CONTAMINATION CONTROL

STRATEGY
Sep/2024

Pharm. CAO NGUYỄN NGỌC ÂN

ORIOLED HUB

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CONTAMINATION CONTROL STRATEGY
1. DEFINITION

2. BACKGROUND

3. CASE STUDIES FOR CONTAMINATION CONTROL

4. ELEMENTS OF CCS

5. CONTAMINATION CONTROL STRATEGY IMPLEMENTATION PROCESS

6. EXAMPLE FOR ANALYSIS OF AN ELEMENT’S CCS

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1. DEFINITION

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DEFINITION

Contamination control strategy (CCS):

What is CCS?? A planned set of processes and measures for the identification,
assessment, control, and monitoring of contamination risks
that include microorganisms, pyrogens/endotoxins, and
foreign particles, derived from current product and process
understanding, that assures process performance and product
quality.
Like a Site Master File (SMF), which provides an overview of the
facility, the CCS document provides an overview of the totally of
contamination control measures and their linkage to an
overall strategy.
Annex 1, EU-GMP
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2. BACKGROUND

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BACKGROUND

The manufacture of sterile products is subject to special requirements

in order to minimize risks of microbial, particulate and
endotoxin/ pyrogen contamination.

Measures affect different stages of a manufacturing Annex 1 introduces the concept of This is a new and specific documentation
process and often fall under the responsibility of other “Contamination Control Strategy” requirement for Annex 1
departments (e.g., quality control, quality assurance, or
manufacturing)

Annex 1, EU-GMP
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BACKGROUND

Annex 1 (2022) "Manufacture of Sterile Medicinal Products" deals with

the demanding challenge of controlling contamination in a wide range
of sterile product types:
• Finished products, or Drug Products
• Active Substance, Active Ingredients
• Excipients
• Primary packaging material

Annex 1, EU-GMP
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BACKGROUND

However, some of the principles and guidance, such as

contamination control strategy, design of premises, cleanroom
classification, qualification, validation, monitoring and personnel
gowning, may be used to support the manufacture of other products
that are not intended to be sterile such as certain liquids, creams,
ointments, and low bioburden biological intermediates but
where the control and reduction of microbial, particulate and
endotoxin/pyrogen contamination is considered important."

Annex 1, EU-GMP
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3. CASE STUDIES FOR
CONTAMINATION
CONTROL

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CASE STUDIES FOR CONTAMINATION CONTROL

Case study 1: Contamination related to Blow-Fill-Seal

Equipment Design and Maintenance

Background: A firm experienced both sterility and media-fill

failures. Stenotrophomonas maltophilia was identified as a
sterility failure isolate. Media-fill isolates included Pseudomonas
spp. and Acinetobacter spp. The prior sterility history of the
blow-fill-seal (BFS) processing line was good.

PDA, TR 90
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CASE STUDIES FOR CONTAMINATION CONTROL

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CASE STUDIES FOR CONTAMINATION CONTROL

Case study 1: Contamination related to Blow-Fill-Seal Equipment Design and

Maintenance

GMP Issues: Mold plates used to form the primary product container were chilled with
cooling water. This demineralized potable water was held in a tank at a low temperature prior
to use. When sampled, the cooling water yielded very high microbial counts. Leaks
developed in the mold plates, allowing contaminated water to infiltrate into the product,
causing non-sterility. Based on this significant breach in equipment integrity, among the most
relevant GMP deviations were the unsuitable processing equipment and the lack of an
adequate preventive maintenance program.

PDA, TR 90
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CASE STUDY FOR CONTAMINATION CONTROL

Case study 1: Contamination related to Blow-Fill-Seal

Equipment Design and Maintenance

Quality System Context: The facility and equipment system

were the most deficient. The unsuitable equipment and
inadequate preventive maintenance program were key factors in
the product contamination.

PDA, TR 90
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CASE STUDIES FOR CONTAMINATION CONTROL

Case study 1: Contamination related to Blow-Fill-Seal

Equipment Design and Maintenance

Outcome: Both the sterility failure and media-fill failure were

attributed to contamination by cooling water. Pinhole leaks in the mold
plates of the aseptic filling machine allowed cooling water to directly
contaminate the product. The exact date the problem occurred was
unknown, making the corrective and preventive action plan more
difficult. Numerous lots were rejected.

