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Background on QRM. Pharma EXPO September 2015 Las Vegas, NV. Your QRM Program. Paul H. Ahlijanian

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(1)

Using Quality Risk Management to Evaluate

Compliance for Multiproduct Manufacturing

and Inventory Facilities in the Pharmaceutical

Industry

Paul H. Ahlijanian

Senior Manager, Pharmaceutical Sciences Quality Assurance

Pfizer, Inc.

1

Background on QRM

The International Conference on Harmonisation (ICH) Q9 document

states that

QRM is a systematic process for the assessment, control,

communication, and review of risks to the quality of the drug product

across the product lifecycle

In all likelihood you are already building QRM into your

work processes when you make risk-based decisions.

QRM formalizes these decisions and provides a way for

different workstreams to collaborate and determine an

outcome based on science, engineering, and quality.

Do you have a documented QRM Program?

Do you have one or more SOPs describing your

company’s QRM Program?

Does your QRM SOP allow for and delineate formal

and

informal

QRM evaluations?

Do you have a Consistent, Time-Based QRM Review

Program or are Reviews conducted Ad Hoc?

(2)

Identify all risks in a

proposed change or

continuous

improvement

initiative

• Risk to patient

• Risk to compliance

• Risk to business

Define an acceptable

level of risk

“Quantify” the level

of each risk

• Multidisciplinary

team assessment

Is risk at an

acceptable level?

• Yes –

can it be

further reduced to as

low as is reasonably

possible?

• No –

can measures be

put in place to reduce

this risk to an

acceptable level?

• Yes – risk is mitigated,

change can take place

• No – change or CI

initiative not acceptable

Overview of the QRM process

QRM Process Lifecycle & Communication (ICH Q9)

Keep line

management

informed

Risk assessments

teams:

Multi-disciplinary

membership

Knowledgeable QRM

facilitators

Results are formally reviewed

and approved (including by the

Quality Unit)

Periodic review to assess any

changes that could impact the risk

assessment

.

(3)

Define the Risk Question

The Risk Question needs to include:

Risk Factors

Results

Scope (Define what is in and out)

Example Risk Question:

What is the risk to patient safety, product quality and

compliance

of manufacturing different higher risk classes of

compounds

in a multiproduct facility?

Key Step - Choose Assessment Tool

Suitable for facilities,

equipment, and

processes.

Capable of assessing

process systems and

their physical and

operational

environments

Capable of

assessing

operational and

procedural controls

Selection based on

products/process/systems

knowledge

Consider product/process

expertise of team and

experience with QRM

Risk severity – do risks need to

be quantified, or is L/M/H

sufficient to determine a

course of action

Factors to Consider

Key Step - Determine Risk

Criteria & Scales

Probability

Severity

Detection

Risk to:

Patient

Compliance

Business

Scales

Low, Medium, High

1, 3, 5, 7, 10

1, 2, 3

Etc., Discretion of QRM Team

Examples only!

The QRM Team

will determine the

(4)

QRM Practical Application

Multi-Product Manufacturing or Inventory

Management Facility Cross Contamination

Control

Background

Why are we doing this?

Industry Regulatory Observations

Recent market regulations have

mandated the segregation or separation

of certain classes of compounds

manufactured in a multiproduct facility

(5)

Why are we doing this?

Facility Cross Contamination Statistics

Review of 2013 and 2014 FDA 483 observations

(non-company specific) reveal approximately 10% attributed

to cross contamination findings related to product

handling and storage, equipment, and/or facilities.*

Business Driver/Initiative

Our company needs a comprehensive risk-based

program to ensure that potential cross-contamination

and mix-up risks within multi-product facilities are

appropriately identified, systematically assessed and

controlled.

* -

(http://www.fda.gov/ICECI/Inspections/ucm381526.htm)

(http://www.fda.gov/ICECI/Inspections/ucm424098.htm)

Begin the Process

Global Alignment

• Identify global manufacturing/inventory management

locations. Review product class storage and inventory.

