September 2006PQRI Training Course1 Best Practices for OINDP Pharmaceutical Development Programs Leachables and Extractables VIII. Quality Control and

September 2006 PQRI Training Course 1

Best Practices for OINDP Pharmaceutical Development Programs Leachables and Extractables

VIII. Quality Control and Specification Setting

PQRI Leachables & Extractables Working Group

PQRI Training CourseSeptember 20-21, 2006

Washington, DC


Definition ReviewDefinition Review

► A A Leachables StudyLeachables Study is a laboratory investigation is a laboratory investigation into the qualitative and quantitative nature of a into the qualitative and quantitative nature of a particular OINDP leachables profile(s) over the particular OINDP leachables profile(s) over the proposed shelf-life of the product. Supports:proposed shelf-life of the product. Supports: Developing an extractables/leachables correlationDeveloping an extractables/leachables correlation Establishment of drug product leachables acceptance Establishment of drug product leachables acceptance

criteria.criteria.► Routine Extractables Testing Routine Extractables Testing is the testing by which is the testing by which

OINDP container closure system critical OINDP container closure system critical components are qualitatively and quantitatively components are qualitatively and quantitatively profiled for extractables, for:profiled for extractables, for: Establishing extractables acceptance criteriaEstablishing extractables acceptance criteria Release by established acceptance criteria.Release by established acceptance criteria.


Control of Leachables Through Control of Leachables Through Control of ExtractablesControl of Extractables

► Specifications and acceptance criteria are Specifications and acceptance criteria are required for leachables profiles in OINDP.required for leachables profiles in OINDP.

► Implementation of routine leachables testing Implementation of routine leachables testing and specifications/acceptance criteria is a and specifications/acceptance criteria is a policy matter.policy matter.

► If extractables/leachables correlations can If extractables/leachables correlations can be established, then leachables be established, then leachables specifications/acceptance criteria may be specifications/acceptance criteria may be established as “established as “if tested will comply”if tested will comply”..

► Therefore, in the ideal situation leachables Therefore, in the ideal situation leachables can be controlled through routine testing of can be controlled through routine testing of extractables.extractables.


Routine Extractables TestingRoutine Extractables TestingPerformed on all critical components of OINDP container Performed on all critical components of OINDP container

closure systems with following general goals:closure systems with following general goals:

► To establish extractables acceptance criteria for OINDP To establish extractables acceptance criteria for OINDP critical container closure system components.critical container closure system components.

► To help ensure that the leachables profile in the drug To help ensure that the leachables profile in the drug product is maintained within appropriate limits.product is maintained within appropriate limits.

► To release OINDP container closure system critical To release OINDP container closure system critical components according to established acceptance components according to established acceptance criteria, which are designed to:criteria, which are designed to: Confirm the identities and levels of known extractables;Confirm the identities and levels of known extractables; Detect “unspecified” extractables which could be present as Detect “unspecified” extractables which could be present as

the result of component ingredient changes, manufacturing the result of component ingredient changes, manufacturing changes, external contamination, or other causes.changes, external contamination, or other causes.


Recommendations for Routine Recommendations for Routine Extractables TestingExtractables Testing

► Analytical methods for Routine Extractables Analytical methods for Routine Extractables Testing should be based on the analytical Testing should be based on the analytical technique(s)/method(s) used in the technique(s)/method(s) used in the Controlled Extraction Studies. Consider the Controlled Extraction Studies. Consider the following:following:

Simplicity relative to R&D methodsSimplicity relative to R&D methods Ruggedness and robustnessRuggedness and robustness TransferabilityTransferability Cost effectivenessCost effectiveness


Possibilities for Routine Extractables Possibilities for Routine Extractables Testing Analytical MethodsTesting Analytical Methods

►GravimetricGravimetric Potentially useful in combination with Potentially useful in combination with

other more sophisticated methods.other more sophisticated methods.►Bulk spectroscopic (e.g. UV, FTIR)Bulk spectroscopic (e.g. UV, FTIR)

Potentially useful in certain situations Potentially useful in certain situations (e.g. non-contact critical component)(e.g. non-contact critical component)

►Chromatographic (w/o MS or NMR)Chromatographic (w/o MS or NMR) Gas chromatography (FID, etc)Gas chromatography (FID, etc) Liquid chromatography (UV detection)Liquid chromatography (UV detection)


