Process Controls in Aseptic Manufacturing: An Overview

Jrg Zimmermann

PQRI-FDA Workshop on Process Drift, December 01-03, 2010, Bethesda, Maryland

Overview

Introduction Aseptic Process Designs

Conventional Clean Room, RABS, Isolator Automation: Automatic Loading of Lyophilizers

Process controls

fill volume Stopper and closure part position

Microbiological Monitoring Conclusions

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Introduction: Regulatory Expectations

EC Guide to Good Manufacturing Practice, Annex 1 FDA Guidance for Industry: Sterile Drug Products Produced by Aseptic
Processing Current Good Manufacturing Practice

Maximum product contamination control Maximum environmental control Minimum operator interference with product

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Conventional Clean Room

Definition and Design Features

> > > > > >

Laminar flow cover, curtains, etc. Operator handling in ISO 5 environment Manual transfer steps Most common operation still Currently approx. 2200 lines in operation worldwide Likely to become unapprovable for new lines in coming years

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Process Design: Conventinal Clean Room

Courtesy of: J. Lysfjord, ex. Bosch Packaging Technologies

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Conventional Clean Room

Pros

Cheap Simple set-up Easily adaptable for process changes Useful for early clinical work Useful for terminally sterilized products

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Conventional Clean Room

Cons

Manual processes need much more monitoring than automized

processes

Manual processes need much more supervision than automized

processes

Expectations for the aseptic process are the same: product must be
sterile!

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Conventional Clean Room

Cons

Media Fill validation can be challenging Manual processes difficult (impossible) to validate Reduced sterility assurance

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Isolator

Definition
> > > >

Full isolation of machinery from environment Handling on the line via gloves Chemical disinfection after batches, usually with H2O2 Currently approx. 400 lines in use worldwide

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Isolator

Courtesy of: J. Lysfjord, ex. Bosch Packaging Technologies

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Isolator

Pros
> > >

Highest level of separation of operator and product Automized, validated decontamination Best solution for high potent drugs

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Isolator

Cons
>

Requires well running processes to avoid opening of the isolator Less classified area as background (ISO 8) Time consuming change over procedures reducing running time

> >

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Isolator

Operational aspects
>

Validation of H2O2-decontamination well established by now (i e with support of the isolator-vendors) Focus these days on rapid decontamination Decontamination is always on top of dismanteling/cleaning/set-up of the line Campaigning of production

> >

>

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PQRI-FDA Workshop on Process Drift, December 01-03, 2010, Bethesda, Maryland

ISPE RABS Definition

Definition developed in 2005, by a group

led by J. Lysfjord ( then Bosch Packaging Technologies)

Members:

Rick Friedman, FDA Michael Porter, Merck John Shabushnik, Pfizer Ian Symonds, GSK Jrg Zimmermann, Vetter

Industry Feedback was considered Final Definition issued on www.ispe.org

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ISPE RABS Definition: Key Features

Rigid wall enclosure ISO 5 LAF environment Gloves Automation Sterilisation of all equipment High level disinfection Rare open door interventions Currently approx. 250 lines in use worldwide

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ISPE RABS Definition: Diagram

Courtesy of: J. Lysfjord, ex Bosch Packaging Technologies

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RABS in Operation

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RABS in Operation

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Best Practise in using RABS

No open door interventions allowed

>

Open door leads to full line clearance/line cleaning

High level disinfection after each production batch using a

sporicidal agent

Gloves tested and steam sterilized after each batch Maximum automation of the process

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Daily Operation of a RABS Filling Line

1st step in set-up: installation of steam sterilized gloves Installation of all filling equipment using the gloves All manipulations using the gloves Disassembly of the line at the end of the fill, cleaning of the line with sporicidal agent, integrity testing of the gloves

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Automated Loading of Lyophilizers

Manual loading of lyophilizers problematic with no LAF in

the lyophilizer, temperature differences between air and shelf etc.

Automated loading is expectation of authorities for new

lines

Various loading systems on the market for vials and

syringes

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Loading system for a Lyophilizer

Loading a freeze-dryer: tray system, row-by-row

Transfer of the units from filling line to the lyophilizer via a monorail system

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In Process Controls

Fill volume:
100% check-weighs for vials inline In-line fill-weigh checks for syringes (non-destructive) Expellable volume for syringes off-line (destructive)

Stopper position and total length Visualization of all parameters directly in the cleanroom

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Visualization of IPC-results in the cleanroom

Configured as Monitoring Station: All FreeWeigh.Net Monitoring Functions are available at the
filling machine

All values of the IPC Lab are available online The operators have an better overview about the IPC
parameters

The same views as the supervisors of the IPC Lab:

>

All Trends and statistics are indicated

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Monitoring of Variables:

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Histogram of the individual values is indicated:

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Monitoring of Multi-Head Filling-Lines:

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Separate Trends of every Filling Head

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Detailed statistical Data of the batch, sample or Filling Head are available

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Visualization of IPC data in the cleanroom

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Optimization using the visualization

Before: communication via telefone
B1
0,325 0,324 0,323 0,322 0,321 0,32 0,319 0,318 0,317 0,316 0,315 0,314 0,313 0,312 0,311 0,31 0,309 0,308 0,307 0,306 0,305 0 5 10 15 20 25 30 35 40 45 50 55 60

After: visualization in the cleanroom

B1
OSG
0,325 0,324 0,323 0,322 0,321 0,32 0,319 0,318 0,317 0,316 0,315 0,314 0,313 0,312 0,311 0,31 0,309 0,308 0,307 0,306 0,305 0 5 10 15 20 25 30

B2

B3

B4

B5

B6

B2

B3

B4

B5

B6
OSG

Batch change

Batch change

OEG

OEG Soll UEG

Soll
UEG

USG

USG
35 40 45 50 55 60 65 70 75

fill volume not on target batch-to-batch variation outliers

fill volume consistently on target no batch-to-batch variation no outliers

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Microbiological Environmental Monitoring

air monitoring: Gelatine-membrane-filtration (GMF): correlation to volume Sedimentationsplates: correlation to exposure time

surface monitoring personel monitoring

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Example for a monitoringplan:

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Monitoring plates and how they are packed:

Tripple baged

Double baged

Single baged

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Equipment for GMF sampling

Air sampler MD8 (Sartorius)

Sampling point

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GMF sampling for class A 1 m is sucked through the filter in approx. 10 min.

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Surface monitoring

Contact for 5-10 sec.

Correct: lid is held without exposing the inside

wrong: lid is held exposed

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Surface monitoring
Surfaces in class B need to be disinfected directly after monitoring

Surface is wiped. Sterile wipe is sprayed with IPA

One wipe per monitoring point. Do not fold.

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Monitoring Personel - arms

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Monitoring Personel - fingers

or

All five fingers need to be pressed firmly against the agar-plate.

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Monitoring Personel - hands

Wrong: Only finger tips are in contact One finger is not contacted Fingers are contacted on the side.

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Conclusions

RABS or Isolator:
both can be used for a safe, aseptic process

Proper aseptic technique is the basis Automation: use it as much as possible Process controls:
visualization helps operators run the lines Non-destructive checks are coming more and more

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THANK YOU:
Eva Zolg Ute Pape Matthias Piloty

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Thank you for listening!

Jrg Zimmermann Director Process Development and Process Implementation Vetter Pharma-Fertigung GmbH & Co.KG joerg.zimmermann@vetter-pharma.com

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