• Establish Project Leads/Facilitators from each location

and facility

• Initial facility assessments/walkthroughs

• Develop an assessment approach and template that is

consistent throughout all sites and facilities

• Form facility and site QRM teams and initiate the

process.

Begin the Process – Site & Facility Teams

• Select Team Members

• All participants should be trained in QRM SOPs prior to any QRM sessions,

including kickoff meeting.

• Give them Lunch!!

Experienced

QRM

Facilitator

Mfg Area

Compliance

Manufacturing

Engineer or

Coordinator

(may not be staffed for IM Facility)

Facilities

Expert

(Quick access to plans, P&IDs, HVAC, etc.)

Environmental

Health & Safety

(Industrial Hygiene Experience)

Shift Lead

(Production Expertise)

QA

(Specific Facility Quality Experience)

Process

Technician

Mfg Area

Manager

(6)

Begin the Education Process

Cross Contamination

Need a risk assessment to

determine how to balance:

Processes sharing of

common facility areas

or equipment (e.g.,

reactors, raw material

storage, personnel,

support areas, etc.)

Prevention of

potential

cross-contamination

through process

containment and

facility design and

controls

Begin the Process

Documents Needed to Get Started

• Facility Design Documents

Facility Diagrams (flows, HVAC plans, etc.)

PFDs (Process Flow Diagrams)

• Key Facility Operating SOPs including:

Procedures governing open operations

Cleaning and inactivation SOPs (including spill

response)

Facility & surface sanitization SOPs

Changeover SOPs

Maintenance

• Maintenance/Calibration Vendor Practices

Detailed information will need to be gathered to ensure

the assessments are both effective and comprehensive

Cross-contamination – how it happens

Cross contamination between processes is dependent upon three events

occurring together:

Approach: prevent or control each of these events so

that the “equation” cannot be satisfied

Transport

Unintended carriage of hazards

between manufacturing areas via

flow of materials, product,

equipment, personnel, waste etc.

across doorways, through

piping, pass-throughs, etc.

Release

Unintended hazard

release from spills,

open operations,

material mix-ups,

waste, etc.

Ingress

Unintended hazard ingress

into a receiving process due

to breach of system closure,

material additions, open

(7)

How does material escape? Determine facility boundary and scope of

operations

Components

– physical items or pathways that could intentionally or

inadvertently carry product or materials throughout the facility, i.e., how

material carried is out

Air (HVAC)

Sampling

Cleaning

Personnel

Equipment

Packaging

Materials

Utilities

Warehouse Operations

Waste

Dispening/Weighing

Assessment of Facility Interfaces

Hazop Tool

HAZOP is based on a theory that assumes

risk events are caused by deviations from

design or operating intentions

Break up processes into individual steps

for analysis

Risk Identification: Identify deviations

from design or operating intentions in a

systematic fashion

Similar to a “what if?” analysis

Hazard

Operability

Analysis

(HAZOP)

chosen as the

primary risk

assessment

tool

Risk Analysis: Risk Rating System

Likelihood of Deviation Occurrence

Low:

Hazard condition or contamination event not common or expected,

but theoretically possible.

Medium:

Hazard condition or contamination event is not a routine

occurrence, but has been observed.

High:

Hazard condition or contamination event is likely, common, or

observed routinely.

Note:

The rating scales may be customized for each manufacturing

facility as applicable

LOW

MEDIUM

(8)

Risk Analysis: Risk Rating System

Severity of Deviation Consequences

Low:

No product impact anticipated.

Medium:

Direct impact on assessed component elevated, yet not

anticipated to have product impact.

High:

Direct impact on assessed component is high or product impact

likely. Direct ingress of contamination directly into product or product

components (includes non-product areas, solutions and equipment).

