eenvironmental monitoring regulatory aspects

ENVIRONMENTAL MONITORING ENVIRONMENTAL MONITORING ––Regulatory AspectsRegulatory Aspects

Victor MaquedaVictor Maqueda

DCVMNDCVMNNovember 12, 2007November 12, 2007

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Comparison of deficiencies found from 1995 to Comparison of deficiencies found from 1995 to 2005. source: PDA, October 2007.2005. source: PDA, October 2007.

292956/19356/193TotalTotal

3.63.677EnvironmentalEnvironmental MonitoringMonitoring1111

4.14.188SterilitySterility AssuranceAssurance1010

5.25.21010EnvironmentalEnvironmental ControlControl88

5.75.71111PersonnelPersonnel issuesissues. . HygeneHygene / / ClothingClothing77

10.410.42020ContaminationContamination, , microbmicrob. . –– potential forpotential for22

IncidenceIncidence(%)(%)

NumberNumberCategoryCategory of of CriticalCritical GMP GMP deficiencydeficiencyRankingRanking

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Regulations and Guidelines for Regulations and Guidelines for Environmental Air MonitoringEnvironmental Air Monitoring

WHY ?WHY ?

–– Requirement of Good Manufacturing Requirement of Good Manufacturing Practice Practice

–– EM program provides information on the EM program provides information on the quality of the environment during quality of the environment during manufacturingmanufacturing

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Environmental MonitoringEnvironmental Monitoring

Total ParticlesViable Particles (microorganisms)Differential PressureTemperatureRH

– WHICH ARE THE PARAMETERS ?

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SurfacesPeopleAir

– WHAT TO MONITOR ?

Classified areas PDA Technical Report Number 13: PDA Technical Report Number 13:

sample at or above the work height for sample at or above the work height for the process being performed.the process being performed.

WHERE TO MONITOR ?

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Surfaces & People: Rodacs, SwabsAir: Passive, Active

HOW TO MONITOR VIABLES ?

Air: Active Particle Samplers

HOW TO MONITOR TOTAL PARTICLES ?

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Environmental Monitoring Environmental Monitoring Guidelines for qualification and monitoring Guidelines for qualification and monitoring

cleanrooms (ISO, PIC, FDA, WHO)cleanrooms (ISO, PIC, FDA, WHO)

–– Classifications of air for static and dynamic conditions Classifications of air for static and dynamic conditions (at rest, in operation)(at rest, in operation)

–– Test methods for air filters, air velocity, air pressure, Test methods for air filters, air velocity, air pressure, temperature, humidity.temperature, humidity.

–– Sampling plans for qualificationSampling plans for qualification

–– Testing equipmentTesting equipment

–– Prevention of contamination (gowning, cleaning, Prevention of contamination (gowning, cleaning, controlled entry, etc)controlled entry, etc)

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Environmental Monitoring Environmental Monitoring Establishment and implementation of a routine EM Establishment and implementation of a routine EM

programmeprogramme

–– Limits and frequencies not well defined for Limits and frequencies not well defined for manufacture of bulk biologicals.manufacture of bulk biologicals.

–– Guidelines focus on final product (aseptic fill).Guidelines focus on final product (aseptic fill).

–– Guidelines for tests, test methods and test equipment Guidelines for tests, test methods and test equipment for qualification apply for routine EM for Biologicals.for qualification apply for routine EM for Biologicals.

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Environmental Monitoring Environmental Monitoring Implementation of a routine EM programImplementation of a routine EM program

–– Need to develop a specific EM program for each type of Need to develop a specific EM program for each type of biological product, based on:biological product, based on:

Validation (PQ): Intensive & Intelligent sampling to look for Validation (PQ): Intensive & Intelligent sampling to look for representative contamination spotsrepresentative contamination spots

Risk based approach to look for critical operations (ManRisk based approach to look for critical operations (Man--Material)Material)

Ready & Aware of changes (ManReady & Aware of changes (Man--MaterialMaterial--Product)Product)

Regulations (WHO or EU+USFDA)Regulations (WHO or EU+USFDA)

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Environmental Monitoring: main Environmental Monitoring: main regulatory framework:regulatory framework:

trend analysis, OOL results, and CAPA.trend analysis, OOL results, and CAPA.

