Control Strategy

In manufacture of Sterile Pharmaceutical/ Drug products.

PHSS ‘White paper’ on principle considerations for a Control Strategy

including additional detail on strategy for contamination control.
Guidelines to create and manage a control strategy in
pharmaceutical manufacturing processes need to be
better defined. This PHSS White paper communicates
principle considerations for a Control Strategy in sterile
pharmaceutical/ drug manufacturing and includes additional
detail on strategy for contamination control.
Introduction
A Control Strategy sets out a documented approach and rationale taken to control product quality,
efficacy and patient safety in manufacture of sterile Pharmaceutical/ Drug products (and substances).
Product quality, efficacy and patient safety can be compromised by contamination as microbiological,
chemical, another product(s) or other biological entities. A control strategy and risk control measures
(technical and organizational) are required in order to help minimise the risks of such compromise.
It is considered Control strategies are increasingly required to support risk based initiatives and new
more complex products and processes to make clear objectives in manufacture of sterile medicines/
pharmaceuticals, biopharmaceuticals, drug products and substances and the approach to control of
manufacturing facilities/ processes, product efficacy/ quality, regulatory compliance and importantly
patient safety.
A Control Strategy should be considered to include: All are inextricably linked.
• Manufacturing control strategy; based on product type, demand, process and risk.
• Quality control strategy; based on understanding of risk with control of Critical
Quality Attributes (CQAs) in a manufacturing process meeting regulatory
requirements.
• Contamination control strategy including cross contamination control that may
include requirements for containment/ product segregation.
The Control Strategy ‘White paper’ has been prepared by a Pharmaceutical and Healthcare Sciences
society - PHSS Bio-contamination special interest who prepared (2014) a monograph (no. 20) on Bio-
contamination related to environmental contamination (airborne and surfaces) in controlled areas/
zones.
The PHSS monograph 20 on Bio-contamination covers the life cycle in microbiological contamination
in controlled areas, with the following topics covered;
• Bio-contamination characterization and risk profiling.
• Control including strategy (based on the White paper), attributes and best
practice.
• Monitoring, including overview of Rapid Micro Methods (RMM).
• Deviation management (investigations, Corrective and Preventative Actions - CAPA.
PHSS definitions relative to the PHSS Bio-contamination monograph and this White paper.
• Bio-burden in a controlled area is microbiological flora, airborne or on surfaces,
pre and post cleaning/ disinfection/ sanitization step. Depending on the
manufacturing stage microbiological bio-burden may be uncharacterised; not
differentiated as isolates or micro-flora.
• Micro-flora is the characterised as ‘‘typical flora’ being typical microbiological
flora found in a classified or controlled area under controlled conditions.
• There should be no typical flora in Grade A controlled areas and
significantly limited flora in Grade B areas. Characterisation includes
identification of microorganisms by groups or isolates (as required)
including genus, species or sub-specifies (as required) and includes whether
organisms are objectionable to products and potentially harmful to
patients. Note: ISO14698 also references the term; micro-flora.

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 • Bio-contamination, as environmental microbiological contamination, is detected
contamination in a monitoring program above set levels/ limits and reported
as colony forming units (cfu’s). Alert levels (user set) and action levels (from
regulatory guidance) and adverse trends are studied for deviation together with
determination/ identification of isolates and atypical micro-flora.
• Bio-contamination detected as an adverse trends, where levels of cfu
counts increase above typical levels or the micro-flora profile changes,
indicate a change in control conditions that may not yet have reached
action levels but does warn of increased risk and potential shift towards
loss of control.
• Bio-contamination is a combination of all biological contamination,
including viruses, and related components. Bio-contamination includes
microbiological contamination, endotoxins and pyrogens.
The increasingly complex nature of Pharmaceutical products and interactions between critical quality
attributes, processes, manufacturing environments and patients make the process of assuring
compliance to the three pillars of ‘quality, efficacy and patient safety’ more challenging.
A Control Strategy should be based on a holistic view of all aspects that contribute towards product
quality, efficacy and patient safety. Considerations should include, but not be limited to, product type
and dose form, regulatory requirements, critical quality attributes, manufacturing process, facilities
in manufacturing; including utilities, personnel/ interactions, practice, waste management and any
energy saving management related to control conditions of cleanrooms.
By setting an approach to sterile product manufacturing control in the form of a documented Control
Strategy the objectives are clearly set-out for any given product/ process with principle requirements
established for implementing a risk based approach in product manufacturing.
The Control Strategy should be supported by risk assessments that assist key decisions on how the
product manufacturing control objectives are met with the control steps considered as sequential;
firstly by design (facilities and process), followed by process control and then by procedural control in
operations with reaction to deviations in a well-designed monitoring system.
The Control Strategy should be maintained as a ‘live’ document recognizing building knowledge of
products, process and risk. Holistic considerations and a proactive response to risk escalation should
be inherent in a control strategy.
There should be a recognition that through the process of establishing control leading to a formal
state of control, and approval as a manufacturing process, formal change control will apply where any
change subject to risk/ impact assessment considering risks to quality, efficacy and patient safety.
The Control Strategy should be referenced in a validation master plan (EU GMP Chapter 5 and Annex
15 refer). It should be noted the main principles of the Control Strategy may apply to manufacture of
other non-sterile dose forms where risks to patients need control/ management.

