2013-09-18 USP Stability 4 Investigation

IV. Conduct Out-of-Spec (OOS)IV. Conduct Out of Spec (OOS) Investigation for Stability R ltResults

Critical Stability Systems

Regulations ProceduresRegulations(I)

Procedures(II)

Stability Systems

Operations(III)

Investigations(IV)

Copyright USP. All rights reserved.

Course Agenda

4. Out-of-Spec investigation for Stability Results

` Data Evaluation` Review FDA draft guidance on OOS` Averaging and Outlier Test` Averaging and Outlier Test` Determine Root Cause Analysis ` Documentation of an investigation` Documentation of an investigation` Recognize OOT results


Data Evaluation

` Three types of data can be collected during stability studies

t d i l lt h l reported as a single result such as assay, loss on drying, etc.

data with multiple results such as dissolution testingdata with multiple results such as dissolution testing third type is degradation product


Data Evaluation

` For impurity, there are 3 thresholds to be considered

Reportingepo t g

Identification

Qualification Qualification

` A special situation arises when a new peak forms during the analysisthe analysis.


Data presentation

` A systematic approach to present and evaluate stability information

Ph i l t ti Physical testing Chemical testing Biological testingBiological testing Microbiological testing

` The results should be presented both as a table and as a pgraph

` Each attribute should be evaluate separately. Including t ti ti l l tistatistical evaluation.


Data presentation

` Long-term data show little or no variability and little or no change over time, no statistical evaluation is needed.

` Proposed retest period or shelf life = double of period covered by long-tem data (X) but NMT X + 12 months

A t t i d h lf lif t d th b i f` A retest period or shelf life granted on the basis of extrapolation should always be verified by additional long-term stability data g y


ICH-Q1E Evaluation for Stability Data

Carstensen, J.T. Drug stability

Out of Specification Results

` OOS is important` Cant occur if:

the method is validated analysts are qualified

i t i lib t d d ll i t i d equipment is calibrated and well-maintained notebooks have full record of testing


FDA - Guide to Inspections

4.A. GENERAL: ` Most manufacturers use systems that provide for the

investigation of laboratory test failures. These are generally recorded in some type of log. Ask to see results of analyses of lots of product that have failed toresults of analyses of lots of product that have failed to meet specifications and review the analysis of lots that have been retested, rejected, or reworked. Evaluate the decision to release lots of product when the laboratorydecision to release lots of product when the laboratory results indicate that the lot failed to meet specifications and determine who released them.


Data Scrutiny Type of samples

The scope of the investigation is dependent on sample type

Release test

Stability test

Validation test

Release Testing Results at other stages Other release testingOther release testing Release testing for other batches NEGATE: Effect lots on market


Stability Testing Other packaging configurations Other test intervals

Oth b t h f th d t Other batches of the same product Initial release NEGATE: Effect expiry of product NEGATE: Effect expiry of product


Validation Testing Routine release testing In-process testing Extensive testing NEGATE: Effect the entire study and control

testingtesting


Guide To Inspections

RETESTINGRETESTING

` Retesting following an OOS result is ruled appropriate only after the failure investigation is underway and theonly after the failure investigation is underway and the failure investigation determined in part whether retesting is appropriate.


Guide To Inspections

INCONCLUSIVE LOT FAILURE

` It is appropriate when analyst error is documented or the review of the analysts work is inconclusive, but is not appropriate for known and undisputed non-process or process related errorsprocess related errors.

` In that case, you need to step up surveillance of future lots.


Investigating OOS Results

Four basic steps to be followed for any OOS result:

recognize issueSTOPSTOP

Impact on data lab controls related results

ASSESS

Investigation & Determine resolution Inform AgenciesField AlertsPLAN CAPA

PLAN

Make planp Documentation Follow-up within timeframe

IMPLEMENT

Structure of An OOS Investigation

Identifying and assessing OOS test

Investigation: Methodical, Systematic and Consistent

y g gresults

PHASE I L b t I ti tiPHASE I: Laboratory Investigation

PHASE II F ll S l OOS I ti tiPHASE II: Full Scale OOS Investigation

C l i d D iConclusions and Documentations

CAPA

Responsibility of Analyst

Using Checklist

` To follow test procedure as written` To be alert to errors and to STOP a test BEFORE obtaining

the result if error is suspected

I lt i ti bl h lt th l i` In a case, a result is questionable, halt the analysis, save all solutions and prevent instrument change. Label equipment, if needed.

