Pharmaceutical Engineering Forum 28 Jan 2017 (135 Slides)

F O R U M O B J E C T I V E
To provide a strong
foundation of
interface among
multidisciplinary
teams capable to
talk in language of
science without
confusion
To provide opportunity of
discussion and transfer of
knowledge among
pharmaceutical professionals
of multidisciplinary
educational background
A platform for
engineers to
exchange
knowledge and
learn expanding
regulatory
expectations

Thanks All of you &
Team
Almas, Noman, Zainab and Esther
Ref: USFDA, ISPE, WHO

Discussion Forum on
Pharmaceutical Engineering
(Designing & Maintenance of Pharmaceutical Manufacturing Facilities)
Forum’s Opening talk
Roohi B. Obaid, Deputy Director,
Drug Regulatory Authority of Pakistan

Not the view of
DRAP
Current
judgment of
speaker
No obligation
on DRAP
Regulatory
experience
It has nothing to do
with any specific
commercial
product
It is just a
knowledge sharing
exercise nothing
more than that
D
I
S
C
L
A
I
M
E
R

Science Regulation Quality
Designing & Maintenance of Pharmaceutical Manufacturing Facilities
What, Why & How

What will happen if design is not
part of GMP standards???
Discuss and enlist

Prevent
Contamination & mix up

What will happen if Cleaning & Maintenance
is not part of GMP standards???
Discuss and enlist

Lets think
In a working room air supply and exit both are on the
ceiling at two different terminals
How can we make it efficient and compliant

Insanitary Condition & Contamination
Microorganisms, dust, dirt, chemicals

Can we design/outline a Raw Material Store?
Please indicate Men Flow & Material Flow

Can we design/outline a sampling facility in
Raw Material Store?
Please indicate Men Flow & Material Flow

Discussion Forum on
(Designing & Maintenance of Pharmaceutical Manufacturing Facilities)
Obaid Ali, R. Ph., Ph. D.
28 Jan 2017

Element Component
QUALITTY
G.M.P.

Design and Construction
Size Cleaning Maintenance Operation
Construction Location

Movements & Flow
Holding & Stocking
Process & Equipment

Mix up
Confusion
Contamination

Contamination & Mix up
Controls
Separate Area
Defined Areas

Receipt, ID, Storage and withholding from use
of components, drug product containers,
closures & labeling pending QC sampling,
testing or examination

Holding rejected components, drug product
containers, closures & labeling before
disposition

Storage of released components, drug product
containers, closures & labeling

Storage of in-process materials

Manufacturing & processing operations

Packaging & labeling operations

Quarantine storage before release of drug
products

Storage of drug products after release

Control and laboratory operations

Contamination
Aseptic Processing
Easily cleanable floors, walls, ceiling of smooth hard surfaces
Temperature & humidity controls
An air supply filtered through HEPA under +ve pressure,
irrespective off whether flow is laminar or non-laminar

HEPA & Pressure Differential Control

Avoiding Contamination/Cross-contamination
HEPA
Filter
Efficiency
testing
Integrity
testing

Avoiding Cross-Contamination (Pressure Differential Control)
Pressurization
Between
environments
From adjacent
areas into
production

Pressure gradients provide critical environments with higher
pressures than less critical areas
Sweeps contaminants
away from work surface
area
Provides pressure
cascade

High pressure areas
receive more air
supply and less air
exhaust
Difference in air pressure
between areas should be
adequate to maintain desired
direction of air flow
Pressure differentials should be measured with
doors open and closed

Positive air
pressure
Prevents ingress
of contaminants
from
less clean area

Negative air
pressure
Containment or
prevention of
dispersion of
sensitive or highly
toxic materials

Avoiding Cross-Contamination
(Unidirectional or Laminar air flow)
An air flow moving in a single direction, in a robust &
uniform manner, and at sufficient speed to reproducibly
sweep particles away from the critical processing or
testing area

