergum method is one of the most important tools for Content Uniformity and Dissolution data assessment
32

(http://www.pharmtech.com/pharmtech/data/articl estandard/pharmtech/382004/122726/article.pdf)

Probability of Passing USP CU Test

September 2004

33

(http://www.pharmtech.com/pharmtech/data/artic lestandard/pharmtech/402004/125957/article.xls)

Probability of Passing USP CU Test

34

Application of Bergum Method

Blend Uniformity data i.e. blend sample mean and RSD may be evaluated using Bergum method to predict a high probability of passing USP CU test for the upcoming validation CU data

35

(http://www.pharmtech.com/pharmtech/article/artic leDetail.jsp?id=282728)

Probability of Passing USP DR Test

36

Probability of Passing USP DR Test

January 2006

37

Probability of Passing USP DR Test

(Obtained from cpramote2000@yahoo.com)

38

Coating Suspension Preparation

Critical Quality Attributes (CQAs) are as follows: Appearance (microscopic view x100) satisfactory? Viscosity it is tested for information Microbial count testing is based on available test method

39

Film Coating
Critical Quality Attributes (CQAs) are as follows: Appearance (x10) Loss on drying (LOD) Gastric resistance Dissolution rate Degradation Product Microbial count
40

Sampling Plan Gastric Resistance Test (Enteric Coated Tablet)

Stage 1: Test 300 tablets, after 2 hours, 1 tablet should disintegrate (if > 1 but 4 tablets disintegrate; proceed to stage 2) Stage 2: Test 600 additional tablets, 4 out of 900 tablets should disintegrate Acceptance Criteria: 1% of the lot will disintegrate in gastric fluid medium at 95% confidence
41

Gastric Resistance Test (Enteric Coated Tablet)

42

Sampling Plan Gastric Resistance Test (Enteric Coated Tablet)

AQL: Acceptable Quality Level

43

Acceptance Sampling Plan: AQL = 1%

44

Acceptance Sampling Plan: AQL = 2%

45

Acceptance Sampling Plan: AQL = 3%

46

Microbial Count

Follow normal procedure Microbial limit

Total aerobic microbial count: NMT 100 CFU/g Yeast and/or mold: NMT 100 CFU/g Pathogenic bacteria: absent

S. aureus, P. aeroginosa E. coli, Salmonella sp.

All microbiological count limits are required to update and comply with compendial limits.

47

Tablet PV Sampling Plan Summary

Critical Quality Attributes (CQAs) Assay Content Uniformity Dissolution Rate Microbial Count Gast. Resistance Loss on Drying Rel Substance * Plain Tablets Plain or Core Film Coat Sugar Coat Tablets Tablets Tablets 3x40s 3x40s 10x7s 3x30s 3x48s 3x48s 3x48s 1x100s* 1x100s 1x100s 1x900s 1x900s 3x30s* 3x30s 3x30s 3x20s* 3x20s 3x20s Follow Specs Follow Guide 48

Supporting Data
Product Data Required in PV Report Supporting Data Mfg Steps PV Data 1 2 3 Blending Blend Storage Tableting Film Coating 1 = Optimization data, 2 = QC data, 3 = IPC data
49

QC Sampling in Validation Batch

QC testing in conformance with the product specification (testing to document quality) is still ongoing QC samples should be separate from the validation samples QC test parameters (quality attributes) in common with validation can be taken from the validation data e.g. assay
50

Remaining Part of the Protocol

Definitions obtainable from guidelines e.g. PIC/S GMP guideline References obtainable from the end of this presentation Appendix e.g. manufacturing formula, product specifications, process flow chart Attachments e.g. Optimization, IPC & QC data sheets, CPP data sheets

51

Process Validation of Other Dosage Forms

Critical Steps Powders Dry Sterile Caps 1dose 2dose Syrups Pdrs

Mixing Dosage unit filling Filling Mixing: Perform Blend Uniformity test & related parameters

52

Process Validation of Other Dosage Forms

Critical Steps Powders Dry Sterile Caps 1dose 2dose Syrups Pdrs

Dosage unit filling Filling Dosage unit filling: Perform Uniformity of Dosage Units test separately using 3 sets of samples (3x10s) from 3 locations (beginning, middle & end) and statistical evaluation of the test data. Review IPC & QC data.