GC/MS Extractables Profile of an ElastomerGC/MS Extractables Profile of an Elastomer

5.00 10.00 15.00 20.00 25.00 30.00 35.000

200000

400000

600000

800000

1000000

1200000

1400000

1600000

1800000

2000000

2200000

2400000

2600000

2800000

3000000

3200000

3400000

T im e-->

A bundanc e

T IC : 07300307.D

Internal standard


Potential Routine Extractables Control Potential Routine Extractables Control Method – GC/FIDMethod – GC/FID

min5 10 15 20 25 30 35

pA

0

50

100

150

200

250

300

350

400

Internal standard


Potential Routine Extractables Control Potential Routine Extractables Control Method – HPLC/UVMethod – HPLC/UV

min0 2 4 6 8 10 12 14 16 18

mAU

0

25

50

75

100

125

150

175

DAD1 A, Sig=200,4 Ref=550,100 (I:\HPCHEM\1\DATA\022569\022569\JAN31008.D)

2-propanol (Reflux)


Routine Extractables Testing- Method Routine Extractables Testing- Method Development and Validation-ReferencesDevelopment and Validation-References

1.1. ICH Harominzed Tripartite Guideline, “Text on Validation of ICH Harominzed Tripartite Guideline, “Text on Validation of Analytical Procedures Q2A”, International Conference on Analytical Procedures Q2A”, International Conference on Harmonization of Technical Requirements for Registration of Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use.Pharmaceuticals for Human Use.

2.2. ICH Harominzed Tripartite Guideline, “Validation of Analytical ICH Harominzed Tripartite Guideline, “Validation of Analytical Procedures: Methodology Q2B”, International Conference on Procedures: Methodology Q2B”, International Conference on Harmonization of Technical Requirements for Registration of Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use.Pharmaceuticals for Human Use.

3.3. ““Reviewer Guidance – Validation of Chromatographic Reviewer Guidance – Validation of Chromatographic Methods”, Center for Drug Evaluation and Research (CDER), Methods”, Center for Drug Evaluation and Research (CDER), United States Food and Drug Administration, November, 1994.United States Food and Drug Administration, November, 1994.

4.4. ““Guidance for Industry – Analytical Procedures and Methods Guidance for Industry – Analytical Procedures and Methods Validation – Chemistry, Manufacturing, and Controls Validation – Chemistry, Manufacturing, and Controls Documentation”, Documentation”, Draft GuidanceDraft Guidance, Center for Drug Evaluation , Center for Drug Evaluation and Research (CDER), United States Food and Drug and Research (CDER), United States Food and Drug Administration, August, 2000.Administration, August, 2000.

5.5. Michael E. Swartz and Ira S. Krull, Michael E. Swartz and Ira S. Krull, Analytical Method Analytical Method Development and ValidationDevelopment and Validation, Marcel Dekker, Inc., New York, , Marcel Dekker, Inc., New York, 1997.1997.


Routine Extractables Testing- Method Routine Extractables Testing- Method Development and ValidationDevelopment and Validation

► Extraction procedures for critical Extraction procedures for critical components should be based on the components should be based on the optimized procedures from the quantitative optimized procedures from the quantitative Controlled Extraction StudiesControlled Extraction Studies Demonstrate asymptotic levels of extractables.Demonstrate asymptotic levels of extractables.

► The linear dynamic range of the analytical The linear dynamic range of the analytical method should be established based on method should be established based on levels of extractables anticipated from levels of extractables anticipated from quantitative quantitative Controlled Extraction StudiesControlled Extraction Studies

► The Limit-of-Quantitation of the method The Limit-of-Quantitation of the method should be established with consideration of should be established with consideration of the appropriate AET.the appropriate AET.


Routine Extractables Testing- Method Routine Extractables Testing- Method Development and Validation (cont.)Development and Validation (cont.)

► Method validated according to the ICH validation Method validated according to the ICH validation characteristics of a quantitative impurity test, characteristics of a quantitative impurity test, Include: Accuracy, Precision (Repeatability, Intermediate Include: Accuracy, Precision (Repeatability, Intermediate

Precision), Specificity, Limit-of-Quantitation (LOQ), Linearity, and Precision), Specificity, Limit-of-Quantitation (LOQ), Linearity, and Range. Range.

