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BRIEFING

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〈 1110〉 Microbial Contamination Control Strategy Considerations. This new chapter proposal provides the main requirements and
considerations for defining controls and assessing the effectiveness of the controls for microbial, endotoxin and/or pyrogen contamination

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sources in the manufacturing of pharmaceutical products. A contamination control strategy (CCS) should be implemented for the
manufacturing of sterile products and is recommended for low bioburden and/or nonsterile product manufacturing.

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The companion chapter Microbial Contamination Control Strategies for Cell Therapy Products 〈1114〉 appears in this issue of PF.
(GCM: H. Tu)
Case ID—SUB-785

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Add the following:

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〈1110〉 MICROBIAL CONTAMINATION CONTROL STRATEGY
CONSIDERATIONS
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GENERAL INTRODUCTION
Microbial contamination must be appropriately controlled for all drug product manufacturing per CFR §211.113 Control of microbiological
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contamination. This chapter was developed with the intent of converging with global standards and regulations. Some global regulatory
agencies require a contamination control strategy (CCS), which encompasses all aspects of contamination control. This USP chapter will
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only focus on microbial considerations.

A CCS is a document supported by existing site and/or global microbial risk assessments that describes the approach to controlling
contamination. It is intended to be a planned set of controls to minimize the risk of microbial contamination to assure product quality.
Contamination control requirements for the manufacture of sterile drug products have been in place for many years. Historically these
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controls were developed individually. The newer, global CCS regulations advance the approach to contamination control making it holistic
with individual elements being assessed and linked together for an overall effectiveness to a site’s contamination control program.
A CCS should be implemented for the manufacturing of sterile products and is recommended for low bioburden and/or nonsterile product
manufacturing (see Bioburden Control of Nonsterile Drug Substances and Products 〈1115〉). The CCS should be holistic and include all
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elements of the entire manufacturing facility and process. Although the microbial contamination controls are usually assessed and
monitored individually, the collective effectiveness of the controls should be evaluated as described in this chapter. The CCS should use
quality risk management (QRM) principles, and appropriate risk assessments for contamination should be performed to support the
effectiveness of the CCS.
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The CCS should be documented as a compilation of the approaches adopted by an organization to ensure that the control of microbial
contamination is applied to the products it manufactures. Multiproduct facilities may document their CCS in multiple documents such as a
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parent document for all shared elements and controls and then product- or process-specific CCS documents for the unique elements and
controls. The facility CCS document(s) should be an overall summary document that briefly highlights the contamination controls per
element and references all of the supporting technical documents (e.g., risk assessments, validations, qualifications, and technical
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documents).
An important piece of the CCS is ensuring that the proper technical and process knowledge is included in the development. The details of
the product and manufacturing process should be fully understood to adequately assess hazards and ensure that controls in place are
adequate to reduce the risk of contamination. The monitoring of the product and process must also be adequate to detect contamination.
 The CCS includes layers of controls that should be in place for the different elements. QRM is also a foundational piece of the CCS. Figure 1
represents CCS elements and microbial control that should be considered.

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Figure 1. Consideration for CCS elements and microbial controls. Note: This diagram is not intended to identify every contamination
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control element, but it is indicative of the overall philosophy which is recommended to be applied.
This chapter will describe the elements that should be included in a CCS to minimize the risk of microbial and endotoxin/pyrogen
contamination.
The CCS document should be a life cycle document and undergo ongoing and periodic review. It should be updated as required and its
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effectiveness should be measured and reviewed as part of the quality management review.

