Saturday, September 01, 2001

`Fill it up`
Features
Maria Hagen and Christoph Dette of Aventis Pharma S.A. explain the multi dose unit filling line
and compare isolators and LF-barrier handling
The merger of the German company Hoechst Marion Roussel and the French company Rhone
Poulenc Rorer led to the foundation of Aventis Pharma S.A. in 1999. Within the Aventis world,
Frankfurt is one of the eight strategic manufacturing sites. A new filling line for multi dose units
(bottles: 20 100mL) was installed recently including an isolator.

LAYOUT OF MDU
The filling line for bottles (between 20 and 100mL) was installed in a Class B area (10,000).
Operators are able to access the filling machine from Class B. Technical access is also possible
from the outside (unclassified area at the moment). It will become classified as class C after the
refurbishment of the area has been completed.

Description of the MDU-system:

Automatic depalletising and unpacking of the bottles.
Pallets containing sealed packages of bottles are delivered to the depalletiser by forklift. This unit
automatically picks up single sealed packages of bottles and moves them to the automatic
unpacking machine. There the plastic wrapper is cut open and discarded by downward suction.
The bottles are carried to the bottle washer (BOSCH RRU 3043) of the filling line.
Bottle washer (BOSCH RRU 3043):
Firstly the bottles pass through an ultrasonic bath. They are then washed in a heated waterbath,
singled out, picked up by a mechanical grip system and turned by 180C. The bottles then
undergo a cleaning and rinsing process (with a total of four steps, alternating between fresh water
and compressed air). After being turned back to the upright position, the bottles are then
transferred to the tunnel.
Laminar flow tunnel (hot air followed by cool air) (BOSCH HQL 5351):
The tunnel is about 10m long and contains three heating segments (for depyrogenation) and five
cooling segments. In the heating segments, air is constantly circulated, by being drawn down
below the conveyer belt and filtered through HEPA filters after passing through heating units,
before it comes into direct contact with the washed and rinsed bottles. A ventilator in the entry
segment of the hot air tunnel constantly removes damp air and thus prevents saturation with
aqueous vapour. Fresh air flows in crossways from the cooling section of the tunnel. Within the
cooling segments of the tunnel, the air is constantly circulated with the aid of a cooler.
Filling machine (BOSCH FLP4060):

The filling machine uses a time-pressure-filling system (see Fig. 2). The size range of bottles is
between 20 and 100mL. The filling rate is 100 units/min for 50mL and 100mL infusion bottles, 150
units/min for all other bottle sizes.
Two large 3000L storage vessels are directly connected to the filling machine (Fig. 1). CIP / SIP
(cleaning in place/sterilisation in place) is also part of the machine. There is a docking station for
rubber stoppers.
During the filling process the bottles undergo a fully automated inprocess weight control. Each
bottle is replaced onto the transportation band at its corresponding place after the weight has
been recorded. The movement of the filling needles is synchronised with the bottles on the
transporting system. The isolator can be flooded with nitrogen and thus filling can be carried out
in an atmosphere >98%N2 atmosphere. The bottles are also prefilled with nitrogen before the
actual filling takes place.
Isolator (INP 1000, Skan):
There are two hard wall isolators. Part one covers the section where the incoming bottles from
the tunnel are singled out (7m3) and part two covers the filling unit of the machine (16m3). There
are eight double walled glass doors with pneumatic seals for easy access. There is a total of 13
gloves for handling operations within the isolators. The surfaces are decontaminated using H2O2
vapour.
The isolator covering the filling equipment can be filled with nitrogen prior to the filling process of
O2 sensitive products. The pressure controls for both isolator units are independent.
There are six different modes for the operation of the isolator:
a production using conventional LF-Barrier handling,
b production with isolator using air;
c production with isolator using N2,
d decontamination (dehumidifying, conditioning phase with H2O2, H2O2 decontamination using
a SIS 700 system, aeration),
e initial flooding of the isolator with N2,
f revision function.
Autoclave (Webeco):
The size of the autoclave chamber is 9m3. The autoclave is completely automatic and is
controlled by the computer governing the whole system. Depending on the chemical
characteristics of the product being filled, there are two options: either the bottles undergo
terminal sterilisation (heat stable products), or they undergo a washing process ( heat labile
products).
Visual inspection (Eisai AIM W1088) and tightness inspection (Bosch, KLD1042):

There is a cosmetic control of the filled and sealed bottles. They are also checked for particles
and the correct filling volume. After this the tightness of the sealed containers is checked by a
separate control machine using a high voltage.
Automatic stacking systems (Rotzinger):
There are three of these automatic stacking systems: one stacking bottles after the filling and
capping process (Fig. 3). After the cooling-down section (following the sterilisation or washing
process of the bottles) there is a second one to de-stack the bottles and to feed them into the
visual inspection machines. A third one stacks the bottles after the inspection and tightness
controls are completed.
Automated guided vehicles (AGV) and main computer system (MLD):
A main computer controls the whole production process (filling, sterilisation, visual inspection) for
the MDU line. This means that the state of each individual machine is supervised and known to
the computer. In addition, all of the components used for each batch are recorded. At the end of
each completed batch, a printout is provided. This lists all of the components used, the
sterilisation batches, and lists the number of bottles counted at each one of the Rotzinger
systems.
The bottles stacked by the automatic stacking systems are guided along the production process
by two AGVs. They are also controlled by the main computer. The two AGVs cover different parts
of the whole filling line.

