Spotlight Cleaning Validation in Continuous

COVID-19 Update Manufacturing

November 16, 2016
Analytics
Elizabeth Rivera , Paul Lopolito
Drug Development Equipment and Processing Report

Manufacturing Equipment and Processing Report, Equipment and Processing Report-11-16-2016,

Volume 9, Issue 11
Outsourcing

Quality Systems

2020 Bio/Pharma Virtual Congress

A lifecycle approach can be used to develop GMP-compliant cleaning procedures
for continuous manufacturing of solid-dosage pharmaceuticals.

It is now possible, as demonstrated by Janssen (1), for

drug manufacturers to convert their processes to adopt
continuous production of oral solid-dosage forms
produced in compact, closed units, with a higher level
of automation and minimal manual interventions. In
Topic See All >
continuous manufacturing, the sequential production
Analytical Method Development steps that are part of a classic batch process are
integrated into a continuous process. To ensure GMP
Now
APIs compliance, cleaning is required on some frequency
Design/Shutterstock.com
Aseptic Processing between batches of the same product and when
switching between different products.
Biologic Drugs
What is continuous manufacturing?
Dosage Forms
It is important to de ne continuous manufacturing and to understand the
Drug Delivery characteristics that differentiate it from a typical batch process. The classical

Equipment de nition involves the following:

Excipients All crucial steps involved to produce something from its starting
materials to the end-product must be integrated into a steady
Formulation uninterrupted process.

Packaging The systems should operate continuously (non-stop) targeting at least 50

Process Control/PAT weeks per year.

Process Development There should be no signi cant downtime in product or process

changeover.
QA/QC
Some variations of this processing mode may be foreseen over the years. Processes
Regulatory Action that do not t the above de nition, such as infrequent manufacture (e.g., operates

Supply Chain only once or twice per year) or a multi-product process train (i.e., same equipment
used for many different products), are generally not considered continuous
manufacturing (2).

Cleaning concerns
Although most companies do not have immediate plans for implementation of
continuous manufacturing, many GMP professionals have questions concerning the
impact of this type of process on cleaning and cleaning validation. People involved
in quality, engineering, operations, and validations are asking about applying
cleaning validation to pharmaceuticals produced in a continuous manufacturing
process. The purpose of this article is to provide a review of the regulatory
expectations on cleaning and cleaning validation and to help drive e ciency by
rethinking the design of the cleaning process in continuous manufacturing.
 Professionals interested in understanding cleaning and continuous manufacturing
PARTNER RESOURCES
must become familiar with the following aspects:
2021 PDA Annual Meeting
Mar. 15-17 | Online The regulatory perspective on cleaning validation and applicability to
continuous manufacturing

2021 PDA Visual Inspection The importance of the lifecycle model and risk assessment tools to
Forum successfully design and implement a cleaning procedure for continuous
Apr. 14-15 | Online
manufacturing

Testing, sampling, process analytical technology (PAT), and equipment

PDA Fundamentals of Aseptic
Processing design concepts that should be reviewed and considered to optimize
Mar. 8-11 | Bethesda, MD
cleaning in continuous manufacturing

How to establish cleaning residue limits explicitly for continuous

PDA Quality Culture
Assessment manufacturing.
May 19| Online
Regulatory perspective
In the United States, the regulatory expectation is that equipment be cleaned prior to
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manufacturing to prevent contamination or adulteration of products (3). Similarly, in
Europe, Canada, Asia, Latin America, and other territories, equipment cleaning is a
regulatory requirement cited in their applicable GMPs. According to 21 Code of
Federal Regulations (CFR) Part 211.67 Equipment cleaning and maintenance,
“Equipment and utensils shall be cleaned, maintained, and sanitized at appropriate
intervals to prevent malfunctions or contamination that would alter the safety,
identity, strength, quality, or purity of the drug product beyond the o cial or other
established requirements” (3). Also, in 1993, FDA issued the Guide to Inspections of
Validation of Cleaning Processes to assist the industry in compliance with GMP
requirements (4). The European Medicine Agency (EMA), Health Canada, and others
subsequently issued similar guides to assist the industry in complying with the
relevant regulations (5–6).

