Out of specification shravan

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Out of Specification

By: Shravan Kumar

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Definition

If the analytical result(s) of a batch or material is/are falling out side of the established specification ranges, is called / considered as Out of Specification.

Or

The term OOS test results includes all suspect results that fall outside the predetermined Specification

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Out of Specifications

There are lot of guidelines are available for defining to handle the OOS products/materials/batches as:

MHRA guideline for OOS CDER guideline for OOS PIC/S guideline for OOS

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The OOS may be observed during the analysis of:

Stability study Finished API Intermediates In-process Raw materials Packing materials

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OOS found due to the following reasons but not limited to: OOS

Laboratory Process related Sample homogeneity

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Laboratory errors:Laboratory errors

Method of Analysis

Use of Non Calibrated

instrumentsError in

calculationAnalyst

errorInstrument Failure

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Process Related:

Process Related

Operator Error

Equipment Failure

Deviation form the validated

procedure

Quality of Raw material /

Intermediate used

In-Process Control During Manufacturing

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Homogeneity sample :

Sample Homogeneity

Sampling error

Handlin of samples

Pooling of sample

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OOS Investigations

As per MHRA (EU GMP)

Phase – I Investigation (Primary & extended lab investigation)

Phase – II Investigation(Manufacturing investigation)

Phase – III Investigation(Extended manufacturing, Re-sampling and

re-analysis)

Procedures of OOS investigations

As per CDER (US FDA)

Phase – I Investigation(Primary & extended lab investigation)

Phase – II Investigation(Manufacturing investigation and re-

sampling and re-analysis)

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OOS Investigations

Phase – I Investigation: Laboratory investigation

Laboratory investigation is related to the Quality control

department along with rechecking of documents with same

analyst and re-testing with different analyst with original sample.

Phase – I is sub divided in to two sections as:

Phase – Ia (Primary Lab investigation), and

Phase -Ib (Extended Lab investigation)


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OOS Investigations

Phase – II Investigation: Manufacturing Investigations

In manufacturing investigation, production person investigate :

Process parameters

Drying parameters

Input raw materials quality

training of persons

Cleaning of equipment

Environmental information

Contamination & etc….


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OOS Investigations

Phase – III Investigation: Extended Manufacturing Investigations

In Phase III investigation, Quality Control / Quality Assurance & Production

department investigate the following:

Sampling error by person

Authorized for re sampling (if required)

Re-analysis of re-sampled material with different Analyst

If root cause found, define the CAPA or if not

Diverted the matter to R&D / ADL or PD Lab

Conclusion by all team member (QA, QC, PRD, ADL R&D, PD Lab)

Decide the fate of batch by QA Head


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OOS Investigations

Re-testing:The analysis of original sample at the time of phase- I laboratory investigation.

Re-sampling:The original batch is sampled by QA second time after QA head authorization for re-

analysis.

Re-analysis:

The analysis of re-sampled material for the verification of results, if

manufacturing investigation does not have root cause.

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OOS Investigations


Laboratory investigation is related to the Quality control

department along with rechecking of documents with same

analyst and re-testing with different analyst with original sample.

Phase – II Investigation: Manufacturing investigation

Process related investigation is to be carried out by

Production department along with re-sampling and re- analysis.

As per CDER (US FDA)

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OOS Investigations


Analyst observed the OOS result

Re-calculate the results (if required)

If analytical results remain same

Report the OOS result to QC In-charge

Log the OOS

Start the Primary Laboratory investigation

Review the documents along with solutions as (Potency / STP & Specs /

buffer solutions / calibration of instruments / standard solutions /

Column efficiency / weights / storage condition of sample and many

more)

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OOS Investigations

Phase – I Investigation: Laboratory investigation If there is no abnormality observed during the primary

lab investigation then Report same results and considered as valid OOS and report

Quality Head review the primary lab investigation and

evaluate for re-testing (if QA Head permits)

Repeat the analysis as thrice with original sample with

different analyst

Report the average result of repeat analysis

Report the average result

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OOS Investigations

Phase – I Investigation: Laboratory investigation If the result complies

Report as complies and invalidate the OOS

Release the batch

If any of result if not complies (among three)

Report as OOS and continue the OOS

Report to QA head

QA head will recommend for the Phase – II investigation (manufacturing

investigation)

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OOS Investigations


Production persons shall investigate the following:

Input quantity of raw material

Input RM quality

Process parameters details

Critical process parameter details (time / temp)

In-process results

Out put of the material

Re-conciliation of raw materials

Utility pressures

Calibration / Preventive maintenance of equipment

Attached ancillaries status

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OOS Investigations


Production persons shall investigate the following:

Cleaning of equipments

Training of personnel

Brain storming with operators

Contamination verifications

Environmental review

If there is no assignable cause observed during manufacturing

investigations, same is to be reported to Quality Assurance Head.

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OOS Investigations


QA, QC and production department will evaluate the investigations and after that:

Sampling procedure review, if suspected

QA head may recommend for re-sampling

QC analyst shall analyze the sample as per STP

Report the result (Pass / Failed)

If Pass

Define the CAPA

Release the Batch

If failed

Reject the batch

Divert the matter to R&D / ADL / PD Lab

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OOS Investigations


R&D / ADL / PD Lab shall:

Take the user trial with the material

Investigate the failure based on experiments / experiences

Various types of experiments

To find out the root cause

To identify, is this material can b e reprocessed / reworked

Make a summary report

Defined the corrective actions

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OOS Investigations


QA/QC/Production department shall:

QA head shall define the fate of batch for reprocess / rework / destruction

Accept the corrective and preventive actions

Training to all concerned for root cause / corrective action / preventive

action

Monitor the activity for corrective actions

Evaluate the results of corrective actions

Implement the preventive actions

Verify the implementation of preventive actions

After satisfactory implementation close the OOS & CAPA

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OOS Investigations

All these activity for investigation / corrective actions / preventive

actions should be recorded and reviewed and archived.

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OOS Investigations

If OOS batch is to be reprocessed / re-work:

Follow the written approved BMR for re-process / Rework

Sample as per SOP for sampling of material

Analyze the material according to the specification and STP

Evaluate the quality of the batch

Keep this batch for stability (Accelerated / Long term)

Evaluate the stability results of the batch

Communicate the OOS to the customers (as mentioned in to the

Quality agreement)

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OOS Investigations

Impact of OOS on REGULATORY:

Stability study required

OOS should be reported to RA

OOS batch should not be sold to Regulatory market

OOS batch can not be blend with fresh approved batch

OOS batch can not be directly sell to the market

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Abbreviations

CDER : Center for drug evaluation and research

OOS : Out of specification

RA : Regulatory affairs

STP : Standard testing procedure

EU-GMP : European good manufacturing practices

PIC/s : Pharmaceutical inspection co-operation

scheme

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Thank You

Health & Medicine

Out of specification shravan