Isolator/environment interface:
In order to connect the stoppers to the isolator without direct contact of the staff with the sterilised
stoppers, a new technical approach was taken. Large process containers are used to wash,
siliconise and autoclave the rubber stoppers. At the end of this process, the container valves are
closed and the container remains under pressure until it is aseptically connected with the stopper
feeding tube of the filling machine. The staff therefore do not come into direct contact with the
stoppers. The batch number of the stoppers is automatically scanned and passed to the
centralised computer of the system. The capacity of each of these SMEJA process containers is
150L. Since the total weight including the stoppers is about 750kg, a HANAG crane system was
installed to move the container up to the feeding tube of the filling machine.

Benefits of using an isolator filling line

Employing this innovative technology reduces the contact between staff and product to a
minimum. Therefore, a higher sterility assurance level for the filling of aseptically produced
multidose units is achieved. In addition, the handling of parts in contact with the product can be
minimised.
One example of the improvement in sterility assurance is the direct connection of storage vessels
of the filtrate with the filling line. Each of these components are CIP/SIP-ed independently. The
piping from the vessels to the filling line are cleaned and sterilised together with the filling
machine. The piping can also be cleaned separately.

During the filling of oxygen sensitive products by flooding the isolator with nitrogen, the protection
of the operator during the fillling process is guaranteed. Although the recommendations at present
justify setting up the isolator in a Class D controlled area, this particular isolator was installed in a
class B area.
The reasons are as follows: Firstly, in a Class B area the filling machine can be operated as a
conventional LF-barrier system. This allows staff to familiarise themselves with the equipment
well before it is run as an isolator. The LF-barrier system means that it is possible to open one of
the doors of the isolator during the production process should this be necessary in order to carry
out repair work which can otherwise not be carried out. This process was validated by completing
media fills. Secondly, this mode of operation is used for terminally sterilised products only.

Operational qualification of the isolator:

Initially the OQ (operational qualification) checks the overall ergonomic properties of the isolator.
This is carried out to ensure that all areas of the isolator can be reached with ease during
production. Secondly the H2O2 decontamination cycle is tested. Thirdly, while the isolator is in
production mode using a nitrogen atmosphere, the residual O2 concentration is measured.
The following steps were tested during OQ:
cleanroom classification
HEPA/ULPA filters
air velocity
temperature distribution within the isolator
flow properties and differential pressure
leakage test
The Class 100 in operation is regularly monitored. This is done in accordance with US-Federal
Standard 209E, i.e. <100 particles = 0,5mm/ft2.
All HEPA/ULPA filters of the two isolators (total of 14 HEPA filters) were tested for any leakage
using the DEHS (Di-ethyl-hexyl-sebazate) test. This test is carried out at regular intervals. To
guarantee a virtually particle free atmosphere the rate must be 0.01% for all EU14 filters. The
certificates of the filters from the manufacturer were also checked. All filters were clearly identified
and checked for any mechanical strains and/or damages.
The air velocity of a vertically directed constant air flow for a cleanroom class A has to be =
0.45m/s with an acceptable deviation of +/- 20%. Ten different points per filter unit were used and
the measurements were taken 300mm below the filter supplying the air to the isolator. Laminar air
flow was proven and documented by video. While in the decontamination mode, the air velocity
inside the isolator is reduced to 0.2ms-1 in order to increase the H2O2 concentration within the
isolator.
The temperature distribution within the isolator was determined. Firstly, it is of importance to mark
all cold spots which can lead to condensation of the steam/hydrogen peroxide mixture. Secondly,

