Aseptic Line Procedures Handbook PL01284 THP Rev0

ASEPTIC LINE
PROCEDURES HANDBOOK
PL01284
Aseptic Line Procedures Handbook_PL01284_THP_Rev0
Page 1 of 34
INDEX
1.
OPERATOR STANDARD ACTIVITIES
Pag. 3
2.
PROCEDURE A Manual titration of the sterilizing solution
Pag. 7
3.
PROCEDURE B How to use object transfers box
Pag. 11
4.
PROCEDURE C Cleaning and replacement of bottle and cap treatment nozzles
Pag. 15
5.
PROCEDURE D Sterile water and empty bottles sampling for Lab
Pag. 19
6.
PROCEDURE E Verification of peroxide residual into the bottle
Pag. 21
7.
PROCEDURE F COP/SOP rotary nozzles replacement
Pag. 22
8.
PROCEDURE G Replacement of the sterile filter cartridges on Uniflux
Pag. 23
9.
PROCEDURE H - NOT IN THE SCOPE OF SUPPLY
Pag. 26
10. PROCEDURE I Microbiological isolator HEPA filters replacement
Pag. 29
11. PROCEDURE J Capping heads sterilization procedure
Pag. 30
12. PROCEDURE K Operations required for a Production Scheduled Long Stop
Pag. 32
13. PROCEDURE L NOT IN THE SCOPE OF SUPPLY
Pag. 34
14. PROCEDURE M - NOT IN THE SCOPE OF SUPPLY
Pag. 34
Enclosures:
Encl. 1
Machines List of the Aseptic Line
Encl. 2
N. A.
Encl. 3
Line General Flow Sheet
Encl. 4
N. A.
Encl. 5
Guidelines for microbiological samplings and analysis
Encl. 6
Essential Controls Handbook
Encl. 7
Recommended List of Chemicals
Encl. 8
Aseptic Laboratory Specification
Encl. 9
Line operational and QA checks
Page 2 of 34
1. OPERATOR STANDARD ACTIVITIES

The correct functioning of the machine often depends on the conduct of the operators, who
further to maintain a correct comportment, conformable to a contamination controlled
environment, are called to a constant interaction and maintanance of the system.
1.1 OPERATORS BEHAVIOUR
Of the millions of cells in the human organism, approximately 40% has a human genome, the
remainder is composed of micro-organisms. Of these, many are in the intestinal mucous where
they supervise essential functions (such as the absorption of vitamins, of aminoacids, etc .), a
number are in other mucose (eg. mouth) and many on the skin.
The skin houses a large quantity of micro-organisms; the fingertips, especially under the nails,
house a great number.
Hair, dandruff and the microscopic fragments of skin that we continuously introduce in the
environment, transport a numerous amount of micro-organisms.
A thorough washing of the skin, using disinfectants, is able to reduce the number of microorganisms present but however cannot remove them completely.
Humans in general, spread contamination in two ways:
a) by dispersion, by releasing in the air, particles that may transport micro-organisms
b) by contamination, transferring substances from one material to the other with the hands
For the above mentioned reasons, the operators must observe certain fundamental rules about:
- personal hygiene
- clothing
- filling area conditions
PERSONAL HYGIENE:
- prior to entering the filling area, operators must wash their hands thoroughly
- operators are called to keep their nails short and their hair clean
CLOTHING FOR ENTERING THE FILLING ROOM:
- clean clothes, possibly white
- clean shoes
- head cover which ties and covers operators hair completely
FILLING AREA CONDITIONS:
- filling area must be kept clean and tidy
- a stainless steel closet (more hygienic and easier to clean) is recommended, for
enclosing overalls, gloves, tools, etc.
- a stainless steel table is recommended as well
Page 3 of 34
1.2 INTERVENTIONS INSIDE THE ASEPTIC BLOC AND AUTOMATIC ACTIONS

For the interventions inside the aseptic bloc, it is necessary to use dedicated tools, which:
- must be kept in a closed box, separately from the standard tools.
- every time, before using them, it is necessary to carefully clean the tools using a paper
cloth soaked in ethyl alcohol (ethyl at 70%).
The Aseptic bloc (Sterilizer, Rinser and Filler) is fitted in such a way to allow the operators to
intervene without breaking its sterility; in case tools are needed, they must be transferred inside
the aseptic bloc through the appropriate object transfer box (as described by the Procedure B How to use the object transfer box)
However, there are some interventions that require the opening of the hatches, in said cases:
- operators must always wear disposable latex gloves that must be disinfected with ethyl
alcohol (ethyl at 70%) once worn
- hatches of the machine must remain open only for the time required for the intervention
- in the event that an operator has to go inside the machine for intervention purposes, he
must always wear an overall and disposable shoe covers
When working inside the aseptic bloc, operators should follow the steps described in the tables
below:
Table 1 FILLING BLOCK ON REST (NO CYCLES SELECTED)
STERILIZER / RINSER / FILLER / STERILCAP
MINOR MAINTENANCE:
MAJOR MAINTENANCE:
-
interventions lasting less than 15 minutes

interventions performed from outside of the
isolator
1. Before opening the hatch:

1.1 Perform CIP/COP cycles
1.2 Spray the operator gloves with ethyl
alcohol
2. Open the hatch
3. Perform the intervention
4. Perform SIP/SOP cycles before restarting
production
interventions lasting over than 15 minutes

intervention performed by entering inside the
isolator
1. Before opening the hatch:

1.1 Perform CIP/COP cycles
1.2 Wear shoe-covers if necessary
1.3 Spray the operator gloves with ethyl alcohol
2. Open the hatch
4. Thorough manual foaming of the area of
intervention
5. Perform CIP/COP cycles
6. Perform SIP/SOP cycles before restarting
production
Page 4 of 34
Table 2 FILLING BLOCK IN PRODUCTION OR IN SANITATION

STERILIZER
RINSER / FILLER/STERILCAP
1. Wait for PAA vapours to be exhausted:

1.1 press the emergency button
1.2 wait for 5 minutes
2. Prior to opening:
2.1 wear a safety mask
2.2 spray the operator gloves with ethyl alcohol
3. Open the hatch
5. Close the hatch and re-start the sistem
6. Specific AUTOMATIC ACTIONS of the system
will occur
1. Wait for PAA vapours to be exhausted:

1.1 press the emergency button
1.2 wait for 5 minutes
2. Prior to opening: spray the operator gloves
with ethyl alcohol
3. Open the hatch
5. Close the hatch and re-start the sistem
6. Specific AUTOMATIC ACTIONS of the
system will occur
The system is built to preserve sterile conditions and running safe aseptic productions; for that
reason, in case of hatches opening, there are the following automatic actions:
HIGH ACID / ESL PRODUCTION
Sterilizer
Hatches opening:
with bottles inside the
machine
Hatches opening:
without bottles inside the
machine
Rinser
Filler
Sterilcap
Bags Tunnel
Topening < 120 s Topening < 120 s Topening < 120 s Topening < 120 s Topening < 120 s
Short SOP P
Short SOP P
Short SOP P
Short SOP P
Short SOP P
Topening 120 s Topening 120 s Topening 120 s Topening 120 s
Short SOP P
CIP/SIP
CIP/SIP
CIP/SIP
Topening 120 s
CIP/SIP
Topening< 120 s
Start up
Topening < 120 s Topening < 120 s Topening < 120 s Topening < 120 s
Short SOP P
Short SOP P
Short SOP P
Short SOP P
Topening 120 s
Start up
Topening 120 s
CIP/SIP
Topening 120 s Topening 120 s

CIP/SIP
CIP/SIP
Topening 120 s
CIP/SIP
LOW ACID / FDA PRODUCTION WITH CAPS DOWNLOAD SYSTEM AVAILABLE
Hatches opening:
with bottles inside the machine
Hatches opening:
without bottles inside the machine
Sterilizer
Rinser
after 3 s
Long SOP P
after 3 s
Start up
Filler
Sterilcap
after 3 s
CIP/SIP
after 3 s
CIP/SIP
after 3 s
CIP/SIP
after 3 s
CIP/SIP
after 3 s
CIP/SIP
after 3 s
CIP/SIP
Page 5 of 34
LOW ACID/FDA PRODUCTION WITHOUT CAPS DOWNLOAD SYSTEM AVAILABLE

Sterilizer
Rinser
Filler
Sterilcap
Hatches opening:
with bottles inside the
machine
after 3 s
CIP/SIP
after 3 s
CIP/SIP
after 3 s
CIP/SIP
after 3 s
CIP/SIP
Hatches opening:
without bottles inside the
machine
after 3 s
Start up
after 3 s
CIP/SIP
after 3 s
CIP/SIP
after 3 s
CIP/SIP
CIP/SIP:
SOP P:
Start up:
machine in SANITATION mode

External sterilization cycle with PAA, run when in PRODUCTION mode:
Long SOP P = spraying time as external sterilization run when in SANITATION mode (SOP)
Short SOP P = reduced spraying time
Only sterilizer Start Up cycle in production longer then normal heating machine cycle (120 s) with machine in
rotation.
1.3 END OF PRODUCTION ACTIVITIES

At the end of production, it is necessary to perform the microbiological controls as reported in
the ECH Essential controls Manual. These operations must be performed by the laboratory
personnel. Therefore it is the operators duty to alert the laboratory when the
production is about to finish.
At the
1.
2.
3.
end of microbiological sampling operations, operator have to:

Switch the bloc to SANITATION mode
Select and run the plant drainage cycle
Carefully remove all the production residues (bottles and caps into the
machine)
4. Select and run COP and CIP cycles
It is necessary to keep a copy of the ECH- ESSENTIAL CONTROLS HANDBOOK near the
aseptic bloc. This will permit the operators to know which controls have to be made, when they
have to conduct them and which parameters they need to observe; it is moreover necessary to
keep a production notebook in which the operators must record all the interventions and visual
checks made during production runs.
Page 6 of 34
2. PROCEDURE A Manual titration of PERACETIC ACID (PAA) and

HYDROGEN PEROXIDE (H2O2)
In order to ensure the asepsis of the system, the efficacy of the sterilizing treatments and the
absence of sterilizing solution residuals in the end product, it is necessary to perform the
following checks:
1. Titration of the peracetic acid based sterlizing solution
2. Titration of the drum of hydrogen peroxide (if present)
3. Titration of the drum of peracetic acid concentrate
2.1 TITRATION OF THE PERACETIC ACID BASED STERILIZING SOLUTION
Chemical Reagents:
- Sulphuric Acid (H2SO4) 25% (v/v)
- Potassium Iodide (KI) solution (166 g/l)
- Potassium Permanganate (KMnO4) 0,1N
- Sodium Thiosulphate Solution (Na2S2O3) 0,1N
- Starch (Thyodene Solution)
Equipment:
- 50ml pellet burette for Potassium Permanganate
- 50ml pellet burette for Sodium Thiosulphate
- Pipettes (1ml, 10ml, 25ml)
- Pipette filler
- Erlenmeyer Flasks (250 ml)
- Magnetic stirrer
2.1.1 Hydrogen peroxide titration
1. Put 10 ml of the sterilising solution into an Erlenmeyer flask
2. Add 20 ml of the H2SO4 solution
3. Keeping the sample under continuos stirring, titrate with Potassium Permanganate (KMnO 4)
till the solution assumes a pale violet colour
4. Record the Potassium Permanganate, ml
Formula:
ppm Hydrogen Peroxide = ml Potassium Permanganate 5 34
Page 7 of 34
2.1.2 Peracetic acid titration

