pda: a global achieving meticulous aseptic standards ... pda aidan... · pda: a global association...
TRANSCRIPT
![Page 1: PDA: A Global Achieving Meticulous Aseptic Standards ... PDA Aidan... · PDA: A Global Association Achieving Meticulous Aseptic Standards & Control in a Filling Isolator – Lessons](https://reader031.vdocuments.mx/reader031/viewer/2022020104/5addbbb37f8b9a9d4d8d9013/html5/thumbnails/1.jpg)
PDA: A Global Association
Achieving Meticulous Aseptic Standards & Control in a Filling Isolator –Lessons for Design
Aidan Harrington PhDSenior ConsultantDPS Engineering, CorkIreland
![Page 2: PDA: A Global Achieving Meticulous Aseptic Standards ... PDA Aidan... · PDA: A Global Association Achieving Meticulous Aseptic Standards & Control in a Filling Isolator – Lessons](https://reader031.vdocuments.mx/reader031/viewer/2022020104/5addbbb37f8b9a9d4d8d9013/html5/thumbnails/2.jpg)
Preface
Agalloco, J.; Akers, J. Aseptic Processing, Elephants, Blind Men, and Sterility: PDA J Pharm Sci and Tech 2002, 56 231-234
2
![Page 3: PDA: A Global Achieving Meticulous Aseptic Standards ... PDA Aidan... · PDA: A Global Association Achieving Meticulous Aseptic Standards & Control in a Filling Isolator – Lessons](https://reader031.vdocuments.mx/reader031/viewer/2022020104/5addbbb37f8b9a9d4d8d9013/html5/thumbnails/3.jpg)
Agenda
3
Background Classification – Is Grade D Good
Enough?
Sterilize Vs Surface Biodecontamination of
Indirect Parts
Gloves & Pinholes – a Real Risk?
![Page 4: PDA: A Global Achieving Meticulous Aseptic Standards ... PDA Aidan... · PDA: A Global Association Achieving Meticulous Aseptic Standards & Control in a Filling Isolator – Lessons](https://reader031.vdocuments.mx/reader031/viewer/2022020104/5addbbb37f8b9a9d4d8d9013/html5/thumbnails/4.jpg)
EU Annex 1: 1997 to Date
4
![Page 5: PDA: A Global Achieving Meticulous Aseptic Standards ... PDA Aidan... · PDA: A Global Association Achieving Meticulous Aseptic Standards & Control in a Filling Isolator – Lessons](https://reader031.vdocuments.mx/reader031/viewer/2022020104/5addbbb37f8b9a9d4d8d9013/html5/thumbnails/5.jpg)
FDA - 2004
5
![Page 6: PDA: A Global Achieving Meticulous Aseptic Standards ... PDA Aidan... · PDA: A Global Association Achieving Meticulous Aseptic Standards & Control in a Filling Isolator – Lessons](https://reader031.vdocuments.mx/reader031/viewer/2022020104/5addbbb37f8b9a9d4d8d9013/html5/thumbnails/6.jpg)
ISPE Baseline Guide 2011
6
ISPEClassification Grade
FDA, CDER September 2004Guideline on Sterile Drug Products for Aseptic Processing
European Commission Annex 1, 2008 – Manufacture of Sterile Medicinal Products
In Operation Descriptive Descriptive/Grade At Rest In Operation
Grade 8 3,520,000ISO 8(100,000)
100 (50) Controlled Areas
Grade C 352,000ISO 7
2,900ISO 7
3,520,000ISO 8
29,000ISO 8
100
ISPE Baseline Guide: Sterile Manufacturing Facilities 2011
![Page 7: PDA: A Global Achieving Meticulous Aseptic Standards ... PDA Aidan... · PDA: A Global Association Achieving Meticulous Aseptic Standards & Control in a Filling Isolator – Lessons](https://reader031.vdocuments.mx/reader031/viewer/2022020104/5addbbb37f8b9a9d4d8d9013/html5/thumbnails/7.jpg)
Isolator Background
7
An Open, Positive Pressure Isolator is a Closed System
Product Protection
Room Environment
HVAC System
Facility / Building
![Page 8: PDA: A Global Achieving Meticulous Aseptic Standards ... PDA Aidan... · PDA: A Global Association Achieving Meticulous Aseptic Standards & Control in a Filling Isolator – Lessons](https://reader031.vdocuments.mx/reader031/viewer/2022020104/5addbbb37f8b9a9d4d8d9013/html5/thumbnails/8.jpg)
Isolator Background
8
Aseptic Processing Complexity –
The Holistic Facility*
* R. Friedmann- FDA, 2014
![Page 9: PDA: A Global Achieving Meticulous Aseptic Standards ... PDA Aidan... · PDA: A Global Association Achieving Meticulous Aseptic Standards & Control in a Filling Isolator – Lessons](https://reader031.vdocuments.mx/reader031/viewer/2022020104/5addbbb37f8b9a9d4d8d9013/html5/thumbnails/9.jpg)
Consequences
9
€
![Page 10: PDA: A Global Achieving Meticulous Aseptic Standards ... PDA Aidan... · PDA: A Global Association Achieving Meticulous Aseptic Standards & Control in a Filling Isolator – Lessons](https://reader031.vdocuments.mx/reader031/viewer/2022020104/5addbbb37f8b9a9d4d8d9013/html5/thumbnails/10.jpg)
• Integrity breach during transfer / interventions
Area Practices
• Integrity breach during processing
• Set-up Bioburden load
RISK
ASSESSMENTS
INPUTS
![Page 11: PDA: A Global Achieving Meticulous Aseptic Standards ... PDA Aidan... · PDA: A Global Association Achieving Meticulous Aseptic Standards & Control in a Filling Isolator – Lessons](https://reader031.vdocuments.mx/reader031/viewer/2022020104/5addbbb37f8b9a9d4d8d9013/html5/thumbnails/11.jpg)
Autoclave Prior to VHP ?