it is for defining the worst case position for the decontamination process. Bio-indicators are
placed in the cold spots. The points chosen for these measurements were those where either an
interruption of the air flow was possible or where the total mass of the metal is large. In addition,
two measuring sensors with no contact to the surface have been installed as references for the
air temperature.
The air flow properties were checked by carrying out a smoke test. The whole chamber of the
isolator covering the filling machine was tested in production mode and also in critical transitional
conditions (e.g. beginning and end of filling process). The tests proved that there was low
turbulance displacing flow in the aseptic central area and no turbulant air flow in the isolator.
These smoke studies were documented on video.
The differential pressure was checked to verify the setting point. It was also carried out to check
that regulation of any pressure differences during standard working conditions and transitional
conditions takes place. Between the two isolators and the class B cleanroom the pressure
difference is 15 Pa +/- 5Pa with all doors closed during all the production modes. It also includes
the flooding modes (H2O2 and N2) of the isolator. The differential pressure is not regulated by the
isolator while in the revision mode or the decontamination mode. Under transitional conditions the
pressure difference has to be = 1Pa. Unidirectional flow and differential pressure prevent crosscontamination within the isolator.
To ensure that there is no H2O2 leakage during the decontamination cycle, the leakage test of
the isolator is carried out. The leakage rate has to be less than 10% of the internal volume of the
isolator per hour. The leakage rate was determined by measuring the time needed for an
equilisation of the pressure within the isolator while the doors were closed.

Product validation strategy:

There are two parts depending on the chemical characteristics of the products.
heat stabile products which can undergo terminal sterilisation - using conventional LF-barrier
technology
heat labile products using aseptic processing and isolator techology
For the operating staff to become familiar with the equipment the multi unit dose filling line has
been validated for conventional LF-barrier use as a first step
The requirements for conventional LF-barrier production: During conventional LF barrier
production the doors of the isolator are closed and the door seals activated. Since the isolator is
placed in a class B cleanroom, the operating personnel are fully gowned according to Class A/B
requirements. The surfaces of the isolator are disinfected with 70% ethanol. The routine handling
is carried out by using the gloves on the isolator doors. Minor repairs (e.g. straightening of the
needles) are performed by opening one of the isolator doors, if it is not possible to use gloves for
access and repair.
There was an initial microbiological validation of the process for conventional LF barrier system
routine production. Three media fills were done with the smallest and also with the largest bottle
size (i.e. 20mL injection bottles and 100ml infusion bottles). These were carried out according to
the SOPs for media fills. The routine handling operations which are simulated include the
following:

 fallen over bottles which are either straightened up by opening the appropiate door of the
isolator or by using the handling gloves
realigning the rubber stoppers in the feeeding tube using those forceps placed inside the
isolator.
After the initial microbiological validation of the filling line, the process is necessary for using the
isolator as conventional barrier technology for terminally sterilised products.
This is followed by product validation of the heat stable products. Product bracketing was used to
cover all of these products with the minimal number of batches neccessary. The most
concentrated product was used for the validation of the compounding and the least concentrated
product was used for the validation of the filling process. The cleaning validation was also part of
the product compounding validation step.
Since this part has been completed, media fills for the initial microbiological validation of the
aseptic filling process with isolator-technology will follow.
Three media fills will be carried out with the smallest bottle size in use (20mL). The machine is
running at different speeds and different routine handling operations which can be done using the
gloves will be carried out. This ensures that worst case conditions are simulated during media
fills. After the initial validation this aseptic process will be revalidated every six months with one
media fill. Once these initial media fills are completed, the product validation covering the
compounding and filling and cleaning validation for the corresponding heat labile products will
follow.
Conclusions
With this new filling machine we can chose conventional LF-barrier technology or isolator
technology according to the requirements of the different products.
Monday, October 01, 2001
A clean resorbable plastic implant
Features
Dipl. Ing. Gernod Dittel of Dittel Cleanroom Engineering and Dr. Ing. Erwin Brkle of Krauss
Maffei discuss the manufacturing of a resorbable plastic implant under cleanroom conditions and
look at the project up to serial production
When installing a cleanroom production site in existing buildings, many obstacles must be
overcome. Consistent and comprehensive planning is extremely important. It is advisable to set
up a project team that considers the framework conditions of the planned production site and is
able to estimate and prevent risks.
In the course of expanding production, a cleanroom production site for the medical engineering
sector was to be set up at Createchnic AG, Nrensdorf/Switzerland. Among other things, the
cleanroom was intended for the manufacturing of dispenser systems, of disposable items for
cardiology and orthopedics, and of resorbable human implants for traumatology. The
classification of the products complying with MDD/93/42/EWG ranges from IIa to III.
The new production facility had to be integrated in an existing infrastructure in order to be able to
carry out a general audit. Finally, the cleanroom facility had to be planned complying with US Fed.

