PRINCIPLES OF DESIGN - STERILE BULK APIS

General
Particles present in solid, sterile drug substances are characterized as either viable or nonviable. The methodology for controlling these are both related.
Simply stated, the goal is to maintain sterility, prevent the ingress of particles, and ensure that
the processing system itself does not produce particulates.
A typical method of producing a sterile a sterile API is the recrystallization of a drug substance,
sterile filtration, and isolation/drying in an agitated Nutsch filter. Following are some of the
design approaches that apply.
Internal Finish
Ensure product contact surfaces of equipment satisfy the following criteria:
a)
b)
c)
d)
e)
f)
g)

Inert
Non-porous
Non-shedding
Crevice free
Self draining
Readily cleaned
Readily inspected

This usually results in the specification of either 316L SS or glass lined vessels.
Additionally, if the equipment must provide for disassembly, then the following requirements
should also be satisfied:
h) Minimum number of component parts
i) Shake-proof fastenings
Mirror polish (BS1449 No. 8) or Electropolish finish are often specified for internal finish, but the
high degree of surface finish obtained by grinding and buffing does not necessarily result in the
most readily cleaned surface. Very fine scores which can harbor microorganisms may be left by
a poorly executed grinding and buffing process.
Experience has shown that the use of rouge (iron oxide) for polishing should not be allowed as it
will continue to shed particulates over years.
Electropolish is standard with most products as any irregularities remaining are more rounded,
giving better cleanability.

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External Finish
The external finish of equipment depends on the classification of the room or area in which it is
to be located, i.e., Clean Rooms (e.g., parenteral pharmaceutical processes) require stricter
building finish than hygienic areas (e.g., fermentation processes) within.
Room classification must be specified both realistically and before equipment specification to
ensure that cost penalties are not incurred through over specification of equipment finish.
In general, all exterior or non-product contact surfaces should be arranged to prevent harboring
of soils, bacteria or pests in or on equipment floors, walls or supports. All external surfaces
should be easily cleanable and capable of withstanding frequent hosing down and other
cleaning procedures.
The following details should generally be avoided:
a)
b)
c)
d)
e)

Ledges and dirt traps

Uneven surfaces and hollows
Recessed corners
Unfilled seams
Projecting bolt threads, screws, and rivets

The degree of polished finish to such surfaces should likewise be critically reviewed.
The goal is to keep the external environment of the system as clean as possible.
Preventing Entry of Contaminants
The prevention of particles entering into a system is much preferred to the subsequent removal
by filtration. Also, the maintenance of sterility relies upon preventing the entry of contaminating
organisms which can grow through microscopic clearances. The design philosophy should
adopt the following:
a) Operate in totally closed system (see following section on solids handling)
b) Operate closed system under slight positive pressure (including empty equipment after
sterilization)
c) Filter all streams entering the system with a 0.2 filter (solvents, water, nitrogen, etc.)
d) Minimize size of system
e) Minimize number of entry points to system, minimize the number/size of gaskets
f) Use double mechanical seals or preferably eliminate rotating seals altogether
g) Use bursting discs rather than safety valves (or eliminate need for relief altogether)
h) Locate bearings outside the product zone if possible
i) Provide sterilizing facilities at vents, drains, and sample points (e.g., hydrophobic microbial
air filters)
j) Ensure that potential leakages are readily visible (double tube sheet exchangers)
k) Flush rotating seals with steam or another sterilizing medium. Where a high degree of
sterile protection is required, the steam flushing of static joints should be considered.

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Solids Handling
The largest ports on most recrystallization vessels are those associated with solids addition.
While solids addition through open manways may be practiced in the production of bulk APIs, it
should not be utilized in the production of sterile APIs. The reason being the maintenance of
sterility and the prevention of dust/debris entering the system.
Several methods are available to allow for the contained charging of bulk APIs, including:

Glove box isolator

Split butterfly valves

If possible, the APIs should be delivered in stainless IBC or kegs to avoid the use of drum liners
which may cause particles to be brought into the system.
In a similar fashion, filter dryers need to be discharged into clean, sterile containers by means of
a closed system. The most frequently used solution is a glove box isolator.

