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GMP and Quality Audit
Fundamentals of Auditing
Sterile Production Areas
Shabana Chaudhry, CQA
Aseptic Trainer
Allergan Inc.
March 10, 2014
DISCLAIMER
This presentation is made at the request of IVT.
The information provided and opinions
expressed during this presentation are those of
the presenter and are not the position of and
may not be attributed to Allergan, Inc.
The presenter is a full-time employee and
stockholder of Allergan, Inc.
ABOUT THE PRESENTER
Shabana Chaudhry, CQA, Microbiologist
Shabana Chaudhry is the Aseptic Trainer at Allergan, Inc.
At Allergan, Shabana oversees the Aseptic Processing Program for the Waco, TX facility which is part
of the Operational Compliance Department.
To date, Shabana has trained over 400 employees on Microbiology, Personal Hygiene, Gowning,
Aseptic Processing, Aseptic Techniques, Cleanroom Conduct, Cleaning, and Good Manufacturing
Practices.
During her employment at Allergan, Shabana has also managed the Aseptic Processing (Media Fill)
Program, Bioburden/Water Testing, and Endotoxin Testing Programs.
Shabana has over 15 years of Pharmaceutical Manufacturing experience, she has worked for three (3)
Fortune 500 Corporations and supervised two (2) QA/QC Pharmaceutical Microbiology Laboratories
and one (1) Clinical Blood Bank Microbiology Lab and also was previously employed at a well-known
laundry service provider for cleanroom garments.
Shabana is a current member of PDA (Parenteral Drug Association), ASQ, and member of the Aseptic
Process Technical Forum and is a Certified Quality Auditor (ASQ) and Certified Green Belt.
INTRODUCTION
GOOD MANUFACTURING PRACTICES
The Pharmaceutical/Medical Device Industry
where Sterile Products are produced is among
the most heavily scrutinized and regulated in the
U.S.
GMP compliance is a mandatory aspect in
pharmaceutical manufacturing
It is the company's responsibility to determine
the most effective and efficient quality process
It is important to identify what factors
should be examined when performing an
inspection of the manufacturing and filling
areas
How do you ensure that your facility is
always in an “audit ready” mode?
GOOD MANUFACTURING PRACTICES
This module is intended to help you perform an internal audit of your facility from a GMP auditor’s perspective
based general guidelines from:
FDA, ISO, WHO, PIC/S and EU standards
There are many guidance documents out there on what the expectations are Aseptic Processing, Manufacture of a Sterile Product
Why do we need to perform Internal Audits?
The Regulatory bodies expect you to perform internal audits within your facility
Ensure we are producing a Quality, Sterile product
o FDA (to ensure Safety, Purity, Potency, Identity, and Strength)
o Prevent Injury to Patients
o Company Reputation
o Be Proactive instead of Reactive
o Checks and Balances
START WITH THE BASICS
An effective audit will be Hands-On
Cannot be a desk audit only
Procedures(SOPs) against Observations
Follow your Company’s Internal Audit Program
Guidelines
Follow Good Manufacturing Practices Guidelines
Current Good Manufacturing Practices
(cGMPs) emphasize:
• The size, design, construction, and location of
buildings and construction materials
• The appropriate material flow to facilitate cleaning
• Maintenance, and proper operations for the
manufacture of drug products
• Prevention of the drug product from becoming
contaminated with chemical disinfectants as a result
of the inherent toxicity of the disinfectants when
disinfectants are used in a manufacturing
environment
Familiarize yourself with your facility
Partner with Dept. Management
Every facility (even within the same company) is different
Every process is different
Every product is different
Learn Personnel and Material Flows
Question Standard of Housekeeping
Obtain Access to Aseptic Manufacturing Areas (if possible)
Examine Trends and Deviations
Take a class in Pharmaceutical Microbiology Research 483s, Warning Letters
WHERE DO YOU START?
FACTORS TO CONSIDER: • Manufacturing process- clearly defined and controlled
• All critical processes- validated to ensure consistency and compliance with
specifications
• Any changes to the process are evaluated
• Instructions and procedures - written in clear and unambiguous language
(Good Documentation Practices)
• Operators - trained to carry out and document procedures
• Records – created during manufacture demonstrate all the steps required by
the defined procedures/ instructions taken and quantity and quality of the drug
was as expected
• Deviations are investigated and documented
• Complete records- manufacture history of a batch to be traced are retained in
a comprehensible and accessible form
SCOPE
PEOPLE-Personnel Records
EQUIPMENT-Equipment used for Process
FACILITY-Facility Design, Maintenance
Records
TESTING- Raw mat., in-process, finished
product
VALIDATION-Validation Results
SCOPE
EVALUATE:
o Sterile Production/Personnel Interactions
oHandling/Cleaning equipment used in Manufacturing
oRisk of Contamination
o Entry procedures (clothing, hair cover, tacky mats, etc.)
o Access to critical (high risk) areas
oRestricted access of personnel
oGowning Procedure
oGowning Area
SELECT A PRODUCT OR PROCESS
Take the time to study the product/process which you want to audit
Focus on one product/process at a time
Assume each one is unique
Create an agenda,
Notify affected departments
Execute the audit in an organized fashion
Professional manner
Take seriously
Identify the procedures/batch records used
Identify the areas where the manufacturing activities take place,
familiarize yourself with the area(s)
Prepare a Checklist
SELECT A PRODUCT OR PROCESS
Identify the personnel involved in the processes and evaluate their qualifications
Identify the equipment used for the manufacturing process
Cleaning Procedures/Logs
Testing (raw mat., in-process, finished product)
Validations
Calibration/PMs of Equipment
THE QUALITY SYSTEM CONSISTS OF: PRODUCTION SYSTEM
FACILITIES AND EQUIPMENT SYSTEM
LABORATORY CONTROLS SYSTEM
MATERIALS SYSTEM
PACKAGING AND LABELING SYSTEM
SYSTEM CONTROLS
Gowning Program
Environmental Monitoring Program
Disinfectant Qualification
Equipment Validations
Equipment Cleaning Validations
Filter Validations
Media Fills
Hold Time Studies
Auditor Hat
ASEPTIC PROCESSING
• Critical areas where products, in-process materials and components are exposed to the environment and receive no further sterilization.
