Effective Contamination Control
Strategy Through Robust
Quality Risk Management System
Outline
1 Introduction/Scope of the presentation 7 Sterile Drug Product Process Control
2 Regulatory Expectations 8 Non-sterile Drug Product Process Control
3 Potential Sources of Contamination 9 Personnel Awareness and Quality Culture
Fundamental elements of Contamination Control
4 10 Conclusion
Strategies
5 Quality Risk Management/Risk Assessment 11 References
6 Microbial Impact Assessment
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Introduction: What is a contamination control strategy
(CCS)?
A contamination control strategy (CCS) is a system that considers all the
integral elements of pharmaceutical product manufacturing. A good CCS
should consider the following holistic approaches:
In-process Controls
Personnel
Processes
Equipment
Utilities
Facility design
Process control
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Regulatory Expectations
The pharmaceutical industry is required to manufacture medicines that are safe,
effective, and of consistent quality, meeting both patient expectations and regulatory
requirements.
FDA Good Manufacturing Practice (GMP) regulations (21 CFR Part 210) require that
a drug maintains its identity, strength, quality, and purity as represented.
Any failure to comply with GMP requirements during manufacturing, processing,
packaging, or storage renders a product adulterated under the Federal Food, Drug, and
Cosmetic Act.
Beyond chemical composition and potency, protection from harmful contamination is
essential to ensure patient safety.
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Scope of this presentation Definitions: Contamination is defined as: “the undesired
introduction of impurities of a chemical or microbiological
Contamination Control Strategy nature, or foreign matter, into or onto raw material,
Development in Pharmaceutical intermediate or API during production, sampling, packaging
Manufacturing focuses on or repackaging, storage or transport.”
contamination control practices
against microbial and other CCS is a holistic, systematic set of control mechanisms that
adventitious agents, pyrogens acts together to provide a high degree of assurance of
such as endotoxin, and foreign
elimination of contaminants in a finished product.
particulate matter in the
manufacture.
The key purpose of CCS is to allow the assessment of the
What is not covered? strategies being implemented by an organization to
Secondary and tertiary packaging determine ongoing effectiveness evaluation and monitoring.
considerations, chemical Provide a platform for necessary continual improvement
contaminants including product and corrections based on prevailing risks associated with
cross-contamination, and inherent the products manufactured onsite. CCS is not a collection of
particulate matter are out of the risk assessment or validation of processes.
scope.
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Scope of this presentation Definitions: Contamination is defined as: “the undesired
introduction of impurities of a chemical or microbiological
Contamination Control Strategy nature, or foreign matter, into or onto raw material,
Development in Pharmaceutical intermediate or API during production, sampling, packaging
Manufacturing focuses on or repackaging, storage or transport.”
contamination control practices
against microbial and other CCS is a holistic, systematic set of control mechanisms that
adventitious agents, pyrogens
acts together to provide a high degree of assurance of
such as endotoxin, and foreign
particulate matter in the
elimination of contaminants in a finished product.
manufacture.
The key purpose of CCS is to allow the assessment of the
What is not covered? strategies being implemented by an organization to
Secondary and tertiary packaging determine ongoing effectiveness evaluation and monitoring.
considerations, chemical
Provide a platform for necessary continual improvement and
contaminants including product
corrections based on prevailing risks associated with the
cross-contamination, and inherent
particulate matter are out of the products manufactured onsite. CCS is not a collection of risk
scope. assessment or validation of processes.
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Potential Sources of Microbial Contamination to Consider
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Foundational Elements of CCS
Scientific knowledge and technical knowledge of the process of preventing
contamination are both foundations of the CCS. They are used to inform the quality risk
management (QRM) foundational element of the CCS, including the elements outlined
below. These elements should be summarized and/or referenced in the CCS document.
When establishing the CCS, knowledge of how to prevent contamination for each step of
a manufacturing process should also be considered.
For Example:
Potential ingress points for contaminants to enter the process stream including
particulates, microorganisms, viruses/bacteriophages, spores, endotoxins, and
other microbial by-products (e.g., exotoxins, proteases, and other metabolites)
Potential proliferation points for microorganisms and viruses, including
bacteriophages, to grow in the raw materials, solutions, process equipment, and
process stream, thereby, allowing formation of undesirable microbial by-products 8
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Elements of a Contamination Control Strategy
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Credit: Elements of a Contamination Control Strategy (courtesy of Sanofi) © 2023 USP
Risk
Assessment
When carrying out risk
assessments, the process mustn’t
be used to justify poor design and
bad practices.
Control should foremost be achieved
through good design, followed by
appropriate procedures. Monitoring
is a means to assess the
effectiveness of control, rather than
a control in its own right.
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Microbial Impact Assessment
This example presents a methodology for impact
assessment of in-process action level bioburden
events,
Establishing the affected process steps is a key
part of the assessment. Recommended actions to
take are:
• Establish the boundary for impacted process
steps using worst-case assumptions where
information is lacking.
• Include the process steps between the known
ingress point and the next bioburden removal/
reduction step.
• If the ingress point is not clearly known,
evaluate the process step(s) between the
previous and next bioburden removal/reduction
steps, OR between the previous and next
sample points that yield acceptable results.
