FACILITY & EQUIPMENT

QUALIFICATION

QUALITY RISK MANAGEMENT BASED

APPROACH FOR FACILITY & EQUIPMENT

QUALIFICATION

“Quality System by Innovation”

IVT 21st Annual Validation Week

Philadelphia, PA

Prof. Jack C. Chu, PE

October 29, 2015

2

Oct 29, 2015

• Prior to Ben Franklin Bridge, Philadelphia and

Camden were connected by ferry service only.

• Plans for a bridge crossing the Delaware River began

in the 1800s.

• An 1818 plan involved making use of a then-existent

Smith/Windmill Island in the river, but it wasn’t until the 1910s

that efforts for a bridge took hold.

• The Delaware River Bridge Joint Commission (now the

DRPA) was created in 1919.

• Work on the bridge began in 1922, and it was opened

to traffic on July 1, 1926, three days ahead of the

originally targeted opening on the nation’s 150th

anniversary.

• At the peak of construction 1300 people worked on

the bridge, and 15 died during its construction

Oct 29, 2015 3

Oct 29, 2015 4

Facility Guideline Hierarchy

ISO 9000

GOOD ENGINEERING

PRACTICES

cGMP

Objective

Science and Risk-Based Approach for the Delivery of

Facilities, Systems, and Equipment (ISPE) provides direction

to industry on the implementation of pharmaceutical and

biopharmaceutical facilities, operating systems, equipment,

and associated automation and demonstrates that are fitted

for intended use and comply with regulatory requirements

How to be successful in delivering of Pharmaceutical

Manufacturing Facility/Equipment that is regulated

by various authorities and is posed significant

challenge to manufacturers, engineering

professionals, and equipment suppliers.

5

Oct 29, 2015

Topics

6

•Industry Standard Practice & Regulatory

Requirements•Product & Process Understanding

•Science & Risk based Approach

•Application of Quality by Design Concept

•Applying industry Standard Practice and

Regulatory Requirements to Ensure Project

Deliverables:•Define CQP and CPP

•Assess the System Impact

•Evaluate the Criticality of Process Equipment and

Control Instrument

•Performance Reliability Assessment

Oct 29, 2015

Oct 29, 2015 7

Validation – Discussion

"Validation is establishing ________evidence that provides a high _______ of __________ that a specific process will ________ produce a product meeting its pre-determined specifications and _____ attributes.“

Validation?

Oct 29, 2015 8

Validation – CFR

"Validation is establishing documented evidence that provides a high degree of assurancethat a specific process will consistentlyproduce a product meeting its pre-determined specifications and quality attributes.“

Does it make

Scene?

Oct 29, 2015 9

Definition: Validation in EU

• "Validation studies should reinforce Good

Manufacturing Practices and be conducted

in accordance with defined procedures.”

• “Results and conclusions should be

recorded."

Oct 29, 2015 10

Validate the Process, Process Equipment, and

Production Facility Systems

• FDA requires that we validate all of our systems and processes according to 21 CFR part 211

• Validation is a way of assuring quality product

• Validation demonstrates that a process can consistently perform as expected

• Validation can lead to quality improvements and optimization

• Demonstration of the Controlled Status

Oct 29, 2015 11

EU Regulations

• It is a requirement of GMP that

manufacturers identify what validation work

is needed to prove control of the critical

aspects of their particular operations…….

• A risk based approach should be used to

determine the scope and extent of

validation.

Oct 29, 2015 12

Typical Validation Approach……..

• Focused on achieving the approved qualification report• Missed right contents and accuracy of data

• Missed project deadline

• Field changes and deviations

• Lag of resources and accountability• Validating system without system knowledge

• Classifying everything is critical

• Poor FEL strategy with complicated CR control mechanism

• Incredible paperwork and burden on validation engineers

• Qualification program to satisfy regulators• Missed the functioning manufacturing capacity and

business intended

Oct 29, 2015 13

FACILITY & CRITICAL

UTILITIES

• Design Considerations

• Installation

• Qualification

Oct 29, 2015 15

Understand - Facility Design Baseline• CFR Subpart C

• Must be designed to facilitate cleaning and maintenance

• Must be adequate for placement of equipment and materials to prevent of mixed-up

• Need monitoring system for environmental conditions

• Need cleaning/disinfecting system for manufacturing facilities and process equipment

• Require proper HVAC, air filtration

• Proper slope for process and plumbing piping

• Treatment system for discharging waste water, solids and contaminated exhaust air

• Proper maintenance, preventive maintenance program, and predictive maintenance programs

Oct 29, 2015 16

Classification of SpacesSPACES TYPICAL AREA Typical Garments

EXTERNALOutside of GMP area.

Personal Clothing

UNCLASSIFIED GMP

General Corridor, Packaging Hall

and Supervisor Office(s) directly

related to the classified GMP

operations, but physically

separate.

Garments

appropriate to area

Grade C Non-aseptic manipulation Gowning

Grade BBackground for aseptic

manipulationSterile Gowning

CLA

SS

IFIED

GM

P

Grade APoint of Fill or other aseptic

manipulationSterile Gowning

Oct 29, 2015 17

Classification of Spaces

SPACES TYPICAL AREA Typical Garments

EXTERNAL Outside of GMP area. Personal Clothing

UNCLASSIFIED GMP

General Corridor, Packaging Hall

and Supervisor Office(s) directly

related to the classified GMP

operations, but physicallyseparate.

