E03 Singhai-Potent Product Process and Facility Design PDF

ISPE Tampa Conference
22-25 February 2010

Tampa, Florida USA
Potent Product Process and

Facility Design
S.C. Singhai
y Laboratories Ltd.
Dr. Reddy’s
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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Our Businesses
•Near- Medium Term Value Creation •Medium-Long Term Value Creation (Proprietary Products)
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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 Six in India, With ISO 14001 and ISO 9001
Units 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 Two Technology Development Centers (TDC) in India and

Pharmaceutical One in Cambridge
Cambridge, UK
Services
Discovery Research Hyderabad, India
Center
Achievements
•NDTV Profit Business Leadership Awards 2007 •Dun & Bradstreet American Express
Business Leader in the Pharmaceutical Sector Corporate Awards 2007
•Best Corporate Social Responsibility Initiative •Pharma Excellence Awards 2006-07 for
2007 sustained Growth
BSE - India The Indian Express
•Asia-Pacific
Asia Pacific HRM Congress 2007
•Best Employers in India 2007 Award
Global HR Excellence Award for Innovative HR
Hewitt Associates & The Economic Times
Practices
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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
8
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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 10µg/m3 of air
• A novel compound of unknown potency
and toxicity
Outline :
What is Potent
Relevance
Failure
Future Facilities
Summary
Q&A
10
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Relevance
“Potent” Drugs in the Pharma Industry 14
Pipeline have increased from 5% in Growth Forecast

1980 to 20% in 2010 12
High-Potency APIs are estimated to 10

have an annual growth of 12%.
Currently around 5-10% of products on $
8
the market contain HP-APIs. Bn

6
Global sales of oncology drugs were $
34.6 billion in 2006 – IMS Health. 4
Th
There are 300-400
300 400 highly
hi hl potent
t t
compounds currently in production for 2
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 – It’s 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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Outline :
What is Potent
Relevance
Failure
Future Facilities
Summary
Q&A
13
• 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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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
15

• Assessing occupational exposure to workers
during actual operations involving the API.
• Avoid Such Interventions (manual—scrap 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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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 ≤10µg/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:
18
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Changing OEL Levels

120
100
OEL (µg / m3)
80
60
40
20 10
1 0.03
0
10 5 0 -1
Years Back
19
Risk Evaluation:
Product & Process Attribute Low Risk High Risk
Process Wet 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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Outline :
What is Potent
Relevance
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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Facility Design Philosophy :

The facility shall be
designed to achieve the Operator Product
Safety
following objectives: Safety
• Protection of Personnel
from Product exposure.
• Protect the Product from
cross contamination
contamination. Environmental
En i onmental
Safety
• Protection of Environment
from Product exposure
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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Current Regulatory Guidance on Facility

Requirements
As per FDA, EU-GMP, J-GMP, WHO-GMP & PIC/S GMP
P i illi D
Penicillin Drugs S t d facility
: Segregated f ilit
Cephalosporin : Segregated facility as per
J-GMP, ICH-API GMP.
Campaign- FDA GMP.
Other ß-Lactams : Campaign as per EU-GMP,
WHO-GMP, PIC/S GMP.
Some Hormones & : Campaign
HPAPIs
Note: Campaign is associated with appropriate cleaning validation.
25
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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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.
27
Containment Measures
Product Personnel Protection Environmental
Protection Protection
• Independent Modules. • Properly designed • Properly designed HVAC
• Close handling Systems Gowning procedure. System
(Isolators/ cRABS / • Use of Space Suits. • Isolators and cRABS
PTS/ DCS) • Use of Exit showers/ • Appropriate De–
• Split valves/ RTP Mistifiers. contamination & Disposal
• Properly designed Systems for solid &
HVAC System Liquid waste.
• Use of Push–Push Or • Restricted Personnel
Safe Change Filters Movement
• CIP / WIP Systems • Restricted Material
Movement.
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Type of containment
Primary Secondary Emergency
Containment Containment Containment
Means non-exposure of Secondary containment Emergency containment
potent product from revolves around processing provisions
equipment. areas excluding equipment.
• Emergency
Equipment selection Includes following; decontamination shower.
criteria: • Specialized design of HVAC • Proper Spill Kit / misting
System. equipment to handle air
• Product Nature : Solid /
• Proper sealing of processing borne contamination.
Liquid.
rooms i .e wall, ceiling etc. • Proper cleaning and
• Concentration of Product :
• Proper
P pressure cascade d d i
drainage system
t with
ith
High / Low.
• Use of bubble/sink air lock decontamination facility.
• Operation type : Open /
Closed. • Use of safe change/push-
• Method of De- toxification. push filters / scrubbers
• PPEs
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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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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.
31

