www.issehs.com Analysis of Exposure Monitoring Analysis of Exposure Monitoring Results and Lessons Learned – Results and Lessons Learned – Pharmaceutical Unit Operations Pharmaceutical Unit Operations Maharshi Mehta, CSP, CIH Maharshi Mehta, CSP, CIH Prasanth K., CIH, Gopal C. Prasanth K., CIH, Gopal C. International Safety Systems, Inc. International Safety Systems, Inc. 1 Pharma Forum 2016 Pharma Forum 2016 AIHCE, Baltimore, May 25 AIHCE, Baltimore, May 25
Transcript
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Analysis of Exposure Monitoring Results and Analysis of Exposure Monitoring Results and Lessons Learned – Pharmaceutical Unit Lessons Learned – Pharmaceutical Unit OperationsOperations
Maharshi Mehta, CSP, CIHMaharshi Mehta, CSP, CIHPrasanth K., CIH, Gopal C.Prasanth K., CIH, Gopal C.International Safety Systems, Inc.International Safety Systems, Inc.
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Pharma Forum 2016Pharma Forum 2016AIHCE, Baltimore, May 25AIHCE, Baltimore, May 25
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ObjectivesObjectives
Analyze API and surrogate monitoring results Analyze API and surrogate monitoring results Identify exposures at unit operations Identify exposures at unit operations Identify effectiveness of exposure controls Identify effectiveness of exposure controls Identify exposure contributory factorsIdentify exposure contributory factors Reduce future exposure monitoring Reduce future exposure monitoring Implement exposure controls based on lessons learned Implement exposure controls based on lessons learned
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This study is beginning of long term study of 10000+ sampling results
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Results OriginResults Origin
~ 5500 results of API and surrogates~ 5500 results of API and surrogates 100+ workplaces 100+ workplaces 21+ countries21+ countries Over a period of last 7 years Over a period of last 7 years Personal and area sampling Personal and area sampling APIs and surrogates APIs and surrogates Only air samples considered, not wipe Only air samples considered, not wipe 11 ISS professionals were involved in collecting data11 ISS professionals were involved in collecting data Only ISS collected data is considered at this time Only ISS collected data is considered at this time
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USAUSA CanadaCanada Mexico Mexico BrazilBrazil ColumbiaColumbia Argentina Argentina
Results Origin: AmericasResults Origin: Americas
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Results Origin : AsiaResults Origin : Asia
IndiaIndia China China SingaporeSingapore IndonesiaIndonesia JapanJapan Australia Australia
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Austria Austria Germany Germany Netherland Netherland France France Ireland Ireland Portugal Portugal Italy Italy Spain Spain UKUK
Results Origin: EuropeResults Origin: Europe
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Challenges Challenges
Result variability – GSD Result variability – GSD Work practices dependent Work practices dependent Engineering controls and particulate Engineering controls and particulate
containment variability containment variability Weight of API/surrogateWeight of API/surrogate
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Methods – API/Surrogate Sampling Methods – API/Surrogate Sampling and Analysisand Analysis Only validated methods from AIHA accredited lab with Only validated methods from AIHA accredited lab with
pharma analytical expertise used and anlyzedpharma analytical expertise used and anlyzed Written protocol for sampling used Written protocol for sampling used
– Sample flow rates/volumeSample flow rates/volume– MediaMedia– Avoiding cross contamination Avoiding cross contamination – Each sample in zip-lock plastic bag Each sample in zip-lock plastic bag
ISPE protocol used for surrogate monitoring ISPE protocol used for surrogate monitoring
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Method – Data Analysis Method – Data Analysis
Sampling notes entered in result sheets in Excel® was Sampling notes entered in result sheets in Excel® was available workplacesavailable workplaces
Result sheets were standardized Result sheets were standardized – Sample id, Sample id, – Sample duration, Sample duration, – Unit OperationsUnit Operations– Weight of API/SurrogateWeight of API/Surrogate– Controls provided Controls provided
Results were sortedResults were sorted
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Unit operations for statistical Unit operations for statistical analysesanalyses As a first stage of the analysis, unit operations with less As a first stage of the analysis, unit operations with less
variability selected variability selected – Laboratory scale weighing with controls (VBSE, or laboratory Laboratory scale weighing with controls (VBSE, or laboratory
fume hoods) and without controlsfume hoods) and without controls– Weighing dispensing in isolatorWeighing dispensing in isolator– Charging/discharging with split butterfly valveCharging/discharging with split butterfly valve– Weighing and dispensing in Laminar Flow BoothWeighing and dispensing in Laminar Flow Booth– QC samplingQC sampling