PDA, TR 90
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CASE STUDIES FOR CONTAMINATION CONTROL

According to Annex 1, EU-GMP:

6.21
• Major items of equipment associated with hydraulic, heating and
cooling systems should, where possible, be located outside the filling
room. There should be appropriate controls to contain any spillage
and/or cross-contamination associated with the system fluids.
6.22

• Any leaks from these systems that would present a risk to the product
should be detectable (e.g. an indication system for leakage).
Annex 1, EU-GMP
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CASE STUDIES FOR CONTAMINATION CONTROL

Case Study 2: Contamination Related to Facility Construction

Background: A firm undertook major construction in a cleanroom next to the
personnel gowning airlock. The construction occurred over a one-month period and
coincided with continued drug product production. Following an initial media-fill failure,
the firm’s investigation concluded that practices unrelated to the construction were the
likely sources of the non-sterile units. The firm corrected the apparent root causes and
then performed a repeat media fill. A second media-fill failure occurred. A second
thorough investigation by the firm concluded that the contaminants in the media-fill
vials had migrated from the area of the construction activity. Spore-forming bacteria
(Bacillus sp.) were identified as isolates in both media fill.

PDA TR90
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CASE STUDIES FOR CONTAMINATION CONTROL

GMP Issues: The firm did

Case Study 2: not adequately assess
Contamination Related
the risk posed by
to Facility
Construction construction activities.

PDA TR90
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CASE STUDIES FOR CONTAMINATION CONTROL

Case Study 2: Contamination Related to Facility Construction

GMP Issues: The production system was most deficient in this case. With any change in normal,

qualified conditions it is essential that it be carefully evaluated by production and quality

management.

Change control systems provide a formal mechanism for evaluating these issues. Written procedures

should address returning a facility to normal operating conditions when construction or other

activities (e.g., maintenance) are considered to have a potentially adverse impact. In these cases, a

firm should either elect not to manufacture product for a specific period or, where appropriate,

implement special precautions and increase monitoring to detect any drift in environmental control.

PDA TR90
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CASE STUDIES FOR CONTAMINATION CONTROL

Case Study 2: Contamination Related to

Facility Construction
Outcome: Multiple lots were found to lack the
assurance of sterility, and those already distributed
were recalled. The firm temporarily suspended
operations. The firm ultimately restored adequate
conditions and resumed aseptic processing following
successful media fill requalification.

PDA TR90
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 4.
ELEMENTS
OF CCS

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ELEMENTS OF CCS

A Contamination Control Strategy (CCS) is implemented across

the facility in order to define all critical control points and
assess the effectiveness of all the controls (design, procedural,
technical and organisational) and monitoring measures
employed to manage risks to medicinal product quality and
safety. The combined strategy of the CCS should establish robust
assurance of contamination prevention.

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ELEMENTS OF CCS

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ELEMENTS OF CCS

PDA TR90
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ELEMENTS OF CCS

•Process
Scientific knowledge
knowledge •Technical
knowledge

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ELEMENTS OF CCS

Potential proliferation
points for
microorganisms

History of Microbial growth

contamination events potential identified for
and trends each process step
Process
knowlegde

Potential ingress points Process removal or

for contaminants to reduction capability for
enter the process potential contaminants
stream (e.g., filtration)

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ELEMENTS OF CCS

Aseptic
processing,
Process
design
Microbial principles Facility,
attributes, equipment
behavior, and utility
and biofilm design
develop principles
Technical
knowledge
Cleaning,
disinfection,
Quality risk
decontamina
management
tion,
principles
sterilization
principles
Raw
material
quality

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ELEMENTS OF CCS

Quality risk management foundation element:

Identify and
Design of new
assess risk
and existing
Employ QRM with the intent
manufacturing
principles to prevent and
processes and
control
facilities
contamination.

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ELEMENTS OF CCS

Personnel awareness and quality culture:

The strength of the quality culture and level of personnel awareness around
contamination controls have a direct and significant impact on the
success of the CCS.
Contamination control should be a priority that is reflected in the goals of
the firm.
Firms should maintain an ongoing campaign to promote contamination
control awareness among all employees engaged in GMP activities, including
shop floor and management staff.

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ELEMENTS OF CCS

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ELEMENTS OF CCS

Training, hygiene,
aseptic behavior,
Design, area Personnel
gowning
classification, Personnel/
Facility Process
Material Flow

Cleaning
Raw material and
Procedure, Validation
Disinfection

Sterile
product
Viable particle, particle,
Design, Qualification, Environment
Utilities temperature, humidity,
control
Maintenance, Monitoring differential pressure

Vendor
Equipment
approval
Product Design, Material
containers transfer, endotoxin
and closures
reduction, sterilization,
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integrity
ELEMENTS OF CCS

CCS Governance and Effectiveness Review:

The CCS lifecycle begins during the design of the facility and
process. Further, the CCS should be considered during quality-
by-design activities and formally documented as a prerequisite
to GMP manufacturing.