FACILITY DESIGN AND OPERATION

Cleanrooms used to manufacture pharmaceuticals must be designed to minimize the risk of microbial contamination in addition to the
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needs of the products and processes. The factors listed below are important for facility design and operation in the manufacture of sterile
products.
Cleanroom design—this includes cascading pressurization and cleanroom classifications to prevent the introduction of airborne
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particulates and microorganisms and to guarantee air pressure according to current Good Manufacturing Practice (cGMP) standards
and biosafety level requirements. Production cleanrooms are preferably located and connected in a manner corresponding to the
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sequence of operations and cleanliness levels. The manufacturing steps that pose the highest risk of microbial contamination (e.g.,
material handling, solution, and/or nutrient media preparation) are physically separated. Additionally, observation of production
activities from outside of the aseptic processing rooms (i.e., use of windows or remote cameras with full view of processes) is
preferred.
Air control systems—this includes controlling temperature, ventilation, and relative humidity.
 Filtered air supply—e.g., introduction of high efficiency particulate air (HEPA) filters. Filters are tested at installation and at suitable
time intervals thereafter using test methods and acceptance criteria for filter leak and attribute (e.g., uniformity of velocity across the
filter) testing.
Cleanroom classification—performed according to ISO-14644-1, the appropriate level of air classification depends on the nature of the
product, the process steps, the environmental conditions required for manufacturing, and whether an open or closed system is used
for the operations. Classified and controlled clean areas capable of providing an aseptic environment (ISO 5 area) are used for the
execution of critical operations (e.g., aseptic manipulations exposed to the surrounding environment). This includes isolators and
restricted access barrier systems (RABS), including the use of robotics, to protect the sterile product from microbial contamination.
Alternate approaches to the use of isolators or RABS may be used and justified within the CCS. The immediate background
classification is based on considerations of isolator design and manufacturing situations (ISO 7 or ISO 8 air).
Cleanroom qualification—demonstrates appropriate environmental conditions (viable and nonviable particulate, temperature, humidity,
air flow visualization, air velocity, and filter integrity testing) at rest and in operational states. Cleanroom requalification is performed at
appropriate frequencies.

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Material selection—smooth surfaces to allow ease of cleaning and disinfection, limited particle generation and adhesion, and chemical
compatibility to disinfection and decontamination agents.

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Process flow—including personnel, material, product, and waste, taking into consideration the production processes and the risk of
contamination. Use of a unidirectional validated process for the transfer of materials, equipment, and components into the most
critical rooms is recommended.

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Gowning area—separated and dedicated areas for entering and exiting the room in the most critical cleanrooms (e.g., in which ISO 5
operational areas are located).

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Facility maintenance—includes planned and unplanned maintenance requirements and vendor and external contractor responsibilities.
In the development of maintenance plans, consider the risk of microbial contamination when setting frequencies and requirements.

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EQUIPMENT AND PROCESS
Contamination control is designed into the manufacturing process. Different processes will have different levels of contamination control

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based on the type of product being manufactured. The risk of contamination should be evaluated early in process development to mitigate
potential contamination risks.
The following factors should be considered for equipment and process design within the CCS:
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Equipment design—use of equipment that is cleanable and/or can be sterilized allowing for removal of contaminants and/or residues.
Cleaning effectiveness should be validated and monitored for bioburden and endotoxin. The use of single use systems which are
supplied presterilized is recommended.
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Equipment life cycle—includes qualification, monitoring, and planned maintenance (e.g., calibration) with rationales to justify
frequencies and responsibilities (i.e., in-house, vendor, and external contractor).
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Process design—closed systems are preferable. If open processing is required, the product should be exposed in an ISO 5 environment
protected by uninterrupted filtered air (e.g., HEPA).
Material transfer—the transfer of material into a Grade A or ISO 5 should be performed using a validated method. Pass through boxes
should be supplied by filtered air. Flow of clean material or equipment should be separated from used materials or equipment.
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Process steps to reduce microbial load—for example, filtration prior to a sterilization step and to limit the amount of microbial
metabolic impurities.
Process hold times—minimize to reduce the potential for microbial proliferation. Hold times should be validated.
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PERSONNEL
Personnel involved in aseptic manufacturing should be kept to a minimum with those present appropriately trained and qualified for all
requirements of their role and responsibilities. This includes operators and any others with access to the aseptic and surrounding controlled
environments (e.g., personnel performing cleaning, maintenance, monitoring).
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Training should be provided by personnel with expertise and knowledge in the training area. Retraining on a defined basis should be
required.
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Basic Training