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Control Strategy Content
1. Principle components of a Control Strategy
2. Manufacturing Control Strategy
3. Quality Control Strategy
4. Contamination Control Strategy
5. Considerations in setting a Contamination Control Strategy
6. 5.1 Process, infrastructure, operations, components including raw materials.
7. 5.2 Microbial control strategy.
8. 5.3 Risk Management of Contamination (RMC)
9. 5.4 Cross Contamination control/ containment strategy.
10. Summary statement

1.0 Principle components of a Control Strategy

As outlined the Control Strategy should be considered in three component parts all of which are
inextricably linked:
• Manufacturing control strategy.
• Quality control strategy.
• Contamination control strategy.
Manufacturing of sterile Pharmaceutical/ Drug products, substances and constituents requires a risk
based approach, in design; Quality by Design (QbD principles) and in quality under the auspices of a
Pharmaceutical Quality System including Quality Risk Management following ICH Q10 integrated in EU
GMP Part I Chapter 1.
The setting of control strategies in manufacturing combines manufacturing control, quality control
and contamination control to deliver the specified product quality, efficacy and patient safety.
Each aspect of manufacturing, quality and contamination control needs consideration in setting a
Control Strategy. This White paper sets out principle considerations for the Manufacturing and Quality
control strategies with more detail around the Contamination control strategy as the main focus of
this White paper.

2.0 Manufacturing Control Strategy

The Manufacturing control strategy should include considerations on the follow areas together with a
defined approach set out how a specified level of control will be achieved/ implemented:
• Whether the product is to be manufactured by terminal sterilization (preferred
for risk management in patient safety) or by aseptic processing (justified for
product type). For some product types that may be impacted by overkill terminal
sterilization processes it may be possible to justify suboptimal sterilization cycles
that deliver the required Sterility assurance level (SAL) over aseptic processing.

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 • What is the product type, dose form, quantity required and for what stage of
supply; clinical batches or production batches following Marketing Authorization
(MA).
• Is the manufacturing process by batch, campaign or continuous (with periodic
shut down) and how will change overs be controlled.
• What is the specified process, equipment used and how will process steps be
integrated to form a defined process design/ flow.
• What are the target end points for manufacturing stages.
• What will be the extent of automation required to meet manufacturing control
requirements and how will personnel/ operators interact with the process.
• How will the facility/ utilities and process equipment combine to meet
manufacturing control targets.
• What are the principle risks in product manufacturing that should be subjected to
risk assessment.
• What regulatory of country specific requirements apply to the given product/
process.