Avoiding Cross-Contamination
(Non-unidirectional or Turbulent air flow)
An air flow that does not meet the definition of
unidirectional airflow
Edges Solid flat surfaces
Person or equipment
moving

Contamination
Aseptic Processing
A system for monitoring environmental conditions
As
Built
At Rest At Operation (Dynamic)

Controlled with respect to
Air borne particles
Viable Non-viable

Temperature
Humidity

Air Pressure
Air Flow

Air Motion
Lighting

A
S
B
U
I
L
T
Complete and ready for operation, with all
services connected and functional
But without equipment & operating personnel

A
S
B
U
I
L
T
With very low particle counts
Reflects quality of supply air & removal efficiency
of the HVAC system

A
T
R
E
S
T
Complete and with all services functional,
with equipment installed and operable
But without operating personnel

Smoke testing should demonstrate unidirectional air
flow over critical equipment surfaces
In case of air disturbance, ADJUST;
A
T
R
E
S
T Equipment Placement Air Velocities

With all services functioning & with
equipment and personnel performing
normal work functions
A
T
O
P
E
R
A
T
I
O
N

Validation studies should demonstrate
that Class 100 is maintained in critical
zones during routine operations
A
T
O
P
E
R
A
T
I
O
N

Contamination
Aseptic Processing
A system for cleaning & disinfecting
Room Equipments
To provide aseptic
conditions

Contamination
Aseptic Processing
A system for maintaining any equipment used to control the
aseptic conditions
Ventilation Air filtration Heating Cooling

Contamination
Aseptic Processing
aseptic conditions
Sewage/ Refuses Washing/ Toilet Sanitation

Contamination
Aseptic Processing
aseptic conditions
Plumbing MaintenanceLighting

Plumbing, Sewage & Refuses, Washing & Toilets

Contamination
Aseptic Processing
A system for maintaining any equipment used to control the aseptic conditions
Potable water supplied under continuous positive
pressure in Plumbing System (free of defects that could
contribute to product contamination)

Contamination
Aseptic Processing
Adequately sized & designed drains (air break or
mechanical device) to prevent back siphoning

Contamination
Aseptic Processing
Safe/ sanitary disposal of sewage, trash & other refuses

Contamination
Aseptic Processing
Building maintained in clean/sanitary condition
Free of infestation by rodents, birds, insects etc.

Contamination
Aseptic Processing
Trash & organic waste held and disposed off in a
timely & sanitary manner
Building maintained in clean/sanitary condition

Contamination
Aseptic Processing
Sanitation Procedure & Program
(schedule, method, equipment materials for
cleaning of building & facilities)

Contamination
Aseptic Processing
Formal Procedure for
(use of suitable rodenticides, insecticides, fuungicides,
fumigation agents & cleaning and sanitization agents to
prevent contamination)

Contamination
Aseptic Processing
Sanitation Procedure for
(contractors & temporary employees as well as full
time employees during the operations)

Production
cleaning
procedures
Data
Laboratory
procedures
Data

How clean is clean?
Test until clean
It is not considered Cleaning Validation

The plant is not constructed in such a manner as to allow
floor or walls or ceiling to be adequately cleaned and kept
clean or kept in a good state of repair
Floor, Walls & Ceiling

Failure to maintain building, fixtures or other physical
facilities in a sanitary condition
Building/ Sanitary

Failure to provide hand washing or hand sanitizing
facilities at each location in the plant where needed
Suitable Location

Lack of drainage in area that may contribute to
contamination
Drainage

Plumbing is not of adequate size and design or adequately
installed & maintained to provide adequate drainage
Drainage

Plumbing is not of adequate size and design or adequately
installed & maintained to properly convey sewage & liquid
disposal waste
Conveying of Sewage

Not adequate or convenient to furnish running water at a
suitable temperature
Hand Washing Facility

Did not maintain plant in repair sufficient to prevent
components or contact surfaces from becoming
contaminated
Physical Plant