1. Add to the previously titrated solution 10 ml of Potassium Iodide (KI)
2. Keeping the sample under continuos stirring, titrate the solution with Sodium Thiosulphate
till the solution assumes a light yellow colour.
3. Add 4-5 Starch solution drops (the solution will turn to black/blue colour)
4. Titrate the solution with Sodium Thiosulphate till the solution turn transparent
5. Record the Sodium Thiosulphate, ml
Formula:
ppm Peracetic Acid = ml Sodium Thiosulphate 5 76
Manual titrations must be performed with the following frequency:
- every 15-20 minutes during start up and validation operations of the line. During these
steps, manual titrations are fundamental in order to verify the correct working of both
Unidox system and PAA concentration automatic probe
- as indicated in the essential controls handbook (ECH) during commercial production
NOTE:
- titration procedure of the sterilising solution used, must receive confirmation from the
supplier of the concentrated product
- when taking the sample for titration, always read the value shown on the PAA concentration
automatic probe and record it for comparison purposes
- manual titration of a sterilizing solution sample must be performed within 10 minutes
from the sampling
2.2 HYDROGEN PEROXIDE CONCENTRATE DRUM TITRATION (IF REQUIRED)
Every time a new concentrate tank is installed, it requires to be titrated.
Chemical Reagents:
Equipment:
- Pipette filler
- Magnetic stirrer
Page 8 of 34
Before titration, it is necessary to make a dilution 1:100 of the H2O2 concentrated

product as per the following procedure:
- Weigh 1 g of H2O2 concentrate
- Add 99 g of de-mineralised water
Titration:
1. Put 10 ml of the sample into an Erlenmeyer flask
Formula:
ppm Hydrogen Peroxide = ml Potassium Permanganate 5 34 100
NOTE: the titration procedure must receive confirmation from the supplier of the concentrated
product
2.3 PERACETIC ACID CONCENTRATE DRUM TITRATION
Every time a new concentrate tank is installed, it requires to be titrated in order to know the
correct concentration of the peracetic acid and to set it on the Unidox control panel.
Chemical Reagents:
- Potassium Iodide (KI) in solution (166 g/l)
- Sodium Thiosulphate Solution (Na2S2O3) 0,1N
- Starch (Thyodene Solution)
Equipment:
- 50ml pellet burette for Sodium Thiosulphate
- Pipette filler
- Magnetic stirrer
Before titration, it is necessary to make a dilution 1:100 of the PAA concentrated
product as per the following procedure:
- Weigh 1 g of PAA concentrate
- Add 99 g of de-mineralised water
Page 9 of 34
2.3.1 Hydrogen peroxide titration

1. Put 10 ml of the sterilising solution into an Erlenmeyer flask
Formula:
ppm Hydrogen Peroxide = ml Potassium Permanganate 5 34 100
2.3.2 Peracetic acid titration
1. Add to the previously titrated solution 10 ml of Potassium Iodide KI
2. Keeping the sample under continuos stirring, titrate the solution with Sodium Thiosulphate
till the solution assumes a light yellow colour.
3. Add 4-5 Starch solution drops (the solution will turn to black/blue colour)
4. Titrate the solution with Sodium Thiosulphate till the solution turn transparent
5. Record the Sodium Thiosulphate, ml
Formula:
ppm Peracetic Acid = ml Sodium Thiosulphate 5 76
NOTES:
- the titration must be performed each time a new tank is installed
- the titration procedure must receive confirmation from the supplier of the concentrated
product
- write down the peracetic acid concentration value on the drum and set it on the Unidox
control panel
Page 10 of 34
3. PROCEDURE B - How to use the object transfer boxes

3.1 OUT to IN object transfer box
The object transfer boxe from the outside to the inside of the machine is installed on the filler
and it is used for introducing items inside the microbiological isolator without breaking its
sterility (i.e.: tools for maintenance operations, material for microbiological verification
procedures, etc.).
PICTURE
PICTURE11
PICTURE 3
PICTURE 2
PICTURE 4
Using procedure:
1. the objects to be introduced must be cleaned and handled with latex gloves; prior to
positioning them into the object transfer box they must be sprayed with ethyl alcohol
(ethyl 70%) and cleaned with a clean wipe.
2. Open the transfer box and put the objects in (PICTURE 1)
3. Close the transfer box and sterilize it with a PAA solution, by using the appropriate
sterilization drum supplied with the rest of the materials (FIGURE 1);
4. After the recommended spraying and contact times, it is possible to open the object
transfer box from the inside of the machine and introduce the objects in the sterile
environment.
Page 11 of 34
In order to load the sterilization drum of the object transfer box with sterilizing solution,
proceed as follows (refer to Figure 1):
FIGURE 1
A: Sterilization tank
B: Level control
C: Air-tight lid
D: Manometer 0-6 bar

E: Rapid spraying connection
F: Rapid pressurization connection
G: Pressure reducer (HMI board)

H: Vent valve
1. Release the residual pressure in the object transfer box tank A through the venting valve H.
Verify that the manometer D indicates 0 bar.
2. Open the air-tight lid C (Picture 2).
3. From the sampling valve installed on the Ecodox, withdraw the hot PAA sterilizing solution
and fill the tank up to half the level control B.
4. Close the air-tight lid C.
5. Via the rapid pressurization connection F, connect the tank with the pressure reducer G,
installed on the filling block. The pressure reducer G must be adjusted at 3 bar.
6. When the manometer D indicates 2,5 bar, remove the pressurizing connector F (Picture 2).
Page 12 of 34
For the spraying phase, proceed as follows:

1. Connect the rapid spraying connector E to the sterilization nozzle P (refer to Figure 2)
positioned on the object transfer box.
2. The valve starts spraying. Wait 2 minutes for the spraying phase and 3 minutes for the
contact time. Remove the rapid connection.
3. The external panel of the object transfer box is fitted with a manual ball valve; this valve is
required to sterilize the fixing ring of the object transfer box. This valve must remain open
for a few seconds during the spraying phase (Picture 4).
NOTES:
- The sterilizing solution must be renewed at least once, every production shift. The
sterilization tank of the object transfer box must be ready for use during the production
phase.
- Always release the pressure of the sterilization tank of the object transfer box prior to
opening it (verify that the manometer indicates 0 bar).
3.2 IN to OUT object transfer box
The object transfer box from inside to outside of the machine must be used for transferring
remainders of production (bottles, caps) without breaking sterility of the microbiological
isolator.
In order to guarantee a correct use of the object transfer box, without risks for the system, the
bags must be always in place. For this reason, every object transfer box is fitted with a
photocell system (Figure 2) that detects the presence of bags. Sensor I and the associated
retroflector M control that bag is correctly positioned on the object transfer box. In the event
that one or more sensors indicate the absence of bags in the object transfer box, the system
generates an alarm BAGS MISSING ALARM. Said alarm stops the machine thereby impeding
the continuation of the phase in progress at the time.
Page 13 of 34
FIGURE 2
I: Bag presence sensor

N: Bag fixing ring
L: Bag (not supplied with the O: Sterilization nozzle
material)
M: Retroreflector
P:
Connection
to
sterilization nozzle
Q: Object transfer box ring