500 + results separated for above unit operations and for 500 + results separated for above unit operations and for weight of API/surrogate weight of API/surrogate
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Statistical Analysis Tool usedStatistical Analysis Tool used
IHSTAT®IHSTAT®– From AIHA Exposure Assessment CommitteeFrom AIHA Exposure Assessment Committee
IHData Analyst® (Bayesian Data Analysis)IHData Analyst® (Bayesian Data Analysis) Results for the unit operations were entered Results for the unit operations were entered Results were separated for weight range Results were separated for weight range 9595thth%tile point estimate and GSD were determine %tile point estimate and GSD were determine Lognormal distribution was determinedLognormal distribution was determined
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Results and preliminary Results and preliminary conclusions – Qualifiers conclusions – Qualifiers The results are indicative and not confirmative The results are indicative and not confirmative The conclusion from the results and lessons learned are The conclusion from the results and lessons learned are
also indicative and not confirmativealso indicative and not confirmative Additional study is neededAdditional study is needed
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Personal exposure: Laboratory Scale Personal exposure: Laboratory Scale weighing in VBSEweighing in VBSE
Sample size: 10Sample size: 10 Range of results: < 0.04 – 0.41 Range of results: < 0.04 – 0.41 μμg/mg/m33 Sample Duration: 27 - 34 MinutesSample Duration: 27 - 34 Minutes Sample Weight: < 1 gramSample Weight: < 1 gram GSD: 2.59GSD: 2.59 9595thth%ile – 1.57 %ile – 1.57 μμg/mg/m33 Lognormal distribution hypothesis is not Lognormal distribution hypothesis is not
rejectedrejected
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Personal exposure: Laboratory Personal exposure: Laboratory weighing- no exposure controls weighing- no exposure controls
Sample size: 12 Sample size: 12 Range of results: 0.078 – 3.84 Range of results: 0.078 – 3.84 μμg/mg/m33 Sample Duration: 5 – 15 minutesSample Duration: 5 – 15 minutes Sample Weight: < 1 gramSample Weight: < 1 gram GSD – 4.48GSD – 4.48 9595thth%ile – 4.21 %ile – 4.21 μμg/mg/m33 Lognormal distribution hypothesis is not Lognormal distribution hypothesis is not
rejectedrejected
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Comparison of laboratory scale weighing Comparison of laboratory scale weighing resultsresults
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Lessons Learned-Laboratory Lessons Learned-Laboratory WeighingWeighing Initial Indication – For < grams of weighingInitial Indication – For < grams of weighing
– OEB 5 (< ug/mOEB 5 (< ug/m33) and low OEB 4 (>1 ug/m3 and < 10 ug/m) and low OEB 4 (>1 ug/m3 and < 10 ug/m33) compounds ) compounds may require isolator may require isolator
– VBE could be used for OEB 4 compounds coupled with sound work-practices VBE could be used for OEB 4 compounds coupled with sound work-practices and PPEand PPE
Work-practices contributing to high exposuresWork-practices contributing to high exposures– Using brush to clean surfacesUsing brush to clean surfaces– Removing API container and other tools out without wipe cleaning and Removing API container and other tools out without wipe cleaning and
without double plastic bags without double plastic bags All size and types of enclosures are used – use only VBSE that All size and types of enclosures are used – use only VBSE that
meets specifications meets specifications – HEPA filterHEPA filter– Port for removal of waste Port for removal of waste
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Personal exposure: Dispensing inside Isolator Personal exposure: Dispensing inside Isolator (Weight Range 20 Kg – 40 Kg)(Weight Range 20 Kg – 40 Kg)
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Sample size: 16 Sample size: 16 Range of results: 0.025 Range of results: 0.025 μμg/mg/m33 – –
Lognormal distribution hypothesis Lognormal distribution hypothesis is not rejectedis not rejected
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Between the two glove ports of main dispensing Between the two glove ports of main dispensing chamber (Weight range: 20 – 40 Kg)chamber (Weight range: 20 – 40 Kg)
Sample size: 9 Sample size: 9 Range of results: < 0.004 Range of results: < 0.004 μμg/mg/m33 – –
minutesminutes Sample Weight : 20 – 40 KgSample Weight : 20 – 40 Kg GSD: 2.9GSD: 2.9 9595thth%ile: 1.88 %ile: 1.88 μμg/mg/m33 Lognormal distribution Lognormal distribution
hypothesis is not rejectedhypothesis is not rejected
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9595thth%ile for Dispensing inside Isolator (for %ile for Dispensing inside Isolator (for weight range of 20-40 Kg)weight range of 20-40 Kg)
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Lessons Learned-Isolator Lessons Learned-Isolator
Do not assume exposure will be below OEB 4-5 APIs as isolator Do not assume exposure will be below OEB 4-5 APIs as isolator is used. is used.
