CLEANING ENGINEERING AND EQUIPMENT DESIGN

CLEANING ENGINEERING AND EQUIPMENT DESIGN

George Verghese and Paul Lopolito

Reprinted from Cleaning and Cleaning Validation, Volume 1 edited by Paul Pluta.

Copyright 2009, co-published by PDA and DHI. All rights reserved.

420-600-0049

8

CLEANING ENGINEERING AND EQUIPMENT DESIGN

George Verghese STERIS Corporation

Mentor, OH

USA

Paul Lopolito STERIS Corporation

Mentor, OH USA

INTRODUCTION

In the previous chapter, we discussed the chemistry of cleaning agents, their mechanisms of

chemical action, the various options available and the factors that need to be considered when

selecting cleaning agents. This chapter deals with the various parameters and factors that

govern or affect cleaning performance. These parameters and factors can be classified broadly

into three categories. These include:

• Cleaner and parameters

This category includes key parameters that relate to the cleaning agent application and to

the cleaning process. There are four key parameters related to the cleaning process that

govern cleaning effectiveness. These include the duration of contact of the cleaning

solution with the surface (time); the application method and extent of action or force

acting on the surface; the concentration of the cleaning agent; and the temperature of

application (LeBlanc, 2000; Verghese, 1998). These parameters — time, action,

concentration and temperature — are commonly referred to by the acronym TACT.

123

124 Cleaning and Cleaning Validation

Figure 8.1 Factors affecting cleaning

Soil

residue

Cleaner

and

parameters

Surface and

equipment

design

• Soil residue

This category includes factors related to the soil residue and its interactions. These include

the amount of soil present on the surface when cleaning begins, the nature and tenacity of

the soil adhesion, and the extent of mixing and dispersion of the soil in the cleaning

solution during the cleaning process.

• Surface and equipment design

This category includes factors related to the surface properties and design of the

equipment being cleaned. The type, configuration and design of the surface being cleaned

play an important role in the cleaning process. The issues that need to be considered

include the materials of construction, surface finish, and other equipment design issues

such as the length and the orientation of dead legs, pitch or slope of piping, crevices,

corners, and surface drainability.

A proper understanding of the combined role and influence of the cleaning chemistry and

application method, the cleaning process parameters, the nature of the soil, and the various

equipment design issues, will help you design and develop a cleaning process that is robust,

eff icient and easily validatable. Developing a sound cleaning process is critical, since it is

difficult to change once it is validated, and can have a signif icant influence on regulatory

compliance and overall cost of manufacture. A review of these cleaning parameters and factors,

soiling effects and equipment design considerations will provide the needed technical

knowledge base and tools for developing an effective and validatable cleaning process.

Cleaning Engineering and Equipment Design 125

CLEANING PROCESS PARAMETERS — TACT

A typical aqueous cleaning process involves a pre-flush using water, one or more wash steps

using a cleaning agent, and subsequent water rinse steps designed to rinse away the cleaning

agent along with the dissolved or dispersed residue. The cleaning parameters — time, action,

concentration and temperature — are applicable for each of the steps in a cleaning process,

except that concentration applies only to the wash step where a cleaning agent is diluted. These

parameters are discussed in more detail below.

Time

To help understand and develop a cleaning process, the total cleaning time may be divided into

its time components — pre-rinse time, wash time, post rinse time and other unused time if any

in between these steps. The effect and implications of these times on the overall cleaning

performance may be assessed. For an automated process these cycle times are preprogrammed

into a microprocessor and for a manual process these are controlled, all or in part, by the

operator following a well-defined standard operating procedure (SOP).

In general, increasing the duration of any step improves residue removal. However, this is

true only up to a point, beyond which there is usually a diminishing return or in some cases an

adverse effect. For example, adequate duration for a once-through pre-flush with water may help

remove loosely adhered soil and reduce the soil load in the subsequent wash step, but excessive

pre-flush with water has no benefit for insoluble soils. Also, increasing the duration of a

recirculation wash step beyond a certain time may be futile if the cleaning solution is either

saturated with the soil at that point or has removed all the soil that could be removed under the

mechanisms and parameters used. Another example: for certain complex soils, an alkaline wash

followed by an acid wash may be necessary to remove all the soil components. In such cases, an

excessively long alkaline wash step, particularly at elevated temperatures, could adversely affect

any remaining acid–soluble residue and impede effective removal during the subsequent acid

wash step.

Furthermore, the effect of dirty hold time (the time between end of production and start

of cleaning), clean hold time (the time between end of cleaning and equipment reuse), and

excessive time in between the various steps of a cleaning process can be significant. These

time-management issues can have an impact on the condition of the soil residue as well as on

the total cleaning time, and will be discussed later in the section dealing with soil conditions.

Action

The shear force acting on a surface during a cleaning process, or the ―action‖ as it is commonly

referred to, is an important parameter that is unfortunately the least understood and monitored,

and is often the cause of inadequate cleaning.

The source and extent of the force acting on the surface depends on the cleaning method

used. For example, in a manual scrubbing or wiping processes, the mechanical action that helps

physically remove the residue comes from the force exerted by the operator on the brush or


wipe. In spray ball applications, the action may come either from the impinging force of the

spray jet or the cascading flow of the liquid down the side wall. In ultrasonic cleaning, high

frequency sound waves provide the cleaning action.

The force acting on the surface may also vary significantly from one area to another

within a system, particularly a large process system, due to equipment design constraints and

flow variations. The effect of the various design and flow rate issues on the turbulence and force

acting on the surface will be discussed further in the section dealing with equipment design.

However, in situations where the action varies from one surface location to another, worst-case

areas corresponding to the lowest level of action should be identified. If the other cleaning

parameters are then chosen at levels high enough to compensate for the low level of action, the

combined effect of the various parameters will result in an effective cleaning process.

Concentration

For aqueous cleaning processes, an increase in the concentration of the cleaning agent will

generally increase the efficacy of the wash step. Higher concentrations could increase reaction

rates, increase solubilization, and in the case of surfactants reduce surface tension and facilitate

emulsification. These effects could result in faster or more thorough soil removal from the

surface, and improved soil dissolution and suspension into solution, which prevents re-deposition.

As with other TACT parameters, increasing the concentration beyond a certain level may

not yield further improvement in cleaning performance, and in some situations may be

detrimental. The use of higher concentrations of a cleaning agent may also result in the need

for more rinse water and time. Depending on the application method and equipment being used,

high concentrations may not be appropriate because of substrate compatibility and personnel

safety constraints. The higher concentrations of alkaline or acidic cleaners will also typically

need to be neutralized before disposal.

To ensure cleaning performance, the concentration of the cleaning agent should be

monitored. If chemical dispensing pumps are used, they should be routinely calibrated and

maintained. An inline conductivity probe may be used to monitor the concentration of alkaline

and acidic use dilutions. Fluid level sensors can also be used to monitor the level of cleaning

agent in the holding tanks. These sensors can also be monitored and interlocked remotely or

linked to the operator interface panel, electronic batch records or purchasing systems.