Stand. 209 / DIN EN ISO 14644 and qualified according to GMP standards, whereby acceptance
tests had to be done according to the effective recommendations.
An injection-moulding machine had to be installed in the cleanroom. In the course of further
processing, the plastic parts were glued, welded, assembled and packaged. Manufacturing is
supported by an integrated quality laboratory for deliveries, process and final tests as well as for
integrating external labs as e.g. for further biological tests. In addition, the facility is equipped with
an integrated monitoring for the most important operating data.
PRODUCT AND ITS QUALITY FEATURES
The bio-resorbable implant to be manufactured is an interference screw made of polyactid for
cruciate ligament plastics at the human knee.
Polyactid screws offer stable primary fixation of the transplant and show a good tolerance. A
decisive aspect is the complete degradation of the screws and its substitution by osseous (bony)
neoformations. The complete degradation and substitution of the less than 1g heavy screw
occurs within 12 to 24 months. In case of repeated surgery, the often difficult removal of the
implant is not necessary.
Of course, design and construction of the interference screws must consider the specific features
of the used materials. Two important aspects were the requirements in terms of consistency and
easy handling. The screw does not have a standard thread, but a thread profile that considers the
consistency conditions between spongiose (spongy internal tissue of the bones) and screw
material, and which is adapted to the macrostructure of the spongiose. The thread profile is
nearly symmetric, because the implant is exposed to diametrally opposed transverse forces at the
bone-cone side and the bone-bed side. The screws are fitted with the help of a special
screwdriver without pilot drilling and thread cutting.
Numerous physical and biological features stand for product quality. In order to ensure product
quality, it is required that prior to, during and after the manufacturing process various measuring
and testing procedures be carried out:

Initial tests
check the primary packaging of the screws in terms of bioburdens,
sight checks to ensure that the poly D, L-lactid granulates are particle-free.

In-process tests
determine the residual moisture of the granulates,
test to determine deviations and tolerances of the screws (30 minutes),
test to ensure that surfaces are particle-free and perfect (30 minutes),
prove adequate consistency of the product via scissors test.
Final tests
check packaged screws in terms of bioburdens,
prove that there are no endotoxins on the sterile product,
prove that the product is sterile.

Project study
To deal with the project in a purposeful way, a project study was initiated to clarify various points:
if the required cleanroom engineering is sufficient,
if there are any reciprocal effects between the product and the techniques, or if the
existing infrastructure could cause problems,

which technical and personnel-related solutions are needed to draw up a preliminary

balance sheet of funding and operation expenses.

Initial inventory and analysis of the actual condition of the building and existing technology made
obvious that for this project a standard solution would not do. The back assembly of the existing
and installed process facilities itself would be quite difficult. This first result already confirmed that
the decision to make a project study was the only right way to proceed.
A further objective of the project study was to define, with the help of the given product
specifications possible solutions, derive from them various facility versions for realising the project
and then determine the best concept.
Altogether five proposals were worked out, each designed for a cleanroom facility with classes 8,
7 and 5 in accordance with DIN EN ISO 14644. The descriptions, calculations and drawings were
submitted with all facility versions, including the necessary construction data and detailed funding
and operation cost calculations.
Ultimately, the project study of the extended basic planning was used to determine the most
favorable combination in terms of architecture, energy and costs. Of course the adherence to the
allowed threshold values for air cleanliness (particles and bacteria) had to be ensured.
Processing procedure
According to a topical branch study, plastics in medical engineering are with 45% the largest
materials group. They are processed to e.g. such products as one-way syringes, blood bags,
infusion tubes, and parts for dialysis facilities or for artificial hearts. In this specific case the
screws are to be manufactured using the injection-moulding procedure.
Suitable for injection moulding under cleanroom conditions are the so-called "unpolluted rooms"
(class ISO 8) and "cleanrooms" (classes ISO 5 to ISO 7). "Super cleanrooms" (classes ISO 1 to
ISO 4) have been more rarely used in plastics custom moulding so far. There is however a trend
in favor of such high-quality manufacturing. Requirements on production facilities are among
other things:
equipment must qualify for cleanrooms, calibration and validation must be possible,
no or very reduced particle emissions,
anti-static equipment and easy cleaning.
Integrating an injection-moulding machine in a cleanroom class 100 involves great efforts,
especially when the products are to be manufactured for medical, biotechnological or
pharmaceutical purposes. The requirements on such production facilities are much stricter than is
the case with technical products.