R: Object transfer box
the
In order to install the bag on the object transfer box, proceed as follow:
1. Insert the hem of the bag L on the fixing ring N.
2. Introduce the hem of the bag L on the object transfer box R and position the ring N so as
to fix the bag on the object transfer box.
3. Once it has been positioned, the bag must be sterilized. For the spraying phase , proceed as
described in the previous paragraph How to use the object transfer box for transferring
objects from outside to inside the machine.
For removing materials when in production:
1. Using operator gloves, open the internal lid Q.
2. Put the material to be removed inside the object transfer box
3. Re-close the object transfer box
At the end of production, bags must be removed even if not completely full, they can be left on
the block and re-used only if empty.
In case it is necessary to replace a bag when in production, ensure the internal lid of the
object transfer box is close before remove the bag.
Page 14 of 34
4. PROCEDURE C Cleaning and replacement of bottle and cap

treatment nozzles
If the sterilizer or rinser nozzles become clogged during a production run, it is possible to clean
or replace them without breaking sterility of the microbiological isolator.
In
-
order to do it, sterilizer and rinser are fitted with dedicated working stations , where to:
keep the spare nozzles
recover the clogged nozzles
clean the clogged nozzles with the appropriate tools (stainless steel blade)
4.1 HOW TO PROCEED IF AN ALARM OCCOURS WHEN IN PRODUCTION

In case a clogged nozzle alarm from smart sensor appears when in production:
1. Verify the clogged nozzle number on HMI.
2. Jog the line in manual mode until the clogged nozzle gets the working station.
3. Remove the clogged nozzle by making sure not to loose the strainer housed inside and
replace it with a clean nozzle (PHOTO 1). NOTE: the nozzle must be manually tightened to
its own stainless steel holder tube, in order to ensure that it is not tightened too much and
that it does not break.
PHOTO 1
PHOTO 2
4. Store the clogged nozzle in the dedicated rack (PHOTO 2).

5. Perform a calibration of the SMART SENSOR by selecting the appropriate key on the
supervision.
In case a clogged nozzle is detected by visual inspection, the operator must immediately
stop the machine and follow the same procedure.
Page 15 of 34
NOTES:
- at the end of production cycle, prior to starting the washing/sterilization cycles, clean the
clogged nozzles by using the appropriate steel blade (Picture 3).
- before starting a sterilisation cycle check for the availability of spare nozzles into the
sterilzer and rinser racks. If there are no nozzles, put some of them immediately, in order to
sterilize them during the sterilisation cycle
- take extreme care when cleaning the nozzles, to avoid damaging the nozzle tip: a damage
could lead to a poor spray pattern!
PHOTO 3
4.2 EFFICENCY MONITORING OF THE BOTTLE INTERNAL TREATMENT NOZZLES

In order to monitor the efficiency of the nozzles, when in PRODUCTION, the operator can
check out the dedicate page (Nozzles Treatment Efficency %) on the HMI.
Three efficiency levels can be displayed for each nozzle (PHOTO 4):
A. in the area between the 2 yellow thresholds (= blue bar), the efficiency is good and the
nozzle is working correctly;
B. in the area out of the red thresholds (below or above = red bar), the efficiency is bad
and the nozzle is not working correctly. The smart sensor gives an ALARM and the filling
bloc stops;
C. in the area between a yellow and a red threshold (= yellow bar), the efficiency is out
of the correct range, but sterilization of the bottle is still ensured. The smart sensor gives
a WARNING signal.
Page 16 of 34
PHOTO 4
4.3 PERIODICAL CLEANING OF BOTTLE INTERNAL STERILIZATION AND RINSING

NOZZLES AND STRAINERS
A periodical cleaning of the nozzles is strongly recommended in order to:
- maintain the correct spray efficiency
- prevent the machine from stoppage due to clogged nozzle alarms
The suggested procedure to perform such periodical cleaning is the following:
A. before the end of production, operator must verify on the HMI for any nozzle in WARNING
condition (efficiency level C);
B. at the end of production, before starting the CIP/COP cycles, remove those nozzles in
WARNING condition, taking care to extract, one by one, their strainers;
C. put nozzle and strainers into a cup with some PAA solution (from Ecodox or prepared
manually);
D. wait 5 minutes for contact time and then clean the nozzles by blowing them with
compressed air from the tip, in counter-flow;
E. Clean the strainers by rubbing them with rough paper;
F. Re-assemble strainers and nozzles and re-install them on the machine.
Page 17 of 34
NOTE:
- disposable sterile gloves or latex gloves disinfected with ethyl alcohol (70%), must always
be worn when performing these operations;
- whenever an intervention is done on Ecodox, sterilizers, rinser or caps sterilizer pipeline, it
is recommended to remove nozzles from the line where the intervention took place and
flush it carefully with water; those interventions in facts could release residuals into the
pipeline (i.e. pipes cutting, weldings, ecc.).
4.4 PERIODICAL CLEANING OF NOZZLES FOR BOTTLE EXTERNAL STERILIZATION,
CAPS STERILIZATION, NECK&BODY RINSING AND BASEMENT WASHING CIRCUITS
For cleaning/replacing the following nozzles:
- bottle external sterilization circuit
- cap sterilization and rinsing circuits
- bottle neck rinsing system
- basement washing circuit
it is necessary to wait the end of production, once the machine manual cleaning has been
completed (bottles and caps removal) and before starting the CIP/COP cycles.
A periodical cleaning, as ordinary maintenance activity, is strongly recommended:
- every 3 months for bottle external sterilization and basement washing nozzles
- every 30 days for cap sterilization/rinsing nozzles and neck rinsing nozzles.
For cleaning procedure refer to section 4.3 (remind: bottle external sterilization and cap
sterilization nozzles do not have strainers).
NOTE:
- disposable sterile gloves or latex gloves disinfected with ethyl alcohol, must always be worn
when performing these operations;
- whenever an intervention is done on Ecodox, sterilizers, rinser or caps sterilizer pipeline, it
is recommended to remove nozzles from the line where the intervention took place and
flush it carefully with water; those interventions in facts could release residuals into the
pipeline (i.e. pipes cutting, weldings, ecc.).
Page 18 of 34
5. PROCEDURE D Sterile water and empty bottles sampling for

microbiological analysis
The microbiological analyses procedures are described in detail in the document Guide lines for
microbiological sampling and analyses; hereunder are described methods for withdrawing
sterile water and empty capped bottle samples, whose will be successively analysed.
5.1 SAMPLING OF STERILE WATER FROM NECK RINSING MANIFOLD INTO THE
FILLER
To take sterile water samplings, select the dedicated key on the HMI (PHOTO 1), when the
PRODUCTION mode is active. Water has to be collected using sterile containers.
PHOTO 1
Page 19 of 34
5.2 EMPTY CAPPED BOTTLES SAMPLING