Working space between equipment and walls are
obstructed or inadequate
Spacing of Equipment

Some examples from FDA Warning letters

Adequate unidirectional airflow studies (smoke
studies) under dynamic conditions are not
performed to determine
how the movement of air & personnel
during aseptic operations could pose risks to
product sterility e.g.
Failure to perform appropriate smoke studies
Sun Pharmaceuticals, India Dec 2015

Significant airflow turbulence, including air moving in a
direction in the laminar air flow unit in which aseptic & tubing
connections are made
No dynamic smoke studies to demonstrate unidirectional air flow
during the manual aseptic transfer of xxx units into the xxx used
for transport to the xxx

Inadequate evaluation of airflow patterns in stopper xxx area,
and turbulence around the stopper xxx.
Lack of smoke studies during aseptic filling line setup activities

Lesson
learned
Without smoke study data to
demonstrate unidirectional
airflows over all aseptic
operations and processing steps,
you cannot show that your
processes are designed to prevent
microbiological contamination or
provide adequate assurance of
product sterility

The floors, walls, and ceilings were not maintained as smooth, hard
surfaces that were easily cleaned. The leaks were present in the form of
water stains and ceiling damage in the Parenteral manufacturing area
personnel corridor.
Buckets with water collected from ceiling leaks and other leaks in the
manufacturing area were observed.
Failure to maintain Aseptic processing Area
Sun Pharmaceuticals, India Dec 2015

Lesson learned
Failure to address environmental control
Leaks in the area could compromise the quality of
aseptically filled products

Inadequate disinfection of RABS e.g. surface xxx
not routinely disinfected, and the the bottom of
the RABS xxx incompletely disinfected
Failure to qualify Disinfectant
CP Pharmaceuticals, UK, Nov 2016

The efficacy of disinfectants used in aseptic processing
cleanrooms have not been sufficiently established. The
disinfectant study only challenged xxx & xxx manufacturing
surfaces. An adequate scientific rationale for not challenging
other representative surfaces, such as glass windowsor other
interior RABS surfaces is not provided
CP Pharmaceuticals, UK, Nov 2016

Qualification of disinfectant xxx failed to demonstrate that it is
suitable and effective to remove microorganisms from
different surfaces. Specifically, the disinfectant failed to meet
qualification criteria when challenged with multiple
organisms
SmithKline Beecham, UK, Oct 2011

However, the procedures for routine cleaning of the aseptic manufacturing area continue to require the
use of unqualified disinfectants during days xxx through xxx of your disinfectant program.
After disinfection, Micrococcus luteus on vinyl, stainless steel, glass, and wall laminate and
Enterobacter cloacae, Rhodococcus sp, Burkholderia cepacia, Pseudomonas aeruginosa,
Methylobacterium mesophilicum and, Acinetobacter lwoffi on glass were recovered.
Disinfectant qualification for xxx and xxx bi-spore disinfectants documented that the log reduction
criteria (Bacteria ≥ 4, Fungi ≥ 3) was not met when challenged with multiple organisms in a variety of
surfaces.

Hands-on exercise: HVAC systems –
assessment of facility layout

WHAT DO YOU HAVE TO DO?:
•  to modify layout
•  to establish classification and/or T/RH conditions
•  to establish differential pressure (flow)
•  to establish differential pressure (D or values)
HOW DO YOU HAVE TO DO?
•  to discuss in team work (brainstorming)
•  to elect a “speaker”
•  to show groups feedback

SOME TIPS:
 layout: 5 rooms have to be modified
 classification: starting classification from class A/B
 T/RH conditions: 1 room needs RH monitoring
 differential pressure: establishing the pressure direction from A/B
class
 values of differential pressure: considering 10 Pa difference for
different classes A-B / C / D / N.C.

