Lecture 21

Environmental Control and Measurement

Mark J. Stannard

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Presentation Outline

What is contamination? How is contamination controlled? Environmental Monitoring Program Environmental Monitoring Issues Regulatory Overview and Citations References and Reading Suggestions

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What is contamination?

Presence of any unwanted substance in the product

Two types of contaminants Viable Non-viable

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Why prevent contamination?

Ensure product quality Protect our customers Comply with cGMP

regulations and laws– 21 CFR 211 and 600– EU GMP and Annex 1

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Sources of Contamination?

WaterAirSurfacesPeople

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How is contamination controlled?

Health and Hygiene Validated Sterilization of Equipment and Components Protective Apparel Aseptic Techniques Clean Room Conduct Cleaning and Disinfection Techniques Facility and Equipment Maintenance Open vs. Closed System Technology Air Flow, Filtration, and Pressurization

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Air Flow and Pressurization

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HEPA Filtration and Pressurization

HEPA Fact: HEPA filters are made of boron silicate microfibers formed into a flat sheet by a process similar to papermaking. The flat sheets are pleated to increase the overall surface area. A HEPA filter is able to trap 99.99% of particles of a diameter greater than or equal to 0.3 microns.

HEPA filtration and laminar flow serve as contamination control devices. HEPA (High Efficiency Particulate Air) filters are used to remove particulates and microorganisms from the air supply to the manufacturing/filling rooms, laminar flow hoods, biosafety cabinets, etc.

Cross-section of a HEPA Filter

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Open System Technology

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Closed System Technology

Bulk Closed Systems– Provide engineered solution to

achieve an advanced aseptic processing environment.

Benefits include– Separation of people and their

contaminants from the aseptic process by enclosing the filling area, thus requiring that personnel interventions, work, and handling of materials be conducted remotely.

– Use of contiguous piping to improve the maintenance culture purity/asepsis in the process.

– Use of clean in place and sterilize in place systems for vessel/piping decontamination

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Closed System Technology Barrier Isolator Technology

– Provides engineered solution to achieve an advanced aseptic processing environment.

Benefits include– Separation of people and their

contaminants from the aseptic process by enclosing the filling area, thus requiring that personnel interventions, work, and handling of materials be conducted remotely.

– Use of validated pass-through device designs to improve the maintenance of asepsis in the isolator.

– Use of gas/vapor decontamination agents with validated decontamination cycles

The Mini Aseptic Filling System (MAFS) from Bosch-TL Systems

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Environmental Monitoring Program for Classified Areas

HEPA filter certification Qualification of Classified Areas Air Flow Visualization Studies Process Simulation Testing Routine Monitoring of Classified Areas and

Utilities Personnel Monitoring Test Processing and Result Analysis Investigations for Excursions Closed System Technology

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HEPA Filter Certification

Equipment utilizing HEPA filter technology must be certified initially and periodically.

Certification tests include: – a velocity profile – induction leak test – particle counts– airflow pattern test– a HEPA filter leak test HEPA Filter

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Area Classification for Style-ogen® Process Steps

•Tank Fermentation•Non Sterile Purification •Buffer/Media Hold

•Solution Prep•Equipment Assembly•Sterile Purification

• Open Sterile Sampling• Open Sterile Transfers

Lighter shading signifies more stringent area classification

• Open Aseptic TransfersO

pen

Proc

essi

ng

Unclassified Space

Clo

sed

Equi

pmen

t

Classified Space

Grade A

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Classified and Aseptic Areas

Classified and Aseptic Areas – Maximum allowable number of viable and non

viable particles per volume of air sampled– Defined by regulatory agencies

Gowning Room

Air Lock

ProcessingRoom

LFH

Hall

Class 100,000/Grade C

Class 10,000/Grade BClass 100/Grade A

Gowning Room

Air Lock

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FDA/ISO Particulate and Microbial Air Classificationsa and Levels

Clean Area Classification (0.5 um particles/ft3)

ISO Designation b

> 0.5 µm particles/m3

Microbiological Active Air Action Levels c

(cfu/m3 )

Microbiological Settling Plates Action Levels c,d

(diam. 90mm; cfu/4 hours)

100 5 3,520 1e 1e

1000 6 35,200 7 3 10,000 7 352,000 10 5 100,000 8 3,520,000 100 50 a- All classifications based on data measured in the vicinity of exposed materials/articles during periods of activity. b- ISO 14644-1 designations provide uniform particle concentration values for cleanrooms in multiple industries. An ISO 5 particle concentration is equal to Class 100 and approximately equals EU Grade A. c- Values represent recommended levels of environmental quality. You may find it appropriate to establish alternate microbiological action levels due to the nature of the operation or method of analysis. d- The additional use of settling plates is optional. e- Samples from Class 100 (ISO 5) environments should normally yield no microbiological contaminants.

