Application Note
Risk Mitigation for CIP/SIP Systems
THE PROBLEM
Batch processing in biopharmaceutical manufacturing
requires effective equipment cleaning to prevent product
cross contamination. Failure of a cleaning process poses
a risk to human health since these products are used for
preventative and curative health purposes. Regulation-
backed manufacturing protocols dictate that all equipment
in pharmaceutical manufacturing lines be adequately cleaned
prior to use.
BACKGROUND
Cost-effective biopharmaceutical cleaning incorporates Clean-
In-Place (CIP) and Sterilize-In-Place (SIP) methods (Figure
1). In these methods, water soluble residues are removed
using ambient temperature rinse water while water-resistant
residues are removed by an alkaline wash. Products of the
alkaline wash and most of the alkaline residues are removed
using ambient or hot water fills and intermittent drainage. An
acid wash neutralizes any alkaline residues and de-mineralizes
the surfaces of process equipment, providing some surface
passivation. Finally, hot water is passed, in bursts, through the
circuit with intermittent drains to remove residues of the acid
cleaning agent and surface passivation. Following the last step
the system is air-blown and drained.
Technical risk in CIP/SIP must be fully evaluated and risk
mitigation applied prior to implementation of any technology.
As part of the assessment, it is necessary to consider
operational and economic risks, including those impacting
production schedules, budgets, resource disruptions,
operations, business sector economics, and regulatory activity.
Technical risk can be broadly quantified as the “expected value
of the conditional probability of the event occurring times
the consequence of the event” [1]. In CIP/SIP, this includes
the probability of detecting a failure event. Quantified risk
for CIP/SIP is composed of three factors — a metric for
the severity of the consequences of failure multiplied by the
probabilities of occurrence and detection. Guidelines are
available for the assessment of technical risk in pharmaceutical
systems [2, 3].
More environmentally friendly CIP processes have been
recently implemented, not only providing environmental
benefits but also lowering total cost of ownership. Fully
“green” CIP protocols require lower quantities of water
than conventional processes, use fewer chemicals, and add
no contaminants to the effluent water coming from the
process. Given the very serious consequences of failures in
CIP protocols, it is imperative that effective risk analyses be
performed prior to implementing a new process. This analysis
should be aimed at fully integrating the new CIP protocol
with an environmental and risk-based approach.
SOLUTION
RISK MANAGEMENT ASSESSMENT
Figure 2 shows the MKS risk assessment paradigm for
implementing CIP/SIP. There are three aspects to this
assessment:
• risk from CIP/SIP activities
• type and impact of risk from each activity
• environmental issues for each activity
This procedure forces review of CIP/SIP proposals using
standard terms that include technical, operational, resource,
and quality/regulatory risks. The results are integrated with
any environmental factors associated with each activity. The
approach uses a 5-point system that considers company
size and culture, the available resources, any strategic
considerations, and the company’s manufacturing horizon
(Figure 3).
RISK ASSESSMENT FOR OZONE-BASED CIP
We can use the MKS paradigm to reduce systematic risks
in using ozonated water to replace chlorinated sanitizers,
peracetic acid and hot water rinses in CIP. Ozone is
3000 times more effective as a disinfectant than chlorine,
destroying bacteria, fungi, spores and viruses, lysing cell walls
and oxidizing cellular components. It kills all micro-organisms,
controls viruses and protozoa, and denatures pyrogens.
Ozone is uniquely safe for CIP since it is generated at
the point of use and its decomposition product is simply
oxygen, which leaves no chemical residues in the system.
Reliable, commercial units for the point-of-use generation of
ozonated water are available from MKS Instruments (e.g. the
LIQUOZON® Ultra). If the existing water system’s wetted
materials of construction are compatible with ozone, ozone
may be an excellent and cost-saving choice for a cleaning
technology.
Page 2
1 2
Pre-Rinse Alkaline Rinse &
& Flush Wash Flush
Figure 1 - The different cleaning steps in a 5-step CIP process.
Ozonated water based CIP (Figure 4) requires only 3 steps
stages 1 and 2 are as in Figure 1):
1. Ambient temperature water rinse removes water-soluble
residues
2. Alkaline wash removes water-resistant residues
3. Ozone sanitization, rinse and flush
The use of ozonated water eliminates the acid wash and final
hot water rinse and flush. Table 1 summarizes the benefits and
concerns of ozonated water use, contrasting the characteristics
with those of other “green” approaches to CIP.
The first step of the protocol previously described in Figure 3
requires a technical assessment of ozone as a cleaning agent.
The question asked is ‘Is this technology proven for the
planned purpose [of sanitization]?” The disinfectant properties
of ozone are well suited to CIP. The ISPE (International
Society for Pharmaceutical Engineering) will release a Good
Practices Guide titled “Ozone Sanitization for Pharmaceutical
Water Systems” in mid-2012, and references ozone frequently
in its latest Baseline® Pharmaceutical Engineering Guides for
New and Renovated Facilities, Volume 4 and Steam Systems
(Second Edition) [5,6]. Therefore, the answer to the question
is clearly “Yes”.
Next, we consider integration of ozone technology into
existing CIP systems. The use of pre-integrated ozonated
water generators ensures system integration and safety.
These systems, such as the LIQUOZON® Ultra, ensure
the generation and proper mixing of the desired amount of
ozone and the destruction of excess ozone. They have sensors,
data collection and transmission capabilities appropriate
for safe operation, process monitoring and control. They
Application Note
3 4 5
Acid Hot Water Pump
Wash Rinse &
Flush
can be configured to inject ozonated water at appropriate
ozone concentrations and integrated at any point in a
biopharmaceutical process line, in-line, as a slip stream or
directly into a tank. In practical terms, the use of commercial
pre-integrated units ensures adequate product lifetime,
since they come with a product warranty. Most importantly,
commercial, pre-integrated ozone units greatly enhance the
safety of the installation since they are equipped with suitably
located detectors to report an ambient release of ozone. These
detectors are integrated into the generator to confirm the
destruction of excess ozone. With any of these systems, the use
of additional room ozone monitors is still recommended.
Step #2 requires an operational risk assessment of the ozone
CIP protocol, beginning with an assessment of system
maintenance issues. System components and maintenance
schedules must be reviewed and the risks due to the use of
ozonated water and MTBF should be determined for system
components in ozone service. Operational and maintenance
risks in auxiliary systems must also be determined. These
systems include gas feeds (i.e. compressed air or oxygen),
ozone injectors, the ozone contact tank, ozone off-gas
destructors, control and measurement equipment, and
circulation and interface systems. Risks associated with
the material interaction between ozone and wetted system
components must be determined during this step.
Wetted components include pumps, seals/gaskets, valve
seats, filters, and sensors. It is recommended that all tanks be
316L SS, filters be PTFE, diaphragms be PVDF or EPDM,
and gaskets be EPDM or PTFE encapsulated EPDM. Any
other wetted plastic components must be screened for ozone
compatibility. System piping should be reviewed and only
recommended materials such as 316L SS, PVDF, PFA and
Page 3
Application Note
reduce the cleaning frequency with ozonated water based CIP
protocols, depending on the quality and regulatory framework
of the biopharmaceutical processing line. For small/mid-size
plants, this reduction can produce savings of up to $200,000
Risk Type & Impact

