defining, achieving, and demonstrating effective ...€¦ · • surrogate monitoring evaluates the...

Defining, achieving, and demonstrating effective performance of containment systems

Gordon Farquharson, July 2017

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!

Objectives and Principles

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.

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.

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

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.

A Typical Hierarchy For Containment This Graphic Is Reproduced Courtesy Of Extract Technology Ltd.

Gordon’s Containment Hierarchy

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.

Use of open fronted MBSC or Specialised Cytotoxic Safety Cabinets

Containment level 3

• Containment

relies upon

effective air

inflow.

• Containment

performance 3-5

log reduction

source

outside.

• Remember

cleaning & Filter

testing and

replacement.

Downflow Booth (Typical arrangement)

Downflow Booth (Enhanced with barriers)

Cross Flow B Dispensary : Better material handling

Think through the manual handling as well

Booth issue – Work practice can destroy the benefit and protection

Airflow Direction

Contamination across operator breathing zone

Personal Monitoring Equipment

Sanofi –Aventis Compiegne. Industrial Hygiene Sampling and Remedial actions

Gravimetric and Real-Time dust

monitors for personnel and

environments

Dust monitoring instruments develop

Charging Potent Drugs

Cup Hermann

Charging Potent Drugs

Cup Herman™ by Bio-Components

Switzerland

Split Butterfly Valve

GLATT valve

< 10 µ/m³

2-3 mg/m³ (1 transfer)

2-3 mg/m³ (5 transfers)

Split Butterfly Valves:

PSL valve

< 5 µ/m³

BUCK valve

< 5 µ/m³

Chargepoint Technology “Pharmsafe” split butterfly valve with extraction.

Cone Discharge + Docking Valve

Photograph courtesy of Matcon Ltd

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.

Potent Compound Dispensing1. Downflow principle 2. Local Containment

Range 1 to 0.1 microg/cu.m

Range 10 to 1 microg/cu.m

Glovebag systems in R & D

Weighing Dispensing Isolator

Automated Solution: Easier to use – minimal operator interface = low dust exposure

Complete Small batch System:

Sub-division Isolator

Poly bottles in 3 sizes

Microcharge Vessel Loading Unit

BULK SUB-DIVISION INTO BATCH SIZES:

RTP PORTS AND CONTAINERS

Interchangeable with other RTP/DPTE Devices

Nanogram level transfer technology

Large Scale Filter Dryer off-load isolator –Continuous Liner

Reactor charging isolator

Image courtesy of

PSL, Powder Systems

ASSESSING PHARMACEUTICALCONTAINMENT EQUIPMENT USINGSURROGATE MONITORINGValidation of containment performance

Based on the ISPE SMEPAC initiative

www.ispe.org

Applied to large Booths

Define a known source challenge of airborne particles inside.

Determine what percentage gets out!

This is a measure

Applied to small enclosures

Applied to bespoke isolators

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.

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

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

Example of contained dust collection system tested

Dust Collection System designed for bag-in/bag-out filter changing and collection drum liner removal

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)

Surface wipe & Swab Samples

(c) Critical Systems 2011

21/07/2017

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.

Example of general air samples

Sample location around a split butterfly valve

21/07/2017

Surface samples

Collect after individual process cycles or steps

Collect at end of overall operation

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).

21/07/2017

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.

Thank you for your time.Questions?

Gordon Farquharson

gordon.farquharson@pharmout.net

www.pharmout.net

Executive Consultant

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.

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