1. Aseptic Processing 2019: Trends and Challenges
James Agalloco
Agalloco & Associates Inc

2. Aseptic Processing: Trends
It’s always been considered a critical activity
It receives an extraordinary amount of regulatory attention
It’s not going away
It’s changing rapidly

3. It’s critical There’s no proof of ‘sterility’.
The best available technologies lack any direct means to confirm their superiority.
Nevertheless, it remains vulnerable to contamination.

4. Influences on Sterile Products
Facility
Equipment Design
Effects from
Seasonal
Design
adjacent
Effects
areas
Personnel Traffic
Flow
Disinfection
Area
HVAC
Environment
Equipment
Equipment
Storage
Conditions
Product
Validation
Personnel
Product
&
Practices &
Material Flow
Training
Cleaning
&
Personnel
Maintenance
Hygiene
Procedures
Product & Materials
Sterilization
Qualification
Adapted from Leonard Mestrandrea

5. It gets lots of attention
The 2017 draft revision of Annex 1: Sterile Medicinal Products hasn’t helped. As the latest regulatory guidance it’s less than stellar.
FDA has been totally silent on Annex 1

6. The attention isn’t always good
50 pages
269 paragraphs
Maintains Grades A,B,C,D instead of ISO 14644
PUPSIT is being mandated
Technology distinctions are ignored
Keeps emphasis on testing and monitoring
Aligned with … ???

7. It’s not going away New sterilization methods can’t handle everything
Low temperature moist heat TS
Low dose radiation (<15 kGy)
New aseptic products abound
Personalized medicine
Combination products
Compounded products

8. It’s changing rapidly - 1
Closed system adoption – cell culture
Isolators
Single use bag w/open process
Single use closed system
Same process, very small lot sizes
Worker safety concerns

9. It’s changing rapidly - 2
Single use disposable systems
Filling – from product supply line to fill needle
Eliminates assembly, cleaning, sterilization on-site
Simplifies / eliminates aseptic connections
Assimilation / implementation with filling equipment
Vendor support for adoption critical

10. It’s changing rapidly - 3
Gloveless isolators
Robotics
Internal automation
Ready to fill components -
Containers
Closures
Wrapped or tray supplied

11. It’s changing rapidly - 4
Closed system filling is on the horizon
Closed vial has been available since 2004
Closed vial and needle soon
Sterile CLOSED Needle
Sterile CLOSED Container

12. It’s changing rapidly - 5
USP Sterility Assurance <1211> changes the game dramatically
New emphasis is on ‘Sterility by Design’ concepts
Monitoring is not control

13. Monitoring

14. Aseptic Processing: Challenges
Not everyone sees the future in the same way
Are RABS a dead end technology?
Absence of usable metrics
Impact of rapid micro methods
How to upscale cell culture processes
The vendors take over?
Can the regulators keep up?

15. The same future?
Industry is still using (and even constructing) manned aseptic suites
If it ain’t broke, don’t fix it!
Is isolation technology too hard to implement?
Are isolators the answer for everything?

16. Do RABS even have a future?
They are an easy upgrade to conventional cleanrooms
Even when properly executed they are the most expensive to operate
Many were installed in aging infrastructure
Image from Boschpharma

17. Absence of usable metrics
What to do when production capabilities far exceed monitoring sensitivity?
When all results are ‘zero’ how do you define acceptable?
Engineering ‘rules of thumb” are just that:
Air velocity
Air change
Eliminate subjective tools – smoke studies

18. “Many of the things you can count, don't count
“Many of the things you can count, don't count. Many of the things you can't count, really count."
sign in Albert Einstein’s office

19. Rapid Micro Method Mayhem
How to integrate rapid methods with existing aseptic controls?
Is this a real improvement to patient safety or just an expensive diversion?
It’s still not control, so does anything really change?

20. Upscaling Cell Culture
How to increase capacity?
Can we use closed systems for all?
Unit operations approach
Changing production paradigm
From: one line  millions of units
To: many different process lines  many lots of very few units
A myriad of potential products / processes

22. The vendors take over Innovation is vendor driven
Isolators
Closed systems
Supply chain
Competing claims confuse customers!
Will this cause standardization problems?
Not a bad thing!

23. Regulatory Stress: A Sampling
Rate of technology change increasing
Changing paradigms means changing expectations
Diminishing utility of current metrics
Will they accept vapor H2O2 sterilization?
Acceptance of increased vendor reliance
Brexit, Annex 1 & FDA, MRA’s

24. The Future Like it or not it’s coming.
Lead, follow or get out of the way!