In order to withdraw the empty capped bottles, the machine must be in PRODUCTION mode:
select the appropriate key on the HMI (PHOTO 2) after having set the number of empty bottles
to withdraw into the dedicated space.
NOTE: prior to performing the sampling, prepare a plastic bag for collecting the empty capped
bottles exiting the tunnel. The plastic bag must be sprayed with ethyl alcohol and latex gloves
must always be worn when performing these operations.
Once the bottles are withdrawn, they must be quickly brought to the laboratory.
PHOTO 2
Page 20 of 34
6. PROCEDURE E Verification of the peroxide residuals into the bottle

This verification must be performed on empty bottles, because the presence of the product
could jeopardise the peroxides residual reading.
The following material is required for the analysis:
-
25 ml pipette
de-mineralised water
Merckoquant Peroxid Test strips for the of the total peroxides analysis
6.1 PROCEDURE
Analyse one bottle at a time:
1. Remove the cap and pour 10 ml (25 ml for those formats bigger than 500 ml) of demineralised water in the bottle;
2. Re-close and swirl the bottle in order to completely rinse the internal surfaces (including
the cap);
3. Take a Merckoquant Peroxide Test strip and re-open the bottle;
4. Rapidly dip the strip in the rinsing water and then shake the strip in order to remove the
water in excess;
5. wait 15 20 seconds and then proceed with the concentration reading (ppm), comparing
the strip colour with the dedicated index scale;
6. for the residual calculation it is necessary to consider the total volume of the bottle, as
per the following equation.
R = C (B/A)
Key:
A = bottle volume
B = ml of de-mineralised water used for the analysis
C = measured peroxides concentration (ppm)
R = residual referred to the total volume of the bottle
The peroxides residual must be lower than 0,5 ppm.
Page 21 of 34
7. PROCEDURE F COP/SOP rotary nozzles replacement

7.1. Verification of a pressure or flow alarm during the SOP cycle.
In the event an alarm occurs for low pressure or low flow rate during the environmental
sterilization cycle (SOP), it is necessary to proceed with the following verifications:
1. verify the correct functioning of the sensor that has given off the alarm; if the sensor
demonstrates anomalies, advise the person in charge during this shift, and successively
contact the maintenance personnel or consult the specific use and maintenance manual.
WARNING!
In case of complete replacement it is necessary to perform the calibration of the new
sensor and repeat the SOP cycle.
2. verify the correct functioning of the Unidox (if the SOP is in the sterilization phase) or the
Unitherm H (if the SOP is in the rinse phase); if the verified unit shows any anomalies,
advise the person in charge during this shift and successively contact the maintenance
personnel or consult the specific use and maintenance manual.
3. verify the correct functioning of all the nozzles controlled by the sensor that has given off
the alarm; in the event that clogged or danmaged nozzles are found, it will be necessary
to replace them according to the procedure described in section 7.2.
At the end of all the above mentioned verifications and possible associated operations, it will be
necessary to reset the alarm and re-start the filling bloc.
7.2. Replacement of clogged or damaged rotating nozzles
This procedure is valid for replacing the nozzles:
- prior to starting the environmental foaming cycle (COP), in this case point A must not be
considered;
- prior to starting the SOP cycle
- SOP started
A. If the alarm occurred during the sterilization phase, it is necessary to wait at least 5
minutes before opening the machine, in order to permit the microbiological isolator
to partially remove the peracetic acid vapours from inside.
B. Following the instructions of Table 1 (see page 4), open the hatch nearest to the nozzle
(or nozzles) to be replaced.
C. Disinfect the nozzle to be installed with ethanol (or the nozzles) and the equipment
necessary for the replacement.
D. Perform the replacement.
E. Re-close the hatch.
Page 22 of 34
8. PROCEDURE G Replacement of the sterile filter cartridges on

Uniflux AS and Uniflux Spin
8.1 UNIFLUX SPIN
8.1.1 AIR and GAS NITROGEN sterile filters replacement
Replacement of AIR and NITROGEN sterile filters occour when:
- Cartridges working life expires
- Cartridges are dirty/clogged or damaged
8.1.1.1 Replacement when the working life expires
The working life of filter cartridges is automatically monitored and can be verified onto the
dedicated page of SERVICE menu of the filler: a sterilization cycles counter is displayed with
filters dwell time at T>100C.
When said counter reaches 50 hours, a pop-up message appears onto the HMI with the
request to replace the filter cartridges.
How to proceed for the replacement:
A. filling block must be on rest, with no cycles selected;
B. ensure that the filters are completely depressurized
C. prearrange a new cartridge (open the package without extracting the cartridge)
D. open the filter housings (K06 and K07 for AIR; HFN01 and HFN02 for NITROGEN);
E. remove and eliminate the primary filter (K06 for AIR; HFN01 for NITROGEN)
cartridge;
F. after having put on a pair of latex gloves, move the secondary filter (K07 for AIR;
HFN02 for NITROGEN) cartridge on the primary filter
G. install the new cartridge on the secondary filter;
H. re-close the filter housings and pressurize the circuit.
I. Reset the dwell time counter onto the dedicated SERVICE page
NOTE:
- cartridges replacement must be properly recorded on a dedicated production/mainteinance
logbook
- if the pop up message appears during a sterilization, it is possible to proceed with said cycle
and perform the replacement at the end of the next production, that is before the new filter
sterilization cycle.
8.1.1.2 Replacement in case of dirty/clogging or damaging
Dirty or damaged filters can be detected with a periodical visual inspection as recommended by
the ECH document.
Extreme dirty could lead to filters clogging, in that case AIR or NITROGEN low pressure alarms
can appear.
Page 23 of 34
How to proceed for visual inspection and replacement:

B. ensure that the filters are completely depressurized
C. prearrange new cartridges (open the package without extracting the cartridges)
D. open the filter housings (K06 and K07 for AIR; HFN01 and HFN02 for NITROGEN)
and visual inspect cartridges;
E. in case one or both filters are dirty or damaged, they must be replaced. Operator
has to wear latex gloves during the operation
F. re-close the filter housings and pressurize the circuit.
G. Reset the dwell time counter onto the dedicated SERVICE page
NOTE:
logbook
8.1.2 WATER sterile filters replacement (IF IN THE SCOPE OF SUPPLY)
Like those for air and nitrogen, also WATER sterile filters, installed on the water micro-filtration
system, replacement occours when:
- Cartridges working life expires
- Cartridges are dirty/clogged or damaged
8.1.2.1 Replacement when the working life expires
The working life of filter cartridges is automatically monitored and can be verified onto the
dedicated page of SERVICE menu of the filler: there is a sterilization cycles counter that is
incremented when the average actual PAA concentration is higher that the set point.
When said counter reaches 30 hours, a pop-up message appears onto the HMI with the
request to replace the filter cartridges.
How to proceed for the replacement:
B. ensure that the filters are depressurized
C. prearrange a new cartridge (open the package without extracting the cartridge)
D. open the filter housings (HFW03 and HFW04);
E. remove and eliminate the primary filter (HFW03) cartridge;
F. after having put on a pair of latex gloves, move the secondary filter (HFW04)
cartridge on the primary filter
G. install the new cartridge on the secondary filter;
H. re-close the filter housings and pressurize the circuit.
I. Reset the dwell time counter onto the dedicated SERVICE page
Page 24 of 34
NOTE:
logbook
- if the pop up message appears during a sterilization, it is possible to proceed with said cycle
and perform the replacement at the end of the next production, that is before the new filter
sterilization cycle.
8.1.2.2 Replacement in case of clogging or damaging
The filters clogging condition is automatically checked by continuos monitoring of the pressure
gap through the filters themselves. In case of cartridge clogging, a pop-up message appears
onto the HMI with the request to inspect the filters.
To verify the filters integrity instead, there is a specific automatic cycle. Such cycle should be
run at the end of production, once COP cycle of the filling block has been performed or, in any
case, before starting the water micro-filtration system sterilization; that is because the integrity
check cycle make the system losing sterility.
When an inspection requested message or an integrity alarm occour, proceed as following:
B. ensure that the filters are completely drained from water
C. prearrange new cartridges (open the package without extracting the cartridges)
D. open the filter housings HFW03 and HFW04) and visual inspect cartridges;
E. if the message/alarm occoured for filter HFW03:
o move the cartridge of filter HFW04 onto filter HFW03
o put a new cartridge onto filter HFW04
if the message/alarm occoured for filter HFW04: both HFW03 and HFW04 cartridges
have to be changed (according to 8.1.2.1 the HFW03 cartridge is the older one)
Operator has to wear latex gloves during the operation
F. re-close the filter housings and pressurize the circuit.
G. Reset the dwell time counter onto the dedicated SERVICE page
8.2. UNIFLUX AS (IF IN THE SCOPE OF SUPPLY)
For monitoring and mainteinance puproses of the Uniflux AS NITROGEN sterile filters (HFN01
and HFN02), please refer to section 8.1.1.
Page 25 of 34
9. PROCEDURE H Sampling of inlet and outlet Active Carbons Filter

water
9.1 PREMISE
The determination of the acetic and peracetic acid contents in the Active Carbons Filter inlet
and outlet water is done in order to verify the good working of the filter itself.
This verification has to be done during the PRODUCTION phase, by taking one sample every 4
hours.
9.2 MATERIALS
Colorimetric strip kit, with different scales, for Peracetic Acid determination up to 160 ppm:
-
INSTA TEST-PEROXIDE-LA MOTTE

PEROXIDE TEST-MERK
Chemical reagents for Peracetic Acid determination with a concentration greater than 160 ppm:
-
Sulphuric Acid,H2SO4, (25%, v/v)

Potassium Iodide, KI, in solid form or solution (166 g/l)
Potassium Permanganate, KMnO4, (0,1N)
Sodium Thiosulphate Solution, Na2S2O3, (0,1N)
Starch (Thyodene Solution)
Chemical reagents for Acetic Acid determination:

-
Sodium hydroxide, NaOH, (0,1N)
9.2.1 Peracetic Acid Methods

1) Draw 10 mL of H2O (better if in a closable container) from DD1 SV W03 on carbon filter inlet
and from DD1 SV W04 (see at P&ID drawing 4-XXXXX) on the carbon filter outlet:
Immerge the reactive part of the strip for one second in the sample to be analysed
Shake off the excess of water and wait 10 seconds for the reaction
Proceed in reading the concentration, by cross comparing the colour of the strip with the
colour scale on the strip packaging.
NOTES
- test has to be made in an environment free of peroxide vapours, better under a laminar
flow hood;
- if the sample concentration turns out to be greater than 160 ppm, proceed with the same
method used to determine the hydrogen peroxide and the peracetic acid concentration at
the unidox.
Page 26 of 34
2) Draw 20 mL of H2O from DD1 SV W04 on carbon filter inlet and from DD1 SV W05 (see at
P&ID drawing 4-XXXXX) on the same filter outlet:
Add 20 ml of the Sulphuric Acid solution
Add 10 ml of sample
Keeping the sample under continuose stirring, titrate with Potassium Permanganate
(KMnO4) till the solution turns to a pale violet colour
Record the Potassium Permanganate, ml
Formula:
ppm Hydrogen Peroxide = ml Potassium Permanganate X 5 X 34
Add to the previously titrated solution 10 ml of Potassium Iodide, KI
Titrate the solution with Sodium Thiosulphate till the solution assumes a light yellow
colour.
Add 4-5 Starch solution drops (the solution will turn to black/blue colour)
Titrate the solution with Sodium Thiosulphate till the solution turn transparent
Record the Sodium Thiosulphate, ml
Formula:
ppm Peracetic Acid = ml Sodium Thiosulphate X 5 X 76
PLEASE PAY ATTENTION: BE CAREFUL WHEN ADDING THE REAGENTS, BECAUSE WITH
SUCH LOW CONCENTRATIONS, THE TITRATIONS CALL FOR ONLY A FEW DROPS TO REACT.
9.2.2 Acetic Acid Method
Draw 25 mL of H2O from DD1 SV W04 on carbon filter inlet and from DD1 SV W05 (see at P&ID
drawing 4-XXXXX) on the same filter outlet.
Add some drops of phenoftaleina indicator.
Drip through calibrated burette, the NaOH 0,1 M (or 0,01 M) solution until the
equivalence point (tone from white to pink)
Formula:
N moles CH3COOH = dripped volume (L) ) NaOH x molarity NaOH
Molarity CH3COOH = n moles CH3COOH / drawn sample volume (0,025 L)
ppm CH3COOH = Molarity CH3COOH x 60.000 (molecular weight CH3COOH)
Page 27 of 34
9.3 CALIBRATION OF THE WATER pH METER