Specifications for the production

Microelectronics
In-house specifications

cleanroom technology

Pharmaceutics
Speciation for the clean environment
after
GMP
FDA

product

QS: internal

GMP / FDA - conformable

Yield after training curve

100 % yield

In the ideal case, the setup of the machine in the manufacturing area is done in consideration of
the ventilation installations. It is best to have the locking unit directly underneath an air outlet in
order to ensure a largely regular flow of the (cleaned) air over the tool.
In clean room class 3 it is generally the case that an almost laminar airflow is directed through the
locking unit, and thus through the tool. The interference-freer the directed airflow through the
machine is, the easier it is to obtain the desired quality level.
The manufacturing of cleanroom suitable injection-moulding tools is quite complicated, since no
lubricants are supposed to be used as far as possible. If this cannot be prevented, care must be
taken that the lubricant does not get anywhere near to the work area (cavity). On the contrary, it
must be directed inwards with the help of an appropriate differential pressure. For deforming
forcibly actuated, mechanical ejectors should be preferred. Hot runner moulds are not appropriate
in all cases because the nozzles are not always 100% leakproof. The best solution is a pin-point
gate.
Depending on each individual case and the regulations, the preforms may fall out of the machine
freely or they must be taken out. Class 100 cleanroom production requires a handling device for
taking out preforms. The fact is that despite special protective clothing and all precaution
measures, the operating personnel are always the greatest creators of dust and dirt.
The changing of tools involves great efforts in cleanroom manufacturing, especially in class 100.
The new tool must be completely disassembled and cleaned under cleanroom conditions. Quite
suitable for this purpose is a laminar box in which assembling can be carried out.
As far as machine maintenance is concerned, a difference must be made between regular
maintenance work and the cleaning work that must also be carried out on a regular basis.
Machine maintenance is quite important because virtually any defect can lead to a contamination
of the machine, the tool or the environment. This would make very extensive cleaning work
necessary. So for this reason it is essential that the maintenance intervals defined by the machine
manufacturer be strictly observed.
For the manufacturing of preforms in a class 100 cleanroom, only plastics are permitted that have
been produced under especially clean conditions. Lactid is processed for the interference screws,
a cyclic dimer of lactic acid that exists in two optical isomers. Poly L-Lactid (PLLA) is a
semicrystalline material with good mechanical features like ultimate tensile strength and low
elongation.
QUALITY SYSTEM
Of importance for the manufacturing of the products are approvals in accordance with ISO 9001,
EN 46001 and MDD/93/42/EWG, appendix II, item 3. The approval in accordance with
MDD/93/42/EWG was granted after an auditing by the authorities thus simplifying the product
approval by the customer. The quality system is process-driven. The five most important are:
management processes
resource processes
customer relationship processes
realisation processes
supporting processes
Within the realisation processes there are 25 subprocesses that regulate the specifics for medical
engineering.
CLEANROOM INFRASTRUCTURE

The product-related quality requirements have a considerable influence on the infrastructure of

the cleanroom. For injection moulding manufacturing and in-process control a cleanroom with
process exit air was selected. Final inspection and packaging in primary and subsequently in
secondary packaging (without labels) is carried out in a separate part of the cleanroom facility.
The concept is acknowledged as being reliable. In this case the cleanroom class 10,000 was
defined in accordance with US Fed. Standard 209E and qualified in accordance with the effective
recommendations.
It considers a maximum tolerable number of 30 germs per implant. This number is derived from
the sterilisation method with gamma radiation from a Cobalt 60 source. The standard for
radiation-sterilised implants demands a provable sterile guarantee of 10 -6. In other words, among
one million sterilised implants one may be non-sterile. This must be proved within the scope of
the validation with a so-called low dose method. What this actually means is that with the fewer
germs per implant a validation is carried out, the easier it is to guarantee sterility.
AMBIENT MONITORING AND MEASUREMENTS
To ensure the cleanliness of the cleanroom a disinfecting scheme was set up that amongst other
things described the items to be cleaned, the allowed cleaning detergents, the cleaning intervals
and the cleaning methods. The given instructions had to be strictly obeyed in order to stay below
the given threshold values for germ levels. Ambient monitoring in the cleanroom requires:
measuring of temperature, air humidity and impact pressure,
measuring of particles in the room air,
measuring of the air germ rate,
measuring of germs on surfaces.
Temperature, air humidity and impact pressure are continuously measured and displayed from
permanently installed, calibrated sampling points. The data is stored in a database. If given
minimum or maximum values are exceeded, an alarm signal or error message is immediately set
off that initiates a predetermined measure.
Particle measurement is carried out on a regular basis at predetermined sampling points. The
target values are given for each room class. In case of limit exceeding, production must be
stopped and remedied according to agreed measures.
Measurements of the air germ rate must also be carried out on a regular basis. Sampling is done
with a RCS sampler "biotest". Tryptic-Soya-Agar is used as culture medium.
The germ levels of all relevant surfaces are measured on a regular basis through a proof using 25
cm-Rodac-dishes. Plate-Count-Agar is used as culture medium. Flocculation must occur in two
steps.
PRODUCTION
The production process is divided into 13 steps starting with entry inspection of the raw materials
up to the delivery of the finished items. Most of these steps are carried out under cleanroom
conditions:
entry inspection of the raw materials in the quality lab class 100 000,
storage and transportation of raw materials into the cleanroom storing place,
production preparation of the injection moulding tools under LF class 1 000,
production preparation of the injection moulding machine and facility class 10 000,
drying of the granulates under class 10 000,
in-process inspection under class 10 000,
final inspection of the products under class 10 000,
primary and secondary packaging of the products under class 10 000,
repackaging of the products under gray room conditions,
bioburden test under lab conditions,
gamma radiation of the products by means of Cobalt 60 source,
checking for endotoxins under lab conditions,
proof of sterility under lab conditions,
storage and transportation of sterile products.