• Highly controlled areas where the air supply, materials, equipment, and personnel are regulated to control viable and non-viable particulates to an acceptably low level.
• Manufacturing activities conducted in a critical
environment using aseptic technique to produce a sterile product
• For aseptic filling: where the product and container/closure are sterilized separately, then brought together
CONTAMINATION
Contamination refers to any material or substance that
is: unwanted”
Adversely affects the product or process
Types of Contamination
Chemical- cross contamination of product, cleaning
agents
Particulate- dust, debris, fibers, lint, smoke
Microbiological- bacteria, fungi
Bacteria are not free-floating in the air they use
particles as a vector and exist on people
They like to “hitch-hike”
CONTAMINATION CONTROL CHAIN
Facility
Process
Product
Personnel
Packaging
Maintenance
Monitoring
Management
ROUTES OF CONTAMINATION
Sterile drug products may
be contaminated via:
Pharmaceutical ingredients
Process water
Packaging components
Manufacturing environment
Processing equipment
Manufacturing operators
Particles
Contact with surfaces
Ensure there no FOOD is allowed
in Production Areas
Air
Water
People
Skin (bacteria and yeasts)
Clothes
Hair
Mucous membranes
ELIMINATION OF BACTERIA
Steam Autoclave
High heat Dry heat oven
Radiation Gamma sterilization
Chemical disinfectants
Filtration
STERILIZATION BY FILTRATION Filtration is one method used to sterilize product (or its
parts) in Manufacture using Aseptic Processing
Confirm that sterilizing filters must have a pore size of
not more that 0.22 µm
Ensure filters:
Do not release fibers in the process
Are not composed of asbestos (asbestos is toxic)
EU GMP recommends 2 filters in series with 1 filter as
close to point of fill as possible
EU Annex 1.83
Used to filter non-viscous liquids(hydrophilic) or
air/gasses (hydrophobic)
Filters do not remove endotoxin
Requires a sterile receiving container
DISINFECTION A control mechanism designed to prevent contamination of
product and maintain the asepsis of the production
environment
Less effective than sterilization
Depends on agent, saturation and contact time
Alcohol has no effect on spores
Microorganisms vary in their sensitivity to disinfectants
A sequence of application is required
Before
After
DEFINITIONS:
ASEPTIC PROCESSING Manufacturing activities conducted in a critical
environment using aseptic technique to produce a sterile product
For aseptic filling: where the product and container/closure are sterilized separately, then brought together
Measurements:
• Media Fills
• Environmental and personnel monitoring
• Finished product sterility testing
GMP-Good Manufacturing Practices
CFR- Code of Federal Regulations
ISO- International Organization for Standardization
DEFINITIONS: Controlled Area
An area where manufacturing is taking place that has restrictions for access (personnel, practices, housekeeping/ maintenance are controlled: temp., humidity, pressure, etc.)
Cleanroom
A room in which the concentration of airborne particles is controlled (incoming air is filtered) to meet standards of purity
Aseptic
Refers to the absence of viable microorganisms capable of causing contamination or infection
Aseptic Processing Area
Refers to the classified areas where products, in-process materials and components are exposed to the environment and receive no further sterilization (Grade A Critical/Grade B Support rooms)
Critical Areas- where sterile products are made over aseptic conditions Exposed materials (product, containers/closures)
Filling/closing operations
Manual manipulations (aseptic connections, sterile ingredient additions)
DEFINITIONS:
Sterile
Absence of living (viable) microorganisms
Bacteria, mold and yeasts
Term often misused
Contaminant
Anything that is not supposed to be there
Cross-Contamination
Occurs when one substance comes in contact with another substance, (or bacteria is transferred to another surface, simply by touch)
Viable
Living structure (i.e. microorganisms)
Non-Viable
Non-living structure (i.e. glass particle)
ZONES OF OPERATION
CRITICAL
Uncontrolled
Controlled
Aseptic Processing Area:
• Critical areas where products, in-process materials and components are exposed to the
environment and receive no further sterilization
• Highly controlled areas where the air supply, materials, equipment, and personnel are
regulated to control viable and non-viable particulates to an acceptably low level
A Particle: One micron is a millionth of a meter (or a thousandth of a millimeter)
(the head of a pin is 2mm)
Just because you can’t see it, doesn’t mean it is not there!
TRAINING 21 CFR 211.25(a) Personnel Engaged in Manufacturing must…
Have education
Training
Experience
21 CFR 211.28 Wear clean clothing appropriate for the duties they perform.”
Who is performing the work?
Production Operators
Cleaning Techs.
What are the gowning requirements for the area?
Personnel pose the most risk
Most common cause of contamination
Emphasis must be placed on training and it must be continuous
Aseptic Techniques
Personnel EM Trends
What is “Common Sense”??? Don’t assume…..
Scenario: A person tells her supervisor she has a tooth infection. The Supervisor asks you if the person can enter the aseptic area. How do you respond?
KD
DOCUMENTS Standard Operating Procedure (SOP)
Look at the procedure as if you are performing the
task
Is what is stated in the procedure being followed?
Ask two people to perform the same task, do they
follow the procedure exactly?