Training should include information on how actions can contribute to contamination, and control strategies to prevent contamination of
products and the environment. At a minimum, personnel training should include information on the following topics and a rationale for why
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these topics are important for product sterility and patient safety:
Basic microbiology
Principles of gowning
Principles of aseptic technique and qualification
 Principles of contamination control
Environmental controls
Cleaning and disinfection
Process design
Material and waste flow
Training should be provided by personnel with expertise and knowledge in the training area. Retraining on a defined basis should be
required.
Information on basic microbiology is imperative to providing context for sources of microbial contamination, the need for contamination
control measures, and the potential impact to product sterility and patient safety. This training should include information on the types of
microorganisms or potentially infectious agents relevant to your process (e.g., bacteria, yeasts, molds, viruses, prions), the potential for their
proliferation, and associated risks based on microorganism and drug type (e.g., type of finished product, target patient population, route of
administration). Training should also cover potential sources of microbial contamination within the cleanroom (e.g., people, utilities, the
environment, raw materials) and ways of mitigating these sources.

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Gowning of Operators

Appropriate gowning materials and practices provide a barrier between the operator, one of the highest potential sources of microbial

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contamination, and the cleanroom environment. Personnel should be trained in the appropriate garb for the manufacturing environment
class in which they work and be provided with information on the purpose of each gowning element in contamination prevention. Aseptic

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gowning is required when working in controlled environments where aseptic manipulations are performed. As part of training, the operator is
instructed on the correct gowning process, with a qualified trainer confirming that the gowning process is strictly followed. The following
should be considered:

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The gowning requirement is commensurate with the cleanest grade level in which the operator may work.
Gowning materials typically required by cleanliness grade are as follows:

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ISO 8 grade areas: At a minimum, operators should wear a coverall, hairnet, and beard cover (if applicable), shoe covers, and
safety glasses. Particle shedding should be considered and minimized.

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ISO 5/7 grade areas where aseptic operations are performed: In addition to the standard gowning above, a sterile hood that
encloses all hair, new sterile coverall, sterile face mask, sterile boot covers, sterile eye covering (e.g., goggles), and sterile
gloves should be worn. Garment sleeves should be tucked into a second pair of sterile gloves and garment pant legs tucked
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into the inside of boot covers. Gloves should be regularly disinfected, and garb immediately changed if damaged or
contaminated.

Suppliers of gowning materials should be qualified.

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Gowning materials should be visually checked for cleanliness and integrity during and after the gowning process, and upon exit from
the classified environment.
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Gowning materials and reuse procedures should be selected to limit particulate shedding.
If the sterile gowns are laundered and reused, the number of usages should be validated, and material deterioration should be
monitored by inspection.
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Suitable hygiene standards for the aseptic processing and surrounding support areas should be followed. These include:
Exclude personnel with exposed, open lesions, and communicable illnesses from entering the classified areas.
Consider vaccinations where necessary and if related to the specific risks of the product.
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Closed shoes must be worn.

Cosmetics and jewelry may not be worn in classified areas.
Fingers should be kept clean, and fingernails kept short to avoid tearing gloves.
Hands should be cleaned and disinfected before entering the classified area.
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If an unqualified person must enter the manufacturing area, a qualified person must always escort them. In these events, entrance by
an unqualified person should be documented.
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Operator Qualification