3.0 Quality Control Strategy

The Quality Control Strategy should be set around an understanding of the product, process and
critical quality attributes (CQAs) in manufacturing. The control strategy should not be used to try to
mitigate or support bad design or practice.
Risks and impact from deviation in CQAs that provide manufacturing and quality control vary with
the type of product and processing operations/ technologies employed. If the product requires aseptic
manufacturing, is sterile and toxic; or sterile and biological, including non-pathogenic products e.g.
biologicals that use viral vectors but are not a high risk to process operators, different combinations of
product protection, operator protection and cross contamination control are required.
The Quality control strategy should take a holistic view of the life cycle of product manufacture with
control measures at every stage to meet specified objectives, requirements and end points.
It should be recognized that there is a need for a methodical and systematic approach, using risk
management based on products and processes, in setting the control strategy but there will be a need
to keep the document ‘live’.
Due consideration should be given to reassessing the initial design strategy if there is significant
reliance on QC as a form of risk management / mitigation
Product, process and risk knowledge may develop iteratively through process development and a
proactive response will be required as knowledge accumulates during manufacturing implementation
with continuation through the product life cycle.
The focus should always be on product quality, efficacy and patient safety so increasing knowledge
that builds assurance of delivering these critical requirements should be acted on.
It is essential within a Pharmaceutical Quality System (PQS) to control all changes via a change control
process, through all stages of product manufacture. A strategy on how changes are managed should
be included in the Quality Control strategy.

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4.0 Contamination Control Strategy
Sterile Pharmaceutical Drug products and substances/ constituents manufactured to GMP need
assurance of quality, sterility or bio burden control (depending on manufacturing stage) and efficacy
that may impact patient safety.
Such assurance that critical quality attributes and patient safety are not compromised by
contamination can only be given by thorough product, process and risk knowledge together with
risk based control aligned with ICHQ9 principles. Control should be implemented through Quality by
Design (QbD principles) and risk control measures defined by risk assessments.
It is well accepted it is not possible to inspect/ test or justify GMP/ CGMP compliance with monitoring
data or media fill results alone as such an approach offers little assurance of robust processes and
assured quality in GMP.
A Contamination control strategy should include a strategy for environmental control of product
manufacturing environments for assurance product sterility is not compromised and patient
safety is not put at risk by loss of microbial control or deviations/ excursions within the controlled
environments.
Strategies in contamination control will vary if the product is aseptically processed/ manufactured,
terminally sterilized, is subjected to sub optimal heat treatment, or a non-sterile ingredient/ constituent
that may require bio-burden control is used.
Relating to the important risks to patients of contamination and cross contamination in product
manufacture it is considered, in accordance with current approaches for Process Validation (PV FDA
2011, EMA draft 2012, EU GMP Annex 15 Glossary, EU GMP Annex 2 point 50), a control strategy
is required based on a holistic consideration and approach to control of all elements that potentially
have an impact on contamination control.
As part of the Contamination control strategy cross contamination should be considered as there
may be risks of cross contamination by chemical adulteration/ residues between processes, product to
product cross contamination, biological entities cross contamination and cross contamination between
patients via cells/ genes if manufacturing is for therapy products.

5.0 Considerations in setting a Contamination Control

Strategy:
The following is a more detailed listing of what should be assessed when setting a Contamination
control strategy based on a holistic view across:

5.1: Process, infrastructure, operations, components including raw materials.

• Facilities, equipment and Barrier technologies.
• Process; control measures and monitoring with deviation management.
• Qualifications, process, equipment and personnel that impact contamination
control.
• Personal and operations.
• Components including raw materials and waste management.

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5.2: Microbial control strategy.
• Microbial Control targets in classified and controlled areas.
• Microbial contamination risks and proactive response to risk escalation.
• Decontamination processes and monitoring to verify control.
• Critical control points and contamination control attributes.

5.3: Risk Management of Contamination (RMC).

• Based on PHSS Monograph 14: RMC – adapted HACCP method.
• Seven steps in Risk Management of Contamination.
• RMC register: Contamination source, control measures, sampling plan.

5.4: Cross Contamination control/ containment strategy.

• Closed system processing and use of single use systems.
• Cross contamination control attributes.
• Containment/ segregation strategies to prevent cross contamination.
• Decontamination between different product manufacturing/ processing.

5.1 Facility infrastructure, process, equipment, operations,

qualifications and components including raw materials.

5.10: Facilities, equipment and barrier technologies

• The methodology in contamination/ cross contamination control should be
reflected in the facility and process design to meet requirements for specified
products or processes.
• Facilities; including utilities, facility layout, equipment, materials, personnel flows,
specification of controlled areas should be considered e.g. zoning; EU Grade
A/B/C/D or ISO classes and requirements for restricted personnel access.
• The Contamination control strategy should include a listing/ statement of
contamination control attributes including physical attributes relating to controlled
environments used for product manufacture e.g. facility zoning, HVAC systems
used to control air quality, pressure differentials and control of temperature plus
(as required) humidity.
• Sterilisation technologies used for product contact parts and critical surfaces that
impact product sterility should be defined.
• Equipment used in process and/or in contamination control should be defined.