Best of isolator would not reduce exposures if work practices are Best of isolator would not reduce exposures if work practices are not followed:not followed:– API container when received has no contamination outside?API container when received has no contamination outside?– In double plastic bags?In double plastic bags?– Isolator integrity test before being used?Isolator integrity test before being used?– Make-shift or real isolator?Make-shift or real isolator?– Disposable spatula and tools used? Wiped and in double plastic bags Disposable spatula and tools used? Wiped and in double plastic bags
before removing?before removing? Develop detailed SOP on selecting, validating and using isolatorDevelop detailed SOP on selecting, validating and using isolator
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Personal Exposure: Charging/Discharging Personal Exposure: Charging/Discharging using SBV (15 Kg – 60 Kg)using SBV (15 Kg – 60 Kg)
minutesminutes Sample Weight: 15 kg – 60 kg Sample Weight: 15 kg – 60 kg GSD : 4.17GSD : 4.17 9595thth %ile : 7.69 %ile : 7.69 μμg/mg/m33 Lognormal distribution hypothesis is Lognormal distribution hypothesis is
not rejectednot rejected
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Area Sample: Charging (weight range: 15 Kg – Area Sample: Charging (weight range: 15 Kg – 60 Kg)60 Kg)
Lognormal distribution hypothesis is Lognormal distribution hypothesis is not rejectednot rejected
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9595thth %ile results: Charging with SBV %ile results: Charging with SBV
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Lessons Learned - Lessons Learned - SBVSBV
Don not assume installation of SBV will reduce Don not assume installation of SBV will reduce particulate emissions below OEB 4/5 OELs. particulate emissions below OEB 4/5 OELs.
Selection, installation, use/misuse and maintenance of Selection, installation, use/misuse and maintenance of SBV resulted in to high area concentrationsSBV resulted in to high area concentrations
Carefully select supplier – initial cost may be high – long Carefully select supplier – initial cost may be high – long term cost savings and exposure reduction benefits could term cost savings and exposure reduction benefits could be significantbe significant
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Personal exposure: API Dispensing Inside Personal exposure: API Dispensing Inside LFB (LFB (Weight: 500 grams – 1.5 kg ) Weight: 500 grams – 1.5 kg )
Personal exposure: API QC sampling inside Personal exposure: API QC sampling inside LFB (60 grams) (results from single site)LFB (60 grams) (results from single site)
Personal exposure: API QC sampling inside Personal exposure: API QC sampling inside LFB (10-100 grams) – Multiple site dataLFB (10-100 grams) – Multiple site data
Lessons Learned during Lessons Learned during Dispensing/QC sampling under LFBDispensing/QC sampling under LFB
Focus on QC sampling same or even more than weighing and Focus on QC sampling same or even more than weighing and dispensingdispensing– Although API weight sampled is much lower than Although API weight sampled is much lower than
weighing/dispensing, exposure is likely to be highweighing/dispensing, exposure is likely to be high– Opening of containers for sampling – opening and closing of poly Opening of containers for sampling – opening and closing of poly
bag and breathing zone near bags during QC samplingbag and breathing zone near bags during QC sampling– Standardization of exposure controls (LFB) is important
What pharma IH community believed is confirmed What pharma IH community believed is confirmed – API exposure is not likely to be below < 50 API exposure is not likely to be below < 50 μμg/mg/m33 during during
weighing/dispensing in LFBweighing/dispensing in LFB– Work practices significantly contribute to higher exposuresWork practices significantly contribute to higher exposures
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Summary: 95Summary: 95thth %ile personal exposure results %ile personal exposure results
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SummarySummary
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Limited sampling results analysis of the selected unit operations Limited sampling results analysis of the selected unit operations identified:identified:– Personal exposure levels likely to occurPersonal exposure levels likely to occur
Additional data analysis and professional judgement would assist in Additional data analysis and professional judgement would assist in implementing controls and work-practices that would reduce implementing controls and work-practices that would reduce exposure below target levelsexposure below target levels
Add required data collection Add required data collection – Sample weightSample weight– Name/brand name/picture of controlsName/brand name/picture of controls
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Summary Summary
PPE and RPE are standardized across all pharma sites for PPE and RPE are standardized across all pharma sites for some companiessome companies– Same approach is needed for pharma containment Same approach is needed for pharma containment
equipment also equipment also Installation of equipment is not enough; SOPs, training Installation of equipment is not enough; SOPs, training
and maintenance are even more critical and maintenance are even more critical Participate in exposure control selection processParticipate in exposure control selection process
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Plans Plans
Invite IHs from other companies and form a group Invite IHs from other companies and form a group Conduct similar data analyses with larger sample sizeConduct similar data analyses with larger sample size Address lessons learned from this limited study Address lessons learned from this limited study
– Weight rangeWeight range– Specific details on engineering controls Specific details on engineering controls
Peer reviewPeer review PublishPublish
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Recognition Recognition
Terry Lane from Merck for reviewTerry Lane from Merck for review Perry Logan for insights on analysis using BDA toolPerry Logan for insights on analysis using BDA tool Current and previous ISS team who diligently conducted Current and previous ISS team who diligently conducted
exposure monitoring exposure monitoring Ankit Sharma, Gopal and Prasanth from ISS who Ankit Sharma, Gopal and Prasanth from ISS who
complied and summarized results complied and summarized results
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Volunteers participate in Volunteers participate in rigorous study? Publication of rigorous study? Publication of papers? papers?
