Environmental Control and Measurement

1
Environmental Control and Measurement

• Mark J. Stannard

2
Presentation Outline

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

3
What is contamination?

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

4
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

5
Sources of Contamination?

• Water
• Air
• Surfaces
• People

6
Presentation Outline

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

7
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

8
Air Flow and Pressurization
9
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
10
Open System Technology
11
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

12
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
13
Presentation Outline

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

14
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

15
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
16
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

Lighter shading signifies more stringent area
classification
17
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
18
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.
19
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

20
Air Flow Visualization Studies

• Verify
• Airflow pattern characteristics and
  unidirectional nature of airflow in the Grade A
  zone under static and dynamic conditions
• LFHs 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.

21
Air Flow Visualization Studies
22
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)

23
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

24
Routine Monitoring Air and Compressed Gas
Testing
25
Routine Monitoring Air and Compressed Gas
Testing (Cont.)
26
Routine Monitoring Surface Testing

• RODAC (Replicate Organism Detection and Count)
  plates contain growth promoting medium

27
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)

28
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

29
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

30
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?
31
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
32
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

33
Presentation Outline

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

34
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

35
Presentation Outline

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

36
Regulations and Guidance
Increasing Requirements
37
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

38
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.

39
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..

40
Presentation Outline

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

41
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 lt1116gt Microbiological Evaluation
  of Cleanrooms and Other Controlled Environments
• ISPE
• Baseline Pharmaceutical Engineering Guide, A
  Guide for New Facilities. Volume 6
  Pharmaceuticals, 2004.

42
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.