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 • Barrier Separation Technology employed e.g. Isolators or RABS: Restricted Access
Barrier Systems, should be defined. If a RABS barrier separation technology is
specified a statement and justification is required defining if the barrier is an Open
Operation RABS (open barrier door - operator access during processing) or Closed
Operation RABS (best practice – no open door access in process) Definitions from
PHSS RABS Monograph 15.

5.11 Process; control measures and monitoring with deviation management

• The rationale for selection of sterilization, disinfection/ sanitization and cleaning
technologies/ methods and associated regimes should be considered including the
combination/ interaction for a given process.
• Process controls for contamination and cross contamination control should be
defined.
• Monitoring systems that provide detectability and early warning of deviation
in critical quality attributes and/or critical control parameters that impact
environmental control and/or product sterility. Where applicable, Process Analytical
Technology (PAT) should be used to enable ‘real time’ monitoring of processes and
environments.

5.12 Qualifications, process, equipment and personnel that impact

contamination control
• Strategy for Process Qualification (PQ), Re-Qualification (RQ) and continuous
verification of contamination control performance (cross referenced to Validation
Master Plan; VMP).
• Qualification of procedural controls, SOPs (Standard Operating Procedures)
in process operations and at critical operator interactions with a process or
products to verify there is no compromise to the manufacturing environment and
potentially product quality/ sterility. The emphasis here is on critical qualification
activities e.g. sterilisation, disinfection, environmental control measures, utilities
etc. with media process simulations/ media fills used as an assessment of in-place
controls.
• Strategies for deviation investigations should include a strategy for Root cause
analysis to determine the root or most probable cause followed by corrective
and preventative actions (CAPA) and related efficacy checks to verify corrections/
changes.

5.13 Personnel and operations

• Control of personnel in the facility and controlled areas in respect to
contamination control and prevention of contamination transfer e.g. personnel
numbers, training, procedures (SOPs), gowning system, gowning practice,
gowning qualifications.
• Training of personnel that have process/ product interactions is an iterative process
e.g. in procedures (SOPs), practice, aseptic technique and qualifications including
finger dabs, gown monitoring, ongoing assessment and associated qualifications
through media process simulations/ media fills, trending of data and analysis of
those trends.
• Control strategy for preventative and corrective maintenance to assure there is no
compromise to contamination control status or assurance of product sterility.

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5.14 Components/ equipment, raw materials and waste management.
• Control of components including equipment, raw materials, excipients, APIs,
container/ closure items and change parts etc. in supply, quality (including sterility
or bioburden if applicable) and transfer into controlled zones for use in a specified
process.
• Control of all consumable/ single use materials in entry to controlled areas of
a higher grade/ class via airlocks, pass-trough’s that include a disinfection step
to prevent contamination transfer and compromise of contamination control
status in receipt zone; For EM plates use of irradiated media where applicable to
the zone. Procedural control using multiple wrapped items with step wise layer
removal at each transfer may apply.
• Control of cleaning/ sanitization/ disinfection materials on entry/ exit from
controlled areas together with use/ storage where there is potential impact on
contamination control status.
• Control of waste, reject materials from a process that may impact contamination
status of the controlled areas or cross contamination to other controlled areas.

