Lessons Learnt During Containment Verification of Potent APIsJune 23, 2021
By:Karen Whitaker, CIH, MPH
Associate Director- GSE, Merck Rahway and Kenilworth
Ankit Sharma, CIH, LFOHAssociate Director- International Safety Systems, Inc, Houston TX.
2021 Pharma Forum
Background● Pharmaceutical industry has undergone significant advancements over last
decade.● Oncology, rare diseases and highly targeted therapies - new modalities in both
the small and large molecule space with complex drug delivery mechanisms● Occupational Exposure Limits (OELs) are getting lower, more frequently in
nanograms per cubic meter (ng/m3) levels.● Increased need to develop robust containment systems to handle the highly
potent APIs.● Containment verification is necessary to validate effectiveness of containment.
Containment Technology Selection and Design● Team Concept
○ Engineer○ End user - operator, researcher○ Industrial Hygienist○ Equipment vendor ○ Containment vendor
● Ensure entire team has complete understanding of all tasks that can lead to exposure ○ Charging, discharging and material transfers○ Sampling○ Manual interventions○ Cleaning○ Waste removal○ Upset scenarios
Lesson Learnt – Ensure team approach and that team members understand all tasks associated with the equipment.
Vendor Selection and Criteria Measuring Success● Develop User Requirements Specification (URS) and include
containment performance target (CPT) and/or design exposure limit (DEL) and criteria for success
● CPT (Emissions) vs. DEL (Operator Exposure) ● Vendor willing to commit to meet CPT and/or DEL and share
containment data for same or similar design● Alignment with vendor on containment verification (CV) at Factory
Acceptance Testing (FAT) at vendor and/or Site Acceptance Testing (SAT)
● Utilize industry recognized practice and agree on data evaluation criteria○ ISPE Assessing the Particulate Containment Performance of Pharmaceutical
Equipment (Second Edition, May 2012)○ Data Analysis - 95th Percentile Point Estimate, Bayesian Decision Analysis,
EN-689:2018, etc.Lesson Learnt – Identify criteria defining successful containment up front
and how data will be evaluated against it.
Surrogate Selection● ISPE provides overview on surrogate selection● Particle characteristics
○ Similar dustiness, particle size of APIs○ Vendor provide right particle size distribution (PSD) and certification or perform size
reduction (e.g., milling, sieving, etc.) in house and perform (PSD) analysis ● Analytical sensitivity appropriate for CPT / DEL
○ Naproxen sodium (0.05 ng or 0.2 ng) preferred/needed for OEB 5 v/s Lactose/Mannitol (2 -2.5 ng)
● Limited handling of surrogate at facility to avoid background contamination○ Lactose and mannitol readily available, but are often used in formulations
● Availability● Cost considerations● Excipient vs. API
Lesson Learnt - Procure surrogate with same size specifications as API.
Surrogate Handling Reminders● Before FAT/SAT
○ Do not handle surrogate in the same suite/department where CV is planned.○ Do not use any parts/equipment/tools and PPE/gowning likely contaminated with
surrogate.○ Ensure test suites are thoroughly cleaned with appropriate cleaning agent for the
specific surrogate prior to CV.○ Ensure sufficient quantity of surrogate so it does not have to be re-used.
● During FAT/SAT○ Do not use the same PPE used during surrogate handling prior to CV.○ Use disposable PPE and change after each iteration during CV.○ Do not change / ease work practices/PPE between API and surrogate just
because surrogate is ‘less hazardous’ than API.
Lesson Learnt – No surrogate handling in equipment or room or perform thorough cleaning to prevent background contamination prior to CV .
Containment Verification Protocol ● Identify CPT, surrogate and media
requirements● List of supplies for IH for CV● List of supplies for operations to
perform CV● Include detailed steps for each task
including technique reminders, especially around cleaning
● Utilize protocol for training prior to CV
Lesson Learnt – Details on the task provide tips on proper technique, which
can be added to SOPs.
Containment Verification Protocol (Contd.)
● List air and wipe sample locations● Include drawings with sample locations● Define the number of iterations● Break sampling into subtasks to discern
if a particular subtask contributes to airborne or surface contamination
● Helps ensure field and office IH personnel execute per protocol
Lesson Learnt - Important to break down sampling into sub-tasks to identify tasks/steps which may contribute to containment failure.
Hands-On Training● Critical for users to understand all features of containment and equipment
so containment performance vs. exposure from improper use is assessed.● Training Tips
○ Schedule a few weeks before the actual containment verification○ Encourage users to continue to perform trial runs after hands-on training○ Use low hazard powders ○ Consider UV activated glow powders to visualize contamination○ All users operating the equipment in CV participate.○ Utilize all the same tools and PPE ○ Follow each detailed step (as expected to be followed during actual API handling). ○ Ensure all functionality demonstrated and tried (e.g., continuous liner, contained transfer
system, etc.)○ Orient operators to the proper use of containment and equipment and good technique.
■ Inspection, testing and PMs■ Alarms■ Equipment capabilities and limitations■ Technique Reminders■ PPE donning and doffing
Lesson Learnt – Hands-on training is key to assessing containment performance and minimizing exposure risk during normal use.