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Qualification of Classified Areas

Initial Qualification– Ensure HVAC systems are performing to specifications and

meeting regulatory levels for environmental control– Select test sites based upon area of room (i.e., ISO

formula) and risk of contamination to product– Air and Surface testing conducted for multiple days to

ensure satisfactory performance Periodic Re-Qualification

– Demonstrate continued satisfactory HVAC performance and continued compliance with regulatory specified levels.

– At periodic intervals (e.g., semi-annually for Class 100/10,000; annually for Class 100,000)

– Following area modifications and/or breaches of room integrity

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Air Flow Visualization Studies

Verify – Airflow pattern characteristics and unidirectional nature of

airflow in the Grade A zone under static and dynamic conditions – LFH’s ability to limit dispersion of viable/non-viable particles

Assess – Appropriate work flow and personnel aseptic technique specific

to the equipment design and airflow patterns – Non-unidirectional occurrences, such as back-flow, ‘pulsing’ of

air, or dead spots.– Optimal environmental monitoring test site locations for

qualification and routine testing.

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Air Flow Visualization Studies

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Process Simulation (Media Challenges)

Simulates aseptic process using growth promoting media in the place of actual product.

Simulates process as closely as possible while incorporating selected worst case conditions

Assures that aseptic process conditions and associated controls are sufficiently rigorous to ensure the manufacture of pure culture or sterile product.

Serves as a continuing assessment of the processes, equipment, procedures, and personnel associated with aseptic manufacturing.

Conducted on predefined frequency as specified by regulations

Conducted following modifications/shutdowns Incubate media, examine for presence of

contamination (e.g., flocculation or turbidity)

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Process Simulations (Cont.)

Aseptic Filling– Twice per year per line per

shift– Min 5,000 vials filled– Target 0 contaminated vials– Perform all representative

interventions– Aseptic PQ of Personnel

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Routine Monitoring: Air and Compressed Gas Testing

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Routine Monitoring: Air and Compressed Gas Testing (Cont.)

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Routine Monitoring: Surface Testing

RODAC (Replicate Organism Detection and Count) plates contain growth promoting mediumDirect contact (by pressing the

plate to the specified surface)

OR Swabbing the surface and subsequently swabbing the plate with the sample or inserting swab into broth filled tube

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Routine Monitoring of Classified Areas

Frequency and extent of testing is commensurate with proximity to product and level of risk of contamination to product

– Class 100,000 Areas Weekly Air and Selected Surfaces

– Class 10,000 Areas Once per use day during processing Air and Surface

– Class 100 Areas Per Process for each operating shift Air, Surface, Personnel Product Contact Surfaces (end of process)

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Utility Monitoring

Conducted for – Initial qualification – Routine monitoring – Following incursions into the utility system

Testing is commensurate with type of system and usage– e.g., Water for Injection (WFI) vs. Potable Water

Water (WFI)– Microbe, Particle, and Endotoxin Testing per use day or weekly– Chemical/Physical test weekly

Clean Steam– Endotoxin and Chemical/Physical test once per month

Compressed Gases– Microbes and Particles– Particles weekly and microbes monthly

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Personnel Monitoring

Personnel greatest vehicle for contamination into cleanrooms

Cleanroom clothing required to protect product from people

Four test site locations– Fingertips of both hands– Forearm and Chest

Avoid unnecessary movements and touching of surfaces

Follow Aseptic Technique Disinfect hands frequently Practice “First Air Rule”

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Test Processing

1. How many CFUs?2. Are they mold or bacteria?

•Record immediate particle air count

• Incubate microbial test plates per procedures

•Count colonies on plate• Identify representative colonies

•Record all test results

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Result Analysis

Action Level: Test result above maximum allowable level.

