1September 19, 2016

Process Validation

Guidelines

by

Pramote Cholayudth

cpramote2000@yahoo.com

Thai Industrial Pharmacist Association (TIPA)

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Process Validation References Hierarchy

Approaches & Strategies

Industry Guidances

Industry Standards

Regulatory Guidelines

Law

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Process Validation (PV) Objective

PV is performed to:

Confirm and register a manufacturing process at

FDA (Law objective)

Prove, confirm and release a manufacturing

process (QA objective)

PV is not performed once but continuously in a

‘lifecycle’ rather than ‘traditional’ approach

PV data is determined as ‘process release’

data while routine QC data is ‘product release’

data (lot by lot)

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GMP Regulation: Process Validation

In the Thai FDA GMP Regulations (BE 2554):

The definitions for PV and PV approaches are

given

Qualification and Validation including PV

requirements are described in Chapter 12 (PIC/S

Annex 15, 1 September 2009)

The new revised/expanded version of PIC/S

Annex 15 was issued on 1 October 2015 and

already translated to Thai version

Retrospective approach is no more acceptable

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Regulatory Guidelines: Process Validation

PIC/S GMP Guidelines and Annexes

GMP Guidelines, Annexes and Recommendations

EU Guidelines

WHO Guidelines

FDA Guidelines

PV: General Principles and Practices

A draft PV guidance was withdrawn in Aug 2013

ICH Guidelines

ASEAN PV Guidelines

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Industry Standards: Process Validation

United States Pharmacopeia (USP)

British Pharmacopoeia (BP)

International Pharmacopeia (IP)

European Pharmacopeia (EP)

Japanese Pharmacopeia (JP)

Thai Pharmacopeia (TP)

ASTM E2709 & E2810

Others

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Industry Guidances: Process Validation

Thai FDA PV Guide - now under drafted version

PDA TR # 60: Process Validation: A Lifecycle

Approach

ISPE PQLI Guide Series

ISPE PQLI Guide: Overview of Product Design,

Development and Realization – A Science- and

Risk-Based Approach to Implementation

ISPE PQLI Guide: Part 4 – Process Performance

and Product Quality Monitoring System

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Recognized Approaches: Process Validation

Traditional Approach

Prospective Approach

Concurrent Approach

Retrospective Approach

Lifecycle Approach

Risk-Based Approach

Science-Based Approach

Bracketing Approach

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Current Process Validation Approaches

Traditional Approach to Process Validation

Prospective approach

Concurrent approach

Lifecycle Approach to Process Validation

Stage 1: Process design

Stage 2: Process qualification

Process facility, utilities and equipment qualification

Process performance qualification (= Prospective PV)

Stage 3: Continued process verification (CPV)

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Lifecycle Approach to Process Validation

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PV Supporting Approaches

Science-based approach

Based on the reason why – e.g. the manufacturing

scale is the outcome of lab & pilot scale, CPP is

the outcome of robustness and optimization study

Risk-based approach

Based on the critical aspects involved – e.g. critical

manufacturing steps, CPP and CQA are taken into

account in PV

Common-sense based approach – focused on

justified common sense

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Process Validation Strategies

PV ‘strategy’ is flexible while PV ‘approach’ is

not – i.e. strategy related to the number of PV

batches can be kept to a minimum as follows:

Traditional approach

A minimum of 3 PV batches

Lifecycle approach

PPQ batches – the number is to be pre-estimated

CPV batches – the number is to be pre-estimated

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Process Coverage

As far as ‘process confirmation’ is involved, the

concept of process representativeness i.e.

Process Coverage is to be applied:

In traditional approach

If using statistics-based acceptance criteria (e.g.

Bergum method), using 3-PV batch strategy may

provide the coverage of NLT 50% i.e. at least 50%

of the normal batches is represented by PV

If using none of the powerful statistical ones, the

coverage is not measurable !!

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Process Coverage

In lifecycle approach

PPQ batches – the number is to be pre-estimated

CPV batches – the number is to be pre-estimated

Such a pre-estimation is illustrated in tables below

The detail on how to calculate the number of PPQ

and CPV batches (including Process Coverage) is

described in TIPA Journal entitled: หมดยคุของ Magic “3 Batches” แลว้ – เป็นแค่วาทกรรมหรือวา่เป็นความจริง

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Traditional Approach

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In-Process Control (e.g. SPC)

Optimized Condition

Input Process Output

Development Background

Manufacturing Background

Consistent Quality

Controlled Materials

Total Process: Integrated View(Development To Manufacturing Scale)

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Man

MethodsMaterials

Environment

Machine

Measurement

Input Process Output

Input

Variables

Output Response

(Quality Attributes)

Process

Parameters

Manufacturing Process: Integrated View(Manufacturing Scale)

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Batch # 2

NC Rate = 1.0%

Batch # 3

NC Rate = 1.1%

Batch # 1

NC Rate = 0.9%

Process

NC Rate = 1%

Sample 1 = 0.9%

Sample 2 = 1.0%

Sample 3 = 1.1%

AV = 1.0%

AV = 0.9%

Sample 1 = 0.8%

Sample 2 = 0.9%

Sample 3 = 1.0%

AV = 1.1%

Sample 1 = 1.0%

Sample 2 = 1.1%

Sample 3 = 1.2%

Average = 1%NC Rate: Nonconforming Rate

NC Rates in Samples

Average = 1%

Manufacturing Process: Spread View

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Test Result 1

Test Result 2

Test Result 3

PV Bat. # 1

PV Bat. # 2

PV Bat. # 3Test Result 1

Test Result 2

Test Result 3

Test Result 1

Test Result 2

Test Result 3

Validation Test Results

Validated Process

Process Validation: Process Confirmation Using PV Batches # 1, 2 & 3

Validation test results are, for example, assay, content uniformity, &

dissolution. These are called Critical Quality Attributes (CQAs).

