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
 GOOD MANUFACTURING PRACTICES

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?
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
 WHERE DO YOU START?
 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
 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
o Handling/Cleaning equipment used in
Manufacturing
o Risk of Contamination
o Entry procedures (clothing, hair cover, tacky
mats, etc.)
o Access to critical (high risk) areas
o Restricted access of personnel
o Gowning Procedure
o Gowning 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 Auditor Hat

 Equipment Validations
 Equipment Cleaning Validations
 Filter Validations
 Media Fills
 Hold Time Studies
 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  Air
be contaminated via:  Water
 Pharmaceutical ingredients  People
 Process water Skin (bacteria and
yeasts)
 Packaging components
Clothes
 Manufacturing environment
Hair
 Processing equipment
Mucous membranes
 Manufacturing operators
 Particles
 Contact with surfaces

 Ensure there no FOOD is allowed

in Production Areas
 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
Before
 Less effective than sterilization

 Depends on agent, saturation and contact time

 Alcohol has no effect on spores

 Microorganisms vary in their sensitivity to disinfectants After

 A sequence of application is required

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
Uncontrolled

Controlled

CRITICAL

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 Scenario: A person tells her
supervisor she has a tooth infection.
The Supervisor asks you if the
 What is “Common Sense”??? Don’t assume….. 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:
Ref:
 Containers FDA 2004, IV
EU GMP 3.1
 Components EU Annex 1.3
FDA 2004, X.A.
 Equipment EU Annex 1.4, 1.5
EU Annex 1.90

 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?
 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
 CONTROLLED AREA REQUIRMENTS

 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
 FACILITY DESIGN
 Verify the Facility is in good condition

 Floor plan
 Is the area big enough? FDA CFR 211.42
EU GMP 2.16
 Is it clean? EU Annex 1.14
 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: o Temperature
 Particles o Pressure
 Airflow o Humidity
 Air Pressure o Specialized Filtration
HEPAs HIGH EFFICIENCY PARTICULATE AIR FILTERS
•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
 AIR FLOW
•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?
 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 SETTLE CONTACT GLOVE
SAMPLE PLATES PLATE PRINT
CFU/m3 CFU/4 hrs. (55 mm Dia.) (5 fingers)
CFU/Plate 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

• 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

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 3, 520, 000 29,000 Not Defined Not Defined

(100,000)*
Classification level- No more than 3 significant figures
*Federal Standards (FS) 209E
 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 6 mos. ISO 14644-1 Annex A
> ISO 5 12 mos.

Air Pressure Diff. All Classes 12 mos. ISO 14644-1 Annex B5

Airflow Volume All Classes 12 mos. ISO 14644-1 Annex B4
Velocity

OPTIONAL TESTING

Test Parameter Class Max. Time Interval Test Procedure #

Installed Filter All Classes 24 mos. ISO 14644-1 Annex B6
Leakage 24 mos.
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 Central TX News Feb 2014
Woman 8 mos. pregnant stores contact lenses in
 Recirculating hot water loop Tap water and goes blind:
 No dead legs
http://www.thedoctorstv.com/videolib/init/9861
 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
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: Ref.
 Effectiveness of gowning FDA CFR 211.42
EU GMP Annex 1.4
 # 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
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 Ref.
EU Annex 1.88
 Cameras EU Annex 1.90

 Manual- extraneous particle contamination and other

defects
 May include Destructive Methods
 Torque testing on closures
 Head space gas concentration
 Dye Bath
 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 Ref.
 Ex. 5% of lot is Tested EU Annex 17.34
EU Annex 1.91

 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
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
ISO REFERENCES
• 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