53

Process Validation of Other Dosage Forms

Critical Steps Powders Dry Sterile Caps 1dose 2dose Syrups Pdrs Review IPC & QC data
54

Dosage unit filling Filling No testing required Perform Content Uniformity Perform Content Uniformity

Content Uniformity
Acceptance Criteria CQA Sampling Plan (n = 10) UPL & LPL within 90 7 units from 110% LA* beginning, middle Content and end of filling RSD 4.2% (if Uniformity cycle; total 20 slightly failed, use units, test 10s SD** 4.2% LA) * Product Specification, if failed test 10 more and RSD for 20s 4.7%, ** in case of blend segregation
55

Miscellaneous

56

Acceptance of a PV Batch

Reviewing Critical Process and Product Parameters data obtained from PV report QC testing data obtained from Certificate of Analysis (COA) Reviewing and evaluating the SPC-based IPC data obtained from BPR

Non-SPC IPC data are evaluated for Cpk; Cpk (min): 1.0, Cpk (target): 1.3

57

Upper & Lower Punches

Upper & lower punches are measured for overall length SDP for punch data is calculated MeanT & SDT for thicknesses of tablets compressed using these punches are calculated Acceptance Criteria: MeanT 3SDP MeanT 3SDT thickness limits
58

For Processes Using Speed Range

For technical reason, some tablet products may use tableting speed range (specified in BPR) instead of single speed The speed range may be 27,000 33,000 tab/hr (30,000 10%), some lots may use 33,000 tab/hr while some use 27,000 In this case, validation data for the two extreme speeds as well as normal speed must be available (one lot each) 59

Multiple Process Equipment

Suppose formulation A has common granulation (same blend) compressed into x mg strength per 150 mg tablet by tableting machine # 1, 2 and 3

60

Multiple Process Equipment

Three granulation/blend batches are validated and

1 3* batches from each tableting machine are validated for compression and coating * depending on the tablet strength

If x is less than 25 mg, 3 batches per machine are required (full sampling/testing) If x is more than 50% of formula, 1 batch per machine is required (reduced sampling/testing)
61

Relocated Process Equipment

For existing products manufactured by existing equipment train relocated to new plant The criteria to determine is that the key product data to support the process must be provided for some extent Process Validation may not be needed at the early stage BUT at least Product Validation is essentially required Stability and Cleaning Validation is another issue62

Non-Normal Processing Steps

Identification of tablets compressed during start-up and ending of the tableting cycle is recommended Individual weights may be out of normal trend (good processes should have no problem) Predetermined number of tablets are intentionally taken for evaluation (WV, DT) If out of trend, discard these particular portions (normally overweighted)

63

Risk Assessment for Product Safety

RMs sieving using Fitzmill, Oscillator or HSG prior to mixing is dangerous, a vibrating screen is preferable due to its non-crushing effect A metal detector is required in-line to remove those dosage units (e.g. tablets) found contaminated with a tiny piece(s) of metal A magnet is used to remove iron pieces in the down-flowing stream of milled sugar from the milling machine

64

More Suitable Production Specs

LOD in QC spec is 2.5% but IPC spec may be, for example (e.g.), 1.5 2.5% Tablet hardness in QC spec is 5 kp but IPC spec may be, for example, 5 10 kp DT in QC spec is 30 minutes but IPC spec may be, e.g., 20 minutes at maximum Friability of 1.0% in QC spec (cores for film coated tablets) is performed at 100 revolutions but IPC spec may be, e.g., 200 or 300 rev.

65

Processes Using Solvents

Processes using solvents must be reviewed for safety a measure to prevent explosion is established Using truck & tray oven with electric heater is prohibited Fluid bed or film coater with electric heater must be used with special care The production area is designed to ventilate well or of ex-proof design

66

Relocated Process Equipment

It seems there is no difference between the validated and non-validated existing processes at the new plant In either case, accumulated data to support the manufacturing processes at the new plant are necessary product validation, IPC, stability and GMP compliance data Then release of products can be made
67

What is Product Validation?

Product Validation is the way to follow the PV sampling and testing plan without process parameters taken into account All process parameter setpoints used in the old plant may not be effective in the new plant, it requires optimization on a number of batches For ongoing validation concept, accumulated data are the ultimate goal of validation to ensure the quality and safety of products 68

How Many Product Validation Batches?