Temperature

In general, higher temperatures improve cleaning eff icacy by increasing solubility and

solubilization, increasing reaction rates such as hydrolysis, oxidation and peptizing, decreasing

viscosity, and increasing diffusion rates. Higher temperatures are also very benef icial for

cleaning waxy and oily residues because they help melt, soften or reduce the viscosity of these

types of residues. Figure 8.2 shows the result of a study on a wax-based product soil that was

cleaned using an alkaline cleaning agent under agitated immersion conditions at various

temperatures, all other parameters being the same. The cleaning performance was the same at

50°C and 60°C, but dramatically improved at 70°C.


Figure 8.2 Residue versus temperature

The relationship between temperature and surfactancy is more complex and will depend on the

type of surfactant being used. Certain classes of surfactants may exhibit a cloud point that may

have an effect on the optimum cleaning temperature.

There are certain soils for which a lower temperature may actually result in better

cleaning. These may include certain inorganic salts, polymeric coatings, and proteinaceous

soils. For most proteinaceous soils a lower temperature (<60°C) pre-rinse is recommended to

remove gross soil prior to the wash step, to prevent the protein from denaturing and becoming

more diff icult to remove.

As with time and action, the temperature will need to be controlled across all surfaces and

for all the steps in a cleaning process. If the temperature does vary, effective cleaning should

be ensured using the worst-case temperature conditions.

FACTORS RELATED TO THE SOIL OR RESIDUE

Soil levels

High levels of soil on surfaces could lead to saturation or depletion of the cleaning agent, solvent,

surfactant, or components of a cleaning formulation, rendering one or more of the cleaning

mechanisms ineffective. This is particularly important when small volumes of cleaning solution

are used to clean large surface areas, as in clean-in-place (CIP) systems. It is also relevant in

situations where the same cleaning solution or solvent is used to clean a series of vessels in a

train, as is the practice in some active pharmaceutical ingredient (API) manufacturing operations.

In these situations, it is useful to estimate the typical soil levels in process equipment and to


determine a worst-case soil-to-cleaning solution ratio. Cleaning studies and pre-validation work

should be done to demonstrate that the cleaning parameters and process are effective at removing

these soil loads from the surface. In many situations a pre-rinse with water can help reduce the

soil levels on surfaces, but this may have its limitations, particularly when dealing with water-

insoluble residues and limited spray action.

Soil condition

The tenacity of the soil adhering to the surface may depend on several factors, including those

related to the manufacturing process and storage conditions. The soil may be dried, baked,

autoclaved, denatured or polymerized onto the surface. In general, the heating of the soil through

baking or autoclaving creates a condition that is harder to clean than wet or dried-on soil. Powder

soils may loosely adhere to surfaces as with solids blending processes, or compressed into

crevices or corners of the equipment as with tableting operations, or smeared as a wet soil when

mixed with a liquid component as in wet-blending operations. Certain manufacturing processes,

such as coating machines, apply several layers or a continuous spray of the soil over a period of

time. This layering phenomenon may also occur at the air–liquid interface such as those in

reservoir tanks for filling lines. At times, certain types of polymeric chemistries may cause the

layered soil to be removed as a film. In some situations involving formulated drug products,

components of the formulation could selectively adhere to the surface such as at the air-liquid

interface during blending operations. In all such situations, the specific soil adhesion

phenomenon must be understood and addressed to assure appropriate cleaning and sampling of

worst-case locations.

Case study #1

A large pharmaceutical company that manufactured over-the-counter (OTC) products noticed

a periodic visual failure along the air–liquid interface of one of their formulation tanks. The

company submitted samples of the final formulation to a laboratory to perform cleaning

evaluations. The cleaning parameters — TACT were determined and adopted based on the ease

of cleaning of the final formulation under worst-case application conditions. However, the

periodic visual failures persisted. An evaluation of each component within the formula was

then performed, and the cleaning effectiveness of the components was compared to that of the

final formulation. In parallel, a sample of the soil along the air–liquid interface was also

analyzed.

The analysis of the soil along the interface revealed a predominance of one of the

components within the formula, microcrystalline cellulose. This component was also the most

difficult to remove in bench-top studies. The cleaning process was successfully modified by

increasing the wash time and concentration of the cleaning agent based on this information.

Hold times (dirty and clean)

The dirty hold time refers to the period of time from the end of the production process,

including active ingredient inactivation if any, to the start of the cleaning process. In general,


the longer the dirty hold time, the more diff icult it is to remove the soil from the surface. Once

the soil completely dries or is baked onto the surface, the difficulty of cleaning generally does

not increase significantly with additional holding time. In some situations, although the

cleaning may start right after the end of production, there can be certain areas of the process

system where the soil has dried onto the surface for a longer time. These may include charge

chutes or pipes that are exposed to the raw material, intermediate, or product from the

beginning of the batch or campaign.

The clean hold time refers to the period of time from the end of the cleaning process to

the start of the next production process. The clean hold time is established to ensure that the

equipment does not become contaminated due to microbial growth or environmental

contaminants. Stagnant water in pipes, dead legs, drains and other surfaces can lead to

microbial proliferation and/or corrosion of the surface. For these reasons, equipment should be

stored dry and covered. The acceptance criteria to quantify justifiable clean hold times include

a demonstration of visual cleanliness and the lack of microbial proliferation.

Soil mixing

In cleaning processes, if the mixing and agitation of the cleaning solution is not adequate, the

solution may not be homogenous and could potentially get saturated with the soil in localized

areas, resulting in sub-optimal cleaning. For example, in laminar flow, the solution very close

to the surface could get saturated with the soil. There could be a decreasing concentration

gradient of the soil in the solution as one moves away from the surface. This could result in a

reduced mass transfer rate away from the surface. Another example is when a long pipe of

uniform diameter with a heavy soil load is cleaned using a once-through flow process. The flow

rate, and consequently the force acting on the inside surface of the pipe, may be the same at the

beginning of the pipe as it is at the end of the pipe. However, the soil at the beginning of the

pipe is constantly exposed to fresh cleaning solution while the soil toward the end of the pipe

is exposed to spent solution that is loaded with soil transported downstream through the pipe.

In this case one would expect the end of the pipe to be cleaned last or to a lesser extent. In

situations like this where it may not be easy to achieve a homogenous solution, it may be

necessary to set higher levels of cleaning parameters such as time or concentration. Surface

swab sampling of accessible worst-case areas (such as the end of the pipe in this case) is

recommended to ensure adequate cleaning and validation.

Water quality and residue

The local water quality varies from site to site, region to region and from industry to industry.

The classification of water is outlined in Table 8.1. As Table 8.1 shows, potable or ―tap‖ water

has the fewest restrictions, while water for injection has the highest quality, with limits set for

endotoxin, bioburden, conductivity, pH and total organic carbon (TOC) as defined by the

current USP Monograph for Water for Injection. Formulated process cleaners may contain

chelants that prevent the adverse effects of hardness-causing ions such as calcium and

magnesium found in some lower quality tap waters.


Table 8.1 Water quality attributes

Endotoxin Organic Inorganic Ca/Mg Salts Bioburden

Potable

x

Softened x x

De-ionized (DI) x x x

Purified (PW) x x x x

Water for Injection (WFI)

x

x

x

x

x

The quality of the final rinse should be consistent with the type of the manufacturing process

and should not introduce contaminants into the system. A water quality that is the same or

better than the water used for manufacturing is generally recommended. The final rinse water

acceptance criteria should not be arbitrarily set to the incoming rinse water specifications but

rather should be based on scientifically justifiable limits.

