diana frank pres 0

Investigating Out of Specification (OOS) and Out of Trend (OOT)

Results in Stability

IVT’s Stability ProgramsDecember 8, 2010Philadelphia, PAFrank Diana

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EFFECTIVE METHODOLOGIES FOR OOS INVESTIGATION OF MARKETED PRODUCTS

INCLUDING OOS OCCURENCES DURING STABILITY SAMPLE ANALYSES

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• Introduction

• OOS Investigations

• OOS Results - Stability Studies

• Deficiencies

•Retest Examples

INTRODUCTION

References/Background

Judge Wolin Decision (2/93)• Averaging OOS with Passing Results• Discarding of Raw Data• Multiple Retests with no Pre-Specified End Point• Inadequacy of Failure Investigations• Method Validation Deficiencies

Investigating OOS Test Results for Pharmaceutical Production (FDA Guidance issued 10/2006)

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INTRODUCTION

(Continued)

SOP(s) should include:

Investigation of OOS Results

Repeat Analysis/Retest/Resample

Release and Stability Samples need to be included

Analyst/Supervisor Responsibilities

Out of Trend or Profile Results

What is OOT?

Can be a separate SOP

Can be part of same SOP but different procedure

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Analyst identifies an OOS result and alerts supervision

Informal lab. inspection including review of notebook/ worksheets, chromatograms, testing procedures, calculations, instrument(s) used, glassware, reagents, standards, solvents, etc.

Can include additional measurements on sample/standard preparations used in original test (e.g. re-injection, re-dilution, additional extraction). This is not a retest, typically called re-analysis.

Review results of other tests performed on the same sample

OOS INVESTIGATION

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ANALYTICAL LABORATORY CHECKLIST FOR ANALYTICAL ERRORS

YES NO N/A ANSWER THE FOLLOWING QUESTIONS

Assignable Analytical Cause

Must be demonstrated/justified. Unsupported speculation is not acceptable.

Document (Analyst/Supervisor)

Repeat as originally tested

Replace original results

Procedural Error during the analysis – stop analysis and document error

No assignable analytical cause – formal investigation

OOS INVESTIGATION(Continued)

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OOSResult

LabInvestigation

Analyst/Supervisor

AssignableCause

FormalInvestigation

Invalidate OriginalResult/Document

Investigation

RepeatTest

Yes

No

Formal Investigation

• Typically led by Quality

• Batch folder review

• Other lots / products affected

• Manufacturing history (i.e. product, equipment, etc)

• Historical stability data

• Actual or probable cause

• Corrective actions and individuals responsible


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Laboratory phase of Formal Investigation

• Retest / resample

• SOP in place

– Decision making process

– Number of sample preparations / number of analysts predetermined

specifically defined in SOP or protocol written prior to retesting

repeated testing until a passing results is obtained is not acceptable (testing into compliance)

– Confirmed / not confirmed

– Timeframes (30 business days)


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Retest/Resample

Invalid Sample

ResampleDocument

RepeatTest

Retest basedon SOP/Protocol

Increased # of Replicates

Results within Spec

OOS ClearlyAtypical

InvalidateDocument

ReportResults

OOSConfirmed

Yes

No

Yes No

Resampling

• Only when evidence that original sample was prepared incorrectly

• Not representative of batch

• Justification for resampling must be fully documented

• Qualified sampling


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Averaging

• May be valid in some cases, i.e. micro assays

• Inappropriate when uniformity is being evaluated or cannot be assumed, e.g. content uniformity, blend uniformity

• To use averaged results for assay, all test results must be within specs.

• Replicate injections vs sample result

– Replicate injections – averaging is acceptable


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Outlier Tests

• Homogeneous sample is tested, such as for assay

• Not applicable for content uniformity, dissolution, release rate

• Use only on rare occasions with full justification

• Statistical evaluation

• See Reference for an interesting discussion on this topic: JD Hofer and EC Richard, “A Guide to Determining Sample Sizes and Outlier Criteria in Analytical Investigations,” Pharmaceutical Technology, March 2001; pages 52-66.