Based on these guidance documents, cleaning validation is clearly a necessity when

the equipment is used to manufacture more than one drug product due to cross-
contamination concerns. A question remains as to whether cleaning validation is
required for dedicated equipment, which may be the case for most continuous
manufacturing processes. The need to validate the cleaning procedure when the
equipment is dedicated to one product is generally left to the company’s discretion,
and it must be supported with proper justi cation. Nevertheless, cleaning validation
of dedicated equipment has been discussed in other publications, and the rationale
behind this can also be applied to continuous manufacturing (7). In the case of
continuous manufacturing, cleaning validation of dedicated equipment should be
done to demonstrate that the cleaning procedure can effectively remove residue
build-up and undesirable residues (including microbial) produced during a speci c
length of manufacturing (i.e., campaign) that may compromise product quality and
patient safety.

As of the time of publication, no speci c regulation or guidance document for

continuous manufacturing has been released. FDA authorities have presented a
general perspective on continuous manufacturing, which addresses the concerns
around “lot” and “batch” de nitions (8). According to the CFR, “batch” and “lot” refer
to a quantity of material with uniform characteristics and do not specify mode of
manufacture; no regulations or guidance documents forbid the adoption of
About Us
Advertise continuous manufacturing. In fact, continuous manufacturing seems to be
Contact Us consistent with philosophies, such as quality by design (QbD) and the lifecycle
Editorial Info approach to process validation, found in current guidance documents (9–12).
Editorial Contacts
Editorial Advisory Board  
Do Not Sell My Personal Information
Privacy Policy Lifecycle approach
Terms and Conditions
In 2011, FDA issued a process validation guide (12) focusing on three main
elements:

Quality needs to be built into the process

 Quality is not guaranteed by in-process or nal process testing

A manufacturing process needs to be de ned and continuously

monitored to ensure consistent quality.
© 2021 MJH Life Sciences™ and Pharmaceutical
Technology. All rights reserved. The elements of the lifecycle model are the building blocks to a harmonized
approach to process validation and subsequently, cleaning validation. The lifecycle
elements of design, validation, and monitoring are also the building blocks to make
continuous processing an e cacious mode of manufacturing. The process lifecycle
approach as discussed in the guidance document focuses on understanding the
processes and ensuring that they are meeting the requirements set forth in the
design stage. The elements of the lifecycle approach should not be limited to
manufacturing since they may also be applied to other processes including cleaning.
With this in mind, the lifecycle model can be used to improve or optimize cleaning
procedures by having a better understanding of the input variables and the output
attributes.

Designing the cleaning process

Process e ciency is important in continuous manufacturing and cleaning is not an
exception. For example, at some pre-established schedule, the continuous
manufacturing facility must be shutdown to perform equipment cleaning and
maintenance. Cleaning procedures are expected to be done quickly and correctly the
rst time in order to meet the optimum changeover time as established in the
production schedule. Also cleaning procedures should be systematically designed
to reduce waste within the cleaning process.

The design stage of the lifecycle model (Stage 1) is of

particular importance because the cleaning process is
de ned based on knowledge gained through
development and scale-up activities. This stage
ensures that the variables are identi ed and their
criticality to the cleaning process is assessed. For
Figure 1: CLICK TO
example, the design inputs or critical cleaning process
ENLARGE. Typical
parameters for the wash step include the cleaning
equipment of oral solid-
agent, concentration, temperature, time, cleaning
dose (OSD) batch process
method, water quality, and environmental factors (13–
and a continuous
14). Laboratory, pilot, or eld studies should be used to
manufacturing (CM)
help de ne the cleaning process and identify
process ow with soil type
conditions that would lead to the desired fast, effective,
considerations for
and lean cleaning process (see Table I). These studies
cleaning evaluations. SOP
may involve cleaning evaluations with wet, baked-on
is standard operating
residue found in the drier as well as dry, compacted
procedure; CIP is clean in
residue for tablet pressing equipment (see Figure 1).
place. All images are
courtesy of the authors.
A formal risk assessment for the cleaning process is
also recommended using a system for identifying and
managing risk such as fault tree analysis (FTA), hazard analysis and critical control
point (HACCP), or failure modes and effect analysis (FMEA) (15–16). Risk
assessment should be based on the knowledge gained through the design stage
and focus should be placed on the issues that have potential impact on product
quality and patient safety. Table II includes items to consider for building a cleaning
process knowledge base. A design of experiments could be used to identify those
parameters that have a signi cant impact to cleaning within a speci ed range (17).

