The Essential Components of

Sterility Assurance Program

Vasanthkumar J
Quality Assurance
Agenda
 Introduction
 Personnel
 Personnel Hygiene and Sanitation practices
 Personnel Flow
 Procedures
 Material Flow
 Equipment
 Sterilization
 Depyrogenation
 Decontamination
 Facility Design
Agenda
 Effects from adjacent areas
 Supplier Qualifications
 Validation and Qualifications
 Decontamination, Cleaning, and Disinfection Programs
 Product and Materials
 Manufacturing Practices
 Laboratory Testing
 Environmental Monitoring Program
 Utility and Water Systems
 Storage Conditions
 Conclusion
Introduction
 Sterility assurance is a level of confidence that a particular
product or unit that is purported to be sterile is sterile.
 Sterility cannot be demonstrated without the destruction of
every unit of product produced.
 Therefore, sterility assurance is achieved through multiple
practices and procedures.
 This topic will discuss on the different variables of
contamination control that help to increase confidence in
sterility assurance.
Introduction
 USP 1211 - The chapter states that “an item is deemed sterile
only when it contains no viable microorganisms.”
 It is well known in the industry that the sterility testing model
described in USP 71 Sterility Tests has limitations.
 Sterility test only indicates that the articles from a lot that are
tested are sterile.
 The test is destructive, every unit that is tested is either
consumed or no longer sterile after testing.
 To help ensure patient safety, additional measures must be
introduced to add assurance that the entire batch or lot of
products manufactured is sterile.
 This is accomplished using a sterility assurance program.
Influences on Sterile Products.
 The first step in developing a sterility assurance
program is to list each step in the process,
beginning at the point of use and ending in
sterile storage. 
 Each step should be evaluated for ways to
prevent contamination in the manufacturing
process or environments.
Personnel
 Personnel must have proper training, education to
be involved with aseptic processing.
 Training concepts should include the importance of
proper aseptic technique and cleanroom behaviors.
 It must be recognized that humans are the primary
source of contamination in the cleanroom
environment.
 Retraining and qualification of personnel should be
done on a routine basis to keep personnel sensitized
to the importance of aseptic technique
Personal Hygiene and Sanitation Practices
 Procedures and training that govern personnel hygiene,
sanitation, aseptic technique, aseptic behavior in the
cleanrooms, and aseptic gowning practices.
 Personnel must follow the procedure/ aseptic practices
to avoid contamination of the test, environment, and/or
product.
 Personnel should report to the supervisor, if he is feeling
ill that may have an adverse effect on a test, product, or
environment.
 Personnel must also be monitored for microbial growth
and undergo gowning qualification training to ensure
aseptic status of the manufacturing or testing
environment.
Personnel Flow

 There must be procedures and practices regarding

personnel flow.
 Personnel must follow established entry and exit routes
to prevent cross contamination.
 The routes should include different levels of gowning for
each grade of the cleanroom environment.
 Should be established in standard operating procedures
(SOPs) and understood by personnel.
Procedures

 All procedures for aseptic processing and

subsequent quality control testing must be
written in accordance with good manufacturing
practices (GMPs).
 Procedures must remain up to date, accurate,
and revised when warranted.
Product and Material Flow
 Procedures in place for product and material
flow to prevent cross contamination.
 The routes should include levels or methods of
sanitization of products, materials, and/or waste
as they enter or exit the cleanroom areas.
 These routes must also be established in
standard operating procedures and understood
by personnel.
Equipment
 The use and preparation of equipment for aseptic
processing must be documented in SOPs.
 Must be designed appropriately for the intended use
and housed in a manner to prevent cross
contamination.
 The equipment must be suitably located for
operation, inspection, cleaning, and maintenance.
 Equipment used for the generation, measurement,
or assessment of data must be tested, calibrated,
standardized, and/or sterilized.
Sterilization, Depyrogenation & Decontamination
 The use and sterilization or depyrogenation of
equipment, components, or other materials for aseptic
processing must be governed in SOPs.
 This could include purchasing items that are ready to use
or preparing the items for use in-house.
 Decontamination practices for aseptic processing must
be documented in SOPs.
 This could include chemically sanitizing equipment to
take into the cleanrooms, wiping items down with
disinfectants, or using decontamination devices such as
vaporized hydrogen peroxide (VHP) generators or
autoclaves.
Facility Design
 The design of the facility should be documented as flow diagrams for ease of
use.
 The facility must be constructed to prevent microbial contamination by
including items like DP, the use of classified areas, and pass box to name a
few items.
 Separate areas for the storage and quarantine of materials.
 The warehouse must be neat, clean, and orderly, with
temperature/humidity controls where appropriate.
 Cardboard or other items containing cellulose fibers should not be allowed
in clean areas as they could be a source of mold contamination. 
 Laboratory practices must also be implemented to prevent microbial
contamination from outside of cleanrooms.
 This could include changing uniforms and shoes and using proper aseptic
gowning practices.
Facility Design