per year in terms of energy and other resources.

Step #4 is the quality/regulatory assessment that evaluates

l
ta
en ns
nm tio
v iro dera
CIP/SIP Activities En nsi
Co
Figure 2 - A risk assessment paradigm.
CPVC used in process lines. PVC is permissable in drain lines.
The selection of commercial pre-integrated ozonated water
generators greatly simplifies this step since many of the issues
have been dealt with by the manufacturer. During Step #2, the
impact (financial, quantity, quality) on critical utilities must be
assessed along with any concerns for the effects of integration
on safety, power, water and facilities management.
Step #3 involves resource assessment. A critical utilities TCO
(Total Cost of Ownership, also called Cost of Ownership
COO) assessment is performed and training needs for safe
operation and maintenance are assessed. TCO will depend on
the frequency of use and specific costs of the ozone system.
Interestingly, some case studies show that it is possible to
whether the ozone-based protocol can achieve the quality
necessary for the cleaning process. Existing cleanliness and
sanitization specifications must be achieved and validated in
accordance with the master cleaning validation plans within
the organization. The system must be protected with software
passwords, authorizations, and procedures. Data and system
integrity must be shown to be maintained and proven over
the equipment lifetime, and failure modes appropriately
documented.
In the final step, the environmental impact of ozone-based
CIP is assessed. Water use and re-use evaluations show that the
lower number of flushes required in ozone based CIP reduces
both water consumption and the environmental impact.
In certain installations it is even possible to re-use all of the
process water. Chemical use is essentially eliminated in ozone
CIP, reducing or eliminating any costs for chemical purchase,
storage and handling. Utilities’ use in ozone CIP is likewise
reduced over traditional approaches. The ozone process works
at ambient temperature without any need for high-cost,
lengthy steam production. With ozone, there is no need to
heat or cool any of the surfaces being treated, and there is no
requirement for additional electricity for rinse water handling.