` Review all records relative to the test to identify possible laboratory error

` Notify the supervisor no later than 24 hours.


Responsibility of Supervisor

Review notebook / worksheet with analyst with checklist:

` Confirm that the method was accurately followed` sampling, weighing, volumetric or transfer issue` instrument or equipment setup or problemq p p p` system suitability and chromatography review` glassware, reagent or standard problem` glassware, reagent or standard problem` analyst error, e.g., not following procedure or incorrect

vial numbering or ordering, calculations

` Check Method Validation` Environment effects


Laboratory Investigation - Retesting

With clearly identified laboratory error, the retest results substitute for the original test results.

The record should be initialed and dated by the involved persons, and include a discussion of the error and supervisory comments.

If no laboratory or statistical errors are identified in the first test, there is no scientific basis for invalidating initial OOStest, there is no scientific basis for invalidating initial OOS results in favour of passing retest results. All test results, both passing and suspect, should be reported and considered in batch release decisions.

Averaging

Passing results should not be given more weight than the failing results.

For averaging results, ALL data should conform to specifications. A high result may lead to concerns about overdosing aA high result may lead to concerns about overdosing a

patient, while a low result may indicate formulation problems with the potential for a subpotent lot.A i f Mi bi l i l Appropriate for Microbiological assays

Outlier Tests

Possible if determined in advance - in an SOP for data interpretation

Allow for specific test With the minimum number of results required to obtain a

statistically significant assessment from the teststatistically significant assessment from the test

CHEMICAL TESTING not allowed Inherently reliable Precision is better than for microbiological and Precision is better than for microbiological and

biochemical testing

Root Cause Analysis

OOS is invalidated:

OOS FoundOOS is invalidated:new results replacedcorrective actionsbatch is released.

Lab errorNo Root

Is there a cause?

No Root Cause YESNO

OOS ConfirmedOOS is inconclusive:OOS not confirmedCause unknown

OOS is confirmed:Investigation completedBatch destroyed or reworked (if allowed)

Phase 2 investigation

Batch destroyed or reworked (if allowed)Introduction to Pharmaceutical Analysis, in press, K. Huynh-Ba, Wiley Publisher

Fish-Bone Diagram: Examples of Root Cause Analysis

Materials Methods

Normality etc.

Solvents

Reagents

Vials

Dish Washing detergent

Column

Any changes to anything relevant to testing

Changes to method

Validation report

Any assumed steps?Calculations

ycalculated correctly

Any chemist observations

Caps of vials

Glassware

to testingChanges to gases (GC)

Pipettes/manual or automated

Any assumed steps?

Training of chemist

Calculations checked

EnvironmentStandards-RT-RF

Instrument type

Detector

Injector

Balance

pH meter Chemist t i i

Chemist experienceTemp control of lab

Humidity of lab

P l

Sonicator

Vortexer

Burette size-able to measure differences?

Temperature control of column

trainingGlassware washing-personnel changes

Equipment People

Pharmaceutical Stability Testing to Support Global Markets, K. Huynh-Ba (ed.), (2009) Springer Publisher

Full Scale OOS Investigation

` QA responsibility with an expanded investigation protocol and end time

` SOP t h diti d d t i lid t` SOP must have conditions needed to invalidate original results

` Documented in the batch record` Documented in the batch record` Involves all aspects of manufacture, quality control

and sampling


Flow of OOS Investigation

OOS Result OOS investigationProduction error

Lab error Suspect Result

YCorrect if possible

Reject batch

Invalidate resultsPerform new test

Assignable cause?

