Challenges in Injectable (Contract) Manufacturing

Manish Bhatkar

Ahmedabad

08th Dec. 2016

Injections USP <1>

Parenteral articles are preparations intended for injection through the
skin or other external boundary tissue, rather than through the
alimentary canal, so that the active substances they contain are
administered, using gravity or force, directly into a blood vessel,
organ, tissue, or lesion.
Parenteral articles are prepared scrupulously by methods designed to
ensure that they meet Pharmacopeial requirements for sterility,
pyrogens, particulate matter, and other contaminants, and, where
appropriate, contain inhibitors of the growth of microorganisms. An
Injection is a preparation intended for parenteral administration and/
or for constituting or diluting a parenteral article prior to
administration.

Injectable Manufacturing Process

Checks
Incoming
Material

Washing
&
Cleaning

Sterilization

Formulation

Filling
&
Sealing

Visual
Inspection

Packaging

Labeling

Checks
Finished
Product

Progressive Pharmaceutical Value Chain

Import

Labeling &
Packaging

Product
Manufacturing

Age/ Maturity

API
Manufacturing

Research &
Development

Product Lifecycle

Time to
market

Capacity

Cost

Traditional Positioning CMOs

Not so long ago, big pharmaceutical companies
turned to CMOs solely to supply:

Cost Efficiencies
Capacity
Time-to-market
Expertise not available in-house

Traditional Relationship CG & CA

CG

CA

Know - How Owner

Manages Technology
Transfer
Needs Capacity for
Short Term
(Unexpected Sale,
Launch Quantities, Limit
Risk on New
Technology)

Limited Know - How

Limited Involvement in
Technology Transfer
Provides Manufacturing
Capacity (Facility/
Equipment, Manpower,
Specific Technology)

Manufacturing Strategy
A Shifting Paradigm:
Focus on core function/ competency as companies
are growing in pharmaceutical value chain
Focus on marketing their products
Reducing time and resources in drug discovery &
manufacturing
Growth in the number of virtual companies

Manufacturing Strategy
Contract
Product/
Process
Development
Contract
Analytical
Method
Development

Contract
Research

Innovator
(Virtual
Company)
Regulatory
Consultant

Contract
Manufacturing*

Marketing
Partner/
Collaborator

* Note: Some CMOs offer more than one service such as formulation, analytical and regulatory expertise

Manufacturing Strategy
In-house

Outsource

Hybrid

Manufactured
completely inhouse
During
development
stage (preclinical/ clinical
stage) or
during
commercial
stage

All
manufacturing
stages
outsourced to a
CMO

A combination
of in-house and
outsourced
manufacturing,
dependent
upon specific
company need

Challenges
Opportunities

Threats

Opportunities
The world market for pharmaceutical contract research
and manufacturing services (PCRAMS) is set to grow by
an average of 13.6% a year to 2017, by which time it
will be worth $136 billion, up from $72 billion in 2012,
according to new forecasts
Source: http://www.pharmatimes.com/news/contract_researchmfrg_market_set_to_grow_13.6_a_year_1005918

Threats
Emerging countries like East EU, Brazil, India and
soon China will provide low cost products that will
meet cGMPs
The old business model will not sustain growth for
North American and/or EU CMOs
The new business model is more complex and
requires different skills

Product Life Cycle Curve

Time to market
Technology Availability
Technical Expertise
Proximity
Quick Reaction
Proven Quality System

High Capacity
Low Cost

Low Cost

Can CMOs make the difference?

The battle will be fought on the technical field:

Technological Challenge
State-of-the-art/ Latest Technology
Scalability & Flexibility
Qualification & Validation
cGMP Compliance
Documentation
Project Management
Safety Health & Environment (SHE)

Technological Challenges
The need to keep pace with next-generation
process technology is challenging
In the case of many emerging pharmaceutical
products, the challenge is to make viable
commercial production possible
CMOs need to invest in technology and people

State-of-the-art/ Latest technology

Need to stay aware of new technology
development
Sometimes old technology is the best option
Staff from R&D, Validation, Production and
Maintenance must be trained and have as much
exposure to information about new technology as
possible

Scalability & Flexibility

New business often starts at lab or pilot scale
CG prefer to scale-up without having to change
manufacturing site
Equipment selection can improve chances of
attracting new business

Qualification & Validation

The need for small scale cGMP batches has
increased so R&D equipment needs to be qualified
(IQ/OQ)
Cleaning validation is one of the biggest challenges
for a CMO since dedicating equipment is not
economical
Change control procedures must be closely followed

cGMPCompliance

Most CGs intend to market product world wide

Quality system must meet regulation in multiple markets
plus clients internal standards
Other clients rely on CMOs quality system since they
dont have internal resources
Quality systems inspection, reviews, audits & gapanalysis must be performed regularly and systems
upgraded accordingly

Documentation
New projects start at pre-clinical stage
Process is improved along the way
Batches are made for development, scale-up, stability,
clinical trials and process validation
PAI may occur years later
Good documentation practices must be followed at all
times (even if clients do not request it explicitly)