Note: The rating scales may be customized for each manufacturing facility as

applicable

LOW

MEDIUM

HIGH

Evaluate Mitigated Risk

High

High

Medium

Medium

Low

Low

Severity

L

ik

e

lih

o

o

d

No Action

Required

One or More

Controls

Required

One or More

Controls

Required

More Than

One

Control

Required

More Than

One

Control

Required

More Than

One

Control

Required

More Than

One

Control

Required

More Than

One

Control

Required

Engineering

Or Design

Control

Required

Controls may be procedural,

training, or engineering / facility

design controls and may

consider the ability to detect

deviations or hazard

components as part of a

mitigating control

(9)

Facility Assessments – GMP Facilities

API

Manufacturing

Area

API Manufacturing

Area 2

(Chromatography)

Solid Dose

Manufacturing

Inventory

Management

Small

Pack/Label

Facility

Liquid Dose

Manufacturing

Facility Assessments – Hazard Classes

Product Classifications in Scope of the QRM– creating the business

case for each facility

“Highly Sensitizing Products”

“Certain Antibiotics”

“Radiopharmaceuticals”

“Certain Highly Active or Toxic Products”

“Certain Steroids”

“Cytotoxics”

“Certain Hormones”

“Immunosuppressors”

“Biologicals”

“Exclusive For Animal Use”

“Non-Medicinal Products”

(pesticides, herbicides)

“Other”

“Not Yet Classifiable”

Product Classifications out of Scope

Segregation Categories

Dedicated Building (For Product Class)

Physically separate building which provides complete and total

separation of all aspects of all operations.

Dedicated Segregated Areas (For Product Class)

Areas within a multiproduct facility dedicated to a product class.

Campaign Segregation

Segregated areas within a multiproduct facility that are used for more

than one product class that require segregation. More than one

product class cannot be processed at the same time. Campaign

segregation is referred to as segregation by time. Validated cleaning

and/or inactivation procedures should be established.

(10)

Facility Assessments –

Facility

and Process Mapping

Facility Interface Example – Defines Boundary

Facility Assessments –

Risk Table

Two Facility Interfaces

• Manufacturing Areas

• Annex (Milling, Storage of raw materials)

and intermediates

Each evaluated based on the following

pathways (components):

For both facilities, 60 operations (elements) evaluated

For both facilities, 90 deviations evaluated

Warehouse Ops

Packaging

Sampling

In-Process Sampling

Dispensing/Weighing HVAC

Manufacturing

Personnel

Example Risk Table

(11)

Facility

Interface Component Element Deviations Possible CausesSafeguards (controls) Probability of Occurrence Seve-rity of Conse-quences Comments/ Risk Evaluation Recom-mended Actions Annex (Labs, Milling, Raw Material Storage, Inter-mediate Storage, Dispen-sing) Manu-facturing Use of Mill Room Airborne Transfer to outside areas Milling Operation

Engineering controls, HVAC system design/preventive maintenance High Med

Reference API Plant and Milling Operations Industrial Hygiene (IH) Surrogate Testing Consider alternative milling area, consider lock out facility entrance during milling Open mill charge Engineering controls, PPE High Low

Unloading mill Engineering controls, PPE High Low Engineering control

failure (i.e., inadequate design)

Visual indication, gage monitoring, batch record

verification Med Low Operations would stop Spillage Open Mill Charge Procedure, engineering controls, PPE Low Low

Human Transfer

Open Mill Charge Procedure, engineering controls, PPE Low Low

No anteroom, improper gowning, improper personnel flow, insufficient training Mfg SOPs, technician

training, PPE High High Potential gap, Swab and air test results to be reviewed to confirm Prob of Occurance/ Severity, IH Surrogate Testing Suggest two person operation at all time to aide in PPE decon Reuse of PPE (i.e.,

hood) Procedures (disposal) Med Low Labeling Errors Human Error Second person verification Low Low Equipment

Transfer Open mill charge contaminating balance carts, scoop, containers

Cleaning procedure, material handling procedure (SOI-GR-API-EQP-1044), engineering control, PPE controls

Low Low

Engineering/ Facility Controls Failure

Inadequate design (i.e., open tray charge)

Procedures, cleaning,

training, PPE Low Med Power Failure Visual indication, gage monitoring, Groton site control

room notification

Med Med Magnehelic gauge installation

Facility

Interface

Component

Element: Use of Mill Room

Annex

Manufacturing

Deviation:

