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?
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
.
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
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
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
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
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
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
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.
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
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:
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.
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.
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
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.
Any Questions
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.
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.