Do they come out with the same end result?
Documentation
Does the paperwork have too many corrections?
Was documentation concurrent?
Was the paperwork reviewed? By who?
Was it reviewed in a timely manner?
SOURCES OF CONTAMINATION IN A CLEAN ROOM
People (80%)
Shedding of skin cells (movement)
Sneezing
Talking/laughing
Carelessness
Sweating
Soil
Dust, dirt
Inadequate surface disinfection of materials
Inadequate cleaning of room surfaces
Transferring of materials from uncontrolled to controlled environments
CONTROLLED AREA REQUIRMENTS
Personnel: Must practice good hygiene
No Jewelry
No Make-up
Uniforms/Dedicated shoes
Wear Gloves
Examples of clothing requirements: Grade A/B- Sterile gloves, hood, mask, coverall, boots, goggles
(no skin exposed)
Grade C-Hair cover, shoe covers, coverall, gloves, safety glasses
Grade D- Hair cover, shoe covers, lab coat/smock, safety glasses
PROPER TECHNIQUES EMPLOYED
“CLEANEST
TO
DIRTIEST”
PROPER CLEANROOM BEHAVIOR
Good Aseptic Technique Human intervention kept to a minimum
Intervene with sterile tools when necessary
Maintenance of sterile tools during processing
Product contact parts untouched
No disruption of laminar airflow
Slow movement
Operators Sanitizing Often
Minimal communication-millions of germs are
expelled every time you open your mouth
Continuous Training
THE MANUFACTURING ENVIRONMENT Verify Protection from Contamination for:
Containers
Components
Equipment
How ?
Transferring of Sterile Materials into Aseptic Area
Conveyor belts
Should not pass from one area to an area of a lower grade classification
Ex. Autoclaves- Double Door, need Grade A for cool down
What processes are in place to prevent contamination?
No Cardboard, wood in Controlled Areas (spores, mold), no paper in
cleanrooms (particles/bacteria), double or triple bagged items
Materials should be disinfected or sterilized
Materials should be decontaminated prior to sanitization/sterilization
Sterilization Processes:
Autoclaving, Dry Heat Oven
Filtration
How are mix-ups prevented?
Ref:
FDA 2004, IV
EU GMP 3.1
EU Annex 1.3
FDA 2004, X.A.
EU Annex 1.4, 1.5
EU Annex 1.90
GENERAL INSPECTION
• Rooms- humidity and temperature controlled
• Garments:
o Worn-appropriate for area
o Garments, sterile supplies- maintained
o Operators- gowning technique
• Gowning Area
o Airlocks or interlocking doors o No two doors can be opened at the same time o Alarms o Air Filtration
• Dedicated clothing and equipment
FACILITY DESIGN
Facility and equipment designed and
maintained to suit the operations
to be carried out
Layout and design facilitate:
Minimizing the risk (of errors)
Effective cleaning and maintenance
To avoid cross-contamination
Build up of dust or dirt
Any adverse effect on the quality of products
CONTROLLED AREA REQUIRMENTS
FACILITY DESIGN Verify the Facility is in good condition
Floor plan
Is the area big enough?
Is it clean?
Is it well maintained?
Aseptic Areas require high levels of Maintenance and regular disinfection
Review Logbooks
Composition of Floors, Walls, & Ceilings Meet Standards
Smooth (non-porous), hard
Easy to clean
Sealed openings
Look for things which are not desirable :
Crevices
Recesses and ledges, cabinets
Electrical wires, conduits
Sliding doors
Evaluate:
Particles
Airflow
Air Pressure
o Temperature
o Pressure
o Humidity
o Specialized Filtration
FDA CFR 211.42
EU GMP 2.16
EU Annex 1.14
•High levels of air filtration required for cleanroom
•HEPAs are capable of filtering 99.97% of 0.3µM particles and greater
•Ask for Detailed documentation (drawings of where HEPA filters are
located)
•Installation (how & where?)
•Efficiency and integrity of filters
•HEPAs get replaced, not cleaned
•Standards:
o ACR
o ceiling coverage
o Airflow velocity
•ACR- Air Change Rate- what is it for the area being audited?
o Replacement with filtered outside air ex. 600X /min.
o ISO does not provide a recommendation for ACR for
pharmaceuticals
o A range is better than one concrete number
HEPAs HIGH EFFICIENCY PARTICULATE AIR FILTERS
•Laminar Flow- ISO 5 (Class 100) and cleaner
o Unidirectional, uniformly supplied filtered air for a fixed velocity, parallel
streams, recirculated (air return vents in walls/floors)
o Air velocity distribution
•Turbulent – ISO 6 (Class 1,000 and above)
o Not regulated, direction or speed
o Contaminants may collect
o Supply airflow rate
• Room air flow velocity and air changes also depends on room size
• Fan Filter Unit (FFUs) = (Air changes/hr. ÷60) X (cu ft. in rooms ÷650)
•What is a Pressure Differential?
o Difference is pressure between two points in a system
o Aseptic Core and Production area – Positive pressure differentials to
outside environment
o Does it exceed 10 Pascals at all times
o Or 0.03-0.05 inches of water
o Are there alarm systems that signal failures in the air supply?