To ensure the correct working of the carbon filter, the pH-meter PHW01 must be properly
calibrated also.
In order to not jeopardise the integrity of the probe installed on the machine, it is not
appropriate to follow the standard calibration procedure as a routinary verification.
The following procedure is to be applied during the line cleaning-sanitation cycles.
Required materials:
- a laboratory pHmeter, correctly calibrated
- a 100 ml.becker
Procedure:
1. open the sampler VMW04 and allow the water to run for at least 10 seconds;
2. rinse the becker thoroughly and then withdraw a sample of water;
3. measure the pH of the sample with the calibrated pHmeter;
4. compare the measured value with the pH value read by the PHW01 and displayed on the
display of the actual sensor :
- If the difference between the two pH values is less than 0,5, the instrument
is reading properlyand no further actions are required;
- If the difference between the two pH values is greater than
0,5, it is
necessary to carry out a calibration of the pHmeter installed on the machine: uninstall
the probe with care and follow the calibration procedure described in the instrument
manual.
Page 28 of 34
10. PROCEDURE I Microbiological isolator HEPA filters replacement

The microbiological isolator is an environment with different working areas, which are
maintained at a pressure constantly higher than the external environment pressure.
When entering the isolator, air is processed by a system of filters with an increasing efficiency:
FILTRATION STEP 1 - Pre-filter; filtration efficiecy of 90% on particles with 3-10 m diameter
FILTRATION STEP 2 - Bag filter; filtration efficiecy
95% on particles with a diameter
0.3 m
FILTRATION STEP 3 - two HEPA filters (High Efficiency Particulate Air); each one with a
filtration efficiecy 99,95% on particles with a diameter 0.3 m
10.1 FILTERS MAINTENANCE
Pre-filters
Once per month they must be visually inspected: if in good condition (quite clean and not
broken), they can be used for another month (max 2 months) but after a careful cleaning
with compressed air, blown in counter-flow with respect to the normal working flow.
Bag filters
They must be changed every 6 months maximum.
HEPA filters
The first HEPA filter must be replaced every year.
The second HEPA, also called terminal HEPA because the last one before entering the sterile
environment, must be replaced after 3 years maximum.
10.2 RULES OF CONDUCT
Store all the spare filters in a clean and dry environment and leave them inside the original
packaging.
It is necessary to pay great attention when replacing a filter: in order not to affect the asepsis
level of the system, the operator has always to wear latex gloves disinfected with ethyl alcohol
and he has to reduce as much as possible the handling of the filters.
Replacemet of HEPA filters must be done after a CIP/COP cycle has been conducted and before
running the next SIP/SOP cycles. For the replacement proceed as described hereunder:
1. turn OFF the microbiological isolator pressurizer or the pressurizer where the filter/filters
have to be replaced
2. remove filter/filters from the housing
3. spray the housing with ethyl alcohol and clean with a wipe
4. install the new filter/filters
5. restart the pressurizer
Page 29 of 34
11. PROCEDURE J Capping Heads sterilization procedure

Further to the ordinary maintenance operations, capping heads have to be periodically
sterilized in autoclave.
11.1 STERILIZATION PROCEDURE
After having performed the ordinary maintenance operations according to the AROL USE
AND MAINTENANCE MANUAL, capping heads can undergo a sterilization process:
1. put the capping head and its chuck into a plastic bag for autoclave (PHOTO 1);
alternatively install the chuck on the head and wrap everything with aluminum foil.
If aluminum foil is used, do not tight it, so as to allow the steam to flow trough the
envelope when in the autoclave
2. Sterilise in autoclave at 121C 20 minutes
3. Upon completion of the cycle, let the heads to cool down
4. bring the heads on the line and re-install them
PHOTO 1
NOTE: when delivering the heads back to the filling block, they must be kept
wrapped in the plastic bag or in the aluminium foil. Bags must be removed only once
the heads are inside the isolator, under the laminar flow of the HEPA filters.
Page 30 of 34
11.2 STERILIZATION FREQUENCY

Capping heads types PK510/PK515/525: every 4 months
Capping heads type PKEE: this type (installed on Equatork PK Eleseptic cappers) does
not need sterilization
Recommendation is to manage the sterilization procedure of capping heads, according to the
following table:
CAPPING
HEAD No.
AUTOCLAVING
PLANNED FOR:
AUTOCLAVING
DATE
OPERATOR
SIGNATURE
MONTH/YEAR
LAB
TECHNICIAN
SIGNATURE
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
Page 31 of 34
12. PROCEDURE K Operations required for a scheduled Production