Monitoring technology
Cleaning processes are often viewed as time- and resource-consuming activities
that only add to the operational costs of product manufacturing. Delays in
equipment readiness due to cleaning failures, lengthy manual cleaning procedures,
or off-line sampling wait times can challenge continuous manufacturing schedules
and result in costly production delays.
Table I: Design space considerations for continuous manufacturing.

Manufacturers using batch processing, including cleaning processes, perform

laboratory testing conducted on pulled samples to evaluate quality attributes. PAT,
however, can be used in continuous manufacturing to provide real-time continuous
analysis and release of the cleaned equipment. PAT is a system for designing,
analyzing, and controlling manufacturing through timely measurements, process
understanding, and process control (18). In cleaning applications, PAT may be
applied to complement the cleaning performance quali cation and later, to support
continued veri cation. For example, concentration-versus-conductivity plots are pre-
established to monitor the nal water rinse for residual cleaning agent (19). Total
organic carbon (TOC) analysis can also be correlated to process residues. In a
published case study, a cleaning process was evaluated using an on-line TOC
analyzer integrated into the return line of a clean-in-place (CIP) system (20).

Table II: Cleaning process knowledge base.

There are sampling options (e.g., rinse and swab) universally acceptable for
monitoring the cleaning performance of the targeted residues; each option has
advantages and disadvantages to consider. For most cleaning applications, rinse
sampling is typically expected to be faster and easier compared to swab sampling,
which may require access to equipment locations through disassembly or con ned-
space entry and consequently compromises personnel safety.

Analytical methods can be speci c or non-speci c to determine the amount of

residue on the surface through direct and indirect sampling methods. Non-speci c
detection methods, such as pH, conductivity, or TOC, can be used to measure
multiple residue types. These types of methods are preferred due to the quick
turnaround time, minimum waste generation, and simplicity of the assay.  Ultra high-
pressure liquid chromatography (UHPLC) instruments measure residue based on
detection of a speci c analyte and is a faster alternative over traditional HPLC (21).

Table III: Faster testing technologies commonly used for cleaning monitoring.
Table III lists examples of at-line and in-line methods that could be used for
detection of residual cleaning agent. For continuous manufacturing, it is
recommended to review testing technologies and select one that makes the most
sense given the analytical resources, type of residue and carry-over risk, speed of
analysis, and/or adaptability to PAT.

Cleaning equipment design

Batch pharmaceutical processes employ a variety of methods to clean process
equipment. Manual cleaning methods using wipes and brushes are common in
legacy batch-mode processes while CIP systems are popular at newer facilities.
Even though both manual and automatic cleaning methods are accepted by drug
regulatory agencies around the globe, companies considering continuous
manufacturing processes should opt for CIP systems because they are effective,
consistent, and reliable. Consistent cleaning results are achieved because there is
minimal operator intervention, reduced likelihood of human error, and consistent
control of critical parameters when combined with PAT technologies. The principal
objective of a CIP system is to achieve the desired cleanliness level without
disassembling the process equipment. Generally, CIP cleaning is done by circulating
cleaning solutions through pipes, pumps, valves, and spray devices that distribute
the cleaning agent over the surface areas of the equipment. PAT technology can be
used to monitor cleaning steps, such as the preparation of cleaning solution to a
pre-established concentration and the rinsing of the equipment down to pre-
established residue limits.

With adequate sanitary design, such as coverage, diaphragm valves, pitch, and dead-
leg orientation, CIP systems can deliver faster and lean cleaning processes suitable
for continuous manufacturing. All sanitary design concepts must be thoroughly
reviewed to ensure equipment cleanability and minimize water consumption.
Multiple sources provide details on sanitary options (22–24). In summary, a
laboratory evaluation to determine critical cleaning parameters combined with a
review of equipment design concepts should help improve speed of the cleaning
procedure, reduce waste generated during cleaning execution, minimize cleaning
agent and water consumption, and reduce human interventions.