AIR FLOW
EU ASEPTIC CLEANROOM GRADE
DEFINITIONS
Particulate concentration changes over time…
Grades A,B,C,D
0.5 um and 5.0 um particles
Non-viable (particles)
EU Annex 1.2
Max permitted number of particles/m3
“At Rest” vs. “In Operation” “As Built” no equipment, no personnel present
“At Rest” no personnel present
“Operational” personnel, working (dynamic)
ROOM CLASSIFICATIONS
• Various parts of manufacturing is performed in separate areas
o Verify this is the case
• Appropriate controls, based on the operation and established air
quality requirements for microbial and particulate contamination for:
o Grade A: Sterile Filling Class 100 (ISO 5).
o Grade B: For aseptic preparation and filling, this is the
background environment for the grade A zone.
o Grade C and D: Clean areas for carrying out less critical stages
in the manufacture of sterile products.
o Examples: Grade C Class 10,000 Preparation of solutions to be
filtered
o Equipment Cleaning Class 100,000 (ISO 8) Grade D Handling
of components after washing
• Tight controls in cleanroom (total environment)
• Sources need to controlled/eliminated
EU RECOMMENDED LIMITS FOR MICROBIAL
CONTAMINATION
Air Sample (CFU/ m3) viable
Air Settle Plate (Fall Out Plate CFU/4 hrs.) viable
Surface Contact Plate (CFU/plate) viable
Glove Print (Finger Impression Plate CFU/glove) viable
EU RECOMMENDED LIMITS FOR MICROBIAL CONTAMINATION
GRADE AIR
SAMPLE
CFU/m3
SETTLE
PLATES
CFU/4 hrs.
CONTACT
PLATE
(55 mm Dia.)
CFU/Plate
GLOVE
(5 fingers)
CFU/Glove
A <1 <1 <1 <1
B 10 5 5 5
C 100 50 25 Undefined
D 200 100 50 Undefined
Grade A is expected to have 0-no contamination
Settle plate is optional
CLEAN ROOM AND CLEAN AIR DEVICE CLASSIFICATION
MAXIMUM PERMITTED NUMBER OF PARTICLES PER m3
EQUAL TO OR GREATER THAN THE TABULATED SIZE
GRADE
AT REST IN OPERATION
EU/ISO/FS* 0.5 μm 5.0μm 0.5 μm 5.0μm
A – 5 (100) 3, 520 20 3, 520 20
B – 5 (100) 3, 520 29 352, 000 2,900
C – 7 (10,000) 352, 000 2,900 3, 520, 000 29,000
D- 8
(100,000)*
3, 520, 000 29,000 Not Defined Not Defined
Classification level- No more than 3 significant figures
*Federal Standards (FS) 209E
• Clean rooms and clean air devices should be classified in accordance
with ISO 14644-1
• Classification should be clearly differentiated from operational process
environmental monitoring
ISO TESTING SCHEDULES
SCHEDULE OF TESTS TO DEMONSTRATE CONTINUOUS COMPLIANCE
(MANDATORY TESTING)
Test Parameter Class Max. Time Interval Test Procedure #
Particle Count Test ≤ ISO 5
> ISO 5
6 mos.
12 mos.
ISO 14644-1 Annex A
Air Pressure Diff. All Classes 12 mos. ISO 14644-1 Annex B5
Airflow Volume
Velocity
All Classes 12 mos. ISO 14644-1 Annex B4
OPTIONAL TESTING
Test Parameter Class Max. Time Interval Test Procedure #
Installed Filter
Leakage
All Classes 24 mos.
24 mos.
ISO 14644-1 Annex B6
Containment Leakage All Classes 24 mos. ISO 14644-1 Annex B4
Recovery All Classes 24 mos. ISO 14644-1 Annex B13
Air Flow Visualization All Classes 24 mos. ISO 14644-1 Annex B7
FACILITY DESIGN: Water System
Starting off Clean
USP/WFI
Recirculating hot water loop
No dead legs
Pseudomonas sp.
Water is a concern in the Grade A environment Check areas for water outlets/drains
Check floor drains for air breaks (preventing backflow), traps cleanable?
No standing water (bacteria proliferate logarithmically)
Should be no water in APA but can be in support areas
No Sinks, Water Coolers
Blow Fill Seal (Unit Dose, BFS) System:
Air-”blow”
Heat-”seal”
Chill H2O- cool
Central TX News Feb 2014
Woman 8 mos. pregnant stores contact lenses in
Tap water and goes blind:
http://www.thedoctorstv.com/videolib/init/9861
PROCESSES
CLEANING A sound cleaning and sanitization program is needed for controlled
environments used in the manufacture of Pharmacopeial articles to
prevent the microbial contamination of these articles. (USP 1072)
Evaluate cleaning for equipment and manufacturing/ filling areas
Pharmaceutical manufacturing process is cleaner than food
processing
Physical verification of work practices
Checking for visual cleanliness, microbiologically, and chemically
• Is equipment maintained in good order?
o Rust
o Dust
o Rouging
CFR 211.65
(a) Equipment shall be constructed so that surfaces that contact components, in process materials, or drug products shall not be reactive, additive, or absorptive
CFR 211.67
(a) Equipment and utensils shall be cleaned, maintained or sanitized at appropriate intervals
CLEANING (CONTINUED) Poor cleaning- If this is noticeable, it is an indicator of deeper problems
There should be detailed written procedures for cleaning (rooms &
equipment)
Are these procedures clear & unambiguous?
Who is performing the cleaning?
Contractors?
These individuals are most commonly the lowest paid workers
Check training records of cleaning personnel
Are cleaning schedules followed?
Is there Rotation of Disinfectants?
Do the cleaning procedures include the removal of batch identification (line
clearance)?
Handling of waste
Cleaning Techniques:
Removal of dirt and debris first?
You can’t disinfect a pile of dirt
Spraying only & no wiping? (physical action)
Overlapping strokes vs. haphazard
WHEN YOU ARE “CLEANING” LIKE THIS, YOU ARE MOVING – NOT REMOVING THE CONTAMINATION PROPER CLEANING TECHNIQUE:
CLEANING (CONTINUED)
Manufacturing is dynamic (operating) conditions or getting ready for
next operating cycle (This includes cleaning)
Is all visible equipment labeled with cleaning status labels
Check for cleaning records
Logbooks
Labels
Is equipment which are claimed to be clean, actually dirty?