–– Trend analysis with ALERT LEVELS is the Trend analysis with ALERT LEVELS is the continuous evaluation of the status of the continuous evaluation of the status of the cleanrooms for viable and non viable counts over cleanrooms for viable and non viable counts over time. Basis for Preventive Actions.time. Basis for Preventive Actions.

–– CAPA is how the company deals with the CAPA is how the company deals with the problems (OOL) occurring in environmental problems (OOL) occurring in environmental monitoring: main tool for continuous monitoring: main tool for continuous improvement as required by modern quality improvement as required by modern quality systems.systems.

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Air Grade Comparison US FDA / ISO / EU / WHOAir Grade Comparison US FDA / ISO / EU / WHO

DD (3,520,000/(3,520,000/--------------))

C C (352,000/3,520,000)(352,000/3,520,000)

B B (3.500/352,000)(3.500/352,000)

------------

A A (3,500/3,500)(3,500/3,500)

EU/WHOEU/WHO(0.5 um particles/m3)

At Rest / In operationAt Rest / In operation

99NANA

8 (3,520,000)8 (3,520,000)100 000100 000

7 (352,000)7 (352,000)10 00010 000

6 (35,200)6 (35,200)10001000

5 (3,500)5 (3,500)100100

ISO (0.5 um particles/m3)

Not defined

US FDA (0.5 um particles/ft3)

In operationIn operation

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AIR MONITORING AIR MONITORING -- VIABLES VIABLES (In operation)(In operation)

DD

CC

BB

AA

EU/WHOEU/WHODesignationDesignation

100 100100 100200200200200

50 5050 50100100100100((<10<100, USP)0, USP)

5 55 510101010((<<20, USP)20, USP)

<<3 3 <<11<<11<<3 3 (USP)(USP)

WHO EUWHO EUEUEUWHO WHO

Passive - Settling Plates (cfu/plate/4 hrs )Active Air (cfu/m3 )

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SURFACE MONITORING SURFACE MONITORING -- VIABLES VIABLES (In operation)(In operation)

DD

CC

BB

AA

EU/WHOEU/WHODesignationDesignation

-------------- --------------50505050

-------------- --------------25252525

5 55 510 (USP, 10 (USP, Ambos)Ambos)

5555

<<3 3 <<113 (USP)3 (USP)

<<11<<33

WHO EUWHO EUEUEUWHOWHO

Glove Plate (cfu/plate/5 fingers)

Contact Plate (cfu/plate )

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GMPs are application specific for Sterile Products GMPs are application specific for Sterile Products Manufacture, and they specify environmental Manufacture, and they specify environmental conditions:conditions:--–– Airborne particulate concentrationAirborne particulate concentration–– Airborne microbiological contaminationAirborne microbiological contamination–– Surface Microbiological contaminationSurface Microbiological contamination

GMPs DON’T specify HOW TO DO ITGMPs DON’T specify HOW TO DO IT--------ISO 14644 Standard DOES !!ISO 14644 Standard DOES !!

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Status of US Fed Std 209EStatus of US Fed Std 209ENovember 2001November 2001

FS 209EFS 209EISO

14644

What What impact ?impact ?

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At Rest In Operation

Grade Max particles/m3 equal to or above0.5 µ 5.0 µ 0.5 µ 5.0 µ

A 3 500 1 3 500 1

B 3 500 1 350 000 2 000

C 350 000 2 000 3 500 000 20 000

D 3 500 000 20 000 Not defined Not defined

EU GMP RequirementsParticle Limits

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EN/ISO 14644EN/ISO 14644--1:19991:1999Classification by ParticlesClassification by Particles

35203520

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ISO 14644ISO 14644--1: Air Cleanliness Classification:1: Air Cleanliness Classification:provides a formula for determining the minimum number of provides a formula for determining the minimum number of sampling locations for total particulate count.sampling locations for total particulate count.Volume (Vs) to be sampled at each location in liters.Volume (Vs) to be sampled at each location in liters.