The quality of the pre-rinse solution varies based on the application. While some use lower

grade water that used in the wash or final rinse steps, others recycle the final rinse and use it for

the pre-rinse. Careful consideration and justification should be given to using lower grade water

as it could potentially introduce chemical, endotoxin or microbial contamination, affect the

performance of the cleaning agent, and potentially impact the maintenance of the equipment.

CLEANING METHODS

The cleaning methods commonly used in the pharmaceutical industry include CIP, agitated or

static immersion, automated parts or glassware washing, ultrasonic cleaning, and various forms

of manual cleaning. The method that is used may depend on a number of factors such as the

size and configuration of the equipment, toxicity and contamination levels, how accessible the

surface is to personnel, worker safety, desired efficiency, validatability, and overall cost. This

section provides an introduction to the various methods only to lay the framework for a

discussion in the following sections on the inter-relationships between cleaning parameters and

cleaning methods, and on equipment design.

Manual cleaning

There are various types of manual cleaning processes. Typically, manual cleaning refers to the

process of using wipes and brushes to remove the soil. This process is common to small and

large processing equipment. Manual cleaning processes can be hard to validate because they

are highly labor-intensive and have the potential for process variability due to the human


element. In a manual cleaning process, operators can focus on hard-to-clean areas and have

direct access to the equipment for cleaning and subsequent inspection. However, a manual

cleaning process will have limitations on temperature, concentration and time for

environmental health and safety reasons.

Besides wipes and brushes, manual cleaning may include the use of high pressure hoses

to dislodge residues from surfaces. Spray hoses may also be used to rinse surfaces that have

been manually scrubbed. Another manual cleaning tool is a foam applicator that dispenses

clinging foam onto vertical surfaces to provide increased wet contact time. This process may

be followed by a typical spray hose for rinsing away the foam.

In order to validate a manual cleaning process, detailed cleaning procedures must be

documented and employee training is critical. Factors such as cleaning tools, chemical

concentration, wash temperature, cleaning time, rinse time, rinse temperature and water quality

should be included in the SOP to ensure reproducibility.

Static soaking

Static soaking refers to filling the equipment with cleaning solution, or in the case of smaller

equipment or parts, immersing the surfaces in a tank, bath, or sink containing the cleaning

solution. This method is often used to pre-clean, loosen, or ―hydrate‖ the soil before manual or

automated cleaning.

Static soaking involves minimal action. During the soaking process, the very slow diffusion

of soil away from the surfaces may lead to premature saturation of the cleaner with soil at the

equipment surface interface. Even though there is minimal action, there is also less handling by

personnel, so higher temperatures, concentrations and times could potentially be used.

Agitated immersion

Agitated immersion, as the name implies, involves higher levels of mixing and flow of the

liquid across the immersed surface than static soaking. Cleaning solution can be agitated in

mixing vessels and reactors using mixing assemblies, and also to some extent in recirculation

systems. In a mixing vessel, the type of impeller, impeller diameter, mixing speed, solution

viscosity and impeller placement within the vessel are factors that affect cleaning performance.

Agitated immersion provides reproducible and consistent action during the wash step, and is an

improvement over static soaking because it replenishes the cleaning solution at the soil–cleaner

interface. However, agitated immersion generally requires an overflow of the vessel and special

attention to removing entrapped air to ensure coverage of the manway and nozzles. This

cleaning method uses a large volume of cleaning agent(s) and rinse water, and requires

excessive time to fill and drain the tank during the wash step and subsequent rinses.

Agitated immersion processes may be applied to parts by using clean-out-of- place (COP)

immersion baths. In these baths, spray jets along manifolds located below the cleaning solution

level create the agitation and turbulence as the cleaning solution is re-circulated through the

bath using a centrifugal pump.


Automated glassware and parts washing Figure 8.3 Automated washer for glassware and parts

Various automated glassware and parts washers, such as cabinet washers and tunnel washers,

are used in the industry. As with CIP systems, these are typically automated for the various

cycle steps including pre-rinse, wash, post-rinse and drying. Action on load surfaces is a result

of spray impingement (typically using rotating spray arms and spindles) and of cascading flow.

For glassware and parts washers, careful consideration should be given to the configuration of

the racks for the specific items being cleaned (f illing manifolds, process tubing, beakers,

bottles and graduated cylinders, for example). Often pre-def ined load configurations are used

when developing robust cleaning cycles, but if spindle equivalency can be demonstrated, it can

allow some flexibility in loading racks.

Ultrasonic cleaning

Ultrasonic cleaning is often used for small delicate items such as filling needles or tableting

tools. The mechanical action is caused by ultrasonic waves that create the collapsing of small

bubbles at the interface of the cleaning solution and the surface of the part being cleaned. Most

ultrasonic baths operate at a frequency in the range of 20 to 200 kHz. The frequency impacts

the degree of action at the surface. A frequency of 20–30 kHz creates a relatively small number

of large size cavities and generates intense implosions. Frequencies greater than 100 kHz are

used to generate small cavities and finer implosions and frequencies greater than 132 kHz are

used to remove sub micron particulates (Awad, 2004).


CIP processes

CIP generally refers to automatic cleaning of process equipment and piping with minimal

disassembling and manual intervention. This is achieved by flowing the cleaning solutions and

rinse water through process pipes and by using spray devices to achieve coverage in process

equipment.

CIP systems typically consist of a CIP unit, supply and return piping, and spray devices

located within the equipment being cleaned. The CIP unit, which is typically skid mounted,

includes one or more tanks, supply and return pumps, a chemical feed system, a heating system,

a process control system and instrumentation. The process equipment being cleaned must be

―CIP-able‖, and the CIP system itself should also be self-cleaning (Stewart and Seiberling, 1996).

The equipment design issues and spray device selection criteria are discussed later in this chapter.

The use of a CIP system allows for better control of the critical TACT parameters. The CIP

controller is typically able to monitor and record the parameters such as timing of the cycle

steps, temperature of the wash and rinse solutions, temperature of the CIP return solution,

conductivity and pH of the wash and final rinse solution, flow rate, supply pressure, and rotation

of the spray ball (if applicable). In addition, an automated process allows higher temperatures

and chemistry concentrations to be used with minimal risk to equipment operators.

Static soaking, manual cleaning, low and high pressure spray application methods and

ultrasonic cleaning are the cleaning methods often used for smaller parts. For larger equipment,

the most-used cleaning methods are manual cleaning, low and high pressure spray application

methods, cascading flow application methods, and foam application. The size and design of the

production equipment and the available cleaning resources often play an important role in the

selection of the cleaning method. A manual cleaning process is fairly easy to implement for

small equipment, but with larger equipment, because of increasing challenges such as operator

safety, reproducibility and labor costs, an automated cleaning method may be favored.

RELATIONSHIP BETWEEN PARAMETERS AND CLEANING METHODS

The various cleaning parameters and methods are interrelated. This allows the cleaning process

designer to increase one parameter and decrease another while maintaining the same cleaning

eff icacy. However, the relationship between parameters is not linear and can at times be quite

complex. Just because a cleaning process is validated to work does not mean that it is

optimized. For this reason, it might be valuable to investigate changes to cleaning parameters

that may lead to improvements in process eff iciency.