Check maximum time limit (interval between use and cleaning)
Cleaning use - re-use must be validated
After Cleaning, clean equipment must be protected
Ex. Covers, wrapping
Procedures should also state: All cleaned equipment will be
inspected immediately prior to use
How often is the cleaning performed?
CLEANING (CONTINUED)
Equipment Cleaning Risk:
Equipment used for more than 1 pharmaceutically
active substance (multi-product equipment)
Traces of previous product to be carried onto other
product
Thorough cleaning is required
Equipment used for only 1 product –pharmaceutically
active molecules degrade over time, builds up on
equipment
Preservatives
Environmental contaminants- Microbiological and
particles
CLEANING (CONTINUED)
Check for Standing Water
All cleaned equipment is dried before storage
Residual water is an opportunity for a contaminant to
increase in number
Especially Microorganisms that are G-R
Even if dead, can produce endotoxins which are
harmful if introduced into the product/process
Endotoxins can’t be killed by autoclave
No inactivation or removal occurs
CLEANING (CONTINUED)
Check Material and equipment used for cleaning
Ex. Buckets, brushes, mops, wipes, detergents
Where are these cleaning materials stored?
Are they in new/clean/dry condition?
Check labels/expiration dates of all solutions used
Are solutions appropriate for intended purpose
Are they all approved?
Is there an approved list of agents?
Are all cleaning agents properly identified (labeled)?
CLEANING (CONTINUED)
Evaluate the cleaning materials being used are qualified
and listed on an approved sanitizing/disinfecting agent
list
Are they of “known effectiveness”?
Appropriate?
Know the differences
Cleaner (surfactant, sheeting action)
Sanitizer (ex. IPA)
Disinfectant (ex.Quats.)
Sporicide (ex. Bleach/SHS)
Isopropyl alcohol (IPA) does not kill spores (ex. Bacillus)
CLEANING (CONTINUED) Sanitizing Solution Effectiveness
Factors:
Concentration
pH
Temp.
Contact Time
USP 1072:
Select & demonstrate the effectiveness of chemical
disinfectants and antiseptics as bactericidal,
fungicidal, and sporicidal agents
Applying disinfectants in manufacturing areas with the
relevant regulations and safety considerations
DISINFECTANT QUALIFICATION
Review Disinfectant Study Protocol
What surfaces were tested?
What challenge organisms were used? Are these the right
organisms to use?
Evaluate the test results
Elements of a Disinfection Program:
Chemical action
Physical action
Selection
Rotation
Efficacy
Equipment
Well defined SOPs
Trained and knowledgeable personnel
TESTING
STERILE PRODUCTION
ENVIRONMENTAL MONITORING
Environmental Monitoring
Aseptic Processing takes place in rooms and also isolators
Are the areas monitored?
Monitoring Criteria
How often?
How is the monitoring performed? Ensure that it (individual taking the
sample or sampling methods, improper technique) does not
compromise the cleanliness of the area
EM Validation
Do methods interfere with “Zone protection”
(The rooms are not sterile)
Examine Data
Analyze what organisms are recovered
Are EM results included in the documentation for Batch Release
ENVIRONMENTAL MONITORING
EM Results can depend on:
Effectiveness of gowning
# of personnel in room
Entries and Exits into Room in terms of frequency
Cleanliness of room and process equipment
Auditor should dig a little deeper….
Microbial ID’s
Although finding the source of the contamination is sometimes difficult,
When microorganisms are isolated, performing an ID will allow us to
identify whether it comes from people, water, or environment fairly
easily
Genus and species
Build a library and establish Environmental Isolates
Ref.
FDA CFR 211.42
EU GMP Annex 1.4
ENVIRONMENTAL MONITORING PROGRAM
Elements of the Environmental Monitoring Program
Total airborne particulate counts (Particles)
Viable air monitoring; active and passive (FOP, SAS)
Viable surface monitoring (RODACS)
Personnel monitoring
Temperature
Relative humidity
Air pressure differentials
Alerts and Action limits
Exceeded limits require investigation
May impact batch release
INTEGRITY TEST FOR FILTERS
Performed manually or with automated system
Sterilizing filters integrity testing required (before & after use)
Critical gas & air vent filters after only (after use)
Value of bacterial retention is typically performed by supplier
Sterile effluent is produced
Challenged with B. diminuta 107 filter surface area (retention
study using smallest bacteria)
ASEPTICALLY FILLED UNITS TESTING
Ampoules 100% Integrity tested for seals, cracks, leaks
Visual Inspection
Cameras
Manual- extraneous particle contamination and other
defects
May include Destructive Methods
Torque testing on closures
Head space gas concentration
Dye Bath
Ref.
EU Annex 1.88
EU Annex 1.90
STARTING MATERIALS
211.84 Testing and approval or rejection of components, drug product containers, and closures.
Each Lot is tested
Representative samples of each shipment (of materials)
Materials for Manufacture
Are the materials verified upon receipt?
How are Suppliers approved?
Are all materials obtained from approved suppliers?
Review most recent supplier audits
What were the findings/observations
Follow-up actions, were they verified?
PROCESS TESTING
EM Test Results
Water Test Results (USP/WFI/Pre-treat, Chill)
Pre-filter Bioburden Results <10CFU/100mL
Endotoxin Test Results(if applicable)
Components/Closures
Sterility Test Results- test is validated for each Finished
Product (Samples from Beg. Mid, End) of batch
Compressed gas (oil free) ex. Air, nitrogen, must be high
quality
*
THE TESTING LAB Lab Error
Ensure samples are taken “aseptically”
Ensure there is no opportunity for cross-contamination during testing
Testing performed in a “controlled area” (once your are in, stay
there for entire test session, preparation is key)
Sample containers, gloves, testing apparatus
Are there Positive/Negative controls?
