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

Process Controls in AsepticManufacturing: An Overview

Jörg Zimmermann

Overview

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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

Introduction: Regulatory Expectations

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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

Isolator

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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

ISPE RABS Definition

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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

Jörg Zimmermann, Vetter

Industry Feedback was considered

Final Definition issued on www.ispe.org

ISPE RABS Definition: Key Features

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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

ISPE RABS Definition: Diagram

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Courtesy of: J. Lysfjord, ex Bosch Packaging Technologies

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RABS in Operation

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RABS in Operation

Best Practise in using RABS

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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

Daily Operation of a RABS Filling Line

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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 newlines

Various loading systems on the market for vials and syringes

Loading system for a Lyophilizer

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

Transfer of the units fromfilling line to the lyophilizer via a monorail system

In Process Controls

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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

Visualization of IPC-results in the cleanroom

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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

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

Visualization of IPC data in the cleanroom

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Optimization using the visualization

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Before: communication via telefone

After: visualization in the cleanroom

UEG

OEG

USG

OSG

Soll

0,3050,3060,3070,3080,3090,31

0,3110,3120,3130,3140,3150,3160,3170,3180,3190,32

0,3210,3220,3230,3240,325

0 5 10 15 20 25 30 35 40 45 50 55 60

B1 B2 B3 B4 B5 B6

UEG

OEG

USG

OSG

Soll

0,3050,3060,3070,3080,309

0,310,3110,3120,3130,3140,3150,3160,3170,3180,319

0,320,3210,3220,3230,3240,325

0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75

B1 B2 B3 B4 B5 B6

• fill volume not on target

• batch-to-batch variation

• outliers

• fill volume consistently on target

• no batch-to-batch variation

• no outliers

Batch change Batch change

Microbiological Environmental Monitoring

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air monitoring:

Gelatine-membrane-filtration (GMF):

correlation to volume

Sedimentationsplates:

correlation to exposure time

surface monitoring

personel monitoring

Example for a monitoringplan:

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Monitoring plates and how they are packed:

Tripple baged Double baged Single baged

All plates are labeled with the product and expiry date

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Equipment for GMF sampling

Air sampler MD8 (Sartorius) Sampling point

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GMF sampling for class A

1 m³ is sucked through the filter in approx. 10 min.

Surface monitoring

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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

Sterile wipe is sprayed with IPASurface is wiped.

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.

Conclusions

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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!

Jörg ZimmermannDirector Process Development and Process Implementation

Vetter Pharma-Fertigung GmbH & Co.KGjoerg.zimmermann@vetter-pharma.com