Case study #2

A medium-sized blood fractionation company was interested in improving the cleaning process

for one of their products. Laboratory cleaning evaluations were performed to determine the

cleaning chemistry, concentration, time and temperature required to remove the soil. The blood

fractionation product was allowed to dry on test coupons for 24 hours in a cold room prior to


cleaning to simulate manufacturing conditions. The cleaning agent used was an alkaline

detergent containing sodium hypochlorite.

The results of the test showed that the cleaning was inadequate when performed at 60°C,

with a concentration of 0.7% v/v and cleaning time of 60 minutes. However, when the

temperature was increased to 80°C, the soil was effectively removed. The data also showed that

cleaning efficiency could be improved further by increasing the concentration at 80°C to 4%

by volume. However, additional testing demonstrated that if the cleaning temperature was

reduced to ambient conditions the efficiency could be dramatically improved, as evidenced by

a reduction in the cleaning time to 15 minutes at a concentration of 0.7% by volume. These

results demonstrate the need for careful evaluation of the product soils to ensure optimal

cleaning performance.

Table 8.2 Effects of cleaning process parameters

Conc. Time Temp. Pre-clean

residue

(mg/cm2)

Post-clean

residue

(µg/cm2)

Visual

0.7 % v/v

60 min

60°C

20.8

>1

Fail 0.7 % v/v 60 min 80°C 27.5 <1 Pass 4 % v/v 30 min 80°C 27.1 <1 Pass 0.7 % v/v 15 min ambient 21.5 <1 Pass

To achieve effective, consistent cleaning, it is important to maintain the appropriate levels and

consistency in the parameters and factors that affect the cleaning process. The consistency of

these parameters and the level of use of these parameters vary with the cleaning method used.

For example, a manual scrubbing process typically uses much higher levels of ―action‖ or force

on the surface than a static spray ball system. However, since the entire surface cannot be

scrubbed at the same time, the duration of that high force or action at any given surface is a few

seconds. In comparison, a CIP system using static spray balls typically provides a cascading

flow across a side wall for a relatively longer period of time. And while a manual cleaning

process may use lower levels of temperature and less aggressive chemicals due to personnel

safety issues, a CIP spray ball cleaning could potentially use higher temperatures and more

aggressive alkaline and acidic chemicals since it is an automated process that does not require

personnel interaction. This is summarized qualitatively in Figure 8.4. We can see from this

evaluation that the TACT parameters that are set to remove residues from surfaces can vary

widely depending on the cleaning method used.

In the case of manual scrubbing, the parameter that is most impactful is the action or force

of scrubbing, which is not easy to reproduce. The other more reproducible parameters, time,

concentration and temperature are used to a limited extent. As a result, the performance is likely

to be less consistent than an automated spray application which has a more consistent action and


Figure 8.4 Comparison of cleaning parameters — manual vs. CIP

uses parameters more evenly. You can see that the quality and consistency of a cleaning process

depends on the extent and manner in which each parameter contributes to the cleaning process.

Even within the same cleaning method, particularly in large process applications, not all

surfaces receive the same combination of cleaning parameters. So, in a static spray ball CIP

application, the tangential shear force acting on the side wall of a vessel is not the same as the

points at which the spray impinges. The shear force acting in pipes is different from that in the

vessel.

The parameters may also vary during the cleaning process. For example, in a dynamic

rotating spray application, the high level of impinging force is not applied to all surfaces

simultaneously, or for the entire duration of the wash cycle. Since there may be variations in

the levels of parameters at various locations, it is important to ensure that you have designed

the cleaning process to achieve at least the minimum parameters required to clean all surfaces

down to acceptable levels. Attention to these details is very important when you are doing

laboratory cleaning evaluation studies to determine cleaning process parameters, or conducting

grouping studies and scaling the results to large-scale process applications. It is also helpful to

have a good understanding of the effects of changing the various parameters if you are faced

with troubleshooting cleaning issues.

EQUIPMENT DESIGN

An important factor in any cleaning program is the design and configuration of the equipment

being cleaned. However, the type of equipment, its accepted design, the residue acceptance

criteria, and product quality expectations vary from one application and industry segment to

another. Therefore, this section provides simply a technical basis and only general guidelines

about key equipment-related issues to consider when designing a validatable cleaning process.


The preferred process design approach is to clean all surfaces in place without the need to

disassemble and manually clean. This is possible only when the design of the process

equipment allows the cleaning solution to make adequate contact with all surfaces that need to

be cleaned. If the TACT cleaning parameters can be met across all surfaces and all the other

factors we have discussed thus far have been considered, the desired cleaning effectiveness

should be achieved. Unfortunately, many production systems are designed and integrated

without enough thought for how they must be cleaned, which leads to excessive disassembly

and manual cleaning, and consequently higher operating and cleaning validation costs. This

section discusses production equipment design considerations, most of which relate to cleaning

equipment efficiently in place. The key issues include cleaning process flow rates and coverage

in pipes and vessels, equipment design issues associated with various process equipment and

components, materials of construction, surface finish, and drainability of equipment and its

effect on cleaning process effectiveness and efficiency (Voss, 1996).

Flow and coverage in process piping

Process pipes are typically cleaned in place by flowing cleaning solutions through the piping.

Since piping is not easily subjected to visual inspection, having a consistent, validated process

that uses proper design and operating practices is key to ensuring drug product safety.

Inadequate cleaning of process pipes could be due to two general issues:

• process flow and cleaning parameters not being adequately achieved

• improper piping and instrumentation design.

Flow through pipes

At very low flow rates, the flow characteristic in a pipe is laminar. Laminar flow in a pipe is

characterized by a parabolic velocity profile as shown in Figure 8.5 with little mixing in the

radial direction. As the flow rate is increased, turbulence begins to set in when a non-

dimensional parameter, the Reynolds number, reaches about 2000 for a straight stretch of pipe.

The fluid turbulence becomes more significant as this number increases.

Figure 8.5 Laminar vs. turbulent flow in pipes


The Reynolds number can be expressed in commonly used US dimensional terms by the

equation: Q

Re = 3162 dk

where Q is the flow rate in gallons per minute, d is the inner diameter of the pipe in inches and

k is the ratio of the viscosity in centipoise to the specific gravity of the liquid flowing through the

pipe. At a minimum, the flow rate in a pipe during the cleaning process should be large enough

to result in turbulent flow. Achieving turbulent flow is important to provide adequate mixing of

the liquid. As will be discussed in more detail, merely achieving turbulent flow in a pipe may be

insufficient for providing full coverage in pipes with instruments or dead legs. A flow velocity of

at least 5ft/s (1.5m/s) is a commonly accepted guideline for cleaning piping systems.

Figure 8.6 Recommended flow velocity in pipes

The 5 ft/s velocity typically translates to a Reynolds number of greater than 30,000 or more,

depending on the diameter of the pipe. Table 8.3 outlines typically recommended flow rates of

various tube sizes. When large diameter pipes (greater than 3 inches) are involved, as in

overhead risers in an API manufacturing facility, the flow rates required to achieve a 5 ft/s

velocity could become excessive and impractical.