Thereafter, the quality systems drive refinement and

continuous improvement in the CCS over the life of product.

The CCS should also be reviewed periodically (preferably reviewed

annually) for effectiveness to ensure it remains current with the
process and aligned with industry standards, specifically the
potential need to adopt new, more effective technologies.
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5. CONTAMINATION CONTROL
STRATEGY IMPLEMENTATION PROCESS

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CONTAMINATION CONTROL STRATEGY IMPLEMENTATION PROCESS

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CONTAMINATION CONTROL STRATEGY IMPLEMENTATION PROCESS

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CONTAMINATION CONTROL STRATEGY IMPLEMENTATION PROCESS

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EXAMPLE FOR
ANALYSIS OF AN
ELEMENT’S CCS

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EXAMPLE FOR ANALYSIS OF AN ELEMENT’S CCS
CONTAMINATION CONTROL STRATEGY IMPLEMENTATION PROCESS

IDENTIFIED RISK
CONTAMINATION CONTROL
CONTROL STRATEGY MEASURESPROCESS
IMPLEMENTATION CCS DOCUMENT
Risk from the specification: Develop relevant specifications that SOP-407 Creation of
Raw material specifications are often developed consider the risk profile of the material specifications and test
by the material manufacturer and relate to the based on its origin, the material’s instructions
amount of control that is understood by the manufacturing process, and the level of
manufacturer, from the material’s origin through quality needed for the drug
its processing. The largest end-user of materials is manufacturing process.
often not the pharmaceutical manufacturer, thus Specifications for raw materials should
supplier-derived specifications may not be include requirements for microbial,
entirely relevant particulate and endotoxin/pyrogen
limits.

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EXAMPLE FOR ANALYSIS OF AN ELEMENT’S CCS
CONTAMINATION CONTROL STRATEGY IMPLEMENTATION PROCESS

IDENTIFIED RISK
CONTAMINATION CONTROL
CONTROL STRATEGY MEASURESPROCESS
IMPLEMENTATION CCS DOCUMENT
Biological contamination risk: A formal risk assessment is needed to Risk assessment
The origin of a raw material is the first factor establish the appropriate control
considered to determine the microbiological risk. measures for raw materials, considering
The origin can predict the scope of possible the material properties, origin, supplier
inherent bioburden and other adventitious agents. history, intended process use, handling,
storage, sampling, and testing. The
output of this risk assessment is a test
plan that establishes the type and
frequency of microbiological testing
needed to monitor the supplier controls
and the possible need for additional
treatment and controls by the end user.

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EXAMPLE FOR ANALYSIS OF AN ELEMENT’S CCS
CONTAMINATION CONTROL STRATEGY IMPLEMENTATION PROCESS

CONTAMINATION CONTROL STRATEGY IMPLEMENTATION PROCESS

IDENTIFIED RISK CONTROL MEASURES CCS DOCUMENT

Sampling of raw materials: For sterile raw materials and SOP-203 Sampling of
Any handling and sampling performed in the excipients, sampling should be starting materials and
facility is risked from extraneous closed. packaging materials
contamination When closed sampling is not
possible, sampling should be
conducted in the same
environmental classification as
production. Otherwise, the sampled
unit should be excluded from
production use.

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EXAMPLE FOR ANALYSIS OF AN ELEMENT’S CCS
CONTAMINATION CONTROL STRATEGY IMPLEMENTATION PROCESS

CONTAMINATION CONTROL STRATEGY IMPLEMENTATION PROCESS

IDENTIFIED RISK CONTROL MEASURES CCS DOCUMENT

Supplier quality system: The supplier of raw materials must be SOP-103 Supplier
Raw materials can be key sources of qualified and a quality agreement with management
contamination and are primarily controlled the supplier should be in place before SOP-107 Audits and self-
through the supplier’s quality system. purchasing. inspections
SOP-117 Quality agreements

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EXAMPLE FOR ANALYSIS OF AN ELEMENT’S CCS
CONTAMINATION CONTROL STRATEGY IMPLEMENTATION PROCESS

CONTAMINATION CONTROL STRATEGY IMPLEMENTATION PROCESS

IDENTIFIED RISK CONTROL MEASURES CCS DOCUMENT

Raw materials can introduce contaminants All raw materials must be sterilised SOP-206 Testing of starting
to the process stream and final drug and aseptically added. Raw materials, packaging
products. materials must be checked for materials,
sterility before use. Testing of raw intermediates, bulk, and
materials will prevent the use of finished products
contaminated raw materials that
may result in excursions of in-
process intermediates, which may
impact product quality and result in
long and expensive investigations

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