ISPE Tampa Conference

22-25 February 2010

Tampa, Florida USA

Potent Product Process and

Facility Design
S.C. Singhai
y Laboratories Ltd.
Dr. Reddys
23-02-2010

Safe Harbor Statement

This presentation includes forward-looking statements, as
d fi d in
defined
i the
th U.S.
U S Private
P i t Securities
S
iti Litigation
Liti ti
R f
Reform
A t off
Act
1995. We have based these forward-looking statements on our
current expectations and projections about future events. Such
statements involve known and unknown risks, uncertainties and
other factors that may cause actual results to differ materially.
Such factors include, but are not limited to, changes in local and
global economic conditions, our ability to successfully
implement
p
our strategy,
gy, the market acceptance
p
of and demand
for our products, our growth and expansion, technological
change and our exposure to market risks. By this nature, these
expectations and projections are only estimates and could be
materially different from actual results in the future.
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ISPE Tampa Conference

22-25 February 2010
Tampa, Florida USA

Our Businesses
Medium-Long Term Value Creation (Proprietary Products)

Near- Medium Term Value Creation

ISPE Tampa Conference

22-25 February 2010
Tampa, Florida USA

Infrastructure Bandwidth
API Facilities

Six FDA-Inspected plants in India

One FDA-Inspected plant in Mexico
One FDA-Inspected plant in Mirfield, UK
More than 2.3 million liters reaction volume

Finished Dosage
Units

Six in India, With ISO 14001 and ISO 9001

certifications, Approved by USFDA (2), MHRA
(UK), MCC (South Africa), TGA (Australia), ANVISA
(Brazil), TPP (Canada)
One FDA-Inspected plant in USA

Biologics Facility

One in India, multiple regulatory agency approvals

Custom
Pharmaceutical
Services

Two Technology Development Centers (TDC) in India and

One in Cambridge
Cambridge, UK

Discovery Research
Center

Hyderabad, India

Achievements
NDTV Profit Business Leadership Awards 2007
Business Leader in the Pharmaceutical Sector

Dun & Bradstreet American Express

Corporate Awards 2007

Best Corporate Social Responsibility Initiative

2007
BSE - India

Pharma Excellence Awards 2006-07 for

sustained Growth
The Indian Express

Best Employers in India 2007 Award

Hewitt Associates & The Economic Times

Asia-Pacific
Asia Pacific HRM Congress 2007
Global HR Excellence Award for Innovative HR
Practices

ISPE Tampa Conference

22-25 February 2010
Tampa, Florida USA

The views expressed here are personal and

does not represent the organization.

Agenda :

What is Potent ?
Relevance
Process Design Considerations
Facility & Equipment Design
Validation Requirements
Containment Systems Common Reasons For
Failure
Future Facilities
Summary
Q&A
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ISPE Tampa Conference

22-25 February 2010
Tampa, Florida USA

What is Potent ?
History
y dates back to 19th Century
y
A pharmacologically active ingredient in
dose of 1 mg or below
Needs special containment during
processing
Has OEL of at or below 10g/m3 of air
A novel compound of unknown potency
and toxicity
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Outline :

What is Potent
Relevance
Process Design Considerations
Facility & Equipment Design
Validation Requirements
Containment Systems Common Reasons For
Failure
Future Facilities
Summary
Q&A
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ISPE Tampa Conference

22-25 February 2010
Tampa, Florida USA

Relevance
Potent Drugs in the Pharma Industry
Pipeline have increased from 5% in
1980 to 20% in 2010

14

Growth Forecast
12

High-Potency APIs are estimated to

have an annual growth of 12%.

10

Currently around 5-10% of products on

the market contain HP-APIs.

$
Bn
6

Global sales of oncology drugs were $

34.6 billion in 2006 IMS Health.

Th
There are 300-400
300 400 highly
hi hl
potent
t t
compounds currently in production for
clinical evaluation or commercial
manufacture.