System Suitability parameters should be established System Suitability parameters should be established Robustness should be evaluatedRobustness should be evaluated Note that in certain cases it may be appropriate to validate Note that in certain cases it may be appropriate to validate

routine extractables methods as “Limit Tests”, in which case routine extractables methods as “Limit Tests”, in which case only Specificity and Limit-of-Detection (LOD) need be considered.only Specificity and Limit-of-Detection (LOD) need be considered.

► Accuracy can be determined through the analysis of Accuracy can be determined through the analysis of spiked samples.spiked samples. Spiking matrix could be an extract taken through the extraction Spiking matrix could be an extract taken through the extraction

procedure minus the component sample.procedure minus the component sample. Spiking levels should be chosen so as to be representative of Spiking levels should be chosen so as to be representative of

anticipated extractables levels based on results from anticipated extractables levels based on results from quantitative Controlled Extraction Studies.quantitative Controlled Extraction Studies.


Specifications and Acceptance Specifications and Acceptance Criteria for LeachablesCriteria for Leachables

► Leachables specifications should include a Leachables specifications should include a fully validated analytical test method. fully validated analytical test method.

► Acceptance criteria for leachables should Acceptance criteria for leachables should apply over the proposed shelf-life of the apply over the proposed shelf-life of the drug product, and should include:drug product, and should include: Quantitative limits for known drug product Quantitative limits for known drug product

leachables monitored during product registration leachables monitored during product registration stability studies.stability studies.

A quantitative limit for “new” or “unspecified” A quantitative limit for “new” or “unspecified” leachables not detected or monitored during leachables not detected or monitored during product registration stability studies.product registration stability studies.


Specifications and Acceptance Criteria Specifications and Acceptance Criteria for Leachablesfor Leachables

► Quantitative acceptance criteria should be based on Quantitative acceptance criteria should be based on leachables levels, and trends in leachables levels, leachables levels, and trends in leachables levels, observed over time and across various storage observed over time and across various storage conditions and drug product orientations during conditions and drug product orientations during product registration stability studies.product registration stability studies.

► Established with appropriate statistical analysis.Established with appropriate statistical analysis.► Comprehensive correlation should obviate the need Comprehensive correlation should obviate the need

for routine implementation of drug product for routine implementation of drug product leachables specifications and acceptance criteria, leachables specifications and acceptance criteria, assuming:assuming: Adequate information from critical component suppliersAdequate information from critical component suppliers Understanding and control of critical component fabricationUnderstanding and control of critical component fabrication Controlled Extraction Studies on critical components.Controlled Extraction Studies on critical components. Validated leachables methods and a Leachables Study.Validated leachables methods and a Leachables Study. Validated Routine Extractables Testing methods and Validated Routine Extractables Testing methods and

database of critical component extractables profiles.database of critical component extractables profiles. Appropriate specifications and acceptance criteria for Appropriate specifications and acceptance criteria for

extractablesextractables


Specifications and Acceptance Criteria Specifications and Acceptance Criteria for Extractablesfor Extractables

► Routine Extractables Testing should be Routine Extractables Testing should be performed on OINDP critical components prior performed on OINDP critical components prior to drug product manufacture. to drug product manufacture.

► Critical components should be released to Critical components should be released to drug product manufacture based on defined drug product manufacture based on defined specifications and acceptance criteria specifications and acceptance criteria established through:established through: Understanding of critical component Understanding of critical component

composition(s), ingredients, and composition(s), ingredients, and compounding/fabrication processes.compounding/fabrication processes.

Comprehensive Controlled Extraction Studies.Comprehensive Controlled Extraction Studies. A significant database of extractables profiles A significant database of extractables profiles

obtained with validated Routine Extractables obtained with validated Routine Extractables Testing methods.Testing methods.

A complete leachables/extractables correlation.A complete leachables/extractables correlation.


Specifications and Acceptance Specifications and Acceptance Criteria for ExtractablesCriteria for Extractables

►Acceptance criteria for OINDP critical Acceptance criteria for OINDP critical component extractables can include component extractables can include the following:the following: Confirmation of extractables identified in Confirmation of extractables identified in

Controlled Extraction Studies.Controlled Extraction Studies. Quantitative limits for extractables Quantitative limits for extractables

identified in Controlled Extraction Studies.identified in Controlled Extraction Studies. A quantitative limit for ”new” or “ A quantitative limit for ”new” or “

unspecified” extractables not detected unspecified” extractables not detected during Controlled Extraction Studies.during Controlled Extraction Studies.