5.2 Microbial control strategy for environmental control

The microbial contamination control strategy should cover all aspects of establishing microbiological
control in controlled and classified areas/ zones, to defined regulatory limits/ levels with trending of
data and appropriate routine analysis to verify a formal state of control where deviations above action
levels or repeated frequencies above alert levels in key locations require investigation and correction to
prevent reoccurrence. Using trend analysis data may also facilitate a proactive response to prevent a
bio-contamination event by an intervention to cease increasing micro flora that may be developing to
unacceptable numbers of counts.
It is recommended in the control strategy that a key performance indicators (KPIs) are developed using
a holistic review of environmental monitoring data to determine the points of contamination risk
escalation but ensuring the KPIs do not normalise the data to such an extent trends are not visible.
Environmental monitoring at targeted risk/ control points in facilities including key interfaces of;
personnel transfer, interactions and process/ material transfers provide an opportunity to detect
increased contamination transfer to adjacent zones or controlled areas.
Adverse environmental monitoring trends which may include increasing cfu counts or a changes in
micro-flora profile (qualitative and quantitative data) at zone to zone interfaces may provide an early
warning in manufacturing stages that the critical manufacturing environments, processes and sterile
products are at increased risk of contamination.
As risks escalate and adverse trends become evident, even before excursions above ‘’not to exceed’’
regulatory limits/ levels of colony forming unit (cfu) microbiological contamination or atypical micro-
flora is detected in the controlled areas, appropriate proactive responses can be taken to avoid
contamination that may impact critical manufacturing environments and sterile products.
Contamination outside regulatory limits/ levels often leads to complex root cause investigations. It
may be difficult to ascertain the source/ root cause in a deviation event or trend shift and therefore
challenged in providing specific effective corrective and preventative measures and also difficult
assessing how much product or batches may be impacted.

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It is better to manage contamination of critical areas and or sterile products by measures of avoidance
with an early warning proactive strategy rather than reactive strategy to deviation events.
Using holistic environmental monitoring data: zone to zone comparisons of pressure differentials, total
particulate and viable counts/ micro-flora can facilitate a proactive response to adverse trends/ events.
Strategies of how such holistic data is collected, analysed and acted on needs defining in the control
strategy.
Considerations for the Microbial control strategy should include:
• Zoning of controlled areas by classification EU GMP A, B, C, and D and/or ISO
classes.
• Flow of the process, products, materials and personnel and their interactions.
• Environmental control, including airflow, air-changes, clean-up times and pressure
differential cascades/ regimes.
• Cleaning, disinfection/ sanitization programs: selection and qualification of
cleaning/ disinfection products used, their target efficacy and the application using
defined techniques. Regimes that use multiple disinfection agents in rotation
should be stated and justified.
• Cleaning and disinfection procedures (SOPs) and associated qualifications.
• Control points for material transfer between controlled/ classified areas/ zones
which may be different depending on the technology used – examples as follows;
• Penetrative (porous load) decontamination/ sterilisation using moist heat.
• Transfer devices with semi or automated disinfection control steps including
Gaseous Disinfection GD-VHP surface bio-decontamination processes.
• Non chemical surface sterilizers e.g. e-beam/ bio-decontamination devices
e.g. UV.
• Transfer hatches with manual disinfection control steps
• Material transfer control points and disinfection/ decontamination methods
should be appropriate/ compatible for materials in transfer with target material
surface bio-decontamination efficacy stated and justified for the specified transfer
method/ device.
• Change room control points for contamination control during personnel access to
controlled/ classified areas/ zones.
• Monitoring systems that provide ongoing (event and trend) information on
status of contamination control via monitoring alert and action levels of microbial
contamination and associated total particulate levels (via continuous monitoring
in critical areas) should be considered. Due consideration should also be given to
facility (unclassified) monitoring where deemed necessary in order to determine
the potential risks placed upon the environmental controls within the classified
cleanrooms. Monitoring systems should be routinely assessed for effectiveness and
open to change and improvement.

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 • Rapid Micro Methods (RMM) that provide real time environmental monitoring
microbial data that are not growth based hence intervention free to sampling
points may offer advantages in proactive response strategies and risk reduction
without the need to enter growth media plates into critical areas. Such
technologies, in development, need careful evaluation in data analysis (generated
bio-counts not cfu’s) and comparability studies to classical growth based
environmental monitoring methods.