0
2004

2006

2008

2010

2012

2014

Year
11

Relevance
Investing in Potent compound manufacturing remains risky
Large capital investment required for manufacturing
High investment required prior to approval low chances of
commercial success & cannot predict the winners.
Duration of commercial success > 6 years
Containment requirement not confirmed until very late in
development Its a Late-Stage Decision
In early clinical, most sponsors will assume highest level of
containment in absence of data
Technologies to catch pace to handle specific issues involved
in processing.
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ISPE Tampa Conference

22-25 February 2010
Tampa, Florida USA

Outline :

What is Potent
Relevance
Process Design Considerations
Facility & Equipment Design
Validation Requirements
Containment Systems Common Reasons For
Failure
Future Facilities
Summary
Q&A
13

Process Design Considerations

Product category
g y
Dosage Form: Parental / Topical / OSD
Scale
Toxicological effect
Route of Ingestion
C t i
Containment
t risk
i k
Environmental impact
Regulations/Standards/Guidelines
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ISPE Tampa Conference

22-25 February 2010
Tampa, Florida USA

Process Design Considerations:

Design the Containment Solution based on;
Potency : Low, Medium, High, OEL / OEB
Dosage Form: Parental / Topical / OSD
Product Diffusion Capability : Aerosol generation, Powder
Spread
Activity Duration : Occasional of Shift based
Product Exposure : Open or Close
Process : Continuous or Batch

Design the process with less manipulation steps

Explore PAT Application
Less validation / routine samples
Sampling Issues
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Process Design Considerations

Assessing occupational exposure to workers
during actual operations involving the API.
Avoid Such Interventions (manualscrap down,
raking, changing contaminated or blocked parts
such as mill screens, extract samples, determine
process end points, perform cleaning).
Practical Dust control concept
Closed Material Handling
Cleaning Validation
Target Shirt Sleeve Operation
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ISPE Tampa Conference

22-25 February 2010
Tampa, Florida USA

OEL?
Airborne concentrations which will not result in
adverse effects in workers (8 hr/day, 40 hours/week,
Time Weighted Averages, TWAs)
Up to 50% of product OELs are at 10g/m3 (i.e.
OEB 4 or 5).
Blend will have different OEL than active alone.
Containment requirement - A Late Stage Decision
of development

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Containment Classification:

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ISPE Tampa Conference

22-25 February 2010
Tampa, Florida USA

Changing OEL Levels

OEL (g / m3)

120
100
80
60
40

10

20

0.03

-1

0
10

Years Back
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Risk Evaluation:
Product & Process Attribute

Low Risk

Process

Wet

High Risk
Dry
y

Particle Size

Coarse

Fine

Nature of Powder

Bulky

Fluffy / Micronized

Operation

Closed / Contained

Open

Activity

Static

Turbulent

Process Area / cabinet , pressure

Low

High

Material handling

Closed

Open

Experience

Relevant

None

Process Steps

One step / integrated

Multiple steps

Sampling

None

More

Cleaning

WIP / CIP

Open

Waste handling

Closed and 100%

Localized and Partial

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ISPE Tampa Conference

22-25 February 2010
Tampa, Florida USA

Outline :

What is Potent
Relevance
Process Design Considerations
Facility & Equipment Design
Validation Requirements
Containment Systems Common Reasons For
Failure
Future Facilities
Summary
Q&A
21

Facility Design
Established global shortage of high
containment manufacturing facilities
facilities.
Earlier the approach was separate rooms
with ve pressure and double air locks
with PPEs to prevent cross contamination
Recently the drive is towards shirt sleeve
operations because;
operations,
The PPEs are uncomfortable and lead to cross
contamination
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ISPE Tampa Conference

22-25 February 2010
Tampa, Florida USA

Facility Design Philosophy :

The facility shall be
designed to achieve the
following objectives:

Operator
Safety

Protection of Personnel
from Product exposure.
Protect the Product from
cross contamination
contamination.
Protection of Environment
from Product exposure

Environmental
En
i onmental
Safety

23

Facility Design Considerations :

Key Factors:
Product(s) to be Manufactured
Dedicated or Segregated facilities / equipment
Vs. Multiple-Product-Multi-Use Facilities
Operational Flows Personnel, Material,
Equipment
Minimize contamination & cross contamination
Clean room Vs. Isolator Technologies
HVAC Requirements
Ergonomics and safety
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12

