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Environmental Control and Measurement. Mark J. Stannard. 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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Presentation Transcript
presentation outline
Presentation Outline
  • What is contamination?
  • How is contamination controlled?
  • Environmental Monitoring Program
  • Environmental Monitoring Issues
  • Regulatory Overview and Citations
  • References and Reading Suggestions

2

slide3

What is contamination?

  • Presence of any unwanted substance in the product
  • Two types of contaminants
      • Viable
      • Non-viable

3

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

Why prevent contamination?

4

slide5

Sources of Contamination?

  • Water
  • Air
  • Surfaces
  • People

5

presentation outline6
Presentation Outline
  • What is contamination?
  • How is contamination controlled?
  • Environmental Monitoring Program
  • Environmental Monitoring Issues
  • Regulatory Overview and Citations
  • References and Reading Suggestions

6

how is contamination controlled
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

7

hepa filtration and pressurization
HEPA Filtration and Pressurization

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.

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.

Cross-section of a HEPA Filter

9

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

Closed System Technology

11

closed system technology12
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

Closed System Technology

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

12

presentation outline13
Presentation Outline
  • What is contamination?
  • How is contamination controlled?
  • Environmental Monitoring Program
  • Environmental Monitoring Issues
  • Regulatory Overview and Citations
  • References and Reading Suggestions

13

environmental monitoring program for classified areas
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

14

hepa filter certification
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

15

area classification for style ogen process steps
Area Classification for Style-ogen® Process Steps
  • Tank Fermentation
  • Non Sterile Purification
  • Buffer/Media Hold

Unclassified Space

Open Processing

Closed Equipment

Grade A

  • Solution Prep
  • Equipment Assembly
  • Sterile Purification

Classified Space

  • Open Sterile Sampling
  • Open Sterile Transfers
  • Open Aseptic Transfers

16

Lighter shading signifies more stringent area classification

classified and aseptic areas
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

Class 100,000/Grade C

Class 10,000/Grade B

Class 100/Grade A

Gowning Room

ProcessingRoom

Gowning Room

Hall

Air Lock

LFH

Air Lock

17

fda iso particulate and microbial air classifications a and levels
FDA/ISO Particulate and Microbial Air Classificationsa and Levels

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.

18

qualification of classified areas
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

19

air flow visualization studies
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.

20

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)

Process Simulation (Media Challenges)

22

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

Process Simulations (Cont.)

23

routine monitoring surface testing
Routine Monitoring: Surface Testing
  • RODAC (Replicate Organism Detection and Count) plates contain growth promoting medium

26

routine monitoring of classified areas
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)

27

utility monitoring
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

28

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”

Personnel Monitoring

29

test processing
Test Processing
  • Record immediate particle air count
  • Incubate microbial test plates per procedures
  • Count colonies on plate
  • Identify representative colonies
  • Record all test results

1. How many CFUs?

2. Are they mold or bacteria?

30

result analysis
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

Action Level

Alert Level

31

investigations for alert levels
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

32

presentation outline33
Presentation Outline
  • What is contamination?
  • How is contamination controlled?
  • Environmental Monitoring Program
  • Environmental Monitoring Issues
  • Regulatory Overview and Citations
  • References and Reading Suggestions

33

environmental monitoring issues
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

34

presentation outline35
Presentation Outline
  • What is contamination?
  • How is contamination controlled?
  • Environmental Monitoring Program
  • Environmental Monitoring Issues
  • Regulatory Overview and Citations
  • References and Reading Suggestions

35

regulations and guidance
Regulations and Guidance

Increasing Requirements

36

risk based approach
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

37

example regulatory citations 483s
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.

38

example regulatory citations 483s cont
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…..

39

presentation outline40
Presentation Outline
  • What is contamination?
  • How is contamination controlled?
  • Environmental Monitoring Program
  • Environmental Monitoring Issues
  • Regulatory Overview and Citations
  • References and Reading Suggestions

40

references and reading suggestions
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.

41

references and reading suggestions cont
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.

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