Monitoring for ComplianceMonitoring for Compliance 1464414644--2 2 Measurement & Testing 14644Measurement & Testing 14644--3 3 Design, Construction, & StartDesign, Construction, & Start--up 14644up 14644--44BioBio--contamination Control Principles 14698contamination Control Principles 14698--11BioBio--contamination Evaluation of data 14698contamination Evaluation of data 14698--22

EN/ISO 14644 & 14698 StandardsEN/ISO 14644 & 14698 Standardsare generic are generic -- for all industriesfor all industries

We have to fit GMPs and Standards together !!

GoodGoodManufacturingManufacturing

PracticePracticeGoodGood

EngineeringEngineeringPracticePractice

CleanroomCleanroomStandardsStandards

GMPGMPAnnexes &Annexes &GuidelinesGuidelines

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Environmental Monitoring:Environmental Monitoring:

Some Regulatory differences:Some Regulatory differences:

EU/US require continuous NVP Monitoring for A areas EU/US require continuous NVP Monitoring for A areas and recommended for B areas.and recommended for B areas.

Stricter limits for viables in EU/US.Stricter limits for viables in EU/US.

No “at rest” requirement in USNo “at rest” requirement in US

Some Regulatory similarities:Some Regulatory similarities:Recognise ISO 14644Recognise ISO 14644

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Examples of operations to be carried out in the various grades.Examples of operations to be carried out in the various grades.

NOTE: No guidance on bulk biological production !!

Annex 1 (September 2003), EU Guide to GMP 2002. WHO

Operations Operations

High risk operations (eg: filling zone, open High risk operations (eg: filling zone, open ampoules or vials, making aseptic connections), ampoules or vials, making aseptic connections), aseptic preparation. Requires LAF.aseptic preparation. Requires LAF.

For aseptic preparation and filling, is the For aseptic preparation and filling, is the background of grade A zone. background of grade A zone.

Preparation of solutions to be filtered. Preparation of solutions to be filtered.

Handling of components after washingHandling of components after washing

GradeGrade

AA

BB

CC

DD

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Criteria for establishing Grades for BiologicalsCriteria for establishing Grades for Biologicals

Aseptic final fill: A w/ B background. Fully regulated.Aseptic final fill: A w/ B background. Fully regulated.

Final Bulk Formulation / Blending of Biologicals (No Final Bulk Formulation / Blending of Biologicals (No Filtration or aseptic connection after filter): A/B, eg: Filtration or aseptic connection after filter): A/B, eg: DPT vaccineDPT vaccine

Final Bulk Formulation / Blending of Biologicals (with Final Bulk Formulation / Blending of Biologicals (with final filtration prior to aseptic fill final filtration prior to aseptic fill –– aseptic connection aseptic connection before filter): LAF/C.before filter): LAF/C.

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Possible Criteria for establishing Air Grades for Possible Criteria for establishing Air Grades for BiologicalsBiologicals

With final filtration steps prior to aseptic fill, eg: tetanus With final filtration steps prior to aseptic fill, eg: tetanus toxoid: toxoid: Upstream Fermentation: LAF in grade D or C depending on Upstream Fermentation: LAF in grade D or C depending on closed/open system, with LAF units at aseptic operations. closed/open system, with LAF units at aseptic operations. (Consider using viable limits of grade C).(Consider using viable limits of grade C).

Downstream / Purification / Inactivation process: Grade C Downstream / Purification / Inactivation process: Grade C with LAF units at aseptic operations. with LAF units at aseptic operations.