 Automated or separative manufacturing designs such as isolators or

restricted barrier access systems (RABS) can be utilized in the
manufacturing areas to prevent cross contamination.
 High efficiency particulate air (HEPA) and heating, ventilation, and
air conditioning (HVAC) systems should be used with differential
pressure cascades, temperature controls, and humidity controls to
prevent microbial contamination.
 If the temperature is too hot or humid, people could sweat,
compromising their cleanroom gowning.
 In addition, when pressure cascades are not controlled properly,
microbes could enter the cleanrooms.
 Excessively humid environments can increase the potential for
fungal contamination.
Effects from Adjacent Areas 
 The effects from adjacent areas should also be considered.
 If an adjoining room has microbial contamination, that contamination
could migrate into the inner core of the cleanrooms.
 Transition areas should be monitored and controlled.
Supplier Qualifications
 Qualifying suppliers is an important approach to control items that are
purchased sterile and ready to use.
 It is important that vendors are trusted to provide quality supplies to
maintain sterility assurance of the final product that is being manufactured.
 Supplier qualifications must be governed by SOPs.
Validation and Qualifications
 Clean areas must be validated and maintained.
 This should include environmental monitoring qualification programs
(EMPQ) and cleanroom qualifications.
 Equipment should also be qualified for use in the cleanrooms.
 There should be cleaning validations that include clean and dirty hold times
of equipment.
 Also, in the realm of validations and qualifications is the topic of process
validations (i.e., media fills).
 Media fills help to demonstrate that the manufacturing process can produce a
sterile final product.
 The manufacturing process should include interventions and aseptic
connections. “An appropriate microbiological media will be treated as if it
were product, and it will be put through an entire manufacturing process
simulation.
 This study will show contamination control effectiveness throughout the
manufacturing process.”
Decontamination, Cleaning, and Disinfection
Programs
 Decontamination, cleaning, and disinfection programs must be established.
 The programs must be governed by SOPs and should describe what gets
cleaned, how the cleaning is performed, how often the cleaning is
performed, what cleaning agents are utilized, and the validation of the
cleaning, decontamination, or disinfection process.
 Room cleanings should include items like the walls, floors, ceilings, and
equipment.
 Again, there should be established clean and dirty hold times for equipment
and the cleanrooms.
 When utilizing disinfectants, consider items like disinfectant efficacy date,
wet contact times, and the method of application of the disinfectants.
 Cleaning, disinfection, and/or decontamination concepts should be
considered for both product contact and non-product contact surfaces.
Product and Materials
 Products and materials must also be controlled to prevent contamination
and increase sterility assurance.
 Raw materials, components, active pharmaceutical ingredients, container
closures, and product contact surfaces should all be monitored and
controlled. “Sterility must be assured for cleaning solutions, tools and
equipment, raw materials, container closures, and any other materials that
will be introduced into the area.”
Manufacturing Practices
 As previously mentioned with media fills, the manufacturing process must
be monitored and controlled.
 This includes interventions and aseptic connections.
 Proper aseptic technique and behaviors must be utilized to prevent cross
contamination of product during manufacturing.
Laboratory Testing
 Laboratory testing to consider when thinking of sterility assurance
programs include items like sterility testing, endotoxin testing, bioburden
testing, raw material testing, in-process testing, and container closure
integrity testing.
 “A sterile product is to undergo analysis for microbial endotoxins and
sterility testing to assure the absence of contamination.”
 This is not an all-inclusive list of laboratory tests, but these quality control
assays help boost the confidence in sterile products by providing a
secondary layer to sterility assurance practices.
Environmental Monitoring Program
 Environmental monitoring assesses the microbial contamination level in the
cleanrooms and adjacent areas.
 This data may highlight areas that need extra cleaning, monitoring, and/or
maintenance.
 Air and surfaces are routinely monitored within the cleanrooms to make
sure the environment continuously meets specifications.
Utility and Water Systems
 Monitoring of utility systems includes water systems, compressed air,
compressed nitrogen, compressed oxygen, or similar systems.
 Depending on the system, testing could include bioburden, total organic
carbon (TOC), conductivity, or non-viable particulate sampling.
 When thinking of utilities, it is important to design facilities so that there
are no drains or sinks in the cleanrooms as these can be a source of
microbial contamination.
Storage Conditions
 When considering storage conditions, it is important to think of warehouse
cleanliness, order, and quarantine areas.
 Temperature and humidity should be monitored and controlled when
required.
 Conditions should be maintained to ensure the sterility of the final product.
 In addition, container closure integrity should be established to ensure the
product remains sterile in its packaging.
Conclusion
 The components described above of a sterility assurance program for an
aseptic manufactured product  do not comprise an all-inclusive list.
 Rather, this list demonstrates the breadth of the items that could impact the
sterility of a product or device that is purported to be sterile.
 When designing a sterility assurance program, consider all the items that
could impact sterility and develop procedures and methods that will
increase the assurance of the sterility of the product or device and minimize
risks to consumers.