To assure good aseptic practices, personnel working in the aseptic processing area must pass a comprehensive aseptic operator
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qualification program.
As a prerequisite to the operator qualification, the operators must successfully complete the basic trainings, with the gowning operators
described above.
 Gowning qualification—This includes the complete gowning procedure within the cleanroom personnel airlocks with access to the
cleanroom under observation by the qualified trainer. The trainer visually assesses if the correct gowning procedure has been
performed. After gowning, personal monitoring is conducted using contact plates. After the initial qualification, including microbial
monitoring and trainer observation, is successfully completed three times, the operator may enter the supporting ISO 7 areas but is
not authorized to execute critical interventions in the ISO 5 grade area until the operator qualification is complete. Operators should be
requalified at least annually.
Training and exercise for interventions in ISO 5 grade areas—This supervised training, which includes practicing all expected
interventions in the ISO 5 area, is conducted outside a critical aseptic processing area.
Qualification for interventions in ISO 5 grade area— Prerequisite is a qualification for ISO 7 cleanrooms and successful training and
exercise for interventions in an ISO 5 grade area. For initial qualification, the operator to be qualified executes critical and noncritical
interventions during at least one aseptic process simulation (APS) run.
The APS for personnel qualification should be part of the APS performed to confirm the aseptic processing of the manufacturing line. For
cell therapy manufacturing, the APS may be specifically designed for operator qualification (e.g., focus on worst case amount and complexity

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of aseptic interventions) and independent to the process-specific APS that may include additional worst-case parameters (see Microbial
Contamination Control Strategies for Cell Therapy Products 〈1114〉). During the APS, personnel monitoring is performed on the hands and

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forearms, and the interventions are observed by an aseptic technique specialist to confirm the correct execution. To pass the qualification,
visual assessment must meet the requirements, personnel monitoring data must meet the acceptance criteria, and the APS run must be
successful. After completing the qualification, all ISO 5 interventions can be carried out independently by the qualified operator during routine

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production. The operator should be requalified periodically (e.g., annually) by performing interventions in an APS run under supervision and
with passing microbiological monitoring of gowns and gloves and successful APS.

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Procedures should be in place to disqualify personnel from entry into controlled cleanroom environments if inadequate performance is
indicated during requalification or an adverse trend is identified during routine personnel assessment. If disqualification occurs, retraining

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and requalification should be completed.

UTILITIES

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Utilities include water of pharmaceutical quality (including water used for the cleaning of cleanrooms and manufacturing equipment), air
as supplied into the clean workspace (controlled environment), and services like compressed gases (e.g., carbon dioxide-enriched air,
nitrogen, oxygen).
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Water of pharmaceutical quality is used for cleaning and manufacturing of pharmaceutical products. Water can present a substantial risk
for microbial colonization and proliferation and therefore is a key factor in the CCS.
Water must be suitable for its purpose, and if the facility has an in-house water system, it should be qualified and monitored chemically
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and biologically. Water for injection should be used for manufacturing operations with product contact. Water for disinfectant preparation
should be appropriate for the classification of the area being cleaned. If storage tanks are used to store water, hold time studies should
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demonstrate that storage conditions are adequate.

Process gases should be of suitable quality and should comply with appropriate microbiological requirements to ensure that they do not
negatively alter the quality of the products they contact. Gases that come in direct contact with the product should be sterile filtered with the
use of a 0.2-µm pore size sterile filter at the point of use. Regular integrity testing of these sterile filters is required to guarantee sterility of
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the sterile filtered gas. The filter integrity test frequency should be risk-based.
For more general guidance on water testing, refer to Water for Pharmaceutical Purposes 〈1231〉, and for gases, refer to Sterilizing Filtration
of Gases 〈1229.15〉.
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RAW MATERIAL CONTROLS

A risk assessment should be performed to establish efficient raw material controls and to minimize the risk of microbial ingress. Several
key risk factors are listed below.
Origin (e.g., biological or synthetical origin)
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Material manufacturing process (e.g., chemical synthesis, fermentation using genetically modified hosts, purification steps using
organic solvents, purification steps using water-based solvents, temperature conditions during manufacturing, etc.)
Growth promoting properties of the raw material
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Storage and shipment

It is preferable for raw material controls to be established by the supplier, in addition to incoming inspection by the pharmaceutical
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manufacturer.