Verify that appropriate media/neutralizers/sampling containers are used
Data Analysis and Interpretation How to read Micro. plates ex. spreaders
Techs. Are trained to investigation procedure
Comments on paperwork- clear and concise
Examine Trends and Deviations (has Mgmt. been notified when Alerts are
reached?) This needs to be done.
No “Testing into compliance”
STERILITY TESTING
Parametric Release:
A system of release that gives the assurance that the product is
of the intended quality based on information collected during the
manufacturing process and on the compliance with specific GMP
requirements
Not based on Sterility Test Results
Ex. 5% of lot is Tested
Review Sterility Test failures
Fail can indicate:
Lab error
Gross contamination (In-process or finished product)
Ensure a strong justification is given if batches were not rejected
Check other batches, other products manufactured with the same
process
Ref.
EU Annex 17.34
EU Annex 1.91
PROCESS SIMULATIONS (MEDIA FILLS)
Process Simulations- all parts of the process that may
have risk where contamination may be introduced
(asepsis)
Media Fills
Not for products in final container
Use of a micro. media (TSB) instead of product
Protocols- performed as close to actual production
process as possible
Any difference must be justified and documented
Interventions- Same as production but simulated
Designed to be more rigorous than actual Incorporating risk factors
and “worst case” scenarios
Ref.
EU Annex 1.42
EU Annex 1.55
PROCESS SIMULATIONS (continued)
Expected Frequency :
Initial: 3X (Validation)
Routine: 2X/year (Qualification)
As needed : Changes in equipment/process
Expected Results:
No Contaminated Units
Investigation for positive/missing units
Micro. Identification Genus & species
Growth Promotion-Controls on media batches
Prove growth can be supported of microorganisms
Ex. Environmental isolates and as specified in USP
Without GP test is invalid
Ensures any contamination (if present) would be detectable
Process Simulation only validates the process to control contamination
Part II
VALIDATION
Validation is a process of establishing documentary evidence
demonstrating that a procedure, process, or activity carried out in
production, testing, or to maintain the desired level of compliance at
all stages
Establishing documented evidence that provides a high degree of
assurance that a specific process will consistently produce a product
meeting its pre-determined specifications and quality
attributes.".[FDA (1987). Guidelines on General Principles of
Process Validation.
The Validation Master Plan is a document that describes how and
when the validation program will be executed in a facility.
Ref.
FDA CFR 211.13
EU GMP 1.3 & 5.37
EU Annex 1.36, 1.54, 1.55
VALIDATION
Must validate equipment and process controls (used to sterilize
products and components)
Individual sterilizing processes validated separately
Installation qualification (IQ) – Demonstrates that the process or
equipment meets all specifications, is installed correctly, and all required
components and documentation needed for continued operation are
installed and in place.
Operational qualification (OQ) – Demonstrates that all facets of the
process or equipment are operating correctly.
Performance qualification (PQ) – Demonstrates that the process or
equipment performs as intended in a consistent manner over time
Does it work?
Prove it
Document It
THE PROTOCOL:
Methods of sampling should be specified
Analytical methods are sensitive enough to detect residues at those
limits of detection
For Swabs, Supplier code/composition of swab material must be
specified
Protocol is a formal evaluation of equipment itself
Sample location is important, should not be just the easiest to
access
Requires a sensible approach for which surfaces to sample
Revalidation requirements (on-going) should be referenced in
the protocol
Any significant change to equipment/process requires revalidation
Cleaning Method
Cleaning Agents
Product Range used in conjunction with equipment
o ex. single vs. multi & concentration
THE VALIDATION FINAL REPORT:
Verify Testing should have occurred after the Protocol was approved
Verify report states the cleaning process reported on has been
validated to prove that residues have been reduced to acceptable
levels
Verify the cleaning and testing has been repeated a sufficient
number of times
(at least 3X)
Production SOPs must provide instructions which reflect the
cleaning validation
Written Procedures to follow….
VERIFY VFR STATES THE CLEANING
PROCESS IS VALID
The data should support a conclusion that residues have
been reduced to an "acceptable level.“
If Validation is not performed, or postponed, then there
must be a documented justification as to why.
Ex. Dedicated to a single product (soluble) and easy
to clean
Final Report
Has a Conclusion & formally approved
Since the validations are dependent on the individual
process for each piece of equipment, the rationale for
limits must be documented
If detergents are not easily removable, a different
detergent should be considered
AUDITING VALIDATION OF
EQUIPMENT CLEANING
AUDITING VALIDATION OF CLEANING Risk: There is a high potential of cross-contamination due to
inadequate cleaning procedures
Cleaning procedures should be of “known” effectiveness
Verify:
Controls
Testing
Ruggedness (Reproducibility)
The degree of reproducibility of test results with variation which
is expected
Robustness (Reliability)
Remain unaffected by small, but deliberate variations provides
indication of reliability under normal usage
AUDITING VALIDATION OF CLEANING
Verify written procedures (SOP's) detailing the
cleaning processes used for various pieces of
equipment.
Any residues from the cleaning process itself
(detergents, solvents, etc.) also have to be
removed from the equipment.
Verify written general procedures on how
cleaning processes will be validated
AUDITING VALIDATION OF CLEANING
Verify the general validation procedures must address:
o Who is responsible for performing and approving the validation
study?
o The acceptance criteria
o When revalidation will be required?