Quality / Environmental
Technical Operational Resource
Regulatory Impact

• Proven • System • Training • Results • Water use

technology for maintenance • Ease of use comparable to and reuse
this purpose • Auxiliary existing • Chemical use
• Critical
• System equipment specifications
utilities • Critical utility
design • Material • Software reduction
• Faster
• System interactions password
cleaning
integration level
• Integration cycles and
protection
• Sensors and • Software higher
alarms throughputs • Documen-
protection
tation
• Data • Chemical • Costs
collection, • Validation of
storage
extraction, equipment
• C&O and data
and transfer
• Data • Data Integrity
• Product
collection and
lifetime
extraction
• Safety
considerations

Figure 3 - A 5-point risk assessment protocol.

Page 4
Application Note
CONCLUSION
1 2 3 A simple risk assessment model that evaluates risks for
replacing traditional CIP protocols with ozone-based CIP was
described. It was shown that commercially available ozonated
Pre-Rinse Alkaline Pump
& Flush Wash water systems can solve multiple environmental, operational,
safety and economic challenges while simultaneously meeting
CIP objectives and risk concerns. These systems increase
critical utility flexibility leading to higher throughputs and
increased uptimes in biopharmaceutical process lines. Properly
employed, the risk assessment model serves to increase
awareness of risk, benefits and options that can be critical to a
given process situation.
Figure 4 - Proposed ozone-based CIP process.

CIP Method Benefits Concerns REFERENCES

1. H. G. Claycamp, presented at The CDER Advisory
• Can customize specific cleaning • Time & tests to maximize
Chemical-based
CIP ratios combination
Committee for Pharmaceutical Science (ACPS), October
• Chemicals readily available • Changes in water make-up/biopharm 5-6, 2006 Rockville, MD.
• New combinations may perform compounds require tests
better
• Potential for one step clean and
2. “ICH Harmonized Tripartite Guideline on Quality Risk
sterilize Management”, available at http://www.ich.org/fileadmin/
Ozone • More effective than chlorine • Amount of ozone generated depends Public_Web_Site/ICH_Products/Guidelines/Quality/Q9/
on method
• Fast minutes
• Ambient, point-of-use generation • Safety, cost, material interactions
Step4/Q9_Guideline.pdf
• Oxidizes organic compounds • Capital equipment required
• Lower TCO
3. “ICH Harmonized Tripartite Guideline on
• Reduces water use Pharmaceutical Quality System”, available at http://www.
• Mitigates biofilm growth
ich.org/fileadmin/Public_Web_Site/ICH_Products/
Pigging • Reusable
R bl “pigs”
“ i ” mostly
tl for
f product
d t Pi cleaning
• Pipe l i only
l Guidelines/Quality/Q10/Step4/Q10_Guideline.pdf
recovery • Requires specific pipe design
• Established, available tech
• Operable by remote controllers
• Cannot confirm biofilm removal
4. The International Society for Pharmaceutical Engineering
• Capital equipment required
Good Practices Guides “Ozone Sanitization for
Table 1 - A comparison of the benefits and concerns for various CIP Pharmaceutical Water Systems” release date mid-2012.
protocols. 5. Baseline® Pharmaceutical Engineering Guides for New
and Renovated Facilities, Volume 4 Water and Steam
Systems (Second Edition) was released in December,
2011 ISPE CASA chapter seminar, Spring 2009.

For further information, call your local MKS Sales Engineer or contact the MKS Applications Engineering Group at 800-227-8766.
LIQUOZON® is a registered trademark of MKS Instruments, Inc., Andover, MA. Baseline® is a registered trademark of ISPE, Tampa, FL.

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