Clearing regulations check the individual steps against each other. The specifications and
verification documentation in accordance with MDD/93/42/EWG are regulated in a DMF (Device
Master File) and a DHF (Device History File). In this case the documents must be kept for 10
years.
FACILITY QUALIFICATION AND PROCESS VALIDATION
Within the scope of the project study five different kinds of facilities were drafted, compared to
one another, analysed and evaluated. The ultimately released version is a combination of all
worked out proposals with consideration of the product-related specifications.
The detailed project study and the cooperation of all participants enabled an unproblematic
project realisation, which was committed to a tight time schedule. The simultaneously running
qualification process ensured best planning and execution. Through the sound preparation of
engineering and qualification, a complete validation of the whole system at the end of the project
was achieved.
In pharmaceutical manufacturing the GMP standards (Good Manufacturing Practices; guideline of
the EU commission for the manufacturing of drugs) must be observed. FDA inspections (Food
and Drug Administration) check how far these standards are being observed. Various
recommendations set the standards in respect to which parameters are to be qualified and
according to which measuring and checking procedures this must be done.
When qualifying a facility, you must distinguish between an already existing cleanroom facility and
the first-time setup of a facility. The Createchnic AG project was a first-time facility setup only
the building existed which is why a prospective qualification was carried out.
Generally, the project process for pharmaceutical or medical engineering manufacturing is
subdivided as follows:
feasibility study and concept planning,
GMP review with FDA preapproval,
basic engineering and detail engineering,
execution planning and realisation,
startup and operation
It is important and useful to consider the required qualification right at the beginning of all
reflections, in other words, during the feasibility study. The fact is that the qualification process is
fully integrated in basic engineering at the latest.
As soon as the order has been placed, a qualification scheme should be set up in order to
determine at which stage of the qualification the main points ought to be checked. It also defines
the competencies and responsible persons for the individual stages: Design Qualification (DQ),
Installation Qualification (IQ), Operational Qualification (OQ) and Performance Qualification (PQ).
In so far as the user has a general master validation plan, the qualification scheme must adhere
to it.
The master plans determine a processing scheme including the definition of terms, objectives,
procedures, used work materials and the organization of the quality project.
In order to be able to determine the critical points and functions of the facility, a risk analysis must
be performed. For this purpose, the facility components are tested in terms of functionality as well
as analysed to what extent malfunctioning could effect the adherence to the specified values.
Ultimately, risk analysis makes a comparison between the theoretical and practical measures in
the qualification procedure. In so far as the results differentiate in terms of structure and
statement, another comparison must be made.
Starting with the qualification scheme, the next step is Design Qualification (DQ). This is the
systematic and recorded proof that the facilities and equipment have been planned in accordance
with the GMP requirements. They must also comply with the requirements of general quality
security as well as environmental and work safety. Some essential features of the GMP standards
are:
easy cleaning and easy accessibility,
integrated control and logging systems,
available user documentation,

available qualification documentation,

computer flow simulation.

After the facility is installed, Installation Qualification (IQ) verifies that the facilities and equipment
have been built and installed in accordance with the specifications, installation regulations as well
as other standardised rules and regulations. In this stage, the completeness of supplier protocols
and documentation must be checked. IQ ends with a report that among other things can include a
list of defects.
Operational Qualification (OQ) is also the first operational test of the facility over the total range of
the setting parameters. In the planning stage, a decision must be made in terms of which
operational tests should and ought to be executed for which facility components. Included are all
function units that have a direct influence on the specified parameters of a cleanroom.
Operational Qualification includes acceptance measurements of the cleanroom facility.
Performance Qualification is the last stage of the qualification. The facility is tested under
operational conditions with all personnel and running production.
The final report summarises all listed qualification steps in a document. It is thus the formal
release of facilities and equipment for manufacturing after having carried out the validation.
The documentation is an essential part of quality security besides GMP principles. It includes all
qualification plans, the test plans and instructions as well as final report. Included are also all
machine documentation, the relevant switching and facility plans, and user documentation
containing operation instructions and detailed maintenance manuals. The principle of cleanroom
engineering must be considered in this connection. What is meant is that any subsequent
modifications call for a new execution of the total qualification and validation process. Other parts
of the documentation include documents and recommendations concerning staff education and
training, and the in-house implementation of given tasks.
ACCEPTANCE MEASUREMENTS OF THE CLEANROOM FACILITY
In principle the acceptance of a cleanroom is merely a formal act that is preceded among other
things by acceptance measurements and tests. The basis for the acceptance measurements and
tests can be various recommendations that sometimes include details on the methods and
measuring devices to be used. To ensure least possible disagreements within the scope of the
acceptance measurements, it is best that cleanroom manufacturer and cleanroom user agree
already in the specifications on the parameters to be tested.
As soon as the acceptance measurements of a cleanroom have been completed and the room
has been taken into operation, it should be monitored continuously according to a monitoring
plan. The monitoring of the cleanroom facilities is usually not precisely defined in the
recommendations. Thus it is up to the user.
Costs
Costs for execution often have a higher priority for many clients than planning or quality of
execution. But it is planning that influences decisively the development of costs. Conventional
planning calls for much higher additional costs than this is the case with far-sighted planning. It is
important that quality management includes modification and malfunction management.
Basically, it is not advisable to make any modifications within the described project stages. This
may have hardly comprehendible consequences due to the inter-connection of individual
cleanroom subsystems. In case such modifications are nevertheless required, the entire process
for identification and determination of the parameters must be repeated, thus inevitably ruining
every tight cost calculation scheme.
As far as qualification and validation is concerned, it is difficult to estimate the costs in advance.
Experience has shown that these two stages make up for about 8-15% of total investments.
SUMMARY
Prerequisites for concept and execution of an economical cleanroom system are specific
knowledge and experience of the planner as well as of the facility manufacturer and close
cooperation with the operator.
Operators of a cleanroom-manufacturing site must be aware of the fact that such a complex
facility causes additional costs. Adopting the idea of setting up a cleanroom production on a