Verify specific written validation protocols in advance for the studies
to be performed on each manufacturing system (or piece of
equipment) should address issues:
Sampling procedures, and
o Analytical methods to be used including the sensitivity of those
methods.
Verify validation studies are:
Conducted in accordance with the protocols
Documented the results of studies
Verify there is a final validation report which is approved by mgmt.
AUDITING VALIDATION OF CLEANING
Review of IQ/OQ/PQ
Review Protocol- details the chemical analysis methods used (ex.
TOC) and sampling methods used (ex. swabs, rinse)
Formally approved by QA, VAL, PROD
Should Include references for cleaning procedures used
Placebo may be used in cases where the substances are toxic (if
hazardous to personnel)
Should List pharmaceutically active materials and cleaning
agents used on each item of equipment
If validation is not performed, or postponed, then there must be a
documented justification as to why.
Ex. Dedicated to a single product (soluble) and easy to clean
There should be a Facility Cleaning Validation Master Plan
Which includes an index of a current status of each piece of
equipment
EQUIPMENT VALIDATION
1 2 3
EQUIPMENT VALIDATION
All equipment must be validated
Requires Change Control
Bringing in new equipment-Procedures
Equipment Validation
You wont be able to tell if the equipment is
validated just by looking at it but
Only equipment that has been validated can
be used
Prove that the equipment works
Included in Facility Master Validation Plan
EQUIPMENT VALIDATION Individual sterilizing process validated separately using appropriate
strategies
Records
Physical checks –data (ex. Temperature charts) Temp. vs time (sometimes pressure) for each run
Appropriate challenge organisms are used SIP- steam sterilization process- Biological Indicators- extremely resistant to heat,
spore strips, disks, ampoules
Dry Heat (tunnels or ovens)- Bacterial endotoxin
Ethylene Oxide/Chlorine Dioxide Gas
Gamma Irradiation rays destroy chemical bonds which interact with
the microorganisms
Process Validation should be performed annually, unless major
modifications are made
Post Validation- Controlled in its routine application to ensure the
validated conditions are maintained
EU Annex 1.61
EU Annex 1.56
SUMMARY GMP is the heart of Pharmaceutical Manufacturing, and Compliance
is mandatory, not optional
It is imperative that your company has a formal internal audit system
in place, regardless of the type of sterile manufacturing (aseptic
processing or terminal sterilization)
You do not need to be a Technical Expert in all areas but
you do need to recognize when something is not right
By conducting an internal audit, you are serving as a Quality
Representative for your Company. By utilizing the proper auditing
tools, you may identify gaps or “areas for improvement” which can
be addressed {in a proactive and timely manner}. The audit will be
beneficial to both you and your company. It will also help ensure that
your Quality Systems are in check and your facility is always in an
“audit ready” mode for when the agencies show up at your door…
??? QUESTIONS ???
THANK YOU
REFERENCES
1. PHARMACEUTICAL INSPECTION CONVENTION
PHARMACEUTICAL INSPECTION CO-OPERATION SCHEME
“PIC/S Guide to Good Practices for the Preparation of Medicinal Products in Healthcare Establishments” October 2008
“Recommendation on the Validation of Aseptic Processes” January 2011
“Inspection of Aseptic & Sterile Manufacturing” 2009
“Guide to Good Manufacturing Practice for Medicinal Products” PE 009-10 (Part I) January 2013
2. FDA
“ Guidance for Industry: Sterile Drug Products Produced by Aseptic Processing-
Current Good Manufacturing Practice” September 2004
“Guide to Inspections Validation of Cleaning Processes” 11/14/2005
“FDA Compliance Program Guidance Manual ,Sterile Drug Process Inspections Program, Chapter 56-Drug Quality Assurance”
3. EudraLex The Rules Governing Medicinal Products in the European Union
”EU Guidelines to Good Manufacturing Practice (EU GMP)
Medicinal Products for Human and Veterinary Use
Annex 1 Manufacture of Sterile Medicinal Products”
Volume 4 November 2008
4. United States Pharmacopeia (USP 36-NF 31) December 2013
5. WORLD HEALTH ORGANIZATION (WHO)
“Good Manufacturing Practices for Sterile Pharmaceutical Products”
“Water for Pharmaceutical Use”
“Validations”
“Inspections”
6. International Organization for Standardization (ISO)
14644 “Airborne Particulate Cleanliness Classes in Cleanrooms and Clean Zones”
7. PDA J Pharm Sci Technol March/April 2011 65:92-99, July Aug 2012 66:346-353
“The importance of Accurate Microorganism Identification in Microbial Challenge Tests of Membrane Filters-Part I & Part II” G. Haake, I. Kaesler-Neumann, H. Henning, T.H. Meltzer, and M.W. Jornitz
8. Continuing Education and Development, Inc. (CED) Engineering “HVAC Design for Cleanroom Facilities” A. Bhatia cedengineering.com
FDA 21CFR 211.25 & 211.28
21 CFR 211.25(a) states that “Each person engaged in the manufacture, processing, packing, or holding of a drug product shall have education, training, and experience, or any combination thereof, to enable that person to perform the assigned functions”
Training shall be in the particular operations that the employee performs and in current good manufacturing practice as they relate to the employee's functions.
Training in current good manufacturing practice shall be conducted by qualified individuals on a continuing basis and with sufficient frequency to assure that employees remain familiar with CGMP requirements applicable to them.
21 CFR 211.28(a) states that “Personnel engaged in the manufacture, processing, packing, or holding of a drug product shall wear clean clothing appropriate for the duties they perform.”
Protective apparel, such as head, face, hand, and arm coverings, shall be worn as necessary to protect drug products from contamination.
