© Institute for International Research, Inc. 2006. All rights reserved.

Module 3:Aseptic Processing

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Module 3 Purpose and Objectives

Module Purpose:A short session to discuss how aseptic

processing is implemented for lyophilization.

Module Objectives:After this module, you will be able to

Critique a component implementation with respect to sterility.

Know what to look for in an aseptic unit.

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What is Aseptic Processing?

Aseptic Processing is the handling of materials that have been sterilized and will not be sterilized again before sale into the market place.

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Overview

Autoloaders SIP CIP Pizza Doors Isolators General Process Design

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Autoloaders

Basic System Operation (Courtesy of Hull) Infeed collator receives vials from conveyor and

groups them as rows in single shelf batches for transport vehicle pickup.

Transport vehicle cage contains vial batch during trip to freeze dryer

Dryer subdoor opens, shelves are indexed and transport vehicle docks with shelf

Transfer of vials to shelf, transport vehicle retracts and subdoor closes.

Transport vehicle returns to infeed collator for next batch of vials.

Reverse process for unloading.

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Autoloaders

Benefits  Simple operation (simple is easy to say) Reduced vial handling (by humans) Product quality improvement (?) Reduced bio-burden in Class 100

environments (probably) Fast (for large lot sizes)Potentially less error prone when loading

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Autoloaders

DisadvantagesBig – requires real-estateComplex – requires engineers & mechanicsExpensive – in time and dollarsNot flexible – difficult to change vial sizes

Change parts New validations

Time consuming to validate

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Steam In Place

Essential to Pharmaceutical Lyophilization Steam should enter the chamber & condenser Steam should exit at low point drains. Operate or at least open bellows during the steam

cycle.

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Steam in Place

Dead LegsSince lyophilizers have many holes, they are

subject to many dead legs.Evaluate Each.At validation, probe the worst candidates.

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Steam In Place

Minimum Steam design is for 15 psig. Steam Requirement

Because the steam starts cooling (condensing) immediately on contact with the steel, the steam requirement is not easy to estimate. Typical is 200 to 800 lb/hr during sterilization –dependent on chamber/condenser size.

Steam is also used for defrosting the condensers and the amount needed is about 1/3 of the amount used to sterilize.

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Clean In Place

If CIP piping exists, then steam must enter the chamber/condenser through the CIP piping. Otherwise, that piping will not be sterilized.

CIP piping may have to be adjusted during FAT or at start-up. Use Riboflavin and a black light to assure coverage.

CIP for a lyophilizer is a worthwhile addition.

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Sub Doors

Sub-Door: Slot opening in the real door of a lyophilizer which permits loading one shelf at a time if the shelf has been aligned with the slot.

Used mostly by autoloaders.

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Sub Doors

Benefits Minimizes the opening in very large units,

thus reducing potential contamination.Increases probability of a good door seal for

vacuum.

DisadvantagesAdditional complexity = time and money.

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Isolators

Why Use an Isolator? Extremely cytotoxic compounds Class 4 (BL-4) - Agents of extreme hazard

or which may cause serious epidemic diseases.

How? Custom design. There are no standard

offerings.

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Aseptic Process Design

Clean Room Side:Operations:

Door Opening and Closing Loading & Unloading Touch Screen Interaction

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Aseptic Process Design

Door OpeningMechanically how will it be performed?Is a tool involved?Is it an aseptic operation?How long can the door stay open?

What is the air flow pattern when the door is open?

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Air Flow

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Aseptic Process Design

Loading - DesignUse bottomless trays – or not !Load evenly to prevent shelf warp.Calculate Force per vial

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Bottomless Trays

At the back of the lyo, the tray bottom must be removed using a ‘rake’ or grabbing tool along with a tool to hold the tray ring still.

Reinsertion of the bottom is easier because the vials are stoppered and aseptic handling is not required.

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Force per Vial

Ram Pressure x Cylinder Area = Force

Force/(Vials on Shelf) = Force/Vial

Force/(Shelf Area) = Shelf Pressure

Vials begin to break at about 25 lbf (111 N)

Vials fail to stopper with less than 4 lbf (17.8 N)

For most vials a setting of 10 psig is acceptable. Shelf Pressure = 10 psi (69 kPa)

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Exercise 3.1:

Prior to starting a cycle, an operator sees that a group of vials near the front of the lyo have fallen over. There is so little volume in the vials that no liquid has come out. He proceeds to set them up by hand and then proceeds with the lyophilization. His operation is captured on company video and 1st observed 2 weeks later by QA. What to do?

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Module 3 Quiz

Participant Directions:Divide into pairsTake 5 minutes to complete quizCorrect answers will be reviewed as a large

group during debrief

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Question 1 of 3

Calculate the ram pressure range needed for a 120 sq ft lyo made up of 10 shelves, having a 4” dia ram and fully loaded with 5 cc vials. Shelves are 4’ across by 3’ deep and trays are 1’ x 2’. 360 vials fit into one tray. Ram pushes up from below or above – ignore gravity.