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How to Specify Equipment for High-purity Processes
Choosing the right combination of pumps, valves and seals is a crucial step in the design of fluid motion and control systems for the pharmaceutical and biotech industries.
Specifying the proper equipment and ensuring that this equipment works together
in an efficient system can yield virtually contamination-free operation in high-purity
processes. Coupling the right system of pumps, valves and seals with highly trained
plant personnel will ensure successful operation for applications that demand
the highest levels of purity and safety.
In the pharmaceutical, biotech and food processing industries, ingredients are
transported, mixed, heated and cooled assuming the assurance of product purity
required by law and taken for granted by consumers. Process systems for these
industries require a level of purity not found in other applications, so implementing
the right systems of pumps, valves and seals is vital.
Specifying the right combination of
pumps, valves and seals is the key to operating a successful pharmaceutical
or biotech plant. |
The inherent problems linked to high-purity processes can all be traced back to
one root cause: contamination. Any “dead cavities,” corners, seams or obstructions
that exist in processing equipment could produce potential areas for bacterial
growth. For example, a poor surface finish contains microscopic peaks and valleys
that can lead to unnatural biofilm buildup — the formation of a thin layer of
surface bacteria. Also, leakage causes improper mixtures of ingredients, which
in turn allows unwanted chemicals to violate the system. Other potential problems
include rusting, particle generation and oil and grease contamination.
High-purity equipment must stand up to harsh cleaning procedures — from heated
steam to caustic sodas and light acids — without compromising either the integrity
of the product or the equipment itself. Surface finish must be tightly controlled
and dead cavities must be limited so that the flow of the cleaning agent can reach
all parts of the system. This process makes cleaning procedures more effective.
Specify Pumps with Polymers for Clean Operation
The key to the design and selection of pumps for high-purity process applications
is the ability to withstand high temperatures, high pressures and corrosive liquids
while maintaining clean operation and minimizing contamination. Pumps are available
in a variety of shapes, sizes and configurations, but certain factors must remain
constant for any high-purity application.
All wetted surfaces that come in direct contact with the flow of a high-purity
pump must be manufactured from materials that will not corrode, rust or generate
particles during severe with superheated steam or other harsh chemicals. Pumps
that are constructed (or lined) with PFA or PTFE polymers have a higher resistance
to corrosion, lower reactivity and better surface finish properties than pumps
designed using metal alloys or glass. Studies show that accumulated normal biofilm
buildup is far easier to remove from these materials than from stainless steel
or other alloys. Polymers do not rust, offer very low particle generation, and
are inherently pure without the need for refining steps (i.e., electropolishing
and passivation) other materials require. Since the introduction of the first
fully lined PTFE chemical process pump in 1968, polymers continue to provide the
safest, most cost effective solutions for pump materials.
Metallurgy Makes All the Difference for Clean Valves
Example of a sanitary valve widely
used in pharmaceutical and biotech applications. |
The first step in choosing a valve for a high-purity application is to select
the right valve type. Diaphragm valves are by far the most common design of choice
for high-purity industries; their geometry does not trap or contain media, preventing
contamination and cross-contamination and facilitating system clean-up. However,
in some applications, such as fermentation, sterile steam and freeze-drying systems,
ball valves are preferred over diaphragm valves. That’s because they eliminate
catastrophic seat failure, possess better flow characteristics and provide higher
pressure and temperature limits, which can lead to higher system output, improved
efficiency and a much longer cycle life.
After specifying valve type, metallurgy and surface finish preparation are arguably
the most important factors to ensure valve integrity. Clean valves should be forged
316L stainless steel with tightly controlled chemistry and surface finish. Cast
materials are more apt to have exposed pits, inclusions and other imperfections
as their surface finish deteriorates over time.
Valve end connections, called pipe ends or tube ends, should be specified with
a sulfur content between 0.005 and 0.017 percent to meet ASME guidelines and allow
for clean, contamination-free welds for tube bore systems, where all valves are
welded in place. The concentration of ferrite should be less than 5 percent to
prevent an iron film from forming (rouging) on stainless steel surfaces in high-purity
water and steam systems. Some companies recommend less than one percent ferrite
concentration, but this issue is still up for debate. Many studies are showing
that rouging is more closely linked to metal preparation and content of gas atmosphere
in the system than to ferrite concentration.
