© Institute for International Research, Inc All rights reserved. Module 3: Aseptic Processing

2 international 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.

3 international 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.

4 international Overview  Autoloaders  SIP  CIP  Pizza Doors  Isolators  General Process Design

5 international 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.

6 international 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

7 international Autoloaders  Disadvantages  Big – requires real-estate  Complex – requires engineers & mechanics  Expensive – in time and dollars  Not flexible – difficult to change vial sizes  Change parts  New validations  Time consuming to validate

8 international 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.

9 international Steam in Place  Dead Legs  Since lyophilizers have many holes, they are subject to many dead legs.  Evaluate Each.  At validation, probe the worst candidates.

10 international 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.

11 international 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.

12 international 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.

13 international Sub Doors  Benefits  Minimizes the opening in very large units, thus reducing potential contamination.  Increases probability of a good door seal for vacuum.  Disadvantages  Additional complexity = time and money.

14 international 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.

15 international Aseptic Process Design  Clean Room Side:  Operations:  Door Opening and Closing  Loading & Unloading  Touch Screen Interaction

16 international Aseptic Process Design  Door Opening  Mechanically 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?

17 international Air Flow

18 international Aseptic Process Design  Loading - Design  Use bottomless trays – or not !  Load evenly to prevent shelf warp.  Calculate Force per vial

19 international 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.

20 international 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)

21 international 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 1 st observed 2 weeks later by QA. What to do?

22 international Module 3 Quiz  Participant Directions:  Divide into pairs  Take 5 minutes to complete quiz  Correct answers will be reviewed as a large group during debrief

23 international 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.