Establishing cleaning residue limits

In setting acceptable residue limits within continuous manufacturing, two situations
should be considered (25). In the rst situation, the manufacturing process for
Product A is interrupted (a scheduled or unscheduled stoppage) due to a minor
maintenance event or light cleaning such as vacuuming or dry wiping the work
surfaces; when complete, the manufacturing line is back up and running. In this
situation, there is no concern of residual carry-over of the active ingredient because
only one product is being manufactured; therefore, cleaning validation is not
applicable. If a product impurity, cleaning agent, equipment lubricant, or similar
processing aid was introduced, however, a cleaning procedure should be performed
to remove those residues to safe levels prior to resuming production. This type of
interruption will fall into the second situation.

In the second situation, Product A production has stopped and change-out is

occurring to begin continuous manufacturing of Product B. In this scenario, there is
a need to perform an in-depth or heavy cleaning to make sure that active
components from Product A do not affect the quality of Product B, as well as
ensuring that the non-active components (any cleaning agents used, and microbial
residues remaining on the surface) are within acceptable levels. Similar to traditional
batch processing, possible pharmacological and toxicity effects of Product A, as
well as residue impacting the stability of Product B, need to be considered.

In establishing residue limits, safe concentration of the target residue in the

subsequent product (i.e.,  Product B), referred to as Limit 1 (L1), needs to be
understood. The safe dose (L0) or a scienti cally derived health-based limit (i.e., an
acceptable daily exposure [ADE] or permitted daily exposure [PDE]) of the residue
(i.e., of Product A) is calculated using Equation 1, and L1 is calculated using
Equation 2 (26–27).

[Eq. 1] L0 = Toxicity Assessment x Body Weight x Minimum Daily Dose of Product A

[Eq. 2] L1 = L0 / Maximum Daily Dose of Next Product

The L1 value calculated in Equation 2, multiplied by the batch size of the subsequent
product (which, as previously discussed, must be de ned in continuous
manufacturing by the manufacturer), provides a maximum allowable carry-over
value (MAC or MACO value, also known as L2).

From the L2 or MAC value, the limit per surface area can be calculated by dividing by
the shared surface area of the equipment train.

This calculation assumes a uniform distribution of the residue and is considered a

conservative approach to setting limits per surface area. Most cleaning validation
swab sampling plans would include sampling the hardest-to-clean locations based
on a risk assessment.

Strati ed and non-uniform residue limits

The concept of uniform distribution is an ideal scenario and is not always true (28).
This assumption, therefore, may lead to failing results on select equipment or
sampling locations.

Strati ed residue distribution on equipment splits the calculated L2 or MAC residue

among the different pieces of equipment within the manufacturing process based
on a risk assessment. It is important to document the risk assessment used to
determine the strati cation because it will be reviewed by auditors. The strati cation
scheme can also vary based on the target residue. For example, microbial limits may
be set lower for the wet granulation and coating steps because there is a greater risk
for microbial proliferation during these steps.

Non-uniform residue contamination in the product means that the residue on the
surface of the equipment concentrates into the rst units of production and is then
reduced in subsequent units. In a tablet press, for example, the residue from the
previous product will be transferred to the rst tablets (or round of tablets) pressed
at a higher concentration than the second and third tablets pressed. In a lling line,
as another example, the residue from the previous product will be transferred to the
rst vials (or series of vials) lled at a higher concentration than the second and
third vials lled.

Equation 3 shows a calculation for setting limits in a non-uniform contamination

example. The limit (L0) of Residue A in Product B has been calculated (or defaulted)
to be 10 ppm or approximately 10 μg/mL. The total surface area of the lling
equipment and piping is 10,000 cm2, and the limit per surface area of Residue A has
been predetermined to be 1 μg/cm2. Product B is lled in 10 mL vials. If the
contamination of 1 μg/cm2 of the total shared surface area of 10,000 cm2 were
concentrated into the rst vial lled of 10 mL, then the residue level would be 1000
μg/mL or 1000 ppm, which is well above the 10 ppm limit. The rst 10 or 100 vials
should be discarded because the residue in the vials would be less than 100 or 10
ppm, respectfully.

[Eq. 3] (1 μg/cm2)(10,000 cm2)/10 mL = 1000 μg/mL or 1000 ppm  

The understanding of non-uniform and strati ed sampling is important for setting

residue limits within a continuous manufacturing process because a small quantity
of product may migrate through a manufacturing process, concentrating residue
from one piece of equipment to another and defaulting to a traditional uniform
residue limit, which can adversely impact the quality of the product and potentially
impact the health of the patient.