MAL = Material Air Lock
PAL = Personnel Air Lock
1. To modify layout
LAF

2. To establish classification
LAF

N.C.
A / B
LAF
ENTRANCE

N.C.
A / B
B
C
D
D D
C
B
D
DN.C.
N.C.
N.C.
LAF
ENTRANCE

N.C.
A / B
B
C
D
D D
C
B
D
DN.C.
N.C.
N.C.
D
D
DD
DD
D
D
N.C.
D
LAF
ENTRANCE

2. To establish T/RH conditions
N.C.
A / B
B
C
D
D D
C
B
D
DN.C.
N.C.
N.C.
D
D
DD
DD
D
D
N.C.
D
21°C – 30%RH
LAF
ENTRANCE

3. To establish differential pressure (flow)
N.C.
A / B
B
C
D
D D
C
B
D
DN.C.
N.C.
N.C.
D
D
DD
DD
D
D
N.C.
D
21°C – 30%RH
LAF
ENTRANCE

109
N.C.
A / B
B
C
D
D D
C
B
D
DN.C.
N.C.
N.C.
D
D
DD
DD
D
D
N.C.
D
21°C – 30%RH
LAF
ENTRANCE

110
N.C.
A / B
B
C
D
D D
C
B
D
DN.C.
N.C.
N.C.
D
D
DD
DD
D
D
N.C.
D
21°C – 30%RH
LAF
ENTRANCE

0 Pa
10 Pa
20 Pa
30 Pa
40 Pa
50 Pa 60 Pa
4. To establish differential pressure (values)
LAF

Modified lay-out
LAF

If you add any new
product
Its impact on other
products need to be
understood and
evaluated
Building Facility

Construction of new
walls, installation of
new equipment, etc.
Impact on overall
compliance
Cleaning
efficiency
Sanitation
Dust
particle
traveling

If earthquake shock of 5 RS occurs, ….
what we have to do???
Lets think

Design Review
Pre-construction
Review
Construction
Review
Equipment
Qualification Review
Pre-Production
Review

Design
Reviews
Conceptual
Design
Proposed
Plant Layout
Facility
Flow
Diagram
Critical
System &
Areas

Pre construction Reviews
Planned evaluation
& Isometric drawing
for all
manufacturing areas
& utility & process
system for the plant
Drainage
& Water
Systems
HVAC Equipment
Layout &
Piping

Construction & Qualification Reviews
On-site review of
specific portion of
plant while
constrcution is in
progress
Piping
System
Method of
Construction
Reviewed
before they
are
concealed
Etc.

Pre-Production Reviews
Personnel flow
is very
important
Personnel
Clean
Personnel
Transfer
Personnel
Exit

Airlock
Transition
Spaces
Gowning

Airlock
Provides
segregation of
cleanliness
levels
Airlock
Achieved by maintaining
room pressurization by
through doors and isolating
the levels from each other

Scenarios exist when gowning occurs but a
change of air classification does not. e.g. a
multiproduct facility where containment is
crucial
Nature of process dictates adding more
coverage or possibly a change of garments
Change in air classification leads to a
gowning activity
Gowning

In any case, a garment adjustment is necessary
when moving to a new zone
While leaving a cleanliness zone, the potential
to carry contaminants out of the higher air
classification must also be considered.
Gowning

TransitionSpaces
They are airlocks but
there is no change in
cleanliness level
Air classification on both
sides is same but
necessary to maintain
pressurization and
TransitionSpaces
e.g. where containment is
required, in dusty
operations in a oral solid
dosage facility
Transition space allows
for containment within
the process room through
the control of
pressurization and the

Air Arrest … Control and
Restrict movement
Air pressurization
Door exist
Cleanliness
C
O
N
T
A
M
I
N
A
T
I
O
N

B: No direct contact
G: Possibility of indirect contact
W: Direct contact
Materials
Machine

Pharmaceutical Engineering Forum 28 Jan 2017 (135 Slides)

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Pharmaceutical Engineering Forum 28 Jan 2017 (135 Slides)