Establishing Specifications:Establishing Specifications: Widgets vs. Pills Widgets vs. Pills

► Rest of World Rest of World (Planes, (Planes,

Trains & Automobiles…)Trains & Automobiles…)

Known requirements Known requirements that must be met to that must be met to insure product insure product performanceperformance

Establish that Establish that process is capable of process is capable of meeting meeting requirementsrequirements

► PharmaceuticalsPharmaceuticals

Vaguely known Vaguely known requirements (vs requirements (vs product product performance)performance)

Establish Establish requirements from requirements from vaguely known vaguely known process capabilitiesprocess capabilities


Statistical Tools Related to Statistical Tools Related to SpecificationsSpecifications

► Process Capability & Performance AnalysisProcess Capability & Performance Analysis Statistical evaluation of process variability with Statistical evaluation of process variability with

respect to limitsrespect to limits Typically includes both process and Typically includes both process and

measurement variabilitymeasurement variability

► Operating Characteristic CurvesOperating Characteristic Curves Statistical evaluation of decision making process Statistical evaluation of decision making process

related to an individual testrelated to an individual test Considers influence of different test structures: Considers influence of different test structures:

numbers of samples, average vs. individuals, numbers of samples, average vs. individuals, tiered testing…tiered testing…


Types of Quality InspectionsTypes of Quality Inspections► Inspection by AttributesInspection by Attributes

Defect testing (pass/fail by unit)Defect testing (pass/fail by unit)Visual inspection of containers for foreign material or defectsVisual inspection of containers for foreign material or defectsSpray test of MDIsSpray test of MDIs

► Inspection by Variables Inspection by Variables Estimation of Batch Parameters (central Estimation of Batch Parameters (central

tendency, variability)tendency, variability)HPLC Assay of tablets for active ingredientHPLC Assay of tablets for active ingredientDelivered Dose Uniformity of an MDIDelivered Dose Uniformity of an MDIContent Uniformity of a tabletContent Uniformity of a tabletLeachable/extractable testingLeachable/extractable testing


What we would like to have to What we would like to have to establish/verify acceptance criteria:establish/verify acceptance criteria:


What we typically have to What we typically have to establish acceptance establish acceptance

criteria:criteria:

Impurity X

0.24

0.07

0.15

ND


Performance of Limits Established Performance of Limits Established with Small Datasetswith Small Datasets

Fraction of Results Complying with Limits1.00.80.60.40.20.0

100

80

60

40

20

0

Variable

n=7n=8n=9n=10n=20

n=3n=4n=5n=6

Robustness of Establishing Acceptance Criteria with Small Datasets(limits established via +/- 3 standard deviations)

Ris

k of

obt

aini

ng li

mits

wor

se

than

the

ass

ocia

ted

com

plia

nce

rate


Comparison of Different Comparison of Different Approaches to Setting LimitsApproaches to Setting Limits

Fraction of Results Complying with Limits1.00.90.80.70.60.50.40.30.20.1

100

80

60

40

20

0

Variablep(accept) 3 stdp(accept) min/maxp(accept) 95/95p(accept) 99/99

Comparison of Different Approaches to Establishing Limits

Ris

k of

obt

aini

ng li

mits

wor

se

than

the

ass

ocia

ted

com

plia

nce

rate

n=7


Process CapabilityProcess Capability

► Several different ‘Capability Indices’ existSeveral different ‘Capability Indices’ exist► Designed to show whether process+measurement Designed to show whether process+measurement

are capable of meeting limitsare capable of meeting limits

Cp=(USL-LSL)/6σCp=(USL-LSL)/6σww

Cpk=Min{[(USL-Avg)/3σCpk=Min{[(USL-Avg)/3σww],[(Avg-LSL)/ 3σ],[(Avg-LSL)/ 3σww]]}}

► Minimum Cpk of 1.33 expected for new processMinimum Cpk of 1.33 expected for new process► Cp ~ Cpk when process is ‘centered’Cp ~ Cpk when process is ‘centered’► Above is for two-sided limit, for a one-sided limit Cp Above is for two-sided limit, for a one-sided limit Cp

is meaningless and Cpk considers only the range to is meaningless and Cpk considers only the range to the specified limitthe specified limit