Cleaning performance quali cation

In the lifecycle approach to cleaning validation, Stage 2, the performance
quali cation stage, is a readiness check to ensure the cleaning process is able to be
validated. This stage will involve checking that suppliers have been approved,
analytical methods have been validated, personnel performing the cleaning have
been trained, standard operating procedures and validation documents are ready to
be performed or executed, and process equipment and utilities have been
successfully quali ed and ready for use (29).

If the critical process parameters and critical quality attributes were well
characterized during the cleaning design stage, then the performance quali cation
(Stage 2) should be performed using normal operating parameters.

Continued process veri cation

The third stage of the lifecycle model is continued process veri cation.
Implementation of process controls such as change control, preventative
maintenance, and corrective and preventative action systems ensure a validated
state. The cleaning process continuously operates in a state of control. A periodic
review of the cleaning program is also crucial to ensure that the cleaning process
remains in control and is exible to change when required. This periodic review of
the cleaning validation program should be reviewed in a similar manner as the yearly
product quality review. A review of product cleaning is generally part of the yearly
product quality review, but it is generally not thorough enough and often doesn’t
review similarities and difference between multiple products manufactured in the
same equipment.

Table IV: Examples of impact changes.

Items that should be reviewed include change control

data, monitoring data, deviations, corrective and
preventive actions, maintenance, quality records, and
retraining events.

If the review shows control and consistency, then

summarize the ndings and conclude that the cleaning
program is operating in a state of control (i.e., a
validated state). The review can also identify high-risk
or high-waste areas that need to be improved. A
corrective action plan or lean manufacturing event can
be used to develop a plan to correct this de ciency.
Figure 2: Roadmap to the
Managing change cleaning validation

Depending on the type of change being proposed, it lifecycle approach.

may be necessary to go back to the design stage to

determine the impact of the change to the cleaning process. For this reason,
validated cleaning procedures must be included in the change control management
system. This ensures that any proposed changes are evaluated fully for their impact
on the validated state of the procedure.

Table IV is not an all-inclusive list of possible changes but helps provide an idea of
the type of changes and their potential impact (29). The impact of the change to the
cleaning process may have already been assessed during the design stage;
otherwise additional testing within the design stage may be warranted to mitigate
risk prior to implementation of the change. This action is depicted in Figure 2 as
arrows from Stage 3 to Stage 1 or 2 as a result of the change (29). 

Managing change is an important process because the goal of the design stage and
continuous monitoring stage of the cleaning validation lifecycle approach for
continuous manufacturing production facilities is to operate within a state of control
and to drive out waste to improve e ciency and maintain exibility of the cleaning
process.

Conclusion
Continuous manufacturing focuses on streamlining production while minimizing the
process footprint and waste from non-value activities. To ensure cGMP compliance,
cleaning is required on some frequency between batches of the same product and
when switching between different products. Developing a cleaning validation
program using the process lifecycle approach provides a rm understanding of the
critical cleaning process parameters as well as the critical quality attributes that
need to be monitored.

The equipment used for continuous manufacturing may vary based on the type of
product manufactured as well as the method of cleaning. It is important to evaluate
cleaning during the drafting of the user requirement speci cations and functional
requirement speci cations of the production equipment. The development and proof
of concept of a laboratory-scale cleaning model during the design phase of the
cleaning process and equipment fabrication will aid in the validation of cleaning
processes. This model will also help in the ability to conduct additional
investigations to support process and cleaning changes to reduce waste. The use of
health-based limits, such as an ADE or PDE value, for any route of administration,
along with a rationalized use of non-uniform and strati ed residue limits, allows for
setting practical, achievable, and justi ed acceptance limits.

References

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2. G. Malhotra, Contract Pharma. 17 (5) 74- 79 (2015).
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About the Authors

Paul Lopolito and Elizabeth Rivera are technical services managers for the Life
Sciences Division of STERIS Corporation in Mentor, Ohio.

Article Details
Pharmaceutical Technology
Vol. 40, No. 11
Pages: 34–42, 55

Citation
When referring to this article, please cite it as P. Lopolito and E. Rivera, "Cleaning
Validation in Continuous Manufacturing," Pharmaceutical Technology 40 (11) 2016.