N

Sampling error

Report new resultsFull Scale

investigation

ResampleRevise SOP

InconclusiveRetestRetests in spec Result OOS

QA Disposition Reject batch

Handbook of Stability Testing in Pharmaceutical Development: Regulations, Methodologies and Best Practices, K. Huynh-Ba (ed.), (2008) Springer Publisher

End of Investigation

` Need to determine when to end the investigation and accept the results Write an Investigation Report

` Corrective Actions and Preventive Actions` Impact on other lots, batches, products` Impact on method/validation/expiry-depending on sample` If no lab error or statistical error is identified then the

original OOS cannot be invalidated--all results must be reported and taken into consideration for batch disposition

` Batch disposition must be based upon scientific` Batch disposition must be based upon scientific justification and overall data


Documentation

The documents should show the following steps were taken: Reason for the investigation Processing sequences caused the problem summarized A review to see if the problem has occurred previously.

Results of the documentation review are reported along Results of the documentation review are reported along with an assignment of an actual or probable cause.

Corrective actions taken should be described. The general review should include a list of other batches or

products possibly affected and any corrective actions taken, including comments and signatures of appropriate production g g pp p pand quality control personnel regarding any material that may have been reprocessed after additional testing.

Typical Causes: Analyst Error

Recent Warning letters caution against assigning root cause to analyst error and no further investigationL k f t bl hi h i t d Look for system problems which are causing repeated errors by analysts TRAINING ISSUE

Look for the system problem which leads to frequent analyst errors Training inadequate

Analytical proceduresL b ti Lab practices

Lab documentation

Corrective Actions and Preventive Actions

Corrective - correct an immediate problem, short termPreventive - long term permanent solutionPreventive - long term permanent solution

` If an error is identified whether it is a laboratory or` If an error is identified, whether it is a laboratory or processing error, you need to initiate a corrective action and preventive action

` You need to set and meet dates for the closure of the corrective actions. Also, define ownership.

` Log and trend valid OOS results` Log and trend valid OOS results` Document/perform corrective and preventive actions


Trend Analysis

What is Trend Analysis?Method to determine if there is abnormal

behavior.

How to determine Trend Using Quality MarkersUsing Quality Markers Set up Alert Levels (in house limit) Monitor periodicallyy

Determine Quality Markers

Markers beyond which quality of the products are questioned (controlproducts are questioned (control space)

Examples may include: Deviations Deviations Equipment Malfunction Material non-conforming Procedural Product non-conforming

Unknown Unknown

Monitor Quality Markers

Designate a tracking mechanism Computerized Computerized Manual tracking Charts/graphsg p

Monitor Quality Markers Monitor Quality Markers Provide monthly reports

Understanding of the product Understanding of the product Potential issues Monitoring CAPA effectivenessg

Why investigate if the result is within specifications?

21 CFR 211.192 FDA interprets an OOT test result to be an unexplained discrepancyp p y

OOT results identify unintended changes in product performance, when there are clear quality issues

Scope of OOT investigation is post-approval, shelf-life data

Depth of investigation should be based upon an Depth of investigation should be based upon an analysis of risk (good science)

Stability Out of Trend

Types of OOT DataAnalytical Alert Analytical Alert

Process Capability AlertC li Al t Compliance Alert

Analytical Alert

StableStable Properties Unstable

PropertiesProperties


Analytical Alert: Observed Value Method

Observed Value Method Use data as reported with no manipulationp

Used for stable products

Observed Value Method(for stable properties)

106

108

110

100

102

104

R

e

s

u

l

t

94

96

98

R

90

92

0 3 6 9 12 15 18 21 24Time Point

Analytical Alert: Changes Value Method

Used for products with properties change over timeover time

A Change from InitialA. Change from Initial

B. Change from Previous

C. Change from Previous Tiover Time

A. Change from Initial

Change from Initial Calculate change from initial (time zero) at each time point( ) p

Month Result Change from Initial0 100 5 100 5 100 5 0 00 100.5 100.5 100.5 = 0.03 100.0 100.0 100.5 = -0.56 100.2 100.2 100.5 = -0.36 100.2 100.2 100.5 0.39 103.9 103.9 100.5 = 3.412 99.5 99.5 100.5 = -1.018 99.7 99.7 100.5 = -0.824 99.5 99.5 100.5 = -1.036 99 3 99 3 100 5 = -1 236 99.3 99.3 100.5 = 1.2

Change from Initial

B. Change from Previous

Change from Previous Calculate change from previous time point to current time point

Month Result Change from Previous Time 0 100.5 N/A0 100.5 N/A3 100.0 100.0 100.5 = -0.56 100.2 100.2 100.0 = 0.29 103.9 103.9 100.2 = 3.7