For seed consider even using better grade than LAF/C, (eg: For seed consider even using better grade than LAF/C, (eg: LAF/BLAF/B-- (B condition in operation, no B grade “at rest”), ISO (B condition in operation, no B grade “at rest”), ISO 6 at rest, or A/B. 6 at rest, or A/B.

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Possible Criteria for establishing Air GradesPossible Criteria for establishing Air Grades

With With NONO filtration steps up to the aseptic fill filtration steps up to the aseptic fill –– eg: Pertussis: eg: Pertussis:

For seed: A/B, or LAF in BFor seed: A/B, or LAF in B-- (B condition in operation, no B (B condition in operation, no B grade “at rest”, eg: ISO 6 at rest.grade “at rest”, eg: ISO 6 at rest.

Upstream Fermentation: LAF in grade C or A/B or LAF in BUpstream Fermentation: LAF in grade C or A/B or LAF in B--depending on closed/open system. depending on closed/open system.

Downstream / Purification / Inactivation process: Grade Downstream / Purification / Inactivation process: Grade A/B, or LAF in BA/B, or LAF in B--. .

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USP <1116>USP <1116>

provides guidance on sampling plan and sites:provides guidance on sampling plan and sites:

“Consideration should be given to the proximity to the “Consideration should be given to the proximity to the product and whether air and surfaces might be in contact product and whether air and surfaces might be in contact with a product or sensitive surfaces of containerwith a product or sensitive surfaces of container--closure closure systems.”systems.”

“In a parenteral vial filling operation, areas of operation “In a parenteral vial filling operation, areas of operation would typically include the containerwould typically include the container--closure supply, paths closure supply, paths of opened containers, and others inanimate objects that of opened containers, and others inanimate objects that personnel routinely handle.”personnel routinely handle.”

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FDA Guideline on Aseptic Processing, FDA Guideline on Aseptic Processing, 20042004

This guidance document states to sample “room air” This guidance document states to sample “room air” during aseptic processing, media fills, and sterility tests. during aseptic processing, media fills, and sterility tests.

It also gives examples of other sample sites It also gives examples of other sample sites –– mixing mixing rooms, component preparation areas, and filling/closing rooms, component preparation areas, and filling/closing operationsoperations

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VI. ENVIRONMENTALVI. ENVIRONMENTAL

MONITORINGMONITORING

the use of Rodac or surface plates will provide more the use of Rodac or surface plates will provide more information on levels of contamination.information on levels of contamination.

Sampling of critical surfaces, such as operators' gloves, Sampling of critical surfaces, such as operators' gloves, the average of results on plates is unacceptable. The the average of results on plates is unacceptable. The primary concern is any incidence of objectionable levels primary concern is any incidence of objectionable levels of contamination that may result in a nonof contamination that may result in a non--sterile productsterile product

FDA: GUIDE TO INSPECTIONS OF STERILE FDA: GUIDE TO INSPECTIONS OF STERILE DRUG SUBSTANCE MANUFACTURERSDRUG SUBSTANCE MANUFACTURERS

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PIC Guideline on Validation of Aseptic PIC Guideline on Validation of Aseptic Processes (2004)Processes (2004)

7.2 Non7.2 Non--viable monitoringviable monitoring

Sampling locationsSampling locations

The location chosen for monitoring should reflect the worst caseThe location chosen for monitoring should reflect the worst case..–– For room monitoring: locations with most operator activity. For room monitoring: locations with most operator activity.

–– For the filling environment: adjacent to the filling zone and For the filling environment: adjacent to the filling zone and where components are exposed in such way as to detect where components are exposed in such way as to detect operator activity within these areas. operator activity within these areas.

Initial validation confirms that worst case positions have been Initial validation confirms that worst case positions have been identified. identified.

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When? FrequencyWhen? Frequency

FDA Guideline on Aseptic Processing, 2004: FDA Guideline on Aseptic Processing, 2004: “at “at least once daily during production for active least once daily during production for active samplers.”samplers.”