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Product/Process Risk Assessment
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Equipment Design Risk Assessment
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Processing Area Risk Assessment
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Interpreting the Analytical evaluation result 1
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Interpreting the Analytical evaluation result 2
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Approach to Facility Consideration
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Facility Design Consideration
Key elements of the CCS should be decided during the design phase of a production
facility to minimize the risk of contamination based on the specific process design and
hazards. Facility designs provide environmental control through air pressure cascades,
area classifications, cleanability, physical segregation, and flows based on Good
Engineering Practices (GEPs). These design features establish the structure-based
barriers that reduce the airborne movement of contaminants into the manufacturing areas
and enable the removal of contaminants that do enter.
QRM is critical for the design and management of new and existing facilities, equipment,
processes, and manufacturing activities. Appropriate use of QRM tools should identify the
contamination risks to the product and environment, and then mitigate those risks using
appropriate contamination control measures. Risk mitigation for contamination ingress
should be incorporated during equipment design
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Approach to Equipment Consideration
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Approach to Process Control Consideration 1
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Approach to Process Control Consideration 2
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Sterile Drug Product Process control
The manufacturing process of most parenteral drug products (DPs) includes steps
before and after product sterilization. The complete process should be under
microbial control before sterilization, and sterility assurance of the product should
be demonstrated through the cumulation of controls after product sterilization.
Microbial control of DP before the sterilization step is critical because bioburden
may impact safety, potency, and purity similarly to DS. Contamination of the DP
after the sterilization step may result in infections, which could impact patient
safety.
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Non-sterile Drug Product Process control
Solid dosage products, such as tablets and dry powders, are generally less prone
to contamination due to lower water activity; however, they are not contamination-
proof. Specific contamination hazards should be identified in the manufacturing
process and, in the handling and distribution of nonsterile products. Some process
operations can introduce unacceptable levels of contamination, such as tablet-
coating, and there is potential for contamination during handling and dispensing
activities, for example, blister packs protect the product until administration.
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Non-sterile Drug Product Process control
Process monitoring for non-sterile products often includes methods to detect total
microbial counts as well as specific microorganisms that are considered
objectionable for that product, and potentially the patient population, based on its
route of administration. In-process monitoring of nonsterile product manufacture,
which is generally less frequent for low-bioburden drug substance processes,
should be conducted where specific hazards exist in the nonsterile production
process.
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Non-sterile Drug Product Process control
Effective CCS is required for nonsterile finished items that are prone to
contamination. When delivered to patients, microbial contamination
can cause product degradation, potency loss, and potentially unsafe
quantities of germs and by-products. Nonsterile products are widely
available without a prescription, making them accessible to individuals
with underlying diseases or immunological problems. To reduce the
danger of microbial contamination, nonsterile items and
their intermediaries should be handled and kept under settings that
limit microbial entrance and proliferation, considering specific hazards.
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In-process Monitoring Consideration 1
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In-process Monitoring Consideration 2
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Approach to Utility Consideration
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Approach to Personnel Consideration
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Personnel Awareness and Quality Culture
A culture that promotes contamination control is the
The health of the quality hallmark of robust quality system:
culture and level of personnel
• Focus on preventing contamination and other quality
awareness around hazards
contamination controls have a • Willingness to proactively invest time and resources to
direct and significant impact improve quality and prevent contamination
on the success of the CCS. • Strong response to contamination events that identifies
Contamination control should and corrects true root cause(s) and prevents reoccurrence
be a priority that can be • Management that appreciates and values the contributions
reflected in the goals of a and skills of employees
company. A dedicated • Strong, supportive community of practices and network of
subject matter experts (SMEs) who
Personnel/champion or a team • Focus on continuous improvement—good cross-
should oversee the department and cross-site communication and application
performance of the CCS of best practices and lessons learned
• Employees should take ownership of the quality of the
product and process, including contamination prevention
• Employees must understand their responsibility to
highlight quality risks and work toward solutions
• There should be no blame game.
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In Conclusion
Environmental control is a Environmental monitoring (EM) programs do not prevent or
fundamental part of the CCS because
control contamination, but they provide an indicator of
environmental quality through multiple discrete snapshots in
contaminants from the environment
time.
can enter the utilities, raw materials,
equipment, and the process stream The main purpose of the EM program is to measure the
from the air and through surface performance of the contamination controls related to the
transfer. environment and to highlight the potential loss of control due
to a variety of causes, such as personnel behavior,
A spike in environmental disinfection practices, HVAC equipment malfunction, and
contaminants (e.g., seasonal facility age.
variations) can challenge the other
elements of the CCS. For instance, An ongoing generation of EM trends can be used for
molds and spore-forming bacteria are remediation to ensure that the facility continues to operate in
in high concentrations outdoors, and a a state of control and to prevent extrinsic contamination of
spike in these organisms in the the product. The effectiveness of an EM program is
cleanroom can challenge the facility dependent on the level of corrective and preventive actions
cleaning/disinfection and equipment taken as part of the risk control strategy.
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References
- Parenteral Drug Association (PDA) Technical Report No. 90
Contamination Control Strategy Development in Pharmaceutical Manufacturing
- WHO Expert Committee on Specifications for Pharmaceutical
Preparations Forty-seventh report. WHO Technical Report Series No.
981, 2013. [Link] ([Link])
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