RC Sibulo, RPh MBA

Nov 2013

Outline Introduction

PQR as a pillar of quality management

What is Product Quality Review (PQR)?

The rationales behind PQR

What are the Regulatory Guidelines for conducting PQR?

Pre-requisites

Industry Practices

PQR Strategy

PQR tactical

The Pharmacist’s role in PQR

Pharmacy profession and PQR

Pharmacy

Community HospitalManufacturing

Regulatory R&D QA Production

QCPQR QRMGMP

Aspects of Quality Management PIC/S

Quality Management ensure that they (medicinal products) are fit for their

intended use

comply with the requirements of the Marketing Authorization

do not place patients at risk due to inadequate safety, quality or efficacy

“SUM TOTAL of all organized arrangements with the objective of ensuring that medicinal products are of the quality required for their intended use”

Quality AssuranceM

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Design and development

Production and control

operations

Starting and Packaging materials

Intermediates, in-process controls and validations

Finished product processing

Batch release

Storage, handling and distribution

Good Manufacturing Practices “..CONSISTENTLY PRODUCED & CONTROLLED to

the quality standards appropriate to their intended use and as required by the marketing authorisation or product specification."

Man

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Design and development

Production and control

operations

Starting and Packaging materials

Intermediates, in-process controls and validations

Finished product processing

Batch release

Storage, handling and distribution GXPs

Quality Control “..part of GMP..”

“..sampling, specifications and testing, and with the organisation, documentation and release procedures..”

“..quality has been judged to be satisfactory."

Facilities

Sampling

Test methods

Records

Label content

Retention

QC

Quality Risk Management “..systematic process for the assessment, control,

communication and review of risks..”

“..can be..proactive..or retro..”

ICH Q9: US FDA guide

What is PQR? PIC/S: GUIDE TO GOOD MANUFACTURING

PRACTICE FOR MEDICINAL PRODUCTS PART I section 1.4, Jan 2013

“Regular periodic or rolling quality reviews of all licensed medicinal products..”

What is PQR?“..verifying the consistency of the existing process, the

appropriateness of current specifications for both starting materials and finished product to highlight

any trends and to identify product and process improvements.”

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Design and development

Production and control

operations

Starting and Packaging materials

Intermediates, in-process controls and validations

Finished product processing

Batch release

Storage, handling and distribution

What is PQR? Singapore HSA: GUIDANCE NOTES ON PRODUCT

QUALITY REVIEW , Jan 2013

“..a natural progression of GMP quality system implementation..”

Basic Product (R&D) Lifecycle

Literature review

Pre-formulation

Clinical trial

Pilot production

Process Validation

Routine Production

PQR rationale (benefits) Risk reduction – product complaints, product recall,

Out-of-specifications (OOS) results, manufacturing and testing errors

Increase in productivity via:

Process improvements (manufacturing and testing)

Non-critical test parameter reduction

Reduced down-time from calibration and maintenance (required intervals can be reduced)

Optimization of yield limits

Verification of validation status

Regulatory Guidelines PIC/S: GUIDE TO GOOD MANUFACTURING

PRACTICE FOR MEDICINAL PRODUCTS PART I section 1.4, Jan 2013

US FDA 211.180 (e)

Regulatory GuidelinesParameter US FDA PIC/S

Appropriateness of specs Product Product and Starting materials

Appropriateness of processes

Manufacturing procedure and in-process control

Not specified; only consistency with existing process >> re-validation

Grouping/Matrixing Not allowed Allowed

Trend evaluation (including previous reviews)

For corrective actions For corrective actions and process improvements

Pre-requisites Established Quality Systems

Validation

Non-process validation

Utility systems

Equipment qualification

Process validation

Analytical method validation

QA documentation

Change control

Deviation reporting

OOS investigation

Quality risk management

Established Engineering systems

Equipment calibration

Routine preventive maintenance

How to perform PQR What to include:

Relevant Regulatory issuances in the period covered

Routine (and related Changes) > impact on Finished Product

Parameter Routine Changes

Materials Lot to lot variation Material specs change > Material qualification

Equipment and Processes

Equipment setting/PM status, visual endpoint variations

Critical process/equipmentchanges > Process re-validation

Test methods Reagent, analytical equipment settings/PM status

Compendial revisions > verification or re-validation

How to perform PQR - Materials

95

96

97

98

99

100

101

Para006 Para007 Para008 Para009 Para010

API Potency

92.0

94.0

96.0

98.0

100.0

102.0

104.0

Para006 Para007 Para008 Para009 Para010

Product Assay

How to perform PQR – Equipment/Processes

0.02000.04000.06000.08000.0

10000.012000.014000.0

Viscosity

0.0

2.0

4.0

6.0

8.0

10.0

12.0

14.0

Mixing time (min)

How to perform PQR Stability and retention data

Stability data – from critical changes and routine (e.g. annual stability loading)

Retention data – from retention samples analysis, if applicable

QA

Recalls, complaints, adverse events, returns, deviations, OOS investigations, and related CAPA

How to Perform PQR QC data

Identify critical QC parameters (e.g. assay) and product performance indicators (e.g. viscosity)

Perform statistical analysis (assumption: normal distribution)

Parameter Formula Specifications

RSD (SD/mean) x 100 NMT 3.0 – 6.0%

Cp (USL – LSL)/6σ NLT 1.33

CpK min [(USL-mean)/3σ, (LSL-mean)/3σ)

NLT 1.06 sigma: NLT 2.0

How to Perform PQR - Cp

B

USLLSL

target

C DAA B CBD

Cp Type

C P A

> C P B

00> C P0 C

0.67>C P D

How good does the deviation lie between the specified limits?

How to perform PQR - CpK

10 11 12 13 14 15 16 17 18

LSL

10 11 12 13 14 15 16 17 18

LSL USLnominal

X

USLnominal

X

= 1 = 1

Process mean and deviation compared to pre-specified mean and limits

Industry Practice - Strategy Frequency Approach

Periodic

e.g. Annual

By volume

Rolling

Real-time/on-line

Batch documents copy

Release control

•Process Assignment•For products owned by manufacturers

•Internal PQR•Third party review

•Toll manufactured products•Toll manufacturer review•Review by product owner•Third party review

Industry Practice - Strategy Matrixing

Formulation-based

Similar dosage forms

Similar API

Similar Packaging material and closure system

Process and equipment-based

For low risk formulations

Approach should be documented in the SOP

Industry Practice - Tactical Rolling

Routine provision of batch data (process and QC) from production to QA (internal or third party)

e.g. as part of release requirement

Periodic provision of data (monthly or quarterly)

Periodic

Depending on volume of products (annual, semi-annual or quarterly)

Data management

Hard copies, soft copies (pdf files)

Scan on-site or hard copies via courier

PQR and the Pharmacy profession Why a qualified Pharmacist should perform PQR?

Understand impact of PQR parameters on patient therapy

Up-to-date with FDA regulations and requirements

Systematic approach to managing quality

Thank you for your kind attention