Airborne Transfer to outside areas

Possible Causes:

Milling Operations

Safeguards:

Engineering controls, HVAC system design/preventive

maintenance

Probability of Occurrence:

High

Severity of Consequences:

Medium

Comments/Risk Evaluations:

Reference API Plant and Milling Operations Industrial Hygiene

(IH) Surrogate Testing

Recommended Action:

Consider alternative milling area, consider lock out facility

entrance during milling

Facility

Interface

Component

Element: Use of Mill Room

Annex

Manufacturing

Deviation:

Human Transfer

Possible Causes:

No anteroom, improper gowning, improper personnel flow,

insufficient training

Safeguards:

MFG & Cleaning SOPs, Technician Training, PPE

Probability of Occurrence:

High

Severity of Consequences:

High

Comments/Risk Evaluations:

Potential gap, Swab and air test results to be reviewed to

confirm Prob of Occurance/Severity, IH Surrogate Testing

Recommended Action:

(12)

Example Risk Table

API Manufacturing – HVAC

Facility

Interface Component Element Deviations Possible Causes Safeguards (controls) Probabi-lity of Occurre nce Severity of Conse-quences Com-ments/ Risk Evalua-tion Recommended Actions Manu-facturing Area HVAC Air Balancing in Mfg Area

Incorrect

pressure

differentials

result in

migration of

product

from one

Reactor

suite to

hallway or

to another

suite

Makeup/

Supply air

and exhaust

air not

balanced,

system

malfunction

Room balancing is

checked and

certified every 3

years. All

charging is done in

closed hood that

has its own

downflow and

exhaust.

Preventive

maintenance

High

Medium

3 years is

not

sufficient

frequency

to

perform

balancing.

Improve/correct air balance.

Increase frequency of

balance testing and

certification. Provide a clear

status of air pressure at each

room, i.e., individual

magnehelic gauges with

transmitters to allow display

of pressure in hallways,

alarms, etc. Allows for

detectability. Recommend

conducting smoke test.

Incorrect

pressure

differentials

result in

migration of

product

from Dryer

suites to

another

Dryer suite

(134C and

134D) or

129B (and

Processing

Suites)

Current air

balancing has

134C positive,

134D neutral,

and 134B

(common

general

purpose area)

neutral. All 3

rooms

negative to

airlock 134A.

Supply air in

134C higher

flow than

HEPA

exhaust.

Room balancing is

checked and

certified every 3

years. Current

measurement

show air flow out

of balance. Open

solids handling

takes place

directly in front of

HEPA exhaust

(cross flow

exhaust?)

High

High

Positive

pressure

from 134C

could

result in

product

migration

into

general

purpose

area

(134B) and

possibly

134D

dryer

suite.

Recommend conducting

smoke test.

(13)

Facility

Interface

Compo-

nent

Element: Air Balancing in Manufacturing Area

Mfg Area HVAC

Deviation:

Incorrect pressure differentials result in migration of product from one

Reactor suite to hallway or to another suite

Possible Causes:

Makeup/Supply air and exhaust air not balanced, system malfunction

Safeguards:

Room balancing is checked and certified every 3 years. All charging is done

in closed hood that has its own downflow and exhaust. Preventive

maintenance

Probability of Occurrence:

High

Severity of Consequences:

Medium

Comments/Risk Evaluations:

3 years is not sufficient frequency to perform balancing

Recommended Action:

Improve/correct air balance. Increase frequency of balance testing and

certification. Provide a clear status of air pressure at each room, i.e.,

individual magnehelic gauges with transmitters to allow display of pressure

in hallways, alarms, etc. Allows for detectability. Recommend conducting

smoke test.

Facility Interface

Compo-nent Element Deviations Possible Causes Safeguards (controls) Proba-bility of Occur-rence Severity of Conse-quences Comments/ Risk Evaluation Recom-mended Actions Manu-facturing Area HVAC

Cross

contamination

between

Walk-in hood and

Lab hood and

Hallway 129B

One of the exhaust

fans shuts down

Power

failure

Hoods are far

enough away to

avoid migration

from one to

another. This

was confirmed

by recent air

measurements.