Product
Safety

ISPE Tampa Conference

22-25 February 2010
Tampa, Florida USA

Current Regulatory Guidance on Facility

Requirements
As per FDA, EU-GMP, J-GMP, WHO-GMP & PIC/S GMP
P i illi D
S
t d facility
f ilit
Penicillin
Drugs
: Segregated
Cephalosporin
: Segregated facility as per
J-GMP, ICH-API GMP.
Campaign- FDA GMP.
Other -Lactams
: Campaign as per EU-GMP,
WHO-GMP, PIC/S GMP.
Some Hormones & : Campaign
HPAPIs
Note: Campaign is associated with appropriate cleaning validation.
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Facility Design Considerations

Facility:
Single Door to Corridor, No MAL or PAL (-ve Pressure)
PAL & MAL Single Chamber In-and-Out (-ve Pressure)
PAL & MAL Double Chamber In-and-Out (-ve Pressure
with Bubble and Sink Airlocks)

Process:
Open Process : -ve Pressure with Airlocks
Engineering Controls : LEV, Down-flow Booth, Isolator
Barrier System for Category 3 & 4.
Closed Integrated Process
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ISPE Tampa Conference

22-25 February 2010
Tampa, Florida USA

Facility Design Considerations

Recirculation of production area air into non-production
areas not permitted
Exhaust Air to be HEPA filtered and not to be re-circulated
Redundant HEPA Filters required in Certain Cases Eg:
Parenterals
Closed material handling and transfer
Gravitational transfer design preferred
Integrated
g
equipment
q p
or p
processors p
preferred
Split butterfly valves (SBVs) / Alpha-Beta ports for
transfers.
No Air showers. Mist/water showers are preferred.
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Containment Measures
Product
Protection

Personnel Protection

Independent Modules.
Properly designed
Gowning procedure.
Close handling Systems
(Isolators/ cRABS / Use of Space Suits.
PTS/ DCS)
Use of Exit showers/
Split valves/ RTP
Mistifiers.
Properly
designed
HVAC System
Use of PushPush Or
Safe Change Filters
CIP / WIP Systems

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14

Environmental
Protection
Properly designed HVAC
System
Isolators and cRABS
Appropriate
De
contamination & Disposal
Systems for solid &
Liquid waste.
Restricted
Personnel
Movement
Restricted
Material
Movement.

ISPE Tampa Conference

22-25 February 2010
Tampa, Florida USA

Type of containment
Primary
Containment

Secondary
Containment

Means non-exposure of Secondary containment

potent
product
from revolves around processing
equipment.
areas excluding equipment.
Equipment selection
criteria:
Product Nature : Solid /
Liquid.
Concentration of Product :
High / Low.
Operation type : Open /
Closed.
Method of De- toxification.

Includes following;
Specialized design of HVAC
System.
Proper sealing of processing
rooms i .e wall, ceiling etc.
P
pressure cascade
d
Proper
Use of bubble/sink air lock
Use of safe change/pushpush filters / scrubbers
PPEs

Emergency
Containment
Emergency containment
provisions
Emergency
decontamination shower.
Proper Spill Kit / misting
equipment to handle air
borne contamination.
Proper
cleaning
and
d i
drainage
system
t
with
ith
decontamination facility.

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Stage Wise Potent Material Handling

At Warehouse
Dispensing & Sifting
HPAPI dispensed & Sifted in Isolator.
Each
container
is
dispensed
completely in required lot sizes.
Sifted material is collected into bin
using SBV.
Wet Inside Isolator (WIP), then
remove for secondary cleaning.
cleaning
Washings collected into catch pot for
further treatment and disposal.