High purity seals for mixer and agitator
applications have all secondary O-ring seals placed and designed for SIP
and CIP. |
Surface finishes need to be tightly controlled on all wetted surfaces of the valve
through procedures such as electropolishing and passivation. Electropolishing
is the method of passing DC current (approximately five amps) through the metal,
causing the high points of the machined surfaces to be chemically removed. Passivation
is the chemical process used to form iron oxides and chromium oxides on the surface
of the metal to promote chemical resistance to the water or other products. For
high-purity processes, valves that have surface finishes with an Ra of no more
than 20 microinches AARH minimize biofilm buildup, while electropolishing can
reduce the Ra to fewer than 10 microinches. However, electropolishing is more
expensive and not always required for every application.
Inside diameters of the valve components should be chosen with tube bore dimensions
that precisely match the connecting tubing so as to prevent stagnant areas of
water, or “puddles,” from forming in the valve. If these puddles occur, they can
harbor microorganisms and provide a starting point for biofilm buildup. Seats
should be specified as PTFE, reinforced PTFE or Flurofill to ensure bubble-tight
shutoff through the valve without corrosion, even under conditions of high-vacuum
and high-cycle operation.
When installing a valve, one must ensure that it will not introduce any new contaminates
into the system due to manufacturing, transportation or final installation. To
prevent this, valves should be assembled in positive-pressure clean rooms, tested
with helium, double-bagged and sealed to ensure the highest level of cleanliness.
Pre-test Seals to Ensure High Purity
Clean tube bore stainless steel ball
valves are ideal for use in fermentation, sterile steam and freeze-drying
systems. |
When Regeneron Pharmaceuticals, Inc. purchased a new mammalian bioreactor skid,
a vessel used for biological growth and reactions, the company had the same high
expectations that surround any major process improvement. However, Regeneron ran
into some problems when the design of the OEM bottom-entry agitator seal failed
to meet the sterilization requirement for the process. The sterilization of the
interior vessel bore was absolutely essential, but the inner seal was allowing
vapor to enter. The result: Seal integrity was compromised.
To solve this problem, Regeneron installed a custom dual mechanical seal with
a secondary sealing device that would ensure sterilization of the interior vessel.
A customized model of a dual cartridge seal was successfully designed that mounted
directly to the gearbox and bioreactor’s mounting pad. This model maintained absolute
containment of the clean steam condensate during each phase of production.
Examples such as this demonstrate the importance of choosing the right seals when
purity and sterilization are crucial. Seals with gland rings that do not need
to be threaded or ported minimize areas for bacteria to hide. Any threads or sharp
corners can create cavities that cleaning procedures used by major processing
plants cannot reach. Implementing electropolishing and passivation on all wetted
surfaces of the seal makes it much easier to prevent bacterial growth and carry
over that might occur down the line.
Pre-testing can also help to maintain the integrity of the seals for sterile operation.
For example, a large pharmaceutical company in Chicago tests small, one-inch seals
in a laboratory with bacteria to ensure that the seals are compliant with their
purity standards before they are put into operation.
Some seals are manufactured with complete cartridges that can be aerostatically
pressure-tested to ensure integrity before installation. These types of preliminary
testing methods ensure that no defects or contamination occur between manufacturing
and final installation.
Keep in mind that safety and sterilization are not the only concerns for seals
in high-purity processes. Certain consumer products have aesthetic characteristics
that are familiar to the consumer, such as the white color of aspirin tablets.
A seal used in the production of aspirin may have a soft carbon face rubbing on
a hard face, giving off a black carbon residue that can change the color of the
aspirin. Even though the carbon is inert and perfectly safe, consumers would feel
uneasy about buying discolored aspirin tablets. To allay this concern, clean seals
in these types of applications should always be specified with a sanitary gland.