The shaft of the filter dryers impellor not only rotates, but moves up and down. To prevent
any lubricant from being discharged into the process, some fabricators use flexible metal
bellows which act as a seal to the translation of the impellor.

The filter dryer should employ no gaskets, but rather encapsulated Teflon O-rings.

General Design Requirements

Flanges, valves, pumps, and all equipment items which are to be heat sterilized must be
fully insulated. Insulation must be readily removed to permit access for maintenance,
tightening of flange bolts, etc.

Insulation must be clad with impervious material to prevent it becoming wet and ineffective
and a source of contamination.

Areas which may be difficult to sterilize, e.g., points of shaft entry may require use of a
steam jet during sterilization.

Equipment which cannot be cleaned-in-place should be readily dismantled for cleaning.

Where cleaning-in-place (CIP) is used, it must be fully effective: for example, vessels
internals must not obscure other areas of the vessel.

Hollow sections used within or external to equipment (e.g., vessel supports) should be
totaled sealed.

Rotating Seals
Agitator and pump shafts are potential contamination pathways to sterile systems and constitute
a very significant risk.

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Single mechanical seals are normally acceptable for a hygienic service, but are totally
unacceptable for a sterile duty, where double mechanical seals must be employed, the seal
space being purged with steam, pressurized hot water or suitable biocide.
Suppliers of mechanical seals (e.g., Crane) offer a range of seals of increasing hygiene.
Since mechanical seals rely on the passage of fluid between seal faces for lubrication, WFI
quality water (or steam) must be employed as the barrier fluid where the product is a parenteral.
Once useful technique especially for slow speed agitators for providing pressurized hot water of
this quality is to take a tapping from a clean steam header. This is passed through an air
condenser which, since the quantity of water required for the seals is very small, is normally
satisfied by coiling the supply pipe a few turns.
Rotating seals are better eliminated altogether in sterile service by using magnetic drive
installations. Parenteral processes may require the use of labyrinth seals and seal cup (to catch
any shed particles).
Pumps
Many hygienic and aseptic pumps are available, often from manufacturers who primarily supply
the dairy industry. Rotating lobe pumps and centrifugal pumps are available with steam sealed
casing and flange joints, as well as the usual steam purged double mechanical seal.
The American 3A standard is used for hygienic service.
Some pumps are by their design inherently suitable for aseptic duties. Peristaltic pumps have
no seals or joints in contact with the fluid. Magnetically driven lobe and centrifugal pumps are
also suitable for aseptic duties.
Pump drains must be installed on pumps in sterile circuits at the low point of the pump casing to
allow steam/condensate to drain during sterilization procedures. Pumps handling non-sterile
product must either be readily dismantled for cleaning purposes or they must have a low point
drain in the casing to allow water/steam flushing. These drains need not be capped, but should
have a short stub length of pipe downstream of the drain valve to allow connection of a steam or
water hose.
Filter Dryers
Nutsch type filter dryers are the most frequently used in the production of sterile bulk APIs.
There are two major reasons for this:

The device can filter solids from mother liquor and dry the solids in one device.
The system is inherently a closed system.

However, Nutsch type filters designed to produce sterile bulk APIs need special attention to the
following areas to avoid the introduction of particulate matter:

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The filter media should be specified as a sintered metal plate rather than a filter cloth. This
will ease the problems of sterilization and prevent particles being generated by the filter
cloth. A filter dryer designed for sterile operation will have a special media support plate
(bolted from below) which allows for SIP condensate drainage and expansion.

In a similar fashion, the vent filters should be fabricated from sintered metal rather than
some fabric. The shaft of the filter dryers impellor not only rotates, but moves up and down.
To prevent any lubricant from being discharged into the process, some fabricators use
flexible metal billows.

The discharge of the filter dryer needs to be through an isolator system suitable to maintain
sterility and prevent particulate contamination.

Filter dryers leave a heal of material on the filter media. In some API formulation
processes, there is a desire to reclaim this material. Glove bags and glove box isolators
have been used to allow operators to use Teflon pads to scrape the filter media surface.

In a sterile bulk API facility, this is probably not a good idea because it allows for another
point where sterility can be lost and where particulates can be generated by the mechanical
action of the scrapper and the filter media.

Another way of reclaiming the heal material is to redissolve the material and pass it through a
sterile filter back to the next batch.

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