Table 8.3 Recommended flow rates to achieve 5 ft/s

Tube size

Outer Diameter (OD) Inner Diameter (ID) Flow Rate Inches

(in) Millimeters

(mm) Inches

(in) Millimeters

(mm) Gallons/minute

(gpm) Liters/minute

(Lpm)

0.5 12.7 0.37 9.4 1.7 6.5 0.75 19.1 0.625 15.9 4.8 18 1.0 25.4 0.875 22.2 9.4 35 1.5 38.1 1.375 34.9 24 90 2.0 50.8 1.850 47 42.8 162 3.0 76.2 2.875 73 102.0 386

Source: ASME BPE-2007 Table SD-5 Reprinted from ASME BPE-2007, by permission of The American Society of

Mechanical Engineers. All rights reserved


In such situations, the 5 ft/s velocity criterion may at times be compromised. However, careful

attention must be given to ensuring that cleaning solution coverage can be adequately achieved

across all surfaces and any air or vapor trapped, particularly in downward flowing pipes, can be

removed. If coverage cannot be achieved by fluid flow through the pipe, the pipe may need to

be cleaned using spray devices by treating it like a process vessel.

The action or shear force acting on the surface helps dislodge the residue and is therefore

an important parameter. This shear force does not necessarily directly correlate with the

Reynolds number, but is higher as the flow velocity increases. The relationship between

velocity and shear stress on surfaces can be found in text books dealing with fluid dynamics.

The effect of velocity and pipe wall shear stresses has been discussed in literature, and its effect

on the removal of bacterial spores in a CIP application has been reported (Blel et al., 2007).

When pipes include bends, valves, and tees, the cleaning effectiveness is altered. In a recent

study (Prosek et al., 2005), it was shown that the amount of residue per surface area increased

when a pipe included bends and it increased by a larger amount when a pipe included valves.

Coverage in dead legs

Dead legs are sections of tubing which lead to a discontinuity of flow, typically at a valve,

sensor or sampling port. The number of dead legs should be minimized and if dead legs are

unavoidable, the length to internal diameter ratio (as illustrated in Figure 8.7) should be 1.5 or

less. The diameter refers to the diameter of the dead leg and the length is measured from the

inside wall of the main pipe to the end of the dead leg.

Figure 8.7 Recommended L/D for dead legs

Minimizing the number and L/D on dead legs would imply seeking the shortest tees. Several

manufacturers of fittings now offer compact tees, some of which are flush with the inside of

the pipes.

The orientation of the dead legs should also be such as to allow for cleaning solution

coverage and drainage. Figure 8.8 illustrates that a dead leg orientated in upward position can

trap air or vapor resulting in poor contact of the wash solution and poor rinsing. A dead leg

orientated in the downward position would allow full coverage of the cleaning solution and the

rinse solution but poor draining. The downward orientation can allow particulates to settle as


well as offer an opportunity for microbial blooms. A dead leg with an L/D of 1.5, oriented

horizontally with a slight pitch for the dead leg to allow for draining, has been shown to allow

full coverage at a velocity of 5 ft/s.

Figure 8.8 Orientation of dead legs

Flow and coverage in vessels

Process vessels and other large pieces of equipment are cleaned typically by one of three

methods:

• by a manual method such as scrubbing or wiping

• an agitated immersion process (in vessels that have an agitator)

• or by using spray devices as part of a CIP system.

As we have discussed, manual methods are time-consuming and inconsistent. Flooding the

vessel for an agitated immersion process is undesirable because of time, expense, and waste

disposal issues. Besides, agitators are not designed to provide adequate mixing in the dome

areas of vessels and liquid coverage and mixing in those areas can be an issue.

CIP spray application is the desired method for cleaning large vessels and process

equipment. However, for CIP spray to be effective, appropriate spray devices need to be used,

along with the appropriate flow rates and cleaning parameters. In addition, the vessel should be

designed to be ―CIP-able‖.

Flow within vessels

As with cleaning piping, adequate flow rates are critical when cleaning tanks with spray

devices. For a vertical cylindrical tank, the spray device is generally designed to direct the flow

toward the manway and upper third of the vessel. Gravity then forces the cleaning solution or

rinse solution to cascade down the side walls. Typical flow rates for vertical cylindrical tanks

are 2.5 to 3 gpm per foot of vessel circumference, which corresponds to the values reported

based on the internal vessel diameters in Table 8.4.


Table 8.4. Recommended flow rates for cleaning vertical cylindrical vessels having

dished heads

Vessel Internal Diameter (ID) Flow Rate Feet

(ft)

Millimeters

(mm)

Gallons/minute

(gpm)

Liters/minute

(Lpm)

1.5 457 12–14 45–53

2 610 16–19 60–72

3 914 24–28 90–106

4 1219 31–38 117–144

5 1524 39–47 148–178

Source: ASME BPE-2007 Table SD-6 Reprinted from ASME BPE-2007, by permission of The American Society of

Mechanical Engineers. All rights reserved

For horizontal cylindrical tanks, spray device coverage is generally designed to direct the

majority of the flow to the upper third of the vessel. The wash or rinse solution then cascades

down the side walls of the vessel. An adequate flow rate for horizontal tanks as noted in the

ASME BPE-2007 is estimated by the equation:

Flow rate = 0.1 to 0.3 gpm per ft2 of total internal tank surface (4–12 Lpm per m2)

Full coverage from the spray devices and suff icient flow rates are needed to ensure the

cleanability of horizontal and vertical vessels.

Spray devices

Spray devices are used in a CIP system to provide full coverage of the wash or rinse solution

of the surface being cleaned. The type and number of spray devices and location of the devices

within the equipment can affect the coverage and impingement pressure. There are two general

types of spray devices — f ixed and rotary.

A f ixed or static spray device has no moving parts and the holes are generally positioned

to allow upward spray on the top of the vessel, allowing the wash or rinse solution to cascade

down the sides of the vessel. The advantages of fixed spray devices are that they are less

expensive than rotary devices, can be made completely of one type of material (stainless steel,

for example) and generally require less maintenance. They are minimally affected by high

temperature, operate at lower pressures, are self-cleaning and draining, and provide continuous

coverage during operation. The disadvantages to fixed spray devices are that they have limited

radial throw, low direct impingement and require high flow rates.

Rotary or dynamic spray devices have moving parts and are available in a number of

designs for operation at high pressure and low flow rates, or at low pressure and high flow rates.

High pressure dynamic devices can provide significantly higher impinging forces to dislodge


tenacious soils from surfaces and can potentially reduce cleaning time and the amount of water

used. Due to the complexity of the design, these are more expensive than fixed spray devices,

may require increased maintenance, and may develop clogged holes if used indiscriminately in

heavily soiled equipment. Some, but not all units are designed to be cleanable, self-draining,

and to withstand high temperatures. Rotary spray devices may be made of several different

materials, so their documentation should be reviewed to ensure compatibility with specific

cleaning agents. The rotary spray devices provide only an intermittent spray during operation

but offer larger radial throw lengths and higher impingement compared to fixed spray devices

(Tamplin, 1980).

Figure 8.9 Spray devices

Fixed spray balls

Rotary spray devices

Photos of spray devices courtesy of Alfa Laval Inc.

Spray coverage testing

Achieving complete spray coverage of the cleaning solutions across all surfaces of a piece of

equipment or system is critical to cleaning and validation. For this reason, coverage testing is

often specified in the functional requirement specification (FRS) of a new piece of equipment

or when instruments are added. If practical, the coverage testing should be performed during

the factory acceptance testing (FAT) and verified as part of the site acceptance testing (SAT)

or the operation qualification (OQ). Coverage testing is typically performed using riboflavin

(vitamin B2) as a visual indicator for coverage. Riboflavin is readily available, relatively non-

toxic, and fluoresces well under UV light.