11
![Page 12: PDA: A Global Achieving Meticulous Aseptic Standards ... PDA Aidan... · PDA: A Global Association Achieving Meticulous Aseptic Standards & Control in a Filling Isolator – Lessons](https://reader031.vdocuments.mx/reader031/viewer/2022020104/5addbbb37f8b9a9d4d8d9013/html5/thumbnails/12.jpg)
Guidance Documents
12
![Page 13: PDA: A Global Achieving Meticulous Aseptic Standards ... PDA Aidan... · PDA: A Global Association Achieving Meticulous Aseptic Standards & Control in a Filling Isolator – Lessons](https://reader031.vdocuments.mx/reader031/viewer/2022020104/5addbbb37f8b9a9d4d8d9013/html5/thumbnails/13.jpg)
Apparent Limitations of VHP ?
• The application of a sporicidal process is not considered to be a sterilization process
• ...lacks the penetrating capabilities of steam sterilization
• …be mindful of the limitations of surface sterilants
• …their inefficiency in penetrating obstructed or protected components
13
![Page 14: PDA: A Global Achieving Meticulous Aseptic Standards ... PDA Aidan... · PDA: A Global Association Achieving Meticulous Aseptic Standards & Control in a Filling Isolator – Lessons](https://reader031.vdocuments.mx/reader031/viewer/2022020104/5addbbb37f8b9a9d4d8d9013/html5/thumbnails/14.jpg)
What Limitations?
14
![Page 15: PDA: A Global Achieving Meticulous Aseptic Standards ... PDA Aidan... · PDA: A Global Association Achieving Meticulous Aseptic Standards & Control in a Filling Isolator – Lessons](https://reader031.vdocuments.mx/reader031/viewer/2022020104/5addbbb37f8b9a9d4d8d9013/html5/thumbnails/15.jpg)
VHP Controls
15
Temperature & Humidity
Airflow
Slow Motion during VHP to ensure
hidden areas are exposed Chemical
indicators
Biological Indicators –
Establishment of Edge of Failure
BI’s – Mitigation Against Variance
VHP Dosing Rate / Exposure
Time
System D Value Determination
![Page 16: PDA: A Global Achieving Meticulous Aseptic Standards ... PDA Aidan... · PDA: A Global Association Achieving Meticulous Aseptic Standards & Control in a Filling Isolator – Lessons](https://reader031.vdocuments.mx/reader031/viewer/2022020104/5addbbb37f8b9a9d4d8d9013/html5/thumbnails/16.jpg)
VHP Output
16
Consistently Delivers at least a 6 log BI Reduction
Is this no longer good enough?