smaller space to save costs is quite risky. Ultimately, what actually matters is the required quality
of the products to be manufactured.
Saturday, September 01, 2001
Separative enclosures
Features
John Neiger discusses the first public draft of ISO 14644 - 7, the new ISO standard for isolators
and minienvironments
March of this year saw the circulation of Draft International Standard ISO/DIS 14644 -7,
Separative enclosures (clean air hoods, gloveboxes, isolators, mini-environments) for
comment and vote by the participating nations in ISO. For many interested parties, this was their
first official sight of a long-awaited standard as it emerged from the committee drafting stage. For
the small number on the drafting committee, Working Group 7 of ISO TC 209, it represented the
exposure to scrutiny of the result of many years of detailed deliberation.
This paper sets out to summarise and explain the present draft and then to anticipate whether it
will meet the needs of those industries that might be required use it.
SUMMARY OF THE DRAFT

The first point to make about the draft standard is that it is generic and not application specific.
This is clear from the title itself. Who has ever heard of a separative enclosure? Which industry
uses such a device? In fact the word 'separative', which is disliked by spell-check, is defined in
the OED as "tending to separate or to cause separation" and was cleverly chosen by the working
group for its generic nature. However, just to ensure that the title gives some indication of the
subject that the standard covers, it includes in brackets the more application-specific terms 'clean
air hoods, gloveboxes, isolators, minienvironments'.
The draft standard characterises a separative enclosure as having three essential elements.
These are the separative enclosure itself, the access device(s) which are the means whereby
work inside the enclosure is accessed by operators outside, and the transfer device(s) which are
the means whereby materials are transferred in and out. There is a strong emphasis on relative
levels of leak tightness.
In any standard it is important to understand the scope. In 1.Scope, the point is made that "This
part of ISO 14644 specifies the minimum requirements for the design, construction, installation,
testing and approval of separative enclosures where they differ from cleanrooms as described in
ISO 14644-4 and 14644-5".
With one exception, all the references in 2. Normative references are parts of the two groups of
standards being prepared by ISO TC 209, namely ISO 14644 and ISO 14698, most of which are
still to be published. The exception is ISO 10648-2:1994 Containment enclosures - Part 2:
Classification according to leak tightness and associated checking methods.
Most standards contain definitions. 3. Terms and definitions include the following ones of
particular relevance: Separative enclosure - equipment utilising constructional and dynamic means to
create assured levels of separation between the inside and outside of a defined
volume.