A simple riboflavin coverage test procedure:

1. Prepare a 0.2 gram per liter riboflavin solution in water (riboflavin is light sensitive so

store in an opaque bottle or wrap in aluminum foil). Solution should be made fresh.

2. Transfer riboflavin solution to spray bottle.

3. Spray riboflavin on all internal contact surfaces. If the solution is allowed to dry to

represent a worst case, it must be noted that riboflavin has limited fluorescence when dry.


4. Perform a short rinse cycle with water. The duration of the final rinse step is often used as

a guideline for determining the duration of the coverage test.

5. Use a UV light to inspect internal contact surfaces for indications of poor coverage. Areas

that do not receive adequate coverage will display a yellowish green fluorescence.

Riboflavin testing may conf irm the coverage of the spray balls under the operating parameters

of pressure and flow rate, but may not necessarily verify cleanability. In fact, coverage is only

one minimum requirement for any cleaning process. The testing only shows that the necessary

coverage and action or force required to remove riboflavin has been achieved across all surfaces

under the parameters and conditions of the coverage study. The drug product residue may be

more tenacious than riboflavin, and may require higher levels of action or force. For effective

cleaning, the other cleaning parameters of time, cleaning chemistry concentration and

temperature need to be established based on the worst-case coverage or action achievable. Also,

since the riboflavin is applied manually and uniformly across all surfaces, the worst-case

locations identified in a riboflavin study do not necessarily match the worst-case locations of

production, where the actual residue may be more tenaciously adhered. Tenaciously soiled

locations may include air liquid interface in the production process, or other specific locations

in the equipment that may have higher soil levels or where the soil may be excessively dried or

baked on due to heat jacketing. Nevertheless, a riboflavin study has its value in that a test

failure does identify locations that have coverage issues.

Vessel inserts and openings

Inserts in equipment should be designed to facilitate cleaning and draining. Areas of concern

include tank manways, impellers, impeller shafts, mixing assemblies, baffles, screens, sparge

tubes, sampling ports, housings and other assorted components within the system.

Figure 8.10 Shadow areas in vessels

Side view Top view


Nozzles that are designed for cleaning by spray should be located near the spray devices, have the

smallest L/D ratio possible, be oriented to allow drainability, and have seals that are flush to the

side walls. Also, domed vessel tops allow better coverage and drainability (ASME, BPE 2007).

Inserts such as baffles and impellers should be designed with rounded curves, and be

sloped to allow free draining and full coverage by the spray balls. When ―shadow areas‖ are

created as illustrated in Figure 8.10 due to agitator shafts, baffles or other inserts, multiple spray

devices may be necessary. Fasteners, screws and bolt mountings should be avoided. Horizontal

mixing assemblies may require special attention in the cleaning cycle design. A spray ball can

be mounted under the impeller to provide direct spray to the bottom of the impeller, or the

impeller can be submerged during the wash and rinse steps for thorough coverage.

Vessel drains should be sized to ensure that the flow rates necessary to clean the vessel

can be handled. The discharge should flow through the drain without a liquid level build-up

during the cleaning cycle. In some situations, a vortex breaker may be necessary at the drain to

minimize vortex formation and air ingress into the drain pipe.

Component selection

Components include a wide selection of items connected or associated with the process

equipment. Examples of components are seals, valves, instruments and in-line sensors,

pumps, centrifuges, f ilter housings and membranes, chromatography columns and resins,

f illing equipment, and neutralization and bio-waste systems. In addition to designing them

for functionality, these components should also be selected and designed for eff icient

cleanability. The cleaning solution flow rates, temperatures and chemical compatibility of the

component materials should be examined for optimal in-place or out-of-place cleaning.

Surface imperfections, crevices, dead legs, and horizontal non-drainable areas should be

eliminated or minimized.

Seals should be selected based on cleanable design. Elastomeric gaskets and O rings

should have minimal thermal expansion and extrusion into the process stream (Simco, 2002).

The requirements for the medical device applications are specified in USP <87> and USP

<88>, which define six classes of polymers (Class I–VI), the type of testing, and specific test

methods for each polymer class. The USP Class VI is the preferred class for biopharmaceutical

applications (Hutton, 2006).

Diaphragm valves are commonly used for critical process applications since these are CIP

cleanable and they isolate the process fluid from the valve stem assembly. While the weir-style

diaphragm valve is the industry standard, other newer radial diaphragm valves may be suitable

where cleanliness is critical (Bridge, 2007). Other valves such as ball and butterfly valves are

used in API manufacturing or for utilities of pharmaceutical manufacturing. However, these

types of valves have crevices where residue can adhere and be difficult to remove. They may

require manual cleaning intervention, depending on the design and application.

Instruments and in-line sensors such as pressure relief valves, rupture disks, air spargers,

load cells, pressure sensors, pH probes, temperature probes, dissolved oxygen probes, ultraviolet

cells, site glasses, sampling ports, air detection and conductivity probes should be appropriately


designed for CIP applications and be compatible with cleaning agents. The position and design

of the instruments and in-line sensors should be such that crevices and dead legs are minimized.

When possible, direct mounting and properly sized sanitary connections are best.

Peristaltic, centrifugal, rotary lobe and diaphragm pumps are common CIP-cleanable

devices. The positive displacement pumps (peristaltic, rotary lobe and diaphragm) are

commonly used in pharmaceutical manufacturing because they are generally low shear, have a

low flow rate and offer precise flow. The peristaltic and diaphragm pumps offer an advantage

over the rotary lobe pump in that the pumped fluid is not in contact with the mechanical seal.

The peristaltic tubing and diaphragm seals can also be easily replaced during preventative

maintenance or change-over. The centrifugal style pumps are used in high flow rate applications

when increased shear forces are not a concern and when non-pulsating flow is desired.

Various types of centrifuges are used in the industry, including solid bowl, perforated bowl

and disk centrifuges. The chemistry of residues on centrifuge surfaces can vary due to the

separation of solids during the spinning process. They can also be more tenaciously adhered to

the surfaces. While some centrifuges are designed for CIP cleaning, others may require manual

disassembly and/or valve sequencing during cleaning to ensure coverage and turbulent flow

through the lines.

Filter housings and membranes need special attention during cleaning. The ―in-line‖

housing is preferred because it is easier to clean, but it is generally easier to change filters in

the ―tee-style‖ housings. The cleaning process for re-usable filter membranes found in

microfiltration (MF), ultra-filtration (UF) and ultra-filtration/diafiltration (UF/DF) cassettes or

hollow fiber cartridges varies with the chemical and physical properties of the membrane

materials. It is important to note that substrate compatibility testing must be performed for a

cleaning agent with a specif ic filter membrane if it varies from the filter manufacturer’s

cleaning recommendations. A measurement of the trans-membrane pressure (TMP) and

normalized water pressure (NWP) before processing and after cleaning can be used in addition

to rinse water analysis, to ensure successful cleaning.