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ISPE Tampa Conference

22-25 February 2010
Tampa, Florida USA

Stage Wise Potent Material Handling

Granulation, Drying, Milling &
Blending
Transfer of material using SBV.
Granulation & Drying and dry milling in
Single Pot Processor
Discharge into Bin Blender via SBV
and Blend.
Use
U
PAT for
f End
E d point
i t (Torque,
(T
L
Loss
On Drying & Blend Uniformity).
Wash-In-Place / Clean-In-Place for the
equipment.
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Stage Wise Potent Material Handling

Compression / Capsule Filling
Charging of blend using SBV, from bin
blender
Chamber with ve Pressure
Auto rejection, sampling systems and
collection in Running sleeve
Discharge into a Integrated De-duster &
Metal Detector.
Collection of product into an integrated bin
Mechanically Clean, Vacuum, WIP.
Exhaust Air equipped with dry Scrubber and
BIBO Filters.
Wash-Out / Secondary cleaning using PPE.
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ISPE Tampa Conference

22-25 February 2010
Tampa, Florida USA

Stage Wise Potent Material Handling

Coating / Packaging
Charging of tablets using SBV,
from bin
Use contained automatic coater
In case of API is in coating solution,
prepare coating solution in a
contained manner
In-process tests in Isolator
Clean-In-Place for equipment
Packaging in ve pressure

33

Stage Wise Potent Material Handling

OSD PFD

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ISPE Tampa Conference

22-25 February 2010
Tampa, Florida USA

Specifics For Parenterals Manufacturing

Compounding, Filtration
Di
Dispensing
i as shown
h
earlier.
li
Minimum Manufacturing Steps and Checks In Isolators.
Alpha Beta Docking Connections for Filtration and Compounding
Vessel with load cells / level transmitter.
-ve pressure Isolator (Grade C)
Aseptic Filtration using S2S
connection.
Clean-In-Place/Wash-In-Place

35

Specifics For Parenterals Manufacturing

Filling
+ve
ve Pressure Integrated Isolator Line (Grade A or better)
Liquid Path Transfer Port for Connecting Filling Vessel.
Peristaltic Pump is a preferred for filling
Online Monitoring For - P, Weight, Viable & Non-viable particles
Leak tightness for Isolators and Gloves prior to each run.
VHP Decontamination for Machine
and Transfer Isolators.
External surface decontamination
of vials prior to unloading.
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ISPE Tampa Conference

22-25 February 2010
Tampa, Florida USA

Equipment Selection Considerations

Closed operations.
Si l system
Simpler
t
d
designs
i
Easy to clean, Smooth surfaces and contours
Ergonomics
Backup in case of primary containment failure
Easy to maintain
Design to handle process upsets
Minimizing of Material Build-Up & Exposure
Potential Using Barriers and Air Purging
Dynamic Inflatable Gaskets
37

Points to Consider HVAC Design

Class 100,000 containment manufacturing room

Negative pressure,
Single-pass / Re-circulatory HVAC with HEPA-HEPA
Safe-change EU 13 HEPA filters
Pressure cascade with audio visual alarms
Combination of Bubble / Sink designs
HEPA In Return Air Path

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ISPE Tampa Conference

22-25 February 2010
Tampa, Florida USA

Waste Water Treatment

Localized Treatment Vs. Centralized Treatment
Threat: Risk with treated compound
Separate sewage system for highly potent
molecule effluents
100% collection of potentially
contaminated water
Pipe-in-Pipe design
consideration for effluent
transport.
39

Types of Isolators

Positive Pressure Filling Line

40
Courtesy: Getinge

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ISPE Tampa Conference

22-25 February 2010
Tampa, Florida USA

Barrier Isolation Benefits

Minimises Exposure
p
to Operator
p
Lowest Cross Contamination
Smaller contact surface area
Minimal energy requirements
Material Handling without exposure
Id l ffor Aseptic
Ideal
A
ti P
Processing
i
Localized Inert gas environment is possible
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Contamination & Containment

42

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ISPE Tampa Conference

22-25 February 2010
Tampa, Florida USA

Outline :

What is Potent
Relevance
Process Design Considerations
Facility & Equipment Design
Validation Requirements
Containment Systems Common Reasons For
Failure
Future Facilities
Summary
Q&A
43

Validation Requirements
Validate;;
Manufacturing Process
Analytical Process
Cleaning Process
Effluent treatment Process
Containment Process/IH Study
44