Separation descriptor, [Aa : Bb] - numerical abbreviation summarising the

difference in cleanliness classification between two areas as ensured by an
separative enclosure under defined test conditions, where:
A = ISO Class inside
a = particle size at which A is measured
B = ISO Class outside
b = particle size at which B is measured
Pressure integrity - capability to provide a quantifiable pressure leakage rate
under repeatable test conditions
The next two sections are: 4.Specification of requirements, which is a checklist of the items
that must be 'defined, agreed and documented between customer and supplier' in the
specification of a separative enclosure, and 5. Design and construction, which is another
checklist of some of the related design considerations with brief guidance.
The draft continues with 6. Access devices, which is amplified in Annex C. This section explains
a number of means whereby processes, products or tools within the separative enclosure may be
manipulated by hand operation (e.g. through gloves or gauntlets) or by robotic handling. It is
further amplified in annex C. 7. Transfer devices is very brief and is amplified with examples in
annex D.
8. Siting and Installating (sic) is another very brief checklist. 9. Testing and Approval is written
in the most general terms, making reference to other parts of ISO 14644. For the important
aspect of leak testing it refers to the recommendations of annex E.
It is in the annexes that the main interest lies. Annex A introduces the Separation continuum
concept and includes a very helpful graphical illustration of the way in which different levels of
'separation means' provide different levels of 'assurance of maintaining separation'. The means
range from 'unrestricted air over spill (mass flow)' at the lower end of the graph to ' high
integrity/low hourly leak rate enclosures' at the higher end. The means of separation range from
aerodynamic at the lower end to physical at the higher end. Application specific examples are
given in the most general terms.
Annex B Air handling and gas systems is written in a way that suggests the standard is
intended to include inert gas systems and active gas systems within its scope.
Annex C Access devices provides considerable detail on gloves and sleeves, glove materials,
and glove change methods. Half-suits are briefly described, but the annex makes no mention of
remote manipulation or robotic handling. Annex D Transfer device examples classifies transfer
devices according to descriptions and diagrams that originate from Isolators for Pharmaceutical
Applications HMSO 1994. However there are some changes and also some additional devices
such as the class A2 transfer device - examples of which are: dynamic holes and mouse holes.
Annex E Leak testing describes a number of methods for pressure leak detection and
quantitative leak testing. For quantitative leak testing, three methods described in ISO 10648-2
are adopted for separative enclosures, as is the classification according to hourly leak rate. One
of the test methods is the oxygen method, which can only be applied to an enclosure that is at
negative pressure relative to its surroundings. It works by filling the enclosure with Nitrogen and

then detecting changes in the level of oxygen as a result of air entering through a leak. There is a
very useful sub-section E.3.1.4. Equation development, which derives a formula for calculating
hourly leakage where the pressure differential across an orifice (leak) is known and also links
some of the test methods with the combined gas law equation P1V1/T1 = P2V2/T2 where P and
T are absolute. The annex also describes a test known as the Parjo test in some detail. The Parjo
test indicates the magnitude of a leak by the movement of a meniscus in a tube connected to a
reference vessel. If the volume of the separative enclosure, the external barometric pressure and
the internal temperature all remain constant for the duration of the test, then the volume displaced
by the moving meniscus will represent the actual volume through the leak during the period of the
test.
Annex F Design and testing of minienvironments covers ground that appears to be specific to
the semiconductor industry. Annex G Calculation of maximum permissible leak rate sets out a
rationale and a method for estimating different acceptable leak rates into or out of separative
enclosures for different internal or external air change rates by taking into account the dilution
effect.
WILL ISO 14644-7 MEET THE NEEDS OF ITS LIKELY USERS?

The first possibility is that it will not survive. It could be that separative enclosures at the lower
end of the separation continuum will be deemed to be covered by the segregation concepts in
ISO 14644-4, and those at the higher levels of pressure integrity by ISO 10648, to the eventual
rejection of ISO 14644-7. Interestingly, the scope of ISO 10648-1: Containment enclosures - Part
1: Design principles, which has not been adopted either by CEN or BS, states that it applies to
enclosures or enclosure lines intended to be used for work on:
? radioactive and/or toxic products where containment is required for protection
of personnel and environment
? sensitive products requiring a special atmosphere and/or a sterile medium.
It is not certain that the draft of ISO 14644-7 will be accepted by the semiconductor industry.
There is a clue in the inclusion of Annex F. This suggests that, in the perception of that industry,
there is something lacking in the remainder of the draft.
Those organisations that manufacture or use anaerobic chambers will have to judge whether the
draft standard is likely to be of value or whether they might wish to develop a standard that is
more relevant to their own specific needs. Then there is the question as to whether the draft
standard will be acceptable to all the nations that are members of ISO. The Australians already
have a standard of their own AS 4273-1999 (+ Amdt 1/2000.05.02) called Design, installation and
use of pharmaceutical isolators. They may prefer to retain that rather than adopt ISO 14644-7.
The USA healthcare sector has consistently sought to restrict the definition of isolators to those
systems that include gaseous sterilisation and in which control of particulates is not an important
factor. ISO 14644-7 might not be considered relevant by that sector in the USA. One thing is for
sure. That is that being generic ISO 14644-7 will leave room for application specific standards
and guidelines. For healthcare applications the one to watch is the comprehensive new edition of
the UK guidelines "Isolators for pharmaceutical applications" which is due to be published later
this year.
AUTHORS BIOGRAPHY

John Neiger is chairman and a founding director of Envair Limited, a leading independent
manufacturer of biological safety cabinets, isolators and cleanroom facilities in the United
Kingdom. He sits on various standards committees including, for the last two years, ISO TC 209
Working Group 7, which has prepared the draft standard described in this article. He has
addressed numerous technical conferences around the world.