Project Management

New projects involve multiple Partners/ functions/

organisations
All functions from all partners will get involved at one
time or another
Project scope will evolve and scope changes must be
managed carefully
CMOs are becoming technical expertise providers and
they must behave accordingly

Safety, Health & Environment (SHE)

Safety Health and Environment must always be kept in
mind:
CGs may outsource hazardous processes
Large companies have very strict SHE requirements
The hazards of handling multiple processes involving
new chemicals must be evaluated
New drugs are more and more potent

Conclusion
Contract Manufacturing Organisations will have to
adapt to a new business environment
Successful CMOs will be the ones with the strongest
technical staff capable of participating in
multidisciplinary project teams

Business continuity is important element of

trust must be established between CG & CA

Injections Market Trends & Drivers

Industry Focus Shift (Oncology, Biologics)

Novel Drug Delivery Systems (Gaining Prominence)

$312 Bn. (2014) $363 Bn. (2017)

Trends & Drivers

Quality Expectations WLs, Import Alerts/ Bans

Regulatory Requirements (Dose Count, Needlestick Legislation)

Regulatory Scrutiny Approval Delays

Cost Pressure Margins (Standard, Simple & Robust Pkg. Solution)

Drug Requirements Complexity (Simple & Safe Administration)

Self-Injection Technology Patient Focused Care

Supply Chain Need for Risk Mitigation

Best Practices Basis

Best Practices Basis

Future Trends Injectable Packaging Line

Reducing Contamination During Processing

(Pre)washed, sterilized, de-pyrogenated
containers and closures
Reducing Cost (capex & opex) Avoiding
multiple unit operations, such as washing,
sterilization & de-pyrogenation
Reducing Regulatory Review Time
Approval Delays

Future Trends Injectable Packaging Line

Open

Close

Future Trends Injectable Packaging Line

Blow/ Form Fill & Seal

Future Trends Injectable Packaging Line

Limited

Versatile

Future Trends Injectable Manufacturing

Poor solubility is an increasing characteristic of new

pharmaceuticals, freeze drying using organic
solvents such as TBA or TBA-water mixtures is
becoming more common
Growth in the number of siRNA and antibody based
formulations. These compounds regularly require
freeze drying, not because of the active itself but to
maintain the integrity of the formulation or vehicle
to target the siRNA in the body

Emerging Technique Spray-Freeze-Drying (SFD)

Emerging Technique Spray-Freeze-Drying (SFD)

SFD process consists of:

Atomization of liquid solutions or suspension

using ultrasound, one or two fluid nozzles or
vibrating orifice droplet generators
Freezing of the droplets in a cryogenic
liquid or cryogenic vapor
Ice sublimation at low temperature and
pressure or alternatively atmospheric
freeze drying using a cold desiccant gas
stream

Future Trends Visual Inspection

Future Trends Visual Inspection

Future Trends Injectable Packaging

Growth and competition in injectable markets

Use of biologics drugs
Global demand for vaccines
Need of drug delivery in non-medical settings
Focus on more efficient drug administration
Ease of Administration
Compliance patient as well as regulatory
Differentiation

Future Trends Injectable Packaging

Formulation

Device

Future Trends Injectable Packaging (Ease of Administration)

Vetters dual chamber technology, LyoJect syringe and

dual chamber VLK cartridge allows the differing
ingredients and solvents to be prefilled and stored
separately, then easily mixed and administered as needed
just prior to administration. This help mitigate the residual
risk of needle stick injuries allowing non professionals like
patients and family members to safely use the device, in
non-clinical setting.
Watson Pharmaceuticals + West Pharmaceutical Services,
Inc. developed a safe and convenient Wests MixJect
drug transfer device. This device provides ease of
reconstitution with a diluent prior to injection by syringe. The
entire process makes administration and disposal
significantly easier and safer for patients and caregivers.

Future Trends Injectable Packaging (Human Factor, Convenience)

Integrating Human Factor in the Device

Development
Aptar Pharma ProJect is a novel auto
injector
Confirmed benefits of ProJect in terms of
ease of use, ergonomics, and design
Features include push on skin activation,
slow injection, hidden needle, highly visible
indicator window, and audible feedback

Future Trends Injectable Packaging (Human Factor, Needle Safety)

Credence Companion offers the bio-pharm product

manufacturers a new option to differentiate their
products by delivering to their patients and caregivers
the best technologies available.
The cover allows easy attachment by dexteritychallenged users as well. Needle can be attached by
holding the cover in a fist or in a thumb/forefinger
wedge.
Once attached the user receives audible, tactile, and
visual feedback of a successful needle to syringe
connection.
At the completion of the injection, the needle
automatically retracts into the syringe barrel and the
syringe is automatically disabled.

Future Trends Injectable Packaging (Patient Compliance & Self-use)

West SmartDose electronic wearable bolus injector.

The single use, disposable system cGMP
manufactured.
Utilizies a Daikyo Crystal Zenith polymer cartridge
along with Flurotec barrier filmcoated elastomers as
the primary container.
Designed for high volume (>1mL) and/or high
viscosity protein formulations for subcutaneous bolus
administration.
The SmartDose injector can extend the time between
dosing and may improve patient compliance (versus
daily injections).

Thank You...