Defining, achieving, and demonstrating effective performance of containment systems. Gordon Farquharson, July 2017

Transcription

1 Defining, achieving, and demonstrating effective performance of containment systems Gordon Farquharson, July 2017 Slide 1 PharmOut 2017

2 Agenda Objectives and Principles. A hierarchy of containment techniques. Basis of Design & Selection. Proving the performance Safety Qualification. Maintaining safe operation. Things that can go wrong! Slide 2 PharmOut 2017

3 Objectives and Principles

4 What are we trying to achieve? Occupational health & safety containment of radiological, potent, toxic or biologically hazardous compounds and materials. Cross-contamination control. Minimise contaminated space/volume/surfaces. Slide 4 PharmOut 2017

5 Occupational Health & Environmental Protection approach Identify the hazardous agent. If possible use something less hazardous (Eliminate the hazard). Contain the hazard in a closed process, and consider failure mode (might require a secondary containment). Contain an open process is a containment. Use personal protective equipment alone as a final resort. Slide 5 PharmOut 2017

6 What influences containment performance? The inherent capability of the system being employed How to define this is a challenge. The source strength of challenge to the system. The duration of the challenge event. Different phases of the operational cycle of a device: Connect Disconnect Cleaning Failure mode Slide 6 PharmOut 2017

7 Practicalities of containment engineering Difficult to engineer a device with a specific level of containment capability. For practical reasons, we use the following approach: Usually select a standard or adapted device that meets broad objectives. Develop design principles + usually explore some options. GMP and Safety Case review, including failure modes. Tender and procure. FAT, often including functional and containment testing. Install and commission. Quality and Safety Qualification. Start normal operations. Slide 7 PharmOut 2017

8 A Typical Hierarchy For Containment This Graphic Is Reproduced Courtesy Of Extract Technology Ltd. Slide 8 PharmOut 2017

9 Gordon s Containment Hierarchy

10 Reduce the hazard Not possible to remove the hazardous agent. Handling a liquid solution or slurry generally has lower risk of exposure than powder. Consider doing this during dispensing of a potent API. Slide 10 PharmOut 2017

11 Use of open fronted MBSC or Specialised Cytotoxic Safety Cabinets Containment relies upon effective air inflow. Containment performance 3-5 log reduction source outside. Remember cleaning & Filter testing and replacement. Containment level 3 Slide 11 PharmOut 2017

12 Downflow Booth (Typical arrangement) Slide 12 PharmOut 2017

13 Downflow Booth (Enhanced with barriers) Slide 13 PharmOut 2017

14 Cross Flow B Dispensary : Better material handling Slide 14 PharmOut 2017

15 Think through the manual handling as well Slide 15 PharmOut 2017

16 Booth issue Work practice can destroy the benefit and protection Airflow Direction Contamination across operator breathing zone Slide 16 PharmOut 2017

17 Personal Monitoring Equipment Gravimetric and Real-Time dust monitors for personnel and environments Sanofi Aventis Compiegne. Industrial Hygiene Sampling and Remedial actions Slide 17 PharmOut 2017

18 Dust monitoring instruments develop Slide 18 PharmOut 2017

19 Charging Potent Drugs Cup Hermann Slide 19 PharmOut 2017

20 Charging Potent Drugs Cup Herman by Bio-Components Switzerland Slide 20 PharmOut 2017

21 Split Butterfly Valve Slide 21 PharmOut 2017

22 Split Butterfly Valves: GLATT valve PSL valve Air: < 10 µ/m³ BUCK Air: valve Wipe: < 5 µ/m³ 2-3 mg/m³ (1 transfer) Air: 2-3 mg/m³ (5 Wipe: < transfers) 5 µ/m³ 5-15 mg/m³ (1 transfer) mg/m³ Wipe: (5 transfers) 5-15 mg/m³ (1 transfer) mg/m³ (5 transfers) Slide 22 PharmOut

23 Chargepoint Technology Pharmsafe split butterfly valve with extraction. Slide 23 PharmOut 2017

24 Cone Discharge + Docking Valve Photograph courtesy of Matcon Ltd Slide 24 PharmOut

25 Split butterfly valves in action Contained connections Make sure that failure modes are considered. Alignment of split butterfly valves and be critical. FAT and SAT essential. In particular, ensure excessive deflection of hoist is engineered out. Slide 25 PharmOut 2017

26 Potent Compound Dispensing 1. Downflow principle 2. Local Containment Range 1 to 0.1 microg/cu.m Range 10 to 1 microg/cu.m Slide 26 PharmOut 2017

27 Glovebag systems in R & D Slide 27 PharmOut 2017

28 Weighing Dispensing Isolator Slide 28 PharmOut 2017

29 Automated Solution: Easier to use minimal operator interface = low dust exposure Slide 29 PharmOut 2017

30 BULK SUB-DIVISION INTO BATCH SIZES: Slide 30 PharmOut 2017 Complete Small batch System: Sub-division Isolator Poly bottles in 3 sizes Microcharge Vessel Loading Unit