The cleaning of chromatography columns depends on the coverage of the cleaning and

rinse solutions along the column and bed supports at the bottom of the column. The bed support

(diffuser, support screen and gasket) should be made of materials that are compatible with the

cleaning agents and temperatures being used during the cleaning process. For manual cleaning,

these parts may be cleaned in an ultrasonic bath. The chromatography resin must either be

disposed of or cleaned to ensure reproducibility during subsequent uses. Often separate cleaning

agents are used for cleaning the chromatography column and resin, or the resin is removed and

cleaned separately from the column. The compatibility of the resin with the cleaning agent needs

to be checked before cleaning. If the resin is to be cleaned and re-used, the number of re-use

cycles must be determined as a function of the cleaning process (Sofer and Yourkin, 2007).

Filling equipment generally requires some out-of-place cleaning, whether it is the entire

filling line from feed tank to needles or just the needles, manifolds and valves. For CIP-designed

filling lines consisting of a feed tank, filling reservoir, needle manifold, needles, associated

piping and filling lines, there should be sufficient spray coverage in the reservoir tank, adequate

flow through the needles without clogging, and coverage on the outside of the needles.

Automated washers, ultrasonic baths and manual cleaning can be used in lieu of CIP cleaning.


Neutralization and bio-waste systems should periodically be cleaned to remove any

organic residues, mineral deposits and/or rouge on the surface of the vessels that may cause

equipment failure or surface corrosion.

Other components should be designed and/or selected for functionality, material

compatibility to cleaning agents and cleanability. Components that have been designed for CIP

are preferred; however, alternative cleaning methods discussed earlier can be effectively used

for cleaning the components out of place.

Surface type or materials of construction

Materials of construction should be capable of withstanding the process, cleaning and

sanitization/sterilizatio n conditions, including temperature, pressure and chemical

corrosiveness. Common materials for pharmaceutical, biopharmaceutical, cosmetic and

neutraceutical industries are 316, 316L, and 304 stainless steels. Glass-lined or hastelloy

reactors are also commonly used in the small-molecule API industry. In the tableting or solid

dose industry, other metals including hardened steels such as S-7 and D-3 (which are

susceptible to flash rusting) may be encountered. In the medical device industry, aluminum

and titanium trays and tools may be used. Special considerations and techniques need to be

incorporated into the handling and cleaning of these various materials.

Stainless steels (304, 304L, 316 and 316L) and higher grade alloys, when thoroughly

cleaned, have the ability to self-passivate (form a protective layer on the surface). This

protective layer has high chromium to iron ratio, which reduces corrosion. Contaminants or

imperfections in the material can inhibit the formation or affect the quality of the passive layer.

Nonmetallic surfaces composed of materials such as EPDM, silicone, PTFE,

polypropylene, high density polyethylene, low density polyethylene, polysulfone and

polyurethane can wear over time, depending on the process and cleaning conditions. They

require regular inspection to assure that the material is functioning as intended and does not

contribute to contamination of the drug products.

The surface type and material of construction can also be a factor in product or cleaning

agent recovery studies. Researchers collected swab recovery values of different products and

cleaning agents from 16 different manufacturing sites. They found that the materials of

construction can be categorized into groups and that stainless steel could serve as representative

material for most materials used in drug product manufacturing (Forsyth et al., 2007).

Case study # 3

A large manufacturer of solid dose pharmaceuticals produced several products on the same

piece of equipment. The manufacturer reported that their alkaline cleaner was discoloring the

punches. They currently used a three-tank ultrasonic cleaner to clean the tableting tools. The

tableting tools were made of S-7, D-3 and 440C stainless steel alloys.


A different milder alkaline detergent system (1% solution pH ~ 9.6) was evaluated in

bench-top experiments on punches to demonstrate cleaning performance and confirm substrate

compatibility.

The following procedure was implemented.

1. One quart of detergent is added to 40 gal of water and heated to 125°F (52 °C) in the wash

tank.

2. A basket of tooling is placed in wash tank and sonicated for 2.5 minutes.

3. The basket automatically cycled to the rinse tank and rinsed for one minute at 120°F

(49°C).

4. The basket is passed to a drying chamber and dried for five minutes at 135°F (49°C).

5. After the drying cycle, all parts are wiped with an isopropyl alcohol solution.

The surfaces of the punches were thoroughly inspected and swabbed and showed no sign of

discoloration or corrosion.

Surface finish or roughness

Product contact surfaces should be free of corrosion, scratching, etching, crevices, obvious

pitting and engravings or embossing. Such irregularities on the surface allow for soil to

penetrate and adhere to the surface, making it harder to clean. For optimal operation and

cleanability, the interior surfaces of equipment pipes should be smooth and free of weld

defects. Welding should be performed according to an agreed standard, and each weld should

be inspected to ensure that the standard is met. Orbital welding equipment should be used by a

certified welder, and coupons prepared to verify parameters. Completed welds should be

inspected and documented on the weld part and piping drawing (Purnell, 2003).

As discussed in Chapter 7, formulated cleaners may contain surfactants that decrease the

surface tension of the cleaning agent, which improves the wetting characteristics and aids in

soil removal from irregular surfaces.

For very smooth surfaces with a low Ra rating, the effect of surface roughness on

cleanability is controversial. In one published study, surfaces with the lowest roughness (2B or

less) were among the easiest to clean and residual soil levels were more closely related to

surface defects than mean surface roughness. In addition, surface roughness did not correlate

with biofilm removal (Frank and Chmielewski, 2001). Another recent study suggested that

stainless steel surface roughness in the range of 0.01 to 3.3 um Ra had no signif icant influence

on cleanability (Riedewald, 2006).


DRAINABILITY AND RINSING

The process equipment, components and instruments, associated piping and the CIP system (if

used) should be designed for complete draining. Internal angles should have the maximum

radius possible for easy cleaning. Piping should be pitched, nozzles sloped, manways and

bottoms domed, and dead legs oriented horizontally with appropriate pitch to allow full drainage.

The preferred pitch in piping is 1/8 inch per foot, but as little as 1/16 inch can allow good

draining. If flexible hoses are used, they should be supported and sloped for drainability. In

temporary runs, the flexible hoses can be removed and manually drained. The piping should

also be designed to limit wide variations in diameter, which can affect the flow rates and overall

system design.

If complete coverage is not achieved, the soil or cleaning agent may not be completely

rinsed off in the cleaning process. If the rinse water concentration during the rinsing process is

plotted on a log scale against the rinse volume or time, the resultant plot can provide insight

into the efficiency of the cleaning process (Verghese and Lopolito, 2007). A straight line plot

implies that the entire cleaning agent present in any subsequent rinse only comes from the

presence of the cleaning agent in the small amount of solution at a higher concentration left

behind on equipment surfaces from the previous rinse. If equal rinse volumes are used for each

rinse cycle, the dilution factor between rinses is approximately a constant, thus exhibiting itself

as a straight line concentration profile on a log scale. The more easily drainable the process

equipment is, the steeper the slope on this plot.

An air-blow is used in some systems between the wash cycle and the rinse cycle to speed

the drainage of the wash solution. Such air blows are effective in reducing the rinse water usage

and the overall cleaning time. However, if the air-blow is overdone, there may be a risk of the

cleaning agent and entrained process soil drying onto the surface. This could occur particularly

in the upstream sections of pipes through which the air is blown. Such excessive air-blow could

be detrimental to the overall efficiency and efficacy of a cleaning process. Strategies to

optimize the air-blow have been discussed in the literature (Verghese and Lopolito, 2007;

Howard and Wiencek, 2004).