Process PerformanceProcess Performance

► Several different ‘Performance Indices’ existSeveral different ‘Performance Indices’ exist► Designed to show process+measurement Designed to show process+measurement

performance relative to limitsperformance relative to limitsPp=(USL-LSL)/6σPp=(USL-LSL)/6σ

Ppk=Min{[(USL-Avg)/3σ],[(Avg-LSL)/ 3σ]Ppk=Min{[(USL-Avg)/3σ],[(Avg-LSL)/ 3σ]}}

► Minimum Ppk of 1.33 expected for new processMinimum Ppk of 1.33 expected for new process► Ppk ~ Cpk when no ‘special cause’ source of errorPpk ~ Cpk when no ‘special cause’ source of error► Above is for two-sided limit, for a one-sided limit Pp Above is for two-sided limit, for a one-sided limit Pp

is meaningless and Ppk considers only the range to is meaningless and Ppk considers only the range to the specified limitthe specified limit



Quality Decisions: Possible Outcomes and

Consequences

True Situation

Decision

Batch is of Acceptable Quality

Batch is not of Acceptable Quality

Accept Batch

Correct Decision

Type II error (β) (‘consumer’s risk’)

Reject Batch

Type I error (α) (‘producer’s risk’)

Correct Decision

Designing & Evaluating Test Designing & Evaluating Test Structures: Operating Characteristic Structures: Operating Characteristic

CurvesCurves


Quality Standards vs. Quality Standards vs. Acceptance CriteriaAcceptance Criteria

Quality Standard:Quality Standard:► All units must have an All units must have an

assay greater than 95%assay greater than 95%

Test Acceptance Criteria:Test Acceptance Criteria:► Assay of 2 of 2 Samples Assay of 2 of 2 Samples

must be between 98-must be between 98-102%102%

Quality standard should Quality standard should drive acceptance drive acceptance criteria and test criteria and test structurestructure

OCCs used in this contextOCCs used in this context


Operating Characteristic Operating Characteristic CurvesCurves

► Used to characterize the statistical qualities of Used to characterize the statistical qualities of the decision making process associated with a the decision making process associated with a particular test’s structure/formparticular test’s structure/form Test structure/form includes: numbers of samples, Test structure/form includes: numbers of samples,

limits, tiers, decision process flow, quaniti(es) limits, tiers, decision process flow, quaniti(es) compared to limit compared to limit

► Comment on the ability of the test structure to Comment on the ability of the test structure to discriminate between acceptable and discriminate between acceptable and unacceptable ‘batches’unacceptable ‘batches’

► Allows estimation of type I & II error ratesAllows estimation of type I & II error rates risk of failing an acceptable batch risk of failing an acceptable batch risk of passing an unacceptable batchrisk of passing an unacceptable batch


Operating Characteristic Operating Characteristic CurvesCurves

►Plot of the probability of acceptance Plot of the probability of acceptance (or rejection) vs. the quality variable(or rejection) vs. the quality variable P(accept) vs. true batch meanP(accept) vs. true batch mean P(accept) vs. true batch standard P(accept) vs. true batch standard

deviationdeviation P(accept) vs. true % defectsP(accept) vs. true % defects

►Constructed using the appropriate Constructed using the appropriate cumulative density probability cumulative density probability distributiondistribution


Ideal OC CurvesIdeal OC Curves

True Mean (of Batch)

Pro

bability

of A

ccepta

nce

1501251007550

1.0

0.8

0.6

0.4

0.2

0.0

Ideal Operating Characteristic CurveTwo-Sided Limit (85-115)

0.0

0.2

0.4

0.6

0.8

1.0

Pro

bability

of R

eje

ction


Pro

bability

of A

ccepta

nce

11010090807060

1.0

0.8

0.6

0.4

0.2

0.0

Ideal Operating Characteristic CurveOne-Sided Limit (>85)

Pro

bability

of R

eje

ction

0.0

0.2

0.4

0.6

0.8

1.0

True Std. Dev. (of Batch)

Pro

bability

of A

ccepta

nce

543210

1.0

0.8

0.6

0.4

0.2

0.0

Ideal Operating Characteristic Curve

Pro

bability

of R

eje

ction

Variability Limit (std. dev. <2.5)