31 RTP PORTS AND CONTAINERS Interchangeable with other RTP/DPTE Devices Nanogram level transfer technology Slide 31 PharmOut 2017

32 Large Scale Filter Dryer off-load isolator Continuous Liner Slide 32 PharmOut 2017

33 Reactor charging isolator Image courtesy of PSL, Powder Systems Ltd. Slide 33 PharmOut 2017

34 ASSESSING PHARMACEUTICAL CONTAINMENT EQUIPMENT USING SURROGATE MONITORING Validation of containment performance Based on the ISPE SMEPAC initiative

35 Slide 35 PharmOut 2017

36 Applied to large Booths Define a known source challenge of airborne particles inside. Determine what percentage gets out! This is a measure Slide 36 PharmOut 2017

37 Applied to small enclosures Slide 37 PharmOut 2017

38 Applied to bespoke isolators Slide 38 PharmOut 2017

39 Simple explanation of surrogate monitoring Handling or processing lactose or another surrogate material in containment equipment such as an isolator, material transfer valve or other equipment intended to contain active pharmaceutical ingredients (APIs). Conducting air sampling and surface sampling to determine how much dust escapes from the containment. The sampling results provide a means of estimating how effectively the equipment will contain the API under similar conditions of use. Slide 39 PharmOut 2017

40 Purpose and benefits Evaluate containment performance without potential exposures to potent Active Pharmaceutical Ingredients (APIs) Evaluate containment performance in situations where an analytical method has not been developed for the API of interest Evaluate equipment/devices before purchase Obtain baseline data to compare equipment models from different suppliers Obtain baseline data to compare different technologies Evaluate performance of new equipment before initial production begins using potent API Retest to determine if performance of existing equipment has degraded over time versus the baseline Slide 40 PharmOut 2017

41 Some limitations of surrogate testing Does not evaluate exposures to gases or vapours which may escape the containment Results not directly comparable to materials with different physical properties Results do not guarantee compliance with OELs established for specific APIs Slide 41 PharmOut 2017

42 Example of contained dust collection system tested Dust Collection System designed for bag-in/bag-out filter changing and collection drum liner removal Slide 42 PharmOut 2017

43 Surrogate materials Lactose Flow characteristics Analytical limit of detection Low toxicity Availability Low cost of surrogate Cost of sample analysis Solubility Other surrogates to consider Naproxen Sodium Riboflavin (vitamin B2) Mannitol Sucrose Acetaminophen (paracetamol) Slide 43 PharmOut 2017

44 Surface wipe & Swab Samples (c) Critical Systems /07/2017 Slide 44 PharmOut 2017

45 Sampling strategy Prevent ingress of any contamination likely to bling the study. Background air and surface samples should be taken. Take human breathing zone samples. Long term, and Short term (event or task based). Take general air samples. Long and short term. At critical points of actual or potential leakage. Surface wipe or swab samples at critical locations. Slide 45 PharmOut 2017

46 Example of general air samples Sample location around a split butterfly valve (c) Critical Systems 2011 Slide 46 PharmOut /07/2017

47 Surface samples Collect after individual process cycles or steps Collect at end of overall operation Slide 47 PharmOut 2017

48 Surface test results Pharmaceutical companies may or may not have established limit for surface contamination for specific APIs. Often detect contamination where air samples were below detection. May show need for additional cleaning before removing objects from containment or to other areas (e.g. clean contaminated RTP seal when container is undocked). (c) Critical Systems /07/2017 Slide 48 PharmOut 2017

49 Summary Surrogate monitoring evaluates the effectiveness of containment equipment using materials having low toxicity. Lactose is the recommended surrogate material, but others may also be used. The sampling strategy includes both air samples and surface samples. The results can be helpful in selecting containment equipment: Vendor produces data to support sale proposal. Testing can be part of safety qualification of a system; and can support a multi-product, non dedicated facility design. There are limitations. Therefore, exposure to the actual API should also be evaluated once the containment becomes operational in the lab or production setting. Slide 49 PharmOut 2017

50 Thank you for your time. Questions? Gordon Farquharson Executive Consultant Slide 50 PharmOut 2017

51 PharmOut Copyright Notice All rights reserved This presentation and all associated materials are copyrighted and all rights reserved by PharmOut. No part of this presentation may be reproduced or transmitted in any form or for any purpose without the express permission of PharmOut in writing. The information contained herein may be changed without prior notice. Data contained in this presentation serves informational purposes only. PharmOut does not warrant the accuracy or completeness of the information, text, graphics, links, or other items contained within this presentation. This presentation is provided without a warranty of any kind, either express or implied, including but not limited to the implied warranties of merchantability, fitness for a particular purpose, or non-infringement. PharmOut shall have no liability for damages of any kind including without limitation direct, special, indirect, or consequential damages that may result from the use of this presentation. Slide 51 PharmOut 2017