5.3 Risk management of Contamination (RMC)

The PHSS Monograph 14 provides guidance on Risk Management of Contamination (RMC) during
manufacturing operations in Cleanrooms and controlled air devices.
The RMC approach to cleanroom contamination control has been adapted from the Hazard Analysis
of Critical Control Points; HACCP method and provides an effective system to manage the risk from the
various sources of microbial contamination during cleanroom manufacturing.
It consists of the following seven stages;
1. Identification of the sources of contamination and routes of transfer to the product including
assessment of the process and existing control measures; should involve observational
assessment.
2. Assessment of the risk from the sources and routes of contamination and, where appropriate,
remove the source of risk or introduce risk mitigation; introduce new control measures, or
improve existing control measures, to reduce risk.
3. Establishment of a monitoring schedule using valid sampling methods to monitor the hazards,
or their control methods, or both. Establishment of alert and action levels with corrective/
preventative action procedures to be followed, when these levels are exceeded.
4. Verification, on a scheduled basis, that the contamination control system is appropriate
by reviewing the product contamination rate, the environmental monitoring results, the
risk assessment and control methods and the action levels, and where appropriate, modify
accordingly.
5. Establishment and maintenance of appropriate documentation.
6. Training of the personnel.
7. Determine the microbial risk to the patient from the product.
The risk assessment stage is usually the most difficult stage to undertake but is a major component in
the overall risk management process, and calculates the level of risk associated with a contamination
source that should be controlled.
Accurate assessment is critical, and indicates where effort and resource should be best applied.
An assessment based upon the fundamental method of contamination transfer will provide the most
accurate method as it utilizes the actual contamination process.
This approach is therefore appropriate for aseptic manufacturing processes and is used for the risk
assessment stage.

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A documented register should be prepared of each contamination source, the contamination control
methods and the monitoring methods at risk based sampling locations together with sampling
frequency and assigning action/alert levels. The outcome should be to remove identified risks where
possible, mitigate against others and lastly utilization of monitoring methods as a mechanism of
assessment of those risk control strategies.

5.4 Cross contamination/ containment control strategy

Cross contamination may be in the form of chemical (including toxic), biological, product or patient
to patient biological entities (cells, genes etc.). Microorganisms are not considered in the strategy
for cross contamination control unless they are process generated and cross contamination between
processes is a process risk requiring control.
Containment may be required for biological materials including live entities, toxic or cytotoxic products
as powder or liquid form, products at molecular or nano-scale and operator sensitizing products.
Consideration of national environmental health and safety at work legislation is appropriate given the
risks to human health from potential cross contaminating toxic or highly potent chemical or biological
residues.
Product segregation may be required by facility, controlled areas and containment equipment
depending on the toxicological profile of the products.
The Control strategy should be supported by risk assessments to define segregation requirements
related to hazards, risks and contamination/ cross contamination control requirements.
The Cross contamination control strategy should define the risks and approach to management of
cross contamination that may include a requirement for containment. Containment may be localized,
by equipment/ closed systems, or in combination with facility design or by temporal segregation, e.g.
campaign running.
Considerations in a cross contamination control strategy should include both technical and
organizational measures such as:
• Use of closed processing technologies/ equipment and single use systems
(disposable).
• Validated decontamination steps between processes, equipment and product
manufacturing stages.
• Use of containment barriers e.g. Isolators that provide containment boundaries
suitable for product containment and decontamination including cleaning in place
technologies and safe-change HEPA filter systems.
• Airflow and pressure differential schemes based on containment principles.
• Management of all contaminated waste from cleaning and processing.
• Monitoring of working behavior to ensure training effectiveness and compliance
with the relevant procedural controls.
• When all other possibilities have been discounted, the use of dedicated facilities.

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6.0 Summary statement
With increasing complexity in product manufacture, interactions between ‘Open and Closed’
processing systems, interactions between automated processes and manual operations/ interventions a
control strategy provides an important focus on approach taken in control.
Key characteristics of a control strategy for contamination control would be considered as:
• Product and process knowledge together skills in pharmaceutical product
manufacturing and GMP/ cGMP compliance critical to an effective risk based
approach to control.
• Under the auspices of a Pharmaceutical Quality System (PQS) together with
initiatives of Quality by Design (QbD) and Quality Risk Management (QRM).
• All changes as a result of increasing knowledge, process improvements are subject
to a change control process.
• Dynamic and iterative throughout the product life cycle.
• Holistic and proactive.
• Based on targeted/ risk based measures of contamination avoidance
• Uses key performance indicators (KPIs) to assess status of contamination control
• Includes a defined strategy for deviation management: investigations and CAPA.
Acknowledgements
This White paper was prepared by the PHSS Bio-contamination special interest group. The information
and guidance in the PHSS White paper on Control Strategy for manufacture of Sterile Pharmaceutical
products is a consensus view of the PHSS special interest group and does not necessarily represent
the views of individual’s affiliations or host companies, acknowledged in the PHSS Bio-contamination
monograph 20.

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