![Page 17: PDA: A Global Achieving Meticulous Aseptic Standards ... PDA Aidan... · PDA: A Global Association Achieving Meticulous Aseptic Standards & Control in a Filling Isolator – Lessons](https://reader031.vdocuments.mx/reader031/viewer/2022020104/5addbbb37f8b9a9d4d8d9013/html5/thumbnails/17.jpg)
Longer Batch Turnaround Times
Increased Risk of Damage due to Handling
Opportunities for Error in all of the above
Storage Requirements with Control post Autoclaving
Autoclave Loads – Cycle Development / PQ / Requalification/ Hold time studies by Media Fill
CONSEQUENCES
![Page 18: PDA: A Global Achieving Meticulous Aseptic Standards ... PDA Aidan... · PDA: A Global Association Achieving Meticulous Aseptic Standards & Control in a Filling Isolator – Lessons](https://reader031.vdocuments.mx/reader031/viewer/2022020104/5addbbb37f8b9a9d4d8d9013/html5/thumbnails/18.jpg)
18
![Page 19: PDA: A Global Achieving Meticulous Aseptic Standards ... PDA Aidan... · PDA: A Global Association Achieving Meticulous Aseptic Standards & Control in a Filling Isolator – Lessons](https://reader031.vdocuments.mx/reader031/viewer/2022020104/5addbbb37f8b9a9d4d8d9013/html5/thumbnails/19.jpg)
VHP Cycle not effective
Product Contamination
Increased Bioburden load for VHP
Ineffective sanitisation as part of isolator set-up
RISK
ASSESSMENTS
INPUTS
![Page 20: PDA: A Global Achieving Meticulous Aseptic Standards ... PDA Aidan... · PDA: A Global Association Achieving Meticulous Aseptic Standards & Control in a Filling Isolator – Lessons](https://reader031.vdocuments.mx/reader031/viewer/2022020104/5addbbb37f8b9a9d4d8d9013/html5/thumbnails/20.jpg)
Gloves
20
How Risky are Pinholes in
Gloves? A Rational Appeal
for the Integrity of Gloves
for Isolators
Gessler, A. ; Stark, A.; Sigwarth, S. &
Moirandt, C. PDA J. Pharm Sci and Tech
2011 65: 227-241
![Page 21: PDA: A Global Achieving Meticulous Aseptic Standards ... PDA Aidan... · PDA: A Global Association Achieving Meticulous Aseptic Standards & Control in a Filling Isolator – Lessons](https://reader031.vdocuments.mx/reader031/viewer/2022020104/5addbbb37f8b9a9d4d8d9013/html5/thumbnails/21.jpg)
Following 12 batches over two weeks, less than 20% of the gloves (103) showed more than 5 CFU/sample.
Migration of microorganisms through damaged gloves with pinhole was established with high bioload(3.6 x 104 CFU/cm2)
Medium (4.3 x 103 CFU/cm2) and Realistic (5.0 x 101 CFU/cm2) bioloads did not result in contamination
Results
21
![Page 22: PDA: A Global Achieving Meticulous Aseptic Standards ... PDA Aidan... · PDA: A Global Association Achieving Meticulous Aseptic Standards & Control in a Filling Isolator – Lessons](https://reader031.vdocuments.mx/reader031/viewer/2022020104/5addbbb37f8b9a9d4d8d9013/html5/thumbnails/22.jpg)
Conclusions
• Pinholes as a source of contamination does not consider real world situations and may also have enormous economic consequences.
• Defective Gloves will not contaminate a product if proper control of the glove inner side and properly evaluated techniques are respected.
22
![Page 23: PDA: A Global Achieving Meticulous Aseptic Standards ... PDA Aidan... · PDA: A Global Association Achieving Meticulous Aseptic Standards & Control in a Filling Isolator – Lessons](https://reader031.vdocuments.mx/reader031/viewer/2022020104/5addbbb37f8b9a9d4d8d9013/html5/thumbnails/23.jpg)
EM Data (Viable & Non- Viable)
Review of Glove
Spec & Previous
Test Data
Leak Location
on Glove
Process Data -Alarms
Sequence of Events -
Interventions
Risks and Opportunities
23
Previous Deviations
![Page 24: PDA: A Global Achieving Meticulous Aseptic Standards ... PDA Aidan... · PDA: A Global Association Achieving Meticulous Aseptic Standards & Control in a Filling Isolator – Lessons](https://reader031.vdocuments.mx/reader031/viewer/2022020104/5addbbb37f8b9a9d4d8d9013/html5/thumbnails/24.jpg)
Batch is saved – no microbial contamination
The reason the gloves failed in the first place was not helped by excessive environmental monitoring inside the isolator
Where is the contamination going to come from in the first place?
Is this embracing new technology?
Glove Failure Investigations
![Page 25: PDA: A Global Achieving Meticulous Aseptic Standards ... PDA Aidan... · PDA: A Global Association Achieving Meticulous Aseptic Standards & Control in a Filling Isolator – Lessons](https://reader031.vdocuments.mx/reader031/viewer/2022020104/5addbbb37f8b9a9d4d8d9013/html5/thumbnails/25.jpg)
Lessons Learned…or not!
25
As long as some people erroneously insist on
immeasurable perfection, we will have
unreasonable expectations
Agalloco, J.; Akers, J. Aseptic Processing, Elephants, Blind Men, and
Sterility: PDA J Pharm Sci and Tech 2002, 56 231-234