According to

HVAC SME,

makeup air

handlers shut

down when

exhaust fans

shut down.

Low

-Could

change

based

on

Exhaust

and

Supply

air data

Low

-Could

change

based on

Exh. and

Supply

data

Confirm the following:

Mfg Rm 1: EF-1 shuts

down and SF-3 shuts

down.

Mfg Rm 2: EF-2 shuts

down and SF-3 shuts

down.

Mfg Rm 3: EF-3 shuts

down and SF-3 shuts

down.

Dry. Rms: EF-4 shuts down

and SF-3 shuts down.

132 (Subd. Rm.): EF-5

shuts down SF-5 shuts

down.

And vice versa for all

above scenarios.

Recommend

conducting

smoke test.

Air Balancing

at outside

hallway and

entry "airlock"

Outside hallway

pressure is higher

than airlock.

Outside hallway is

exposed to

outside conditions

via an overhead

door. Potential

for dirt, dust, etc.

to migrate

through airlock

and into all Mfg

Area rooms

Air

Imbalance,

pressure in

oustide

hallway too

high. Both

doors to

airlock open

at the same

time (not a

true airlock)

None, other

than open

reactors only in

hoods. Any

product in the

outside

hallway is in

secondary

containment or

drummed or

shrink

wrapped, etc.

High

Medium

Not a true cross

contamination issue, but

critical quality issue due

to the high probability of

dust and debris impacting

product.

Reestablish

as a true

airlock, i.e.,

doors

interlocked

to open one

at a time.

Recommend

conducting

smoke test.

(14)

Facility

Interface

Component Element: Air Balancing at outside hallway and entry “airlock”

Manufacturing

Area

HVAC

Deviation:

Outside hallway pressure is higher than airlock. Outside hallway is

exposed to outside conditions via an overhead door. Potential for dirt,

dust, etc. to migrate through airlock and into all Mfg Area rooms.

Possible Causes:

Air Imbalance, pressure in oustide hallway too high. Both doors to

airlock open at the same time (not a true airlock)

Safeguards:

None, other than open reactors only in hoods. Any product in the

outside hallway is in secondary containment or drummed or shrink

wrapped, etc.

Probability of Occurrence:

High

Severity of Consequences:

Medium

Comments/Risk Evaluations:

Not a true cross contamination issue, but critical quality issue due to the

high probability of dust and debris impacting product

Recommended Action:

Reestablish as a true airlock, i.e., doors interlocked to open one at a

time. Recommend conducting smoke test.

Facility Assessments

35 operations (elements) evaluated

55 deviations evaluated for all facility interfaces

Six Facility Interfaces

Manufacturing Rooms (with and without Misting Showers)

In Process Testing Room

Hallway-type Rooms (No Open Product)

Gown/Degown Rooms for GMP Area

Wash Rooms

Clean Equipment (No product)

Each evaluated based on the following pathways

(components):

Warehouse Ops

Packaging

Sampling

In-Process Sampling

Dispensing/Weighing HVAC

Manufacturing

Personnel

Facility Assessments

Four Facility Interfaces

• Warehouse Area

• Dispensing Booths

• Handoff Areas

• Sampling Areas (future)

Each evaluated based on the following

pathways (components):

Warehouse Ops

Packaging

Sampling

In-Process Sampling

Dispensing/Weighing HVAC

Manufacturing

Personnel

For both facilities,15 conditions (elements) evaluated

For both facilities, 25 deviations evaluated

(15)

Write the Report

What’s Required

Team members

Scope

Scope

Executive Summary

(ES) of Results

QRM Methodology

& Assumptions

Action Item Table

in ES

Periodic Review

Interval

Working Group

Table (Attachment)

References

Summary/Lessons Learned

Obtain Management support up front.

Consider resource utilization

Make sure facility drawings are current for layout and HVAC.

Line up HVAC expert early as this expertise is very important

and can be overlooked when forming the team.

Be specific with scope and risk question.

Facilitator must be energetic and continue to

challenge the group and maintain energy level

Use an agreed upon QRM tool.