The gland filters out the carbon molecules, which are collected and flushed out
of the system. Doing this ensures a consistent product that is both safe and aesthetically
pleasing to customers.
Set Up Cleaning Systems
No matter how well the equipment works, the inevitable buildup of bacteria and
other contaminates in any system is unavoidable. High-purity systems use batch
processing and specialized cleaning systems to combat this problem. During batch
processing, a certain amount of product is created. Next, the entire system is
cleaned with heated steam or light acids before production resumes. This process
prevents any carry over of dirt and bacteria between batches of product. Common
cleaning systems include Steam In Place (SIP) and Clean In Place (CIP), where
heated steam and light acids or caustic sodas are used to flush any contaminates
out the system.
CIP and SIP cleaning methods safeguard public safety by preventing cross-contamination
and keeping purity to acceptable levels. They prevent batch losses and enable
sterilization-in-place by removing dirt deposits that impede mass transfer of
steam to all wetted process surfaces. These cleaning methods can also protect
capital investment in equipment by preventing crevice corrosion that occurs when
an impervious layer of dirt impedes maintenance of the passive metal oxide surface
on stainless steel.
To ensure sterilization, a typical cleaning cycle should include the following
steps: • Pre-rinse with cool saline solutions to reduce the dirt load. •
Decontamination through steam or other caustic materials. • Intermediate rinse.
• Acid-wash to solubilize precipitated materials. • Final rinse to remove
all traces of cleaning agents.
Keep Your Equipment Up to Code
click the image to enlarge
Clean in Place (CIP) or other cleaning systems should be used in
high purity processes to flush all contaminates out of the system between
batches. |
Equipment specified for clean operation must be chosen to conform to certain standards
set forth by organizations such as the American Society of Mechanical Engineers
(ASME), the American National Standards Institute (ANSI) and the International
Organization for Standardization (ISO). In food and pharmaceutical applications,
pumps, valves and seals should also comply with U.S. Federal Drug Administration
(FDA) regulations.
More specifically, clean valves should be specified to conform to ASME BPE (Bioprocessing
Equipment) standards for metallurgy and should meet the specifications of USP
Class 6 set by US Pharmacopoeia for elastomers used in seat materials. US Pharmacopoeia
forms the basis of enforcement actions by the FDA. For high-purity seals, P3-A,
a pharmaceutical standard organized by 3A Sanitary Standards, Inc., has become
widely accepted.
High-purity systems also need to be validated, which can put a large administrative
burden on companies to cross-reference all paperwork with Certified Material Test
Reports (CMTRs) on key components of each piece of equipment. Choose pump, valve
and seal manufacturers that include simplified codes on each piece of equipment
with four critical traceability requirements, easily read and cross-referenced
by an inspector to save time and money on exhaustive paperwork.
The goal of these standards and validation requirements is to increase the efficiency
of the development, manufacturing and supply of products and services while maintaining
safety for consumers. Different standards exist for various applications, and
it is always a good idea to consult an expert when choosing equipment to meet
these regulations.
Complement Training with Experienced Personnel
Once a system of pumps, valves and seals is specified, one critical question still
remains: Who will install, operate and perform maintenance on this equipment?
No processing system is complete without highly trained plant technicians who
can ensure safe and efficient operation of all parts of the system. Often, the
most effective way to achieve this level of efficiency is to implement training
programs for current employees, as well as hiring a few key personnel. The knowledge
and expertise brought in by the new hires will complement current employees’ intimate
knowledge of plant equipment.
When specifying equipment, consult engineers or other experts in fluid motion
and control to ensure that the right equipment is being purchased for each respective
application. High-purity processes are very specialized, and different applications
include varying pressure and temperature requirements, materials, standards and
levels of sterility. No single pump, valve or seal is suitable for every application.
Designing systems to process pharmaceutical and biotech products requires a high level of purity that will only increase with new technology and applications. As equipment and standards for high-purity applications continue to evolve, knowledge of available options becomes even more important. With the right system of pumps, valves and seals operated by well-trained technicians, any plant can meet and exceed these heightened standards and produce a consistent, pure and safe product.
Pharmaceutical Processing
Advantage Business Media
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