Product validation batches are produced until process optimization is complete So it depends on the optimization period After optimization, process validation batch(es) is produced 1 3 validation batches are required depending on the product strength
69

Stability Issue

Whether or not it is required by law, stability data (of a certain condition) for existing products in new plant is required by QA principle For QA reason, it is impossible that there is no data on stability when there is a CHANGE! (facility & HVAC system change) There must be an action with documented evidence to show that Change Control is handled and managed 70

Cleaning Validation Issue

For exiting equipment in new plant, the cleaning facility is new, so cleaning procedures are required to develop For a process using the same set of equipment, revalidation of cleaning procedures may be sufficient by sampling and testing at the areas determined difficult to clean The residual amount tested should be less than the CV protocol acceptance limit (from old plant)
71

Risk Analysis (RA)

What earlier mentioned is concerned about Risk Analysis need for Process/Product Validation, Stability, Cleaning Validation RA could be applied in all cases

72

Components Cleanliness

Containers and closures need to be tested for compliance with established microbial count limits A separate validation study on washing procedure may be conducted For in-line (compressed) air cleaning of the components e.g. tube filling line, the cleaned tubes should be visually inspected and tested for bioburden under validation study

73

Leak Testing

In-process control (IPC) for leak testing and tight sealing test using a torque device is necessary Effective sealing of the containers with closures will protect the product from undesirable environment e.g. air moisture, air oxygen, airborne microorganism, etc

74

Acceptance Criteria for Defect Rate

AQL is the nonconforming rate or defect rate (e.g. 2%) for a quality parameter From the AQL, an acceptance sampling plan can be established It can be applicable to nonconforming in bottle filling, strip sealing, blister packing, and cartoning Note that In-Process Control is essentially required

75

Sampling Plan at Various AQLs (at 95% Confidence Level)

n = 200/600s n = 300/900s Classifica AQL (%) tion c1 c2 c1 c2 1 0* 4 1** 1* Major 2 1* 6 2* 11 3 2 11 4 18 Minor 4 3 16 6 26 * confidence level < 95%; ** confidence level > 95%
76

Statistical Process Control (SPC)

In-Process Control (IPC) using Control Chart technique is an integral part of extended continuous processes e.g. tableting, capsule filling, bottle filling, tube filling Control Chart is a statistical tool to identify special cause variation and process drift Training for personnel involved to properly use and interpret Control Charts is essential

77

Residual Solvents (ICH Q3C)

For processes using solvents, the drug products may be soon required to be tested for absence of residual solvents A guideline for determination of residual solvents in drug products is Impurities: Guideline for Residual Solvents, ICH Q3C (R3); www.ich.org/LOB/media/MEDIA423.pdf Be well prepared for the test
78

References
Division of Manufacturing and Product Quality, Office of Compliance, Center for Drugs and Biologics, US FDA, Guideline on General Principles of Process Validation, May 1987 WHO Working document QAS/03.055/Rev.2: Supplementary Guidelines on Good Manufacturing Practices (GMP): Validation, July 2005 Pharmaceutical Inspection Convention and Pharmaceutical Inspection Co-Operation Scheme, Guide to Good Manufacturing Practice for Medicinal Products, PI 009-2, 1 July 2004

79

References
Pharmaceutical Inspection Convention and Pharmaceutical Inspection Co-Operation Scheme, Recommendations on Validation Master Plan, Installation and Operational Qualification: Non-Sterile Process Validation and Cleaning Validation, PI 006-2, 1 July 2004 European Medicines Evaluation Agency, Note for Guidance on Process Validation, CPMP/QWP/848/96, EMEA/CVMP/598/99, London, 1 March 2001 Final Version of Annex 15 to the EU Guide to Good Manufacturing Practice, Qualification and Validation, Brussels, July 2001

80

References
Center for Drug Evaluation and Research, US FDA, Draft Guidance for Industry: Powder Blends and Finished Dosage Units Stratified In-Process Dosage Unit Sampling and Assessment, October 2003 Center for Drug Evaluation and Research, US FDA, Draft Guidance for Industry: Powder Blends and Finished Dosage Units Stratified In-Process Dosage Unit Sampling and Assessment: Revised Attachments, November 2003 Drug Control Division, Thai FDA, Guide to Pharmaceutical Process Validation of Solid Dosage Forms, 2003
81

References
Drug Control Division, Thai FDA, Guide to Pharmaceutical Process Validation of Liquid Dosage Forms, 2004 Drug Control Division, Thai FDA, Guide to Pharmaceutical Process Validation of Semi-Solid Dosage Forms, 2003 US FDA Compliance Policy Guide (CPG) Section 490.100, Process Validation Requirements for Drug Products and Active Pharmaceutical Ingredients Subject to Pre-Market Approval (CPG 7132c.08)

82

Validation Guideline & Reference Resource (http://www.ivthome.com)

83

ISPE Pharmaceutical Engineering Journal July/August 2003

84