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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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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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.
36
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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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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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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
41
Contamination & Containment
42
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Outline :
What is Potent
Relevance
Failure
Future Facilities
Summary
Q&A
43
Validate;;
• Manufacturing Process
• Analytical Process
• Cleaning Process
• Effluent treatment Process
• Containment Process/IH Study
44
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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
cm²,, limit determination based on OELs)
cm
• New techniques: Ion Trap Mobility Analysis
45
Industrial Hygiene Study – Key Features
• Highly Recommended for OEB 4 & 5

• Operator’s 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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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
Failure
Future Facilities
Summary
Q&A
48
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Containment Systems –
Common Reasons For Failure
• Design:
• Incorrect equipment selection
• Inadequate design
• System cannot achieve the goals set
• Understanding the relationship between OEL’s 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.
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Outline :
What is Potent
Relevance
Failure
Future Facilities
Summary
Q&A
51
Future Facilities …
• Trend towards
• Shirt & Sleeve Design
• Closed integrated process equipment
• Minimal process steps and transfers
• Minimal MAL’s and PAL’s
• Application of PAT for reducing / eliminating
interventions and sampling
• HVAC for people Recirculation, low ACH
• Minimization of disposables
• Hugely reduced carbon footprint
52
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Outline :
What is Potent
Relevance
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
• Don’t Generalize, be Specific.
• Engineering allows us to reduce exposure – It doesn
doesn’tt
guarantee it
• Any containment system is only as good as its weakest link.
• 90% of workplace accidents have human errors as a cause
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Acknowledgement:
• Mr. Julian Wilkins, VP – PharmaConsult US
• Technology Department
Department, DrDr. Reddy’s
Reddy s Laboratories
• ISPE
55
Outline :
What is Potent
Relevance
Failure
Future Facilities
Summary
Q&A
56
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Tampa, Florida USA
Q&A
Question and Answer
57
Thank You
S.C. Singhai, Vice President

Technology Transfer and Facility Projects
Dr. Reddy’s Laboratories Limited,
Hyderabad – 500 072, India
+91 40 44642369
+91-40-44642369
+91-98490 49800
singhaisc@drreddys.com
29

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ISPE Tampa Conference

22-25 February 2010

Potent Product Process and

Safe Harbor Statement

Biologics Facility  One in India, multiple regulatory agency approvals

Custom  Two Technology Development Centers (TDC) in India and

The views expressed here are personal and

Pipeline have increased from 5% in Growth Forecast

 High-Potency APIs are estimated to 10

the market contain HP-APIs. Bn

clinical evaluation or commercial

Process Design Considerations

Process Design Considerations:

Process Design Considerations

• Up to 50% of product OELs are at ≤10µg/m3 (i.e.

Changing OEL Levels

Facility Design Philosophy :

Facility Design Considerations :

Current Regulatory Guidance on Facility

Facility Design Considerations

Facility Design Considerations

Stage Wise Potent Material Handling

• HPAPI dispensed & Sifted in Isolator.

Stage Wise Potent Material Handling

• Transfer of material using SBV.

Stage Wise Potent Material Handling

• Charging of blend using SBV, from bin

Stage Wise Potent Material Handling

• Charging of tablets using SBV,

Stage Wise Potent Material Handling –

Specifics For Parenterals Manufacturing

Specifics For Parenterals Manufacturing

Equipment Selection Considerations

Points to Consider – HVAC Design

Waste Water Treatment

Positive Pressure Filling Line

Barrier Isolation Benefits

Contamination & Containment

Industrial Hygiene Study – Key Features

• Highly Recommended for OEB 4 & 5

Training & Communication

Question and Answer

S.C. Singhai, Vice President

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