0.0

0.2

0.4

0.6

0.8

1.0


Typical OC CurvesTypical OC Curves


Pro

bability

of A

ccepta

nce

1.0

0.8

0.6

0.4

0.2

0.0

Real Operating Characteristic Curve

0.0

0.2

0.4

0.6

0.8

1.0

Pro

bability

of R

eje

ction

True Std. Dev. (of Batch)

Pro

bability

of A

ccepta

nce

1.0

0.8

0.6

0.4

0.2

0.0


Pro

bability

of R

eje

ction

Variability Limit

0.0

0.2

0.4

0.6

0.8

1.0


Pro

bability

of A

ccepta

nce

1.0

0.8

0.6

0.4

0.2

0.0


Pro

bability

of R

eje

ction

0.0

0.2

0.4

0.6

0.8

1.0


0

0.2

0.4

0.6

0.8

1 0

0.2

0.4

0.6

0.8

1

70 80 90 100 110 120 130

True Mean

p(a

ccep

t) P(reject)

Lim iting Q ua lity

Risk o f a c c e p tinguna c c e p ta b le lo t

Risk o f re je c tinga c c e p ta b le lo t

Risks Assoc ia te d with Te stingin Re la tion to O p era ting C ha ra c te ristic C urve


Process for Constructing OC Curves: Process for Constructing OC Curves:

p(accept) vs. Meanp(accept) vs. Mean ► Need model probability distribution for individual Need model probability distribution for individual

measurementsmeasurements► Need estimate of standard deviationNeed estimate of standard deviation

Curve is for an assumed standard deviation of the Curve is for an assumed standard deviation of the individual measurementsindividual measurements

► Calculate probability to accept for a given value of Calculate probability to accept for a given value of the mean from the appropriate cumulative density the mean from the appropriate cumulative density probability distribution based on the test constructprobability distribution based on the test construct

► Alternatively can estimate through numeric Alternatively can estimate through numeric approachapproach

► Repeat over range of means of interestRepeat over range of means of interest


Influence of Different Test Influence of Different Test Designs on the OC CurveDesigns on the OC Curve

►Tests Designed to Control MeanTests Designed to Control Mean Vary n, set requirement on sample meanVary n, set requirement on sample mean Vary n, set requirement on individual Vary n, set requirement on individual

valuesvalues Influence of acceptance criteriaInfluence of acceptance criteria


Control on Batch MeanControl on Batch MeanImprovement in OC Curve as Sample Size IncreasesImprovement in OC Curve as Sample Size Increases

Acceptance Criteria: Sample Mean > 100Acceptance Criteria: Sample Mean > 100

80 90 100 110 120

0.0

0.5

1.0

true mean

p(a

ccep

t) n=1

n=9

n=3

n=5

n=71.0

0.0

p(reject)


Control on Batch MeanControl on Batch MeanEffect on OC Curve as Sample Size IncreasesEffect on OC Curve as Sample Size Increases

for n of n Requirement for n of n RequirementAcceptance Criteria: n of n > 100Acceptance Criteria: n of n > 100

80 90 100 110 120

0.0

0.5

1.0

true mean

p(a

ccep

t) p(reject)

n=1

n=3

n=5

n=7

n=9

0.0

1.0


Relationship of OC Curve to Relationship of OC Curve to Specification Limits (one sided)Specification Limits (one sided)


Relationship of OC Curve to Relationship of OC Curve to Specification Limits (two sided)Specification Limits (two sided)

0

0.2

0.4

0.6

0.8

1 0

0.2

0.4

0.6

0.8

1

60 70 80 90 100 110 120 130 140

true mean

P(ac

cept

)

80-120

85-115

90-110

95-105

P(reject)


Conclusions & Final ThoughtsConclusions & Final Thoughts

►Appropriate L&E testing schemes Appropriate L&E testing schemes should reflect:should reflect: In-depth understanding of component In-depth understanding of component

composition and the L&E characteristics composition and the L&E characteristics of the product/componentof the product/component

Thoughtful selection of critical testsThoughtful selection of critical tests Robust validated methodsRobust validated methods Statistical design and evaluation of tests Statistical design and evaluation of tests

and acceptance criteriaand acceptance criteria

Documents

September 2006PQRI Training Course1 Best Practices for OINDP Pharmaceutical Development Programs Leachables and Extractables VIII. Quality Control and