Summary/Lessons Learned

Choose report author up front.

Minimize sessions by employing full day

meetings if possible.

Lunch and Coffee!!

Management and approver signatures

predetermined (should be in QRM SOP)

Actions item responsibilities

well defined, with timetables.

(16)

Any Questions

(17)

Additional Facility

Assessment Tables

Facility Assessments –

Risk Table

Example – Drug Product Manufacturing

Facility Interface Component Element Deviations Possible Causes Safeguards (controls) Probability of Occurrence Severity of Conse-quences Com-ments/ Risk Evalua-tion Actions Recom-mended for Contain-ment Manufacturing Rooms (with and without Misting Showers) Manufacturing Manufacturing and Open Transfers Open product is transferred to bin (elephant trunk). API sieving.

Product leak Improper transfer technique, product bag rips, bin valve left open.

Experienced technicians, training, all sieves are one time use, then discarded. Only larger sieves that are dedicated to a product are cleaned and tracked as dedicated to that product. Any leaks are immediately cleaned up.

Low Low

Cleaning Cleaning Validation Cleaning Validation Data not available Cleaning Validation Product Assesment (CVPA) checked everytime product is used. ADE values and swab sampling measures assessed as part of CVPA. CVPA Reversioned if toxicity information or classification changes. No notification if classification changes until next use, however QRM assessment is performed to determine risk of products previously manufactured. SOPs in place for individual pieces of equipment. Low Low Marginal solubility increases severity. High solubility would have rinsed off. Low solubility would have been swabbed Consider improved notification from EHS or Master Planner to facility (internal and external coordina-tors when a product classifica-tion changes

Facility Assessments –

Risk Table

Example – Drug Product Manufacturing

Facility Interface Component Element Deviations Possible Causes Safeguards (controls) Probability of Occurrence Severity of Conse-quences Com-ments/ Risk Evalua-tion Actions Recom-mended for Contain-ment Manufacturing Rooms (with and without Misting Showers) Manufacturing Closed contained mfg process, closed transfer to mill Leakage during manufacturing, Transfer sleeve tears during bin to mill transfer

Human error, equipment malfunction, tear in flexible transition piece from one piece of equipment to another, mill screen plugs. Overpressurization /material weakness during transfer to a mill. Sleeve not properly attached

Equipment visually inspected, equipment always under observation, equipment is stopped in case of leak, personnel in PPE within mfg module, processing rooms negative to air locks and corridor. Airflow designed to keep product low and away from clean corridor. Any spill would be cleaned following spill. Technician air shower and PPE removal prior to clean corridor entry. All equipment is cleaned within the module prior to exit. Cleaning is validated or swabbing is performed for compounds with solubility outside of validated range.

(18)

Facility Assessments –

Risk Table

Example – Inventory Management Facility

Facility Interface Component Element Deviations Possible Causes Safeguards (controls) Probability of Occurrence Severity of Conse-quences Com-ments/ Risk Evalua-tion Actions Recom-mended for Containment

Dispensing BoothsSampling Dispensing RoomProduct carried over after sampling and before first wipedown.Product retained on PPE

Minimal quantity of product is sampled/subdivided. Downflow booth minimizes dust that would be on PPE. SOPs and trained technicians minimize product on PPE. Only one material allowed in Subdivision room at a time. Visual wipe down after each subdivision of materials for the same batch, full cleandown between each batch. Sampled product and sample containers move from Dispensing Booth to Airlock. Is not staged post Sampling/Dispensing in Dispensing Room. Low Low Scoops, weigh boat, disposed in Booth, gloves removed after sampling, and new gloves donned for first wipedown, containers wiped 3X before removed from booth. Consider use of disposable sleeves for sampling/dispe nsing.

Other QRM Tools Considered

Failure Modes and Effects (&

Criticality) Analysis – FMEA/FMECA

Fault Tree Analysis – FTA

Hazard Analysis and Critical Control

Points - HACCP

Preliminary Hazard Analysis (PHA)

Risk Ranking and Filtering

References

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