Garments

appropriate to area

Grade D Non-aseptic manipulation Gowning

Grade BBackground for aseptic

manipulation

Sterile Gowning

CLA

SS

IFIED

GM

P

Grade A Point of Aseptic Fill & Capping Sterile Gowning

Grade C Non-aseptic manipulation Over-Gowning

Oct 29, 2015 18

Design Criteria – Hygienic Zoning w/

Unit-Directional Flow

A/

L

A/

L

G

D

G

Grade - D Grade - C Grade - B Grade - A

A/

L

G

A/

L

D

G

A/

L

M

Oct 29, 2015 19

Qualification - Basic Steps

• System Impact Analysis: • GMP or non-GMP

• Equipment Criticality Assessment:• System Boundary

• User’s Requirements Specification: • Foundation of PQ

• Functional/Performance Parameter and Operating Range: • Base-line for OQ

• Detailed Specification and Construction Documents: • References for IQ

• Maintenance/Calibration Tolerance/Critical BOM:• Establishment for System Lifecycle Management

Oct 29, 2015 20

Process HVAC and Process Compressed Air

Oct 29, 2015 21

System Layout and Physical

Boundary

Oct 29, 2015 22

Oct 29, 2015 23

What Do We Want to Know

about the System?

Oct 29, 2015 24

Good Engineering

Practice – Redefine the

Engineering Solution

and System Boundary

Oct 29, 2015 25

System to Be Validated

Oct 29, 2015 26

Compressed Air System

Oct 29, 2015 27

Oct 29, 2015 28

Oct 29, 2015 29

System Boundary - Idetifined

QRMS - Summary Statement

• Define areas of high risk and how they can be

mitigated in the Design and Validation/Verification

Processes

• ICH, ASTM, ISPE and other professional

organizations provide a cutting edge framework

for planning and execution of risk-based

approach to design and implementation of

reliable manufacturing systems to ensure the

product quality and patient safety

Oct 29, 2015 30

“Risk Management” is Universal

31

Company

Strategic Risks Operational Risks Financial Risks Compliance Risks

Competitor

Advantage

Company

Viability

Shareholder

Harm Patient Harm

QRMS Impact

Oct 29, 2015

Quality & Risk Management System: Link

Back to Patient Risk

32

Process

Materials

Design

Manufacturing

Distribution

Patient

Facilities

Opportunities to impact

risk using quality risk

management

Oct 29, 2015

QRM and the Design Space (QbD)

33

What is the chance

(probability) of “falling

outside” of the design space

per unit time?

Risk analysts estimate probabilities

of being outside (or inside!) of design

limits, given various scenarios.

Design parameters and

their intersection in a

“design space” concept

v1

v2

v3

design space

Oct 29, 2015

QRMS: Systems Approach

A systematic process for the assessment, control,

communication and review of risks to the quality of the

drug product across the product lifecyle.

34

“Systems” thinking

and methods!

Oct 29, 2015

ISPE “Science & Risk-based approach for the Delivery of

Facilities, systems, & equipment”

• “Science & Risk-based Approach for the Delivery of

Facilities, Systems, and Equipment” focuses on the

importance of QRM program, the risks to patients

• To improve the way we delivering our products:

• Improving the ability to meet process requirement

• Control risks within the manufacturing process parameter

• Produce high quality products on time/on demand

• Consistent to meet product and process requirements

• Apply the key concepts and principles throughout the project

lifecycle in order to establish and to demonstrate the

Suitability for Intended use

35Oct 29, 2015

Product and Process Understanding

• Establish Basis of Design• Provide inputs to assessing risks

• Set up the basis for deviation management and change controls

• Product Critical Quality Attributes (CQAs)• Provide physical, chemical, biological or microbiological property of

characteristic within an appropriate limit, range, or distribution to ensure the product quality

• Critical Process Parameters (CPPs)• Provide process parameter and its variability has an impact on a

critical quality attribute

• Monitor and control these parameters to ensure process robustness, repeatability, and produce quality products

• Established engineering methods and standards to be applied throughout the project and asset life-cycle• To ensure the effectiveness in manufacturing process

• To meet product CQAs

• To control process CPPs

36

Oct 29, 2015

37

Oct 29, 2015

38

Oct 29, 2015

39

Oct 29, 2015

40

• Rationalize the Business

Decision based on the

Risk Profile

Realize the Business

Benefits based on the

Rationalized Business

Decision

?

?

? ??

?

?

Oct 29, 2015

?

?

Oct 29, 2015 41

Question and Answer

Oct 29, 2015 42

Question and Answer

• In recent years, what are the most

frequent citations in Pharmaceutical

Manufacturing Inspection?

1. SOP

2. Maintenance

3. Equipment & Facility

4. Cleaning Validation

Oct 29, 2015 43

The Answer

• In recent years more than 1/3 of FDA

warning letters cite cleaning practices.

Oct 29, 2015 44

FDA Citation on the Cleaning Practice

"The firms cleaning practices cannot be correlated to

the firms cleaning validation.

For example, preparation of filling equipment does not

specify whether WFI rinses are for individual pieces of

equipment or for rinsing equipment together.

SOP specifies that each piece of equipment is cleaned.

The cleaning validation show equipment rinses were

performed in groups."

Oct 29, 2015 45

Question and Answer

• Validation is proving today that what we did yesterday

can be done tomorrow.

• True/False?

• Why?

Oct 29, 2015 46

Question and Answer

• Why do we validation process system and processes?

1. FDA requires that we validate all of GMP systems and processes according to 21 CFR part 211

2. Validation assures quality product

3. Validation demonstrates that a process can consistently perform as expected

4. Validation can lead to quality improvements and optimization

Oct 29, 2015 47

Question and AnswerWhat is the definition of the

validation activity?

• New product

introduction

• Annually

• Change an SOP

• Change a process,

system or raw material

– initial validation

– continuing validation

– documentation

validation

– revalidation

Oct 29, 2015 48