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ISPE Tampa Conference

22-25 February 2010
Tampa, Florida USA

Cleaning Validation
Risk with product residues
Determine worst case API based on toxicological
data (LD 50, daily dose and solubility)
Challenge worst case positions with worst case
API
Verification by sampling (rinse and swab i.e. 100
cm,, limit determination based on OELs)
cm
New techniques: Ion Trap Mobility Analysis

45

Industrial Hygiene Study Key Features

Highly Recommended for OEB 4 & 5

Operators Exposure Evaluation
Surrogate Material Selection
Validated Method of Analysis - LOD & LOQ
All Processes To Be Evaluated
Sampling Plan
Sampling Techniques
Sample Handling
Results Evaluation & Action Plan
46

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ISPE Tampa Conference

22-25 February 2010
Tampa, Florida USA

Training & Communication

Understanding of Hazards, Exposures, Controls &
Safe Work Practices (SOPs)
Make MSDS & Maintain Chemical Inventory
Labeling & Posters
Effective training through all hierarchical levels
Notify Employees about Industrial Hygiene
Exposure Study Results
Coaching about Risk Control Plans and
Verification of Implementation
47

Outline :

What is Potent
Relevance
Process Design Considerations
Facility & Equipment Design
Validation Requirements
Containment Systems Common Reasons For
Failure
Future Facilities
Summary
Q&A
48

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ISPE Tampa Conference

22-25 February 2010
Tampa, Florida USA

Containment Systems
Common Reasons For Failure
Design:

Incorrect equipment selection

Inadequate design
System cannot achieve the goals set
Understanding the relationship between OELs and performance

Operation:
Operability must be a workable system
Ergonomic aspects correctly addressed
Failure to understand your process

False beliefs:
Increased containment levels -increase cost
Higher containment levels cause loss of efficiency
49

Containment Systems
Common Reasons For Failure ...
Operator
p
involvement:
Good operators make bad processes work they can also make a good process fail!
They know more about the process than
anyone else.

Without training;
No-one will know or understand what they are
doing or why.
In the event of a failure, no-one will know what
to do.
50

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ISPE Tampa Conference

22-25 February 2010
Tampa, Florida USA

Outline :

What is Potent
Relevance
Process Design Considerations
Facility & Equipment Design
Validation Requirements
Containment Systems Common Reasons For
Failure
Future Facilities
Summary
Q&A
51

Future Facilities

Trend towards
Shirt & Sleeve Design
Closed integrated process equipment
Minimal process steps and transfers
Minimal MALs and PALs
Application of PAT for reducing / eliminating
interventions and sampling
HVAC for people Recirculation, low ACH
Minimization of disposables
Hugely reduced carbon footprint
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ISPE Tampa Conference

22-25 February 2010
Tampa, Florida USA

Outline :

What is Potent
Relevance
Process Design Considerations
Facility & Equipment Design
Validation Requirements
Containment Systems Common Reasons For
Failure
Future Facilities
Summary
Q&A
53

Summary
One Size fits all, is not true
Development
p
& manufacture of highly
g yp
potent compounds
p
requires;

Significant planning
Proper equipment and facility design
Extensive employee training
Implementation of the necessary procedures

Dont Generalize, be Specific.

Engineering allows us to reduce exposure It doesn
doesntt
guarantee it
Any containment system is only as good as its weakest link.
90% of workplace accidents have human errors as a cause
54

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ISPE Tampa Conference

22-25 February 2010
Tampa, Florida USA

Acknowledgement:
Mr. Julian Wilkins, VP PharmaConsult US
Technology Department
Department, Dr
Dr. Reddys
Reddy s Laboratories
ISPE

55

Outline :

What is Potent
Relevance
Process Design Considerations
Facility & Equipment Design
Validation Requirements
Containment Systems Common Reasons For
Failure
Future Facilities
Summary
Q&A
56

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ISPE Tampa Conference

22-25 February 2010
Tampa, Florida USA

Q&A

Question and Answer

57

Thank You
S.C. Singhai, Vice President
Technology Transfer and Facility Projects
Dr. Reddys Laboratories Limited,
Hyderabad 500 072, India
+91 40 44642369
+91-40-44642369
+91-98490 49800
singhaisc@drreddys.com

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