FDA 21CFR 211.42
211.42 Design and construction features.
(a) Any building or buildings used in the manufacture, processing, packing, or holding of a drug product shall be of suitable size, construction and location to facilitate cleaning, maintenance, and proper operations.
(b) Any such building shall have adequate space for the orderly placement of equipment and materials to prevent mix-ups between different components, drug product containers, closures, labeling, in-process materials, or drug products, and to prevent contamination.
The flow of components, drug product containers, closures, labeling, in-process materials, and drug products through the building or buildings shall be designed to prevent contamination.
FDA 21CFR 211.42 (Continued)
(c) Operations shall be performed within specifically defined areas of adequate size.
There shall be separate or defined areas or such other control systems for the firm's operations as are necessary to prevent contamination or mixups during the course of the following procedures: (1) Receipt, identification, storage, and withholding from use of components,
drug product containers, closures, and labeling, pending the appropriate sampling, testing, or examination by the quality control unit before release for manufacturing or packaging;
(2) Holding rejected components, drug product containers, closures, and labeling before disposition;
(3) Storage of released components, drug product containers, closures, and labeling;
(4) Storage of in-process materials;
(5) Manufacturing and processing operations;
(6) Packaging and labeling operations;
(7) Quarantine storage before release of drug products;
(8) Storage of drug products after release;
(9) Control and laboratory operations;
FDA 21CFR 211.42 & 211.44
211.42 (10) Aseptic processing, which includes as appropriate: (i) Floors, walls, and ceilings of smooth, hard surfaces that are
easily cleanable
(ii) Temperature and humidity controls
(iii) An air supply filtered through high-efficiency particulate air filters under positive pressure, regardless of whether flow is laminar or nonlaminar
(iv) A system for monitoring environmental conditions
(v) A system for cleaning and disinfecting the room and equipment to produce aseptic conditions
(vi) A system for maintaining any equipment used to control the aseptic conditions
211.44 Lighting Adequate lighting shall be provided in all areas
FDA 21CFR 211.46
211.46 Ventilation, air filtration, air heating and cooling
(a) Adequate ventilation shall be provided.
(b) Equipment for adequate control over air pressure, micro-organisms, dust, humidity, and temperature shall be provided when appropriate for the manufacture, processing, packing, or holding of a drug product.
(c) Air filtration systems, including prefilters and particulate matter air filters, shall be used when appropriate on air supplies to production areas.
If air is recirculated to production areas, measures shall be taken to control recirculation of dust from production.
In areas where air contamination occurs during production, there shall be adequate exhaust systems or other systems adequate to control contaminants.
(d) Air-handling systems for the manufacture, processing, and packing of penicillin shall be completely separate from those for other drug products for human use.
FDA 21CFR 211.58 & 211.63
211.58 Maintenance. Any building used in the
manufacture, processing, packing, or holding of a drug
product shall be maintained in a good state of repair
211.63 Equipment design, size, and location
o Equipment used in the manufacture, processing,
packing, or holding of a drug product shall be of
appropriate design, adequate size, and suitably located
to facilitate operations for its intended use and for its
cleaning and maintenance
FDA 21CFR 211.65 & 211.67
211.65 (a) Equipment shall be constructed so that surfaces that
contact components, in process materials, or drug products shall not be reactive, additive, or absorptive, so as to alter the safety, identity, strength, quality, or purity of the drug product beyond the official or other established requirements
211.67 (a) Equipment and utensils shall be cleaned, maintained
or sanitized at appropriate intervals to prevent malfunctions or contamination that would alter the safety, identity, strength, quality, or purity of the drug product beyond the official or other established requirements
FDA 21CFR 211.84 211.84 Testing and approval or rejection of components, drug
product containers, and closures.
(a) Each lot of components, drug product containers, and closures shall be withheld from use until the lot has been sampled, tested, or examined, as appropriate, and released for use by the quality control unit.
(b) Representative samples of each shipment of each lot shall be collected for testing or examination.
The number of containers to be sampled, and the amount of material to be taken from each container, shall be based upon:
Statistical criteria for component variability,
Confidence levels, and degree of precision desired,
Past quality history of the supplier,
The quantity needed for analysis and reserve
FDA 21CFR 211.113
211.113 Control of microbiological contamination
(a) Appropriate written procedures, designed to prevent
objectionable microorganisms in drug products not
required to be sterile, shall be established and followed
(b) Appropriate written procedures, designed to prevent
microbiological contamination of drug products purporting
to be sterile, shall be established and followed. Such
procedures shall include validation of all aseptic and
sterilization processes
• FDA uses ISO14644 “Cleanroom Classes”
CLEANROOMS AND ASSOCIATED CONTROLLED ENVIRONMENTS
ISO DOCUMENT TITLE
ISO-14644-1 Classification of Air Cleanliness
ISO-14644-2 Classification for Testing and Monitoring for Compliance
ISO-14644-3 Methods for Evaluating and Measuring Cleanrooms and
Associated Cleanroom Environments (Metrology Test
Methods)
ISO-14644-4 Design and Construction and Start-up
ISO-14644-5 Operations
ISO-14644-6 Terms & Definitions
ISO-14644-7 Enhanced Clean Devices
ISO-14644-8 Molecular Contamination
ISO-14698-1 Biocontamination: Control General Principles
ISO-14698-2 Biocontamination: Evaluation and Interpretation of Data
ISO-14698-3 Biocontamination: Methodology for Measuring Efficiency of
Cleaning Inert Surfaces
• ISO 9000: “QUALITY MANAGEMENT” o ISO 19011:2011 Guidelines for auditing management systems
o ISO 1901:2008 Quality management systems -- Requirements
o ISO 9004: 2009 Managing for the sustained success of an organization -- A quality management approach
ISO REFERENCES