OOS INVESTIGATION

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OOS RESULTS - STABILITY STUDIES

Similar investigation to release OOS

Significant change at accelerated conditions

OOS at accelerated or intermediate conditions

Understand typical product trends – identify significant OOT results

Release versus stability specifications

Unknown peaks in chromatograms

Typical sample chromatograms should be reviewed from previous time points

Standard chromatograms

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Release problems that show up on Stability

• High initial degradation product (impurity) level in API

• Atypical variability in tablet assays (content uniformity)

• pH near limits at release (analytical variability)

• Stage 2 dissolution, or atypically low average dissolution result

• High moisture level in tablets (degradation)

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Stability Problems

• Alternative storage condition

• Change package – more protective

• Shorter Expiration Date

• Reformulate product

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OUT OF PROFILE/TREND RESULTS

Alert or in-house limits

• Result vs. previous data point

• + / - from the previous value

• + / - from label

• Set value compared to specification

• Goal is to identify a potential problem before it becomes a major problem

• Notification of supervision

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Degradation product for 200 mg TabletProductStrength=200

Suspect blister lots are LC129(200mg), NB081(200mg), andNC169(300mg)

PackageType

BLISTER HDPESuspectblister

Deg Prod

0.0

0.1

0.2

0.3

0.4

0.5

0.6

Nominal Months onStudy

0 12 24 36 48 60 72

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All data graphed by Package size

PKG 100 500

AC

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

1.1

1.2

1.3

1.4

1.5

MONTHS

0 3 6 9 12 15 18

All data graphed by Package size

PKG 100 500

AC

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

1.1

1.2

1.3

1.4

1.5

MONTHS

0 3 6 9 12 15 18

Field Alert/Interaction with Regulatory Authorities

• GMP 3.14.18

(1) NDA-Field alert report. The applicant shall submit information of the following kinds about distributed drug products and articles to the FDA district office that is responsible for the facility involved within 3 working days of receipt by the applicant.

(ii) Information concerning any bacteriological contn, or any significant chemical, physical, or other change or deterioration in the distributed drug product, or any failure of one or more distributed batches of the drug product to meet the specifications established for it in the application.

REGULATORY IMPLICATIONS

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Proactive Approaches to Minimize OOS

Well thought out and written SOPs

Justifiable/Reasonable Specifications

Good analytical methods – method development/validation/transfer

Well trained analysts and supervision

• Follow SOPs

• Follow Methods

• Training Program/Experience

• Good Documentation Practices

• OOS/OOT are reviewed, investigated and resolved ASAP

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Equipment Program that is in control

Sample flow is clear and documented

Data are reviewed in a timely manner and trended

Recurring problems are reviewed in a timely manner, trended, as necessary and resolved

• Equipment

• Methods

• Analysts

• SOPs

• Standards

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Internal audits performed periodically

Periodic Group meetings

• Audit findings

• Recurring problems

• SOP training

• Metrics

• Discuss issues

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DEFICIENCIES

Examples of FDA 483 citations; information obtained from various sources (GMP Trends, Pink Sheets, Drug GMP Report, Washington Drug Letter)

Investigations

• Lack of thorough investigations; inadequate investigations into OOS

• Failure investigations are not conducted / completed in a timely fashion

• Not conducting timely stability investigations including failures beyond the expiration date

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Investigations (Continued)

• The company’s investigations did not extend to other packages of the failed batches or to other batches Manufactured at the same time

• The batches placed on stability testing each year are a representative sample of the batches manufactured during that year; failure of a stability sample should trigger a review or testing of other batches manufactured during the year

• Investigation report does not include the corrective actions necessary to prevent similar recurrences.

Reports do not indicate if similar OOS results were reviewed and if other lots are affected.

DEFICIENCIES (Continued)

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Investigations (Continued)

• There is no SOP for conducting product investigations or tracking product failures

• Several investigation reports indicate the corrective action plan is to instruct analysts to follow procedures more carefully, however all analysts involved had been certified to conduct the analyses (training program issue)

• OOS results were invalidated without sufficient data to support conclusions, such as poorly trained

analysts and equipment problems.


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Retesting

• Original Assay Test data from an accelerated stability timepoint was discarded without assignable cause and without a written investigation. Reanalysis (same samples, new standard prepared) was performed. The results did not invalidate the original results. There was no evidence that the original, accelerated stability data was not legitimate. All of the results, original and reanalysis, were within specification but generally higher than the initial stability results.


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Retesting (Continued)

• An assay result below the action limit, was “invalidated” without any assignable cause identified and solely on the basis of two retests. The SOP states that unless the working solution is retested, seven out of eight samples are required to be similar in order to invalidate a sample as non-representative. This written procedure is the standard followed by your firm’s other laboratories.


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• The assay result was invalidated with the unsupported assumption that an injector problem caused the low results since higher assay results were obtained for other lots run before and after. There was no justification of why an injector problem was assumed for the four consecutive injections for this lot (with all four injections substantially agreeing) and why no other results from this HPLC run were questioned.