PRODUCT CONTAINERS AND CLOSURES

 The final products should be kept in containers that prevent contamination from the surrounding environment. A container–closure
integrity study as recommended in Package Integrity Evaluation—Sterile Products 〈1207〉, and a hold time and shipping study may be
performed to demonstrate that the container–closure integrity is maintained during storage and transportation. Requirements for containers
and closures of nonsterile product intermediates (e.g., drug substance aseptically filled into bottles or bags for shipment to a drug product
fill-finish facility) are less strict compared to those for sterile products and should be risk-based.

CONTRACT MANUFACTURING ORGANIZATION OR CONTRACT DEVELOPMENT AND MANUFACTURING ORGANIZATION

(CMO OR CDMO) CONSIDERATIONS FOR CCS
When using a CMO or CDMO for manufacturing pharmaceutical products, the development and documentation of the CCS is the
responsibility of the CMO or CDMO. The customer should have quality oversight of the CCS, which should be described in the quality
agreement between the CMO or CDMO and the customer. The customer should review the effectiveness of the CMO or CDMO’s CCS at a
routine frequency.
The CMO or CDMO may have multiple CCS documents. There may be a general facility or site master microbial CCS that is holistic and

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includes all shared elements of the entire manufacturing facility and processes. In addition, client specific or product- or process-specific
CCS documents that detail the specifics for each client or product or process may be created. Because the CCS should be developed with

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detailed knowledge of the products and processes, the customer may need to support the CCS creation at the CMO or CDMO.

MANAGEMENT OF OUTSOURCED ACTIVITIES

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Contamination control can be affected by several outsourced activities, such as:
Testing of materials, process steps, and final drug product

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Testing of environmental monitoring (EM) and media fill samples
Microbial identification
Cleaning of controlled areas

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Sterilization of materials including single use systems and equipment

Suppliers providing services should be properly managed by customers. Examples include:

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Careful evaluation of a service provider's quality system (e.g., change control, change notification of customers, deviation
management, good documentation practice)
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Detailed user requirements specified in contracts between the customer and service provider
A quality agreement between the customer and service provider is needed
On-site audits performed by the customer on a routine basis
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PROCESS CONTAMINATION RISK MANAGEMENT

Process contamination risk management is part of the overall QRM strategy. Risk management is applied to identify, assess, reduce or
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eliminate (where applicable), and control contamination risks.

The output and results of the QRM process includes the rationale for decisions taken regarding risk reduction and acceptance of residual
risk, and it must be appropriately communicated and documented at any stage of the process.
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A process contamination risk assessment must include the identification of known or foreseeable hazards in both normal and fault
conditions and the analysis and evaluation of risk associated with exposure to hazardous situations. Various types of process contamination
risk assessments may be performed to understand the hazards and controls present, such as risk assessments for the manufacturing,
aseptic, cleaning, sterilization, and EM processes. During the risk identification process, use appropriate tools to list and prioritize the quality
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risks identified. Emphasis should be on issues with a high impact on product quality, process performance, and patient safety or with a high
probability of repetition (weak point products or processes). The root cause(s) should be identified; its impact on the product quality, process
performance, and/or patient safety should be analyzed and documented. A risk assessment's output should be either a quantitative
(numerical) estimate of risk or a qualitative description of a range of risk (e.g., high, medium, low).
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Risk control includes decision making to reduce or mitigate and/or accept risks based on the criteria for overall risk acceptability. The
amount of effort used for risk control should be proportional to the significance of the risk. Risk control measures should be defined and
implemented and the decisions, actions [e.g., corrective and preventive actions (CAPAs), performance indicators] and their implementation
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must be documented, verified as implemented, and validated for effectiveness in reducing risk.
QRM activities should be performed by cross-functional teams supervised by quality assurance (QA). Outputs and results of the risk
assessments should be periodically reviewed, considering new knowledge and experience.
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PROCESS VALIDATION
Process validation is a required element for commercial GMP manufacturing. The process considers the data generated in the
development of the product and process, an understanding of the specific quality attributes of the product, and controls and limits required
 to ensure that the desired quality of the product is achieved. For development of a CCS, the original process validation and regular process
monitoring results should be used to evaluate potential sources of contamination.

