A Divine Journey

Of

Authentic Aseptic Technology

P.SineeshPlant Manager Gulf Inject (Julphar Group Of Company)------------------------------------------------------------------------------------------------------------

Bachelor in Pharmacy Post Graduate in Pharmaceutical Business Management

Twenty six years of multi-functional experience in pharmaceutical industry in different capacities.

Experienced in Over-all Management, Operation, Manufacturing, Quality Management, Project Management, Planning & Vendors Management.

OVERVIEW

• Why is it a divine journey ?

• What is advanced aseptic process ?

• Why BFS technology is the most authentic aseptic technology?

• “Quality cannot be tested into products, it has to be built in by Design”

• How BFS can be rooted through Quality by Design principles ?

• “Continued Process Verification”

• “Continued Success With Retrofit”

Why is it a divine journey ?

The market dynamics for global injectables have changed dramatically in the last few decades, due to challenges in sterile manufacturing.

This has forced the industry and regulatory agencies to explore alternative technologies for sustainable supply of high-quality products.

I was fortunate to be a part of that journey, i.e.

Advancement in aseptic processing /Evolution in BFS technology

Join me to rediscover the advanced aseptic processing to honor the whole Pharmaceutical world ….. a Divine Journey.”

What is advanced aseptic process ?

The term advanced aseptic processing was perhaps first used at the Open

Conference on sterile products co-sponsored by USP and PDA in 2002 .

During that conference, only two aseptic technologies were discussed & acknowledged

under the heading of “advanced”.

• Blow Fill Seal

• Isolators

What is advanced aseptic process ? (Conti…)

There is no direct regulatory definition;

however, a working definition is that

One in which direct intervention with open product containers or exposed product

contact surfaces by operators wearing conventional cleanroom garments is

forbidden.

So, to be concluded

Advanced aseptic process should offer a fast, automated process in a controlled

environment, that should be pre-programmed & monitored.

What is advanced aseptic process ? (Conti…)

The basic concept of BFS is that a container is formed, filled, and sealed in a

continuous process without human intervention, in a clean enclosed area

within the machine.

Hence this technology is suitable for aseptic manufacturing.

United States Pharmacopoeia illustrate BFS technology as an

“Advanced Aseptic Process"

Why BFS technology is the most authentic aseptic technology?

Main reasons are:

• Equipment design

• Process controls

• Operational controls

• Robust container closure system

• Compatible to qualification/ validation

• Compatible to Continued process verification (CPV)

“Quality cannot be tested into products, it has to be built in by Design” –J. M. Juran

Quality by Design (QbD) was first outlined by the Quality Management consultant,

Joseph M Juran, in 1992.

The Good Manufacturing Practice (GMP) of the last century was ‘Quality by

testing’ (QbT) but the concept of 21st century is ‘Quality by Design’ (QbD).

US FDA published a report, “Pharmaceutical Quality of 21st Century: A Risk Based

Approach” in 2002.

The concept of QbD was adopted by the FDA in 2004.

How BFS can be rooted through Quality by Design principles ?

“BFS technology embraces quality-by-design principles”

It simplifies the manufacturing process by reducing variables and removing human

intervention and it is heavily based on automation.

BFS technology is designed to drastically reduce the level of viable and non viable

particulates in the vial compared to traditional aseptic manufacturing.

How BFS can be rooted through Quality by Design principles ? (Conti…)

Equipment design

BFS technology is an automated method for forming and filling plastic containers with liquid product in an uninterrupted, continuous process.

The BFS process starts with pellets of virgin plastic, which are fed into a hot melt extruder where the polymers are melted at high temperature and pressure, usually 180°C & 200 Atm.

The filling takes place in a Class A (ISO 4.8) environment and is completed in less than 15 seconds.

There are two types of BFS technologies,

• Rotary

• Shuttle

How BFS can be rooted through Quality by Design principles ? (Conti…)

Equipment design

Melt processing of the resin at high temperature & pressure reduces the

microbe and eliminate endotoxin.

In addition, involves small container openings and short product exposure

times in a Class A environment, further lessening the likelihood of microbial

ingress & foreign particle contaminants.

How BFS can be rooted through Quality by Design principles ? (Conti…)

Equipment design

The closed design of equipment ensures a high level of control. There are three

primary pathways into the equipment for the polymer, compressed air and the

product.

All three are in closed loop and require no human intervention during the

process, during cleaning, during sterilization & during filter drying.

How BFS can be rooted through Quality by Design principles ? (Conti…)

Equipment design

Uniform plastic extrusion (PWTC), hermetical sealing with high pressure ensures

robust container closure integrity.

Hence it complies the container closure integrity test like

• Microbial immersion test

• Dye leak test

• High voltage leak detection

• Vacuum retention

How BFS can be rooted through Quality by Design principles ? (Conti…)

Equipment design

Relatively high levels of nonviable particulates are generated by the plastic

extrusion, cutting process & movements.

Machine manufacturers have taken steps to resolve particulate issues by

improved design

• Black & White area concept

• Exhaust systems like extruder exhaust & knife exhaust

• Static Mandrel system

How BFS can be rooted through Quality by Design principles ? (Conti…)

In contrast

Critical Process Parameters (CPPs)

Quality Target Product Profile (QTPP):

Critical Quality Attribute (CQA):

are Identified, Understood, Controlled & Monitored to achieve a robust

manufacturing process like BFS process.

How BFS can be rooted through Quality by Design principles ? (Conti…)

BFS operations are more predictable than manual operations, less variables

and consistent reproducibility.

Hence it is compatible to

• Aseptic system validation

• CIP validation

• SIP validation

• Filter drying validation

• BFS process validation

Continued process verification (CPV)

“Trust but Verify (Continuously)”

CPV is the collection and analysis of end-to-end production components and

processes data to ensure product outputs are within predetermined quality limits.

Currently pharmaceutical industry (Including Us) started believing & practicing

modern pharmaceutical development concepts at all stages of the manufacturing

life cycle.

Continued process verification (CPV) (Conti…)

“Trust but Verify (Continuously)”

Continued process verification not only helps protect consumers from production

faults, but business also see benefits in implementing a CPV program.

Following process parameters can be included in CPV program

• Extrusion process

• Plastic distribution process

• Blowing process

• Viable count during process

• Non viable count during process

• Filling process

• Sealing process

Continued Success With Retrofit

• Reduction in Plastic scrap Saving of 300000 USD/ year. Reduction in product cost.

• Modification on Mandrel system Elimination of particle generation. Average ninety six hours of saving/ year in preventative maintenance. Saving on change parts.

• Modification on Dosing system Average yield improvement by 1%. Reduction in product cost.

• Inclusion of Additional pack sizes Improvement in productivity. Enhanced the product portfolio.

JULPHAR GROUP OF COMPANY