EU / WHO: “Areas should be monitored during EU / WHO: “Areas should be monitored during operations”. “Where aseptic operations are operations”. “Where aseptic operations are performed, monitoring should be frequent … performed, monitoring should be frequent … Results from monitoring should be considered when Results from monitoring should be considered when reviewing batch documentation for finished product reviewing batch documentation for finished product release”.release”.

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WHEN ?WHEN ?

PDA Technical Report Number 13:PDA Technical Report Number 13:

This document suggests the following frequencies: This document suggests the following frequencies:

–– once/shift for class 100, class 10,000once/shift for class 100, class 10,000

–– daily for aseptic support areas and change roomdaily for aseptic support areas and change room

–– weekly for class 100,000 weekly for class 100,000

Nov 12, 2007Nov 12, 2007 VM 2007 EMVM 2007 EM 3131

VI. ENVIRONMENTALVI. ENVIRONMENTAL

MONITORINGMONITORING

Processing of the sterile bulk drug substance usually Processing of the sterile bulk drug substance usually occurs around the clock, monitoring surfaces and occurs around the clock, monitoring surfaces and personnel during the second and third shifts should be personnel during the second and third shifts should be routine.routine.

WHEN ?WHEN ?FDA: GUIDE TO INSPECTIONS OF STERILE DRUG FDA: GUIDE TO INSPECTIONS OF STERILE DRUG SUBSTANCE MANUFACTURERSSUBSTANCE MANUFACTURERS

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WHEN ?WHEN ?For class 100,000 and non critical operationsFor class 100,000 and non critical operations–– Weekly during active operations for viable and nonviable Weekly during active operations for viable and nonviable

particlesparticles

–– May have less frequent non viable monitoring if historical May have less frequent non viable monitoring if historical data and trends and frequent viable counts show active data and trends and frequent viable counts show active areas is under control.areas is under control.

For Class 100 and critical operationsFor Class 100 and critical operations

–– Viable and nonviable particulate monitoring should occur Viable and nonviable particulate monitoring should occur during all periods of critical activity when product is during all periods of critical activity when product is exposed.exposed.

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HOW. Method, Media & IncubationHOW. Method, Media & Incubation

FDA Guideline on Aseptic Processing, 2004:FDA Guideline on Aseptic Processing, 2004:

–– Active air sampling is essential for aseptic processing Active air sampling is essential for aseptic processing areasareas

–– Specifies the use of a culture media that are capable of Specifies the use of a culture media that are capable of detecting bacteria, yeast, and mold.detecting bacteria, yeast, and mold.

Nov 12, 2007Nov 12, 2007 VM 2007 EMVM 2007 EM 3434

Method, Media & IncubationMethod, Media & Incubation

USP <1116>:USP <1116>:

The USP lists active and passive methods and recommends The USP lists active and passive methods and recommends validation of the method used in microbiological sampling validation of the method used in microbiological sampling of the environment. For media, it states soybean casein of the environment. For media, it states soybean casein digest medium (SCDM) is appropriate in most cases. digest medium (SCDM) is appropriate in most cases.

Alternative media can be used if validated for its intended Alternative media can be used if validated for its intended purpose. Typical incubation is given as 22.5° ± 2.5 °C for purpose. Typical incubation is given as 22.5° ± 2.5 °C for 72 hours and 32.5°±2.5 °C for 48 hours.72 hours and 32.5°±2.5 °C for 48 hours.

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PIC Guideline on Validation of Aseptic PIC Guideline on Validation of Aseptic Processes (2004)Processes (2004)7.2 Non7.2 Non--viable monitoringviable monitoring

Sampling device: Must be located to test the air immediately Sampling device: Must be located to test the air immediately surrounding the critical zones NOT the air from the HEPA surrounding the critical zones NOT the air from the HEPA filterfilter

The location of the sample device should not compromise The location of the sample device should not compromise the laminarity of the air flow in the critical zone. the laminarity of the air flow in the critical zone.