SYSTEM INTEGRATION AND DESIGN

Sanitary design of the equipment and cleaning circuits is just as critical as the selection of

cleaning chemistry and optimization of the cleaning parameters. Once the process and soil

residues have been defined, careful consideration should be given to reviewing the sanitary

equipment design. This will involve a review of the P&ID and equipment walk-down to verify

cleanable design. It also includes verification of wetted components to ensure the chemical

compatibility of the cleaning solutions and to assure that sloped bottoms of tanks, sanitary valves,

dead legs, pitched pipes and inserts/ports have been installed to facilitate cleaning and draining.

The engineering design of the equipment and related instruments must assure full contact

of the wash and rinse solutions. Equipment cleanability assessment should be planned for early

on in the project when configuration changes are easier to make. Factors that affect cleanability


include minimizing and properly orientating dead legs and horizontal areas, and selecting

instruments designed for easy cleaning.

In CIP cleaning, the selection of the cleaning circuits and path are important to

maximizing cleaning efficiency. Some paths need to run in series but others can run in parallel,

which will reduce the cleaning time. The CIP and process piping are interdependent, and

eff iciency in design can be best achieved if CIP is designed into the facility from the beginning

(Forder and Hyde, 2005).

SUMMARY

Designing an effective, efficient and compliant cleaning validation process requires close

attention to the selection and control of cleaning parameters and to equipment design constraints.

To optimize the process, it is helpful to have an understanding of the cleaning process parameters

and factors, the soil condition, and other related factors and their effects on cleaning

performance. The relationship among the various cleaning parameters and methods, and the

ways in which they interact, is also important. Parameters such as time, action, concentration and

temperature have an associated fixed or variable cost, which is an important consideration for

any industry. Investing in a fixed cost of providing higher levels of impingement could

potentially reduce operating costs resulting from the cleaning agent concentration. In contrast,

reducing cleaning time, particularly in plants that operate at high capacity utilization levels,

could also result in very significant cost savings. Finally, equipment design has a significant

effect on cleaning parameters, fluid flow and coverage, drainability, rinsing, and efficiency, and

may also have an impact on cleaning process design and its most efficient application.

REFERENCES

ASME BPE-2007 Bioprocessing Equipment, pp. 8–47.

Awad, S.B. (2004) Aqueous ultrasonic cleaning and corrosion protection of steel components.

Metal Finishing, Sep. 2004, pp. 56–61.

Blel, W., Benezech, T. et al. (2007) Effect of flow arrangement on the removal of Bacillus

spores from stainless steel equipment surfaces during a cleaning in place procedure.

Chemical Engineering Science, Vol. 62, pp. 3798–3808.

Bridge, M. (2007) Optimizing cleanliness and drainability. Pharmaceutical Manufacturing,

Oct. 2007, pp. 44–47.

Forder, S. and Hyde, J.M. (2005) Increasing plant efficiency through CIP. International

BioPharm, Feb.

Forsyth, R., O’Neill, J.C. and Hartman J.L. (2007) Materials of construction based on recovery

data for cleaning validation. Pharmaceutical Technology, Oct., pp. 103–116.


Frank, J.F. and Chmielewski, R. (2001) Influence of surface finish on the cleanability of

stainless steel. Journal of Food Protection, Vol. 64, No 5, pp. 1178–1182.

Howard, T. and Wiencek, M. (2004) Biotech CIP cycle development, Pharmaceutical

Engineering, Sep/Oct, pp. 20–30.

Hutton, T. (2006) Highlights of ASME BPE Subcommittee Report on Polymers and

Elastomers. Ultrapure Water, May/June, pp. 26–29.

LeBlanc, D.A. (2000) Validated Cleaning Technologies for Pharmaceutical Manufacturing.

USA: Interpharm Press. pp. 73–103.

Purnell, S. (2003) Installing clean process lines. Pharmaceutical Technology Europe, Mar, pp.

47–50.

Prosek, M., Krizman, M. and M. Kovac (2005) Evaluation of a rinsing-based cleaning of process

for pipes. Journal of Pharmaceutical and Biomedical Analysis, Vol. 38, pp. 508–13.

Riedewald, F. (2006) Bacterial Adhesion to Surfaces: The Influence of Surface Roughness.

PDA J of Pharm Sci and Technol., Vol 60, No 3, pp. 164–171.

Simco, D. (2002) The effect of thermal cycling on seals in ball valves and clamp type fittings.

Pharmaceutical Engineering, Nov/Dec, Vol 22, No 6.

Sofer, G. and Yourkin, J. (2007) Cleaning and Cleaning Validation in Process Chromatography.

Bioprocess International, Nov. 2007, pp. 72–84.

Stewart, J. C. and Seiberling, D.A (1996) Clean in place. Chemical Engineering, Jan., pp. 72–79.

Tamplin, T.C. (1980) ―CIP —Technology, Detergents and Sanitizers‖ in Hygiene Design and

Operation of Food Plant, R. Jowitt (ed.). AVI. Westport, Conn.

Verghese G. (1998) ―Selection of Cleaning Agents and Parameters for cGMP Processes‖,

Proceedings of the INTERPHEX Conf, Philadelphia, Reed Exhibition Co, Nor walk, CT,

pp. 89–99.

Verghese, G. and Lopolito, P. (2007) Process Analytical Technology and Cleaning.

Contamination Control, Fall 2007, pp. 22–26.

Voss, J. (ed) (1996) Cleaning and Cleaning Validation: A Biotechnology Perspective, Bethesda,

MA, PDA, pp. 1–39.

ABOUT THE AUTHORS

Paul Lopolito is a technical services specialist for the Life Sciences Division of STERIS

Corporation (Mentor, Ohio). He provides global technical support for critical environment and

process research cleaners, which involves field support, site audits, training presentations and


educational seminars. Paul has 13 years of industry experience supporting cGMP/ISO regulated

facilities and has held positions as a technical services manager, manufacturing manager and

laboratory manager. He has specific expertise in managing cross-functional projects related to

process cleaning and critical environment operations in biopharmaceutical and biomedical

industries. He holds a B.A. in Biological Sciences from Goucher College in Towson, MD.

George Verghese is director of technical services in the Life Sciences Division of STERIS

Corporation (Mentor, Ohio), a global provider of contamination and infection control products,

systems and services. He manages the technical services group for formulated chemistries and

oversees the Process and Cleaner Evaluation (PACE) Laboratory. Mr. Verghese has worked in

the areas of manufacturing, product and applications development, and technical services for

more than 20 years. Prior to STERIS, he held engineering positions at Bristol-Myers Squibb and

Calgon Vestal, a subsidiary of Merck & Co. Mr. Verghese has written numerous articles on

topics related to contamination control. As a speaker at industry conferences, he has lectured to

pharmaceutical industry audiences worldwide on various aspects of process equipment design

and cleaning validation. He holds a master’s degree in chemical engineering from the University

of Kentucky and is a member of the International Society for Pharmaceutical Engineering, the

Parenteral Drug Association, and the American Society for Testing and Materials.

Documents

CLEANING ENGINEERING AND EQUIPMENT DESIGN