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Lifecycle Approach:

PPQ vs. CPV

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‘Number of PPQ Batches’ Strategy

% Confidence % Uncoverage % Coverage No. of Lots nL

89% 67 33 2

88% 50 50 3

87% 40 60 4

87% 33 67 5

87% 25 75 7

87% 20 80 9

87% 15 85 12

86% 10 90 19

86% 5 95 39

PDA TR # 60: Table 8.1.2-1

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‘Number of CPV Batches’ Strategy

ConfidenceConformance

RateAccept # nL

% Actual Confidence

90% 0 7 52%

95% 0 14 51%

99% 0 69 50%

90% 0 22 90%

95% 0 45 90%

99% 0 230 90%

90% 0 29 95%

95% 0 59 95%

99% 0 299 95%

50%

90%

95%

PDA TR # 60: Table 8.1.6-1

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PPQ vs. CPV Plan Matrix

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PPQ & CPV Plan (PDA Table 8.1.2-1 Modified)

Validation Stage

Sampling Plan nLAccept

#% Cum.

Coverage% Actual

ConfidenceStatistical

Tools

PPQ Tightened 3 0 50% 88%

Stringent 4 0 75% 87%

Normal 35 0 95% 88%CpK, Control Chart

PPQ Tightened 4 0 60% 87%

Stringent 3 0 75% 87%

Normal 31 0 95% 86%CpK, Control Chart

PPQ Tightened 5 0 67% 87%

Stringent 0 0 0% 0%

Normal 35 0 95% 87%CpK, Control Chart

CPV

CPV

CPV

Tolerance intervals, CpK

Tolerance intervals, CpK

Tolerance intervals, CpK

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PPQ & CPV Plan (PDA Table 8.1.6-1 Modified 1)

Validation Stage

Sampling Plan nLAccept

#% Lot

Conf. Rate% Actual

ConfidenceStatistical

Tools

PPQ Tightened 7 0 90% 52%

Stringent 14 0 95% 51%

Normal 69 0 99% 50%CpK, Control Chart

PPQ Tightened 22 0 90% 90%

Stringent 45 0 95% 90%

Normal 230 0 99% 90%CpK, Control Chart

PPQ Tightened 29 0 90% 95%

Stringent 59 0 95% 95%

Normal 299 0 99% 95%CpK, Control Chart

CPV

CPV

CPV

Tolerance intervals, CpK

Tolerance intervals, CpK

Tolerance intervals, CpK

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PPQ & CPV Plan (PDA Table 8.1.6-1 Modified 2)

Validation Stage

Sampling Plan nLAccept

#% Lot

Conf. Rate% Actual

ConfidenceStatistical

Tools

PPQ Tightened 7 0 90% 52%

Stringent 15 0 90% 90%

Normal 7 0 90% 95%CpK, Control Chart

PPQ Tightened 14 0 95% 51%

Stringent 31 0 95% 90%

Normal 12 0 95% 95%CpK, Control Chart

PPQ Tightened 69 0 99% 50%

Stringent 156 0 99% 90%

Normal 64 0 99% 95%CpK, Control Chart

CPV

CPV

CPV

Tolerance intervals, CpK

Tolerance intervals, CpK

Tolerance intervals, CpK

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PPQ & CPV Plan (Recommended)

Option #

Validation Stages

Sampling Plans# of PV

LotsAccept

#Process

Coverage (%)Confidence Level (%)

PPQ Tightened 3 0 50% 88%

Stringent 4 0 75% 87%

Normal 15 0 90% 90%

PPQ Tightened 4 0 60% 87%

Stringent 3 0 75% 87%

Normal 22 0 90% 95%

PPQ Tightened 5 0 67% 87%

Stringent 0 0 0% 0%

Normal 39 0 95% 90%

PPQ Tightened 7 0 75% 87%

Stringent 0 0 0% 0%

Normal 50 0 95% 95%

CPV

CPV

CPV

CPV

1

2

3

4

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Sampling Plans Involved in PPQ/CPV

Since product quality parameters are not

available online, so the off-line sampling (and

testing) plans (MIL-STD) are applied:

Tightened sampling plan e.g. validation sampling

plans

Stringent sampling plan – i.e. normal sampling

with tightened evaluation (e.g. using CpK)

Normal sampling plan – QC & IPC sampling plans

Reduced sampling plan – not applicable in

pharmaceutical industry

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Process Validation References Hierarchy(Non-Sterile Products)

Traditional & QbD-Based Lifecycle Approaches

(Strategy, Sampling Plan, Accept. Criteria, Stat. Analysis)

Industry Guidances

(PDA TR # 59&60, ISPE PQLI Guide Series)

Industry Standards

(USP, BP, ASTM E2709/E2810)

Regulatory Guidelines

(PIC/S,FDA,ICH,ASEAN)

Law GMP Reg.

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Any Question?