Nov 12, 2007Nov 12, 2007 VM 2007 EMVM 2007 EM 3636

Environmental Monitoring Considerations for Environmental Monitoring Considerations for Biological Bulk Manufacturing.Biological Bulk Manufacturing.

Many biological products are composed of substances that Many biological products are composed of substances that support microbial growth.support microbial growth.

Early manufacturing steps involve cell culture and host Early manufacturing steps involve cell culture and host propagation that can enhance microbial growth.propagation that can enhance microbial growth.

System is open/closed or a combination.System is open/closed or a combination.

Aseptic manipulations and open containers are not the Aseptic manipulations and open containers are not the typical of final aseptic fill.typical of final aseptic fill.

Nov 12, 2007Nov 12, 2007 VM 2007 EMVM 2007 EM 3737

Environmental Monitoring Considerations for Environmental Monitoring Considerations for Biological Bulk Manufacturing.Biological Bulk Manufacturing.

There could be filtration steps and always sterility tests There could be filtration steps and always sterility tests done indone in--process to check sterility.process to check sterility.

Therefore, aseptic techniques are needed at all stages, but Therefore, aseptic techniques are needed at all stages, but are not regulated.are not regulated.

Control of air quality and a comprehensive environmental Control of air quality and a comprehensive environmental monitoring program are critical for bulk manufacturing.monitoring program are critical for bulk manufacturing.

Nov 12, 2007Nov 12, 2007 VM 2007 EMVM 2007 EM 3838

Environmental Monitoring ReferencesEnvironmental Monitoring References

Air Quality Guidelines:Air Quality Guidelines:

Mainly for Aseptic Formulation/Filling processMainly for Aseptic Formulation/Filling process–– ISOISO–– FDA:FDA:

Guidance for Industry: Guidance for Industry: Sterile Drug Products Produced by Aseptic Sterile Drug Products Produced by Aseptic Processing Processing —— Current Good Manufacturing Practice, September Current Good Manufacturing Practice, September 2004 2004

–– PIC:PIC:PI 007PI 007--2, 1 July 2004. RECOMMENDATION ON THE VALIDATION OF 2, 1 July 2004. RECOMMENDATION ON THE VALIDATION OF ASEPTIC PROCESSESASEPTIC PROCESSESPE 009PE 009--6, 5 April 2007, GUIDE TO GOOD MANUFACTURING 6, 5 April 2007, GUIDE TO GOOD MANUFACTURING PRACTICE FOR MEDICINAL PRODUCTS, Annex 1 Manufacture of PRACTICE FOR MEDICINAL PRODUCTS, Annex 1 Manufacture of sterile medicinal productssterile medicinal products

–– EU: EU: EC GUIDE TO GOOD MANUFACTURING PRACTICEEC GUIDE TO GOOD MANUFACTURING PRACTICE

REVISION TO ANNEX 1: Manufacture of Sterile Medicinal Products, REVISION TO ANNEX 1: Manufacture of Sterile Medicinal Products, September 2003September 2003(EMEA/INS/GMP/318222/2005/Correction: proposed revision to (EMEA/INS/GMP/318222/2005/Correction: proposed revision to Annex 1. 21 September 2005 affecting information on Annex 1. 21 September 2005 affecting information on cleanroomcleanroomclassification)classification)

–– WHO: WHO: GMP for Sterile Pharmaceutical Products: TRS 902, Annex 6GMP for Sterile Pharmaceutical Products: TRS 902, Annex 6

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Environmental Monitoring ReferencesEnvironmental Monitoring References

For bulk manufacturing of biological productsFor bulk manufacturing of biological products-- Guidance for Inspection of Bulk Manufacturers of Sterile bulk Guidance for Inspection of Bulk Manufacturers of Sterile bulk

drug substance.drug substance.Office of Regulatory Affairs, FDAOffice of Regulatory Affairs, FDA

eenvironmental monitoring regulatory aspects

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