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• The procedure for rejection of analytical data and reassay of samples is inadequate, in that there is no information explaining in detail how the retesting is conducted. There is also no information explaining at what point testing should end and the product be evaluated.

• There was no communication between the firm and the contract laboratory outlining retesting procedures to follow for samples that fail to meet specifications.


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Retesting

• Failure to investigate, justify and record deviations from written specifications and test procedures when repeated testing is done, due to initial test failures.

• Averaging passing and failing results without investigating cause of OOS

• Discarding test data without just cause.


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Retesting/Resampling

• Lack of personnel training in laboratory procedures and stability testing is evident from the discarding of raw analytical data, samples tested several times and supervisor personnel allowing such events to occur.

• The firm failed to follow their own SOP’s in regard to the resample and the firm did not address this in the investigation report. The investigation implies that a subsequent sample, the resample, was obtained using correct sampling procedures. The firm has no documentation as to when the re-sampling actually occurred.


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Trending / Review of Stability Data / Notification

• There has been no investigation of the increase in particulate matter test results during stability testing through 24 months.

• The firm consistently found dissolution results that had high variability of over eight percent relative standard deviations and / or average results that differed from the average assay result by more than ten percent. No investigation was performed although it was stated on the company’s SOP that values of dissolution test should compare favorably with assay values.


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Trending / Review of Stability Data / Notification (Continued)

• There are no standard operating procedures to conduct investigations or statistically analyze real time stability data points that exhibit abnormal stability patterns. Data submitted in the Annual Reviews demonstrates that several products have unexpected increases in potency that exceed normal data variability. For example:

– Lot ... increased 12% in potency between 0 and 3 months. Lot ... increased 6% in potency between 0 and 3 months, decreased by 9% between 3 and 6 months.

– Lot ... decreased by 7% between 0 and 3 months, remained constant between 3 and 12 months then decreased 6% between 9 and 18 months


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Trending / Review of Stability Data / Notification (Continued)

• There is no system in place to assure that upper management is notified of product deficiencies.

• Supervisory review of analytical data is not performed in a timely manner

• No investigation was done to determine whether highly variable and/or non-linear test results at various stability test stations were due to true product variability or to defects in the testing.


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RETEST EXAMPLES - DIFFICULT DECISIONS

Assay Results - 12 months/25 C/60%RH Timepoint

Results: 99.7% of label

88.9% of label

Limits: 90.0 - 110.0%

Previous Data: 98.5 - 101.8%

The analyst has just alerted the supervisor of these results

What are the next steps that should be followed?

What if the original results were 94.1 and 92.9% of label

What are the next steps that should be followed?

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(1) Assay Results - 12 months/25 C/60%RH Timepoint

Original: 99.7% of label

88.9%

Limits: 90.0 - 110.0%

Previous Data:98.5 - 101.8%

No analytical error found

Retest (7 replicates) 100.8, 99.1, 99.4, 99.7, 99.8, 100.5, 100.4

What decision would you recommend?

Invalidate 88.9%?

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89.4%

Limits: 90.0 - 110.0%



Retest (7 replicates) 91.7, 90.6, 91.8, 90.3, 91.2, 90.2, 91.5

What decision would you recommend?

Can 89.4% be invalidated?

Field Alert?

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88.9%

Limits: 90.0 - 110.0%


During lab investigation, re-shake and re-inject

Result: 99.4%

Analytical cause identified

Next steps?

Assume this has happened several times in the past

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(4) Content Uniformity

Uncoated tablets - release testing

Ten results: 99.9, 71.4%, 99.4%, 98.7, 97.5, 101.6, 98.9, 101.2, 99.5, 100.7


Can 71.4 be invalidated?

What Lot disposition will you recommend?

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(5) The firm consistently found dissolution results that had high variability of over eight percent relative standard deviations and / or average results that differed from the average assay result by more than ten percent. No investigation was performed although it was stated on the company’s SOP that values of dissolution test should compare favorably with assay values• Analyst results for dissolution time point (18 months) is 110% +/- 6%

• Stability results for dissolution for this lot range from 94 – 97 % at earlier time points

• Other lots have had issues consistent with deficiency above

• Assay result is 99.2, 99.7% of label

• What are your next steps?

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diana frank pres 0

Documents

investigation of oos

oos test results

review results

averaging oos

passing results

oos occurences

specification oos

profile results