Long Rest
For a Production Long Rest it is meant a scheduled line production stop, longer than 2
months.
12.1 PRODUCTION LONG REST PREPARATION ACTIVITIES
At the end of last production run, once standard microbiologival samplings have been
performed:
1. Complete removal of bottles, caps and any other production residual, as per the
routinary operations.
2. Execution of automatic CLEANING cycles (CIP/COP).
3. Execution of automatic STERILIZATION cycles (SIP/SOP).
4. Execution of a second Environmental Sterilization Cycle (SOP).
5. Unitherm H and Ecodox must be stopped and drained.
If a water microfiltration system is present instead of Unitherm H, it must be drained
and its filters removed (new filters must be installed at production restart)
6. Let the bloc rest for 48 hours with the microbiological isolator running normally, to
allow for a complete drying of all external surfaces.
7. After 48 hours have elapsed, close with a plastic cover the inlet of sterilizer and the
filler exit tunnel and with a plastic film the inlet of Sterilcap.
8. Shut down the microbiological isolator.
9. Close, by manual forcing, the automatic valves of all the bloc drainages.
10. Shut off all the utilities.
11. Manual drainage (undoing some of the fittings) of the lowest parts of the piping.
12. Shut down of air conveyors and caps hopper/elevator pressurizers.
12.2 PRELIMINARIES TO PRODUCTION RESTART
To prepare the filling block for production restart:
1. Manual clean and disinfect air conveyors and caps hopper/elevator with a 70%
solution of isopropyl alcohol (70% ethylic alcohol solution will work as an
alternative).
2. Removing of plastic covers and films from sterilizer inlet, exit tunnel and Sterilcap.
3. Switch on air conveyors and caps hopper/elevator pressurizers.
4. Switch on all the utilities.
5. Switch on the microbiological isolator and keep it on for 24 hours.
6. After 24 hours, check the HEPA filters integrity with a particle counter, according to
the ECH document. In case of filters out of specification, those have to be replaced
and their housings cleaned with a 70% solution of isopropyl alcohol (70% ethylic
alcohol solution will work as an alternative).
7. Perform Unitherm H CIP/SIP cycles.
If a water microfiltration system is present instead of Unitherm H: install new
filters and run a Sip cycle
8. Perform automatic CLEANING cycles (CIP/COP).
Page 32 of 34
9. Perform 2 complete automatic STERILIZATION cycles (SIP/SOP) one by the other.

NOTE
Before production restart, it is recommended to have spare parts for at least the following
items:
- HEPA filters
- Uniflux Spin/AS filters
- Sterilcap/sterilizer/rinser nozzles
- Environmental foaming/sterilization rotating nozzles
12.2 SCHEDULED PRODUCTION REST SHORTER THAN 2 MONTHS
For scheduled Production Rest shorter than 2 months, it is recommended to stop the line
according to the routinary operations and keep the microbiological isolator on during all the
period, in order to keep the filling block environment under control.
Air conveyors and caps hopper/elevator can be shut down.
If a water microfiltration system is present, it must be sterilized every 15 days.
Routinary operations have to be put in place at the production restart. Air conveyors and
caps hopper/elevator must be cleaned and disinfected
Page 33 of 34
13. PROCEDURE L Gloves integrity check

14. PROCEDURE M Centring cups and air-vent tubes changeover
Page 34 of 34

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ASEPTIC LINE

Aseptic Line Procedures Handbook_PL01284_THP_Rev0

OPERATOR STANDARD ACTIVITIES

PROCEDURE A Manual titration of the sterilizing solution

PROCEDURE B How to use object transfers box

PROCEDURE C Cleaning and replacement of bottle and cap treatment nozzles

PROCEDURE D Sterile water and empty bottles sampling for Lab

PROCEDURE E Verification of peroxide residual into the bottle

PROCEDURE F COP/SOP rotary nozzles replacement

PROCEDURE G Replacement of the sterile filter cartridges on Uniflux

PROCEDURE H - NOT IN THE SCOPE OF SUPPLY

10. PROCEDURE I Microbiological isolator HEPA filters replacement

11. PROCEDURE J Capping heads sterilization procedure

12. PROCEDURE K Operations required for a Production Scheduled Long Stop

13. PROCEDURE L NOT IN THE SCOPE OF SUPPLY

14. PROCEDURE M - NOT IN THE SCOPE OF SUPPLY

Machines List of the Aseptic Line

Line General Flow Sheet

Guidelines for microbiological samplings and analysis

Essential Controls Handbook

Recommended List of Chemicals

Aseptic Laboratory Specification

Line operational and QA checks

Aseptic Line Procedures Handbook_PL01284_THP_Rev0

1. OPERATOR STANDARD ACTIVITIES

Aseptic Line Procedures Handbook_PL01284_THP_Rev0

1.2 INTERVENTIONS INSIDE THE ASEPTIC BLOC AND AUTOMATIC ACTIONS

interventions lasting less than 15 minutes

1. Before opening the hatch:

interventions lasting over than 15 minutes

1. Before opening the hatch:

Aseptic Line Procedures Handbook_PL01284_THP_Rev0

Table 2 FILLING BLOCK IN PRODUCTION OR IN SANITATION

1. Wait for PAA vapours to be exhausted:

1. Wait for PAA vapours to be exhausted:

Topening 120 s Topening 120 s

LOW ACID / FDA PRODUCTION WITH CAPS DOWNLOAD SYSTEM AVAILABLE

Aseptic Line Procedures Handbook_PL01284_THP_Rev0

LOW ACID/FDA PRODUCTION WITHOUT CAPS DOWNLOAD SYSTEM AVAILABLE

machine in SANITATION mode

1.3 END OF PRODUCTION ACTIVITIES

end of microbiological sampling operations, operator have to:

Aseptic Line Procedures Handbook_PL01284_THP_Rev0

2. PROCEDURE A Manual titration of PERACETIC ACID (PAA) and

Aseptic Line Procedures Handbook_PL01284_THP_Rev0

2.1.2 Peracetic acid titration

Aseptic Line Procedures Handbook_PL01284_THP_Rev0

Before titration, it is necessary to make a dilution 1:100 of the H2O2 concentrated

Aseptic Line Procedures Handbook_PL01284_THP_Rev0

2.3.1 Hydrogen peroxide titration

Aseptic Line Procedures Handbook_PL01284_THP_Rev0

3. PROCEDURE B - How to use the object transfer boxes

D: Manometer 0-6 bar

G: Pressure reducer (HMI board)

Aseptic Line Procedures Handbook_PL01284_THP_Rev0

For the spraying phase, proceed as follows:

Aseptic Line Procedures Handbook_PL01284_THP_Rev0

I: Bag presence sensor

Q: Object transfer box ring

Aseptic Line Procedures Handbook_PL01284_THP_Rev0

4. PROCEDURE C Cleaning and replacement of bottle and cap

4.1 HOW TO PROCEED IF AN ALARM OCCOURS WHEN IN PRODUCTION

4. Store the clogged nozzle in the dedicated rack (PHOTO 2).

4.2 EFFICENCY MONITORING OF THE BOTTLE INTERNAL TREATMENT NOZZLES