STERILIZATION PROCESS VALIDATION

As with process validation, the results of sterilization process validation can provide information on areas of focus for a complete CCS.
Some of these areas include: the product composition, storage conditions, and the maximum time between the start of the preparation of a
product or material and the start of its sterilization. Each of these factors can be used in developing the final CCS. For more information
specific to sterilization validation, please see 〈1229〉.

CLEANING AND DISINFECTION

Cleanrooms should be regularly cleaned and disinfected to maintain the appropriate level of cleanliness. The cleaning and disinfection
program should be described in a written procedure and be developed based on the cleanroom classification, risk to operations performed,
and EM trends.

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Disinfectants and Antiseptics 〈1072〉 provides general guidance for the selection and application of disinfectants. The qualification of
materials used in the cleaning and disinfection program should be documented and justified.
Material flow into cleanrooms should be optimized to minimize the potential for contamination. Procedures should describe how materials

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and equipment are disinfected as they are transferred into areas of high classification as these activities have the potential to introduce
contamination. The transfer of material into a Grade A or ISO 5 may require a validated method.

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VERIFICATION OF THE EFFECTIVENESS OF THE CONTROLS
EM, personnel monitoring, and aseptic processing simulations are used to assess the controls (including design and procedures) put in

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place to prevent microbial and particulate contamination. Alternative microbial monitoring methods that enable improved contamination
detection (e.g., due to a faster time to result, continuous monitoring, or higher sensitivity than the traditional method) should be considered

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as part of the monitoring strategy. The CCS should consider the results of these monitoring measures together to assess the collective
effectiveness of the CCS. The effectiveness of the CCS should be evaluated during the quality management review.

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Environmental and Personnel Monitoring

Environmental and personnel monitoring are an important part of the CCS to measure the effectiveness of the contamination controls in
place. Monitoring includes viable air, nonviable air particulate, surface viable, and personnel viable monitoring.
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A comprehensive microbiological EM program should consider the following:
Definition of sampling locations and sampling frequency
Selection of sampling methods, including consideration of alternative methods
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Definition of nutrient media and incubation conditions, or viable particle counting methods
Definition of action and alert levels
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Definition of trends

An EM program is established based on detailed knowledge of the process inputs, the facility, equipment, specific processes, operations
involved, and knowledge of the typical microbial flora found or expected. An EM risk assessment (EMRA) should be performed to define and
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justify the EM program requirements. The microbiological EM program provides sufficient data to show that the classified environment is
operating within a defined state of control. In the case of a negative trend (increased microbiological load in a certain area or reoccurrence of
microorganisms of interest) or new and increased information provided by the addition of new monitoring tools, the EM program should be
reevaluated and adapted as needed.
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Routine monitoring of the cleanroom environment and personnel should be performed during equipment setup and operation. In-process
monitoring should be performed throughout the critical process at locations identified to pose the highest risk to the process and/or product.
Furthermore, appropriate alert and action levels should be established for both viable and total particle monitoring based on cleanroom
qualification testing, the nature of the operations performed, and instruments utilized. These levels should be set such that adverse trends
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can be detected before an out-of-specification event occurs, and reviewed as data is collected. Note that technologies alternative to the
compendial method may report in units of measure different than colony-forming units (CFUs). Alert and action levels appropriate to the
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technology and environment should be considered.