12 99.5 99.5 103.9 = -4.418 99 7 99 7 99 5 = 0 218 99.7 99.7 99.5 = 0.2 24 99.5 99.5 - 99.7 = -0.236 99.3 99.3 99.5 = -0.2

Change from Previous

C. Change from Previous per Unit of Time

Change from Previous per Unit of Time - Calculate change from previous time point to current time point taking into account the amount of time between resultstaking into account the amount of time between results

Month Result Change from Previous Time per MonthTime per Month

0 100.5 N/A3 100.0 -0.5/3 = -0.176 100.2 0.2/3 = 0.079 103.9 3.7/3 = 1.2312 99.5 -4.4/3 = -1.4712 99.5 4.4/3 1.4718 99.7 0.2/6 = 0.0324 99.5 -0.2/6 = -0.0336 99 3 0 2/12 = 0 0236 99.3 -0.2/12 = -0.02

Change from Previous per Unit of Time

Process Control Alert

Several data points are required before this type of trend can be detected.

Statistically more complex. Can often be found at time of Annual Product Review

when stability data is looked at for multiple batches.

Good method is slope control chart Good method is slope control chart Calculate slope using all data up to time point of

interest. Calculate interval for slope at each time point. Slope for each lot should fall within these limits, if not,

ff fthe slope is different then historically found.


1 0 11 0 2

9 89 9

1 0 01 0 1

y

%

9 49 59 69 7

P

o

t

e

n

c

y

9 19 29 39 4

0 6 1 2 1 8 2 4 3 0 3 6

L o w e r l im it

0 6 1 2 1 8 2 4 3 0 3 6A g e (m o n th s )

Compliance Alert

Similarly to process control alert, can often be detected at time of annual product reviewC f f f f f Calculate shelf life following procedure found in first section. If slopes are different, find shelf life for each p ,

batch. Check that all shelf life estimates are greater than

or equal to current shelf lifeor equal to current shelf life.

Compliance Alert

1 0 1

1 0 2 expiry

9 8

9 9

1 0 0

%

9 5

9 6

9 7

P

o

t

e

n

c

y

9 2

9 3

9 4 L o w e r l im i t

0 6 1 2 1 8 2 4 3 0 3 6

A g e ( m o n t h s )

Compliance Alert

How to Prevent OOS

Anticipate and prevent all common cause failures

Method Lab Process

Analyst

Equipment

Preventing OOS/OOT

Physical and chemical attributes of API Critical process parameters and formulation

Product development Critical process parameters and formulationdevelopment

Critical method parameters QC friendly Robustness & Sample Prep Issues Method

Analytical th d Robustness & Sample Prep Issues Method transfermethods

Consistent OOS Investigation ProcessE t bli h d SOP f Q lit S t

QualityEstablished SOPs of Quality Systems (Investigation, CAPA, change control)

ySystems

Identify critical processQuality By Identify critical operation parameters

Quality By Design (QbD)

I ti ti M th di l S t ti d C i t tInvestigation: Methodical, Systematic and Consistent

Critical Stability Systems

Regulations ProceduresRegulations(I)

Procedures(II)

Stability Systems

Operations(III)

Investigations(IV)( ) ( )


Closing Thoughts

y Stability is defined as a Critical Quality Attributey Safety and efficacy of drug product are established

during development via clinical studies Changes must be evaluatedy Change of Drug Stability would risk patient safetyy Change of Drug Stability would risk patient safetyy Quality of finished products decreasey Potential sub-potent or over-dose productsp py Potential toxic unknown impurities

y Uncontrolled process product investigation product recallsy cGMP violations consent decree criminal

prosecutionprosecution

Closing Thoughts

Develop a good pharmaceutical product is everyones responsibility

Handbook of Stability Testing in Pharmaceutical Development: Handbook of Stability Testing in Pharmaceutical Development: Regulations, Methodologies and Best Practices, K. Huynh-Ba (ed.), Springer Publisher, 2008.

Stability Testing of Pharmaceutical Products to Support Global Markets, K. Huynh-Ba (ed.), Springer Publisher, 2010.

Kim [email protected]

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2013-09-18 USP Stability 4 Investigation

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