Alert Level:Possible indication of adverse trend in area/utility performance

Passing Level: Satisfactory results 0

20

40

60

80

100

120

140

Test#1

Test#2

Test#3

Test#4

Test#5

Test#6

Test#7

Alert Level

Action Level

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Investigations for Alert/Levels

Regulatory Requirement Investigation Method

– Trend– Describe Event– Identify Affected Materials and Lot(s)– Identify Root Cause/Corrective Actions– Trend for Same Root Cause Previously– Conclusion and Impact Statement

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Environmental Monitoring Issues

Aseptic versus Sterile Concepts– Cleanrooms are clean to allowable levels and not sterile– Personnel are the predominant source of cleanroom

contamination EM is not equivalent to a quantitative analytical test

– Accuracy is limited at low level concentrations – Results vary with equipment used– Adventitious contamination of the test plate occurs– Therefore, EM levels are not product specifications

EM most appropriate as trending tool to demonstrate continued control and/or changes in area performance

– Continued “snap shots” in time provide picture of overall level of control

– Occasional elevated results do not indicate a loss of control

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Regulations and Guidance

Incr

easi

ng R

equi

rem

ents

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Risk Based Approach

Regulatory Guidance often non prescriptive for EM– Majority of guidance addresses aseptic filling– Identify process steps with highest risk to product

quality– Design program to address the risk(s)– Document rationale for program design

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Example Regulatory Citations (483s)

Air returns within aseptic filling rooms were obstructed by shelves, tables, and disposal cans.

Pressure differentials are not monitored between the filling room xx and the adjacent construction area. There is no documentation to show the physical integrity of the seal surrounding door between filling room xx and the adjacent construction area.

Procedures for the recording of pressure differentials in the fermentation area were not followed mm/dd/yy.

The fermentor in room XXX had a defective “leaking” valve. A pool of water was also observed XXX tank.

A system should be implemented in the airlock to prevent the opening of both doors at the same time.

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Example Regulatory Citations (483s) (Cont. )

Qualification of the method used to detect contamination in the fermentor was incomplete in that raw data did not include counts of the test organisms.

Aseptic personnel practices observed during the fill of XXXXX on mm/dd/yy were inappropriate in that operators did not routinely disinfect gloves between manufacturing operations.

The EM program does not include the use of microbial growth media that is optimum for the propagation of yeast or mold.

The rationale and justification of environmental monitoring samples for all locations is not documented.

The firm has not conducted recovery studies to qualify the ….method and material utilized…..

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References and Reading Suggestions

Title 21 Code of Federal Regulations (CFR) Parts 210, 211 and 600

FDA 2004 Guideline on Sterile Drug Products Produced by Aseptic Processing

Q7A GMP Guidance for API Rules Governing Medicinal Products in the European Union

Volume IV – ‘Good Manufacturing Practice for Medicinal Products’ (EudraLex) –

– Annex 1 ‘Manufacture of Sterile Medicinal Products’– Annex 2 Manufacture of Biological Medicinal Products– Annex 18 GMP for APIs

US Pharmacopoeia– General Chapter <1116> Microbiological Evaluation of Cleanrooms

and Other Controlled Environments ISPE

– Baseline Pharmaceutical Engineering Guide, A Guide for New Facilities. Volume 6 Pharmaceuticals, 2004.

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References and Reading Suggestions(Cont.)

International Standards Organization (ISO)– Cleanrooms and Associated Controlled Environments – Part 1:

14644-1: Classification of Air Cleanliness1.– Cleanrooms and Associated Controlled Environments – Part 2:

14644-2: Specification for Testing and Monitoring to Prove Continued Compliance with ISO 14644-1.

PDA – Technical Report (TR) 13 Fundamentals of Environmental

Monitoring Program– TR 22 Process Simulation Testing for Aseptically Filled Products – TR 28 Process simulation Testing for Sterile Bulk Pharmaceuticals

Books– Microbiology in Pharmaceutical Manufacturing. Editor R. Prince,

PDA and Davis Horwood International Publishing, Ltd. 2001.

Lecture 21

Documents

Transcript of Lecture 21