Containment Device Location● Containment device set up away from high traffic areas● Ensure it is not located near air diffuser that may cause cross drafts.● Locate in facility per manufacturers recommendation● Ensure field IH performs air velocity measurements and smoke test to
visualize airflow patterns.
Lesson Learnt – Ensure containment device is set up in an area away from air diffusers and high traffic areas that can lead to a containment
failure due to turbulence.
Cleaning Practices● Transfer of contamination from ‘red zone’ remains one of
biggest challenges and sources of failure to meet CPT or DEL○ Unsuitable cleaning agent, solubility important, > 20 mg/mL, surrogate
typically better than API○ Cursory quick cleaning vs. detailed thorough cleaning○ Using same wipe to clean multiple surfaces○ Inability to reach all surfaces and/or cleaning tools not available
● Good Cleaning Technique○ Detailed procedure with a suitable cleaning solvent○ Line work surfaces○ Clean as you go○ Avoid smearing contamination by overusing a wipe, use one
wipe/surface○ Clean hard to reach places using cleaning tools○ Post job aids○ Hands-on training demonstrating proper technique
Lesson Learnt – Development of good cleaning technique requires training.
Job AideIsolator Best Practices
Cleaning parts before discarding in waste bags
Cleaning the funnel and wrapping up the funnel in the wet wipe and then discarding to the zip loc waste bag.
Clean and wrap any weigh boat in the same way
Cleaning disposable spatula and wrap it before discarding to the zip loc waste bag
Clean gloves with new wipe after cleaning each of spatula, weigh boat and funnel and frequently between different parts
Cleaning through the funnel stem using the wipe impregnated with cleaning solvent
Wipe Sampling● Identify wipe sample locations assessing migration of
contamination from containment due to breach vs. poor employee technique.
● Ensure area and equipment thoroughly cleaned prior to CV to minimize background contamination.
● Collect background samples prior to CV at all sample locations.
● Mark sample location to ensure same location sampled between iterations.
● Reduce spread of contamination by IHs actions ○ Label vials and write sampling locations in record sheets prior to
sampling.○ Collect floor samples first and don’t stand or touch sampling locations.
● Avoid stepping /standing on or touching sampling locations.
Lesson Learnt – Carefully select wipe sample locations and understand if it indicates a containment breach or poor technique.
Case StudyBackground: ● Containment verification of OEB 5 API with 10 ng/m3
CPT ● Solid subdivision of 10 g surrogate● Three repeat iterations● SAT
Isolator (Negative Pressure) Discovery Lab Isolator: ● Pass-in box, 4-glove main chamber ● Single HEPA air inlet ● Double HEPA exhaust, safe change● Ventilated enclosure to pass out items and performed
final cleaning/materials removal ● Continuous liner for waste removal on side of ventilated
enclosure
1st Monitoring EventPBZ Air Sampling Results Summary
Task Iteration 1(ng/m3)
Iteration 2(ng/m3)
Iteration 3(ng/m3)
Solid subdivision+ Cleaning of Main chamber
0.42 <0.449 2.55
Ventilated chamber cleaning
<0.925 <1.06 2.95
Waste removal from liner
<1.35 <1.35 56.5
1st monitoring event● PBZ air concentration> CPT for waste removal task in 3rd iteration.● Observed highest PBZ air monitoring results from the 3rd iteration.● Surface contamination on external surfaces such as glove-ports and pass-
in box : 25-50% of wipe limit.
● Investigation:
○ Employee had dispensed surrogate at another work-station/another floor during the day (for preparation of surrogate solution for separate analysis).
○ Employee did not change lab coat after this separate dispensing task, before starting the 3rd
iteration for Isolator CV.
○ Potentially contaminated lab coat could have transferred contamination to the test suite, likely contributed to reported airborne concentrations.
2nd Monitoring EventPBZ Air Sampling Results Summary(after incorporating improvements from 1st event)
Task Iteration 1(ng/m3)
Iteration 2(ng/m3)
Iteration 3(ng/m3)
Solid subdivision+ Cleaning of Main chamber
<0.405 <0.364 <0.245
Ventilated chamber cleaning
11.4 <1.12 <0.978
Waste removal from liner
<1.4 <1.4 <1.22
Insufficient cleaning, rushed during cleaning – potential carryover of
contamination on surrogate bottles/waste bags moved from main chamber to ventilated
enclosure.
Key Takeaways● Collaborate with the “right” team and set your pass / fail criteria (CPT and DEL) ● Develop understanding of all tasks performed with the equipment and
containment● Select a vendor that can demonstrate containment success with data and willing
to commit to the CPT and/or DEL● Identify whether CV will be performed at FAT and SAT or just SAT● Select a surrogate that is representative of API and unique to CV● Develop a detailed CV protocol that assesses containment for all tasks● Ensure employees have hands-on training and are knowledgeable in the
sampling protocol prior to CV● Certify containment and assess room conditions prior to CV● Proper cleaning technique is key to successful CV and containment going
forward● Wipe sampling is a key component when assessing containment and cleaning
effectiveness
Thank you!
For any questions, please contact:Karen Whitaker, MPH, CIHAssociate Director – GSE at Merck Rahway and KenilworthEmail: [email protected]
Ankit Sharma, CIH, LFOHAssociate Director- International Safety Systems Inc.Email: [email protected]