Further guidance on EM of aseptic processing environments can be found in Microbiological Control and Monitoring of Aseptic Processing
Environments 〈1116〉.
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Aseptic Process Simulations

APS should be carried out to evaluate the handling and environmental controls around aseptic processes in product manufacturing. All
processing steps included in aseptic manufacturing of a medicinal product may fall under the scope of an APS.
 The APS is performed using a sterile microbiological growth medium instead of the formulated drug product. The microbiological growth
medium is recommended to be of nonanimal origin and certified as mycoplasma/bovine spongiform encephalopathy/transmissible
spongiform encephalopathy (BSE/TSE)-free. The medium may be sterilized in-house as part of the process, otherwise use of gamma-
irradiated medium may be preferable. Further guidance on quality controls for the growth medium may be found in Microbiological Best
Laboratory Practices 〈1117〉.
Prior to performing the APS, detailed planning of how to execute the APS should be carried out. The APS should consider a worst case
challenge of process parameters and include:
All aseptic operations and interventions including equipment setup and utensils used for the manufacturing of the product.
Maximum process time accommodating the normal aseptic process time including the times used for manipulations and
interventions.
Line speed appropriate for the process being simulated.
Maximum environmental challenge in terms of the number of operators in the cleanroom.
If the process includes lyophilization, only a partial evacuation of the filled but unsealed containers should take place. During the

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process, the growth medium must not be frozen. At the time of sealing, aerobic conditions must be restored in the containers.
Sealed containers are swirled or inverted to ensure contact to the inner surfaces of the container closure.

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After filling, all containers should be inspected with all integral units subject to incubation while units with integrity defects should be
rejected. Incubation for a total minimum of 14 days at one or more temperatures within 20°–35 °C may be applied and should be justified. If

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more than one temperature is applied, incubation should start at a lower temperature and with a duration of minimum 7 days at each
temperature. After incubation, visual inspection of all containers is performed. A growth promotion test is performed on containers from the

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APS using a panel of microorganisms appropriate for the process being evaluated.
The initial aseptic process evaluation for a new operation may consider three consecutive runs. Revalidation of APS is required, the
frequency usually being semi-annually but the frequency may be defined based on risk (refer to Process Contamination Risk Management). A

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reduction or increase of APS frequency may be dependent on trending of the microbiological monitoring activities and aseptic performances
and the aseptic operator qualification.

IN-PROCESS CONTROLS

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Monitoring of in-process bioburden is an essential element of the overall contamination control program. Bioburden monitoring should be
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designed for the recovery of a broad range of microorganisms that are likely to be present in the material being processed. Bioburden is a
potential risk to the patient not only because the sterilization process might not be completely effective but also post-processing because of
the possible presence of residual materials such as allergens, endotoxins, and exotoxins. It may also have an adverse impact on product
quality and stability. In-process bioburden monitoring should be risk-based and performed throughout the critical process.
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TRENDING
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Trend analysis on microbial events should be evaluated. The collective effectiveness of the manufacturing controls and monitoring should
be assessed. A review of trends, deviations, and key performance indicators should be utilized for the collective effectiveness assessment to
confirm the effectiveness of the CCS.
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INVESTIGATION OF EXCURSIONS
Investigations of excursions must be thorough, holistic, and allow for identification of root cause by using appropriate investigational tools.
The source of microbial contamination should be identified in investigations whenever possible. Implementing effective CAPAs based on the
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investigational findings is important to ensure that contamination events are not repeated. Effectiveness checks should be performed on
CAPAs. Knowledge gained from microbial contamination investigation events and the effective actions taken should be used to revise the
CCS as appropriate.▲ (USP 1-Jun-2026)
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Auxiliary Information - Please check for your question in the FAQs before contacting USP.
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Topic/Question Contact Expert Committee

<1110> MICROBIAL CONTAMINATION Huiping Tu GCM2022 General Chapters - Microbiology

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CONTROL STRATEGY CONSIDERATIONS Director, Biologics 2022

RS Technical Services GCM2022 General Chapters - Microbiology

REFERENCE STANDARD SUPPORT
[email protected] 2022

DocID: GUID-C75C160A-2C24-463D-84D3-918C2D6BE000_10101_en-US
 DOI: https://doi.org/10.31003/USPNF_M18656_10101_01
DOI ref: f8pxq

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