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 talkRoohi 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

DISCLAI

MER

Science Regulation Quality

Pharmaceutical EngineeringDesigning & Maintenance of Pharmaceutical Manufacturing Facilities

What, Why & How

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

Discuss and enlist

Confusionin

Flow & Holding

Prevent

Contamination & mix up

DIFFICULTIES

What will happen if Cleaning & Maintenanceis not part of GMP standards???

Discuss and enlist

Lets thinkIn 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

Pharmaceutical Engineering(Designing & Maintenance of Pharmaceutical Manufacturing Facilities)

Obaid Ali, R. Ph., Ph. D.28 Jan 2017

Element Component

QUALITTYG.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 ProcessingEasily cleanable floors, walls, ceiling of smooth hard surfaces

Temperature & humidity controlsAn 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 ProcessingA system for monitoring environmental conditions

As Built At Rest At Operation (Dynamic)

Clean Room

Controlled with respect to

Air borne particles

Viable Non-viable


Temperature

Humidity


Air Pressure

Air Flow


Air Motion

Lighting

AS

BUILT

Complete and ready for operation, with all services connected and functional

But without equipment & operating personnel

AS

BUILT

With very low particle counts

Reflects quality of supply air & removal efficiency of the HVAC system

AT

REST

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;

AT

REST Equipment Placement Air Velocities

With all services functioning & with equipment and personnel performing

normal work functionsAT

OPERATION

Validation studies should demonstrate that Class 100 is maintained in critical

zones during routine operationsAT

OPERATION

Contamination

Aseptic ProcessingA system for cleaning & disinfecting

Room Equipments To provide aseptic conditions

Contamination

Aseptic ProcessingA system for maintaining any equipment used to control the

aseptic conditions

Ventilation Air filtration Heating Cooling

Contamination


aseptic conditions

Sewage/ Refuses Washing/ Toilet Sanitation

Contamination


aseptic conditions

Plumbing MaintenanceLighting

Plumbing, Sewage & Refuses, Washing & Toilets

Contamination

Aseptic ProcessingA 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


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

Contamination


Safe/ sanitary disposal of sewage, trash & other refuses

Sanitation & Maintenance

Contamination


Building maintained in clean/sanitary condition

Free of infestation by rodents, birds, insects etc.

Contamination


Trash & organic waste held and disposed off in a timely & sanitary manner

Building maintained in clean/sanitary condition

Contamination


Sanitation Procedure & Program (schedule, method, equipment materials for

cleaning of building & facilities)

Contamination


Formal Procedure for(use of suitable rodenticides, insecticides, fuungicides, fumigation agents & cleaning and sanitization agents to

prevent contamination)

Contamination


Sanitation Procedure for(contractors & temporary employees as well as full

time employees during the operations)

Cleaning Validation

Production cleaning

proceduresData Laboratory

procedures Data

How clean is clean?

Test until cleanIt is not considered Cleaning Validation

Potential Observations

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.

1. To modify layout

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 / BB

C

D

D DC

B

D



DN.C.

N.C.

N.C.

LAF

ENTRANCE


N.C.

A / BB

C

D

D DC

B

D



DN.C.

N.C.

N.C.

D

DDD

DD

D

D

N.C.

D

LAF

ENTRANCE

2. To establish T/RH conditions

N.C.

A / BB

C

D

D DC

B

D



DN.C.

N.C.

N.C.

D

DDD

DD

D

D

N.C.

D

21°C – 30%RH

LAF

ENTRANCE

3. To establish differential pressure (flow)

N.C.

A / BB

C

D

D DC

B

D



DN.C.

N.C.

N.C.

D

DDD

DD

D

D

N.C.

D

21°C – 30%RH

LAF

ENTRANCE

109


N.C.

A / BB

C

D

D DC

B

D



DN.C.

N.C.

N.C.

D

DDD

DD

D

D

N.C.

D

21°C – 30%RH

LAF

ENTRANCE

110


N.C.

A / BB

C

D

D DC

B

D



DN.C.

N.C.

N.C.

D

DDD

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

SanitationDust

particle traveling

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

Lets think

Reviews

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 ReviewsPlanned 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

importantPersonnel

CleanPersonnel Transfer

Personnel Exit

Lets Resolve & Understand

Airlock

Transition Spaces

Gowning

AirlockProvides

segregation of cleanliness

levels

AirlockAchieved by maintaining room pressurization by

direction of air flow 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

Tran

sitio

n Sp

aces

They are airlocks but there is no change in cleanliness level

Air classification on both sides is same but necessary to maintain pressurization and direction of air flow

Tran

sitio

n Sp

aces 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 direction of air flow

Air Arrest … Control and Restrict movement

Air pressurization

Door exist

Cleanliness

CONTAMINATION

B: No direct contact

G: Possibility of indirect contact

W: Direct contact

Materials

Machine

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pharmaceutical engineering forum 28 jan 2017 (135 slides)

Leadership & Management