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

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

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.

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

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

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 … ???

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

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

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

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

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

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

Monitoring

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?

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?

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

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

“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

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?

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

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!

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

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