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Purified Water System


Learn all about Purified Water System including regeneration of Cation, Anion & Mix Bed Ion exchanger, alum dosing, Sodium Hypochlorite dosing, Carbon Bed, frequencies and acceptance criteria.

PURIFIED WATER SYSTEM IN PHARMACEUTICALS

REGENERATION OF RESINS

REGENERATION OF CATION EXCHANGER.

NOTE : DURING REGENERATION OF CATION BED ENSURE THAT THE DEGASSER PUMP IS "OFF".
•  Take approx. 28 L D.M. water in HDPE regeneration tank. Add approx. 14 litres of 33% Hydrochloric acid solution to it. Mix. Keep it ready for injection. (Quantity requirement to be calculated as per system design)
•  Open raw water inlet valve. Open valves of A. C. Filter.
•  Check whether all the valves of cation Exchanger are closed.
•  Dip the free end of PVC tube attached to valve of cation exchanger into the Hydrochloric  acid solution.
•  Open valves & control an injection rate of Hydrochloric acid solution into the cation exchanger required as per the system design. (in order to suck the acid solution by Venturi principle - direction of flow is with gravity during regeneration & against gravity during normal operation).
•  As soon as the injection of hydrochloric acid solution is over, close valve & rinse for 20 minutes.
•  After 20 minutes close the valves & up rinse the Cation exchanger.
•  Check the pH. Continue rinsing until the pH reaches between 2.0 to 3.0. If the pH is less than 2.0, continue up rinsing for some more time.
•  Frequency of regeneration : Twice a week.

REGENERATION OF ANION EXCHANGER.

NOTE : DURING REGENERATION OF ANION BED ENSURE THAT THE DEGASSER PUMP IS "OFF".
•  Take approx. 36 litres of D. M. Water in HDPE regeneration tank.
Dissolve approx. 4 kg of Sodium Hydroxide into it. (Quantity requirement to be calculated as per system design) 
•  Open raw water inlet valve. Check whether valves of A.C. filter of the cation exchanger are open & all the valves of Anion exchanger are closed.
•  Dip the free end of PVC tube attached to Anion exchanger into the Caustic solution.
•  Open valves & control the opening of valve in such a way so as to maintain an injection  rate of 3.5 litres/minute of caustic solution into the Anion Exchanger, required as per the system design. (in order to suck the acid solution by Venturi principle-direction of flow is with gravity during  regeneration & against gravity during normal operation).
•  As soon as the injection of Caustic solution is over immediately close valve  & down rinse Anion exchanger at least for 30 minutes.
•  After 30 minutes, close valve. Open valve for  up rinsing of exchanger for 15 minutes.
•  During up rinsing, switch "ON" the main switch as well as the switch of panel board in order to start the de-gasser pump.
•  Ensure that all other switches are in "OFF" position & level of water is maintained more than half in the de-gasser tank.
•  Check conductivity & pH. Conductivity should be less than 30 mho/cm & pH between 7.5  & 9.5. If the conductivity is higher than 30 mho/cm or pH is higher than 9.5, up rinsing may be continued for some more time.
•  Frequency of regeneration : Twice a  week .

REGENERATION OF MIXED BED ION EXCHANGER

•  Take approx. 6 litre of D. M. water in HDPE regeneration tank & add approx. 3 litres of 33 % Hydrochloric acid Solution to it & mix it. (Quantity requirement to be calculated as per system design)
•  Dip the free end of PVC tube attached to valve of Mixed Bed ion exchanger in to the solution  prepared.
•  Take 10 litre of D. M. Water in another HDPE regeneration tank. Dissolve 1.25 kg of Sodium hydroxide into it. (Quantity requirement to be calculated as per system design)
•  Dip the free end of PVC tube attached to valve of Mixed Bed ion exchanger into the solution prepared.
•  Open raw water inlet valve.
•  Check whether the valves of A.C. filter, valves of cation exchanger, valve between De-gasser tank & de-gasser pump, of Anion Exchanger are open.
•  Switch "ON" the main switch as well as the switch of panel board in order to start the  de-gasser pump. Ensure that all other switches are in "OFF" position & level of water is maintained more than half in the de-gasser tank.
•  Close all valves in use. Open valves for backwash of Mixed Bed ion exchanger for 10 minutes. Then close all the valves of mixed Bed ion exchanger for 5 minutes for setting of mixed resins.
(This operation helps to segregate the anion & cation exchange resins in the mixed bed depending on their density differences.
•  Open valves & control opening of valve such a way that the caustic injection should take minimum 10 minutes.
•  As soon as the injection of caustic solution is over, immediately close valve & rinse for 10 minutes.
•  Open valves, control opening of valve such that the Acid injection takes at least 10 minutes in to Mixed Bed ion exchanger.
•  As soon as the injection of Hydrochloric Acid solution is over, immediately close valve 12 for rinsing of  acid for 10 minutes.
•  After 10 minutes close valves, start the blower for 10 minutes & open valves for allowing air to escape . This will re-mix the resin bed.
•  Immediately open valves to give final rinsing. After 15 minutes, check conductivity & pH; the conductivity should be less than 1 mho/cm & pH between 6.5 to 7.2.
•  Frequency of regeneration : Twice a week
•  Check the level of the Alum solution in the white HDPE tank below the dozer, the level should be more than 1/4th of volume of the tank. If not, then prepare Alum solution as per requirement.
•  Check whether the dozer pump is primed; by switching "ON" the dozer the liquid should be visible in the discharge line. Carry out the priming if required. 
•  Adjust the stroke of the pump through the stroke scale to get the desired rate. The stroke  rate is adjusted to get the required quantity of alum. (Usually the stroke is kept at 35 & the speed is adjusted to 25 and the time is set suitably to achieve dozing of 10 ppm.)

Related: Importance and Method of De-gassing in Purified Water System

Priming Procedure :

•  Remove the four-function valve assembly.
•  Pour the dozing solution through the suction line till the head is filled.
•  Fit the four-function valve assembly.
•  Switch "ON" the power, pull the pressure release knob (red & black) out, until the Alum solution come out in the discharge tube. 

Preparation of Alum solution:

•  Weigh approx. about 1.5 kg. of Alum in a polybag .
•  Take about 70 L of water in a 100 L of HDPE container & add Alum.
•  Stir vigorously to dissolve. Make up the volume to 100 L in HDPE container, stir & then  transfer the solution to 100 L HDPE container below the dozer.

CALCULATION OF QUANTITY OF ALUM DOSING

Example :
Water Consumption per hour                         =       Approximately 5000 L.
Required dosing                                                 =       10 PPM  i.e. 10 g for 1000 L.
                                                                                       50 g for 5000 L.
But the Alum used for dosing is 1.5 % w/v
                                                                                         100
Therefore Alum Dosing required / hr         =   50 X  ----   =  3300  ml.
                                                                                         1.5

Adjustment of dozer pump knobs :

Example :
Full capacity of dozer pump = 40 L per hour if both "Speed" & "Stroke" knobs are at 100% of full rating. Say……
Speed ( Stroke frequency adjustment) is kept at 25 i.e. 25% of full rating.
Stroke( Stroke length adjustment ) is kept at 35 i.e. 35% of full rating .
Therefore Capacity of dozer pump = 25% times 35% of full rating .    
                             25       35
                        =  ----- x  ----   x   40000
                            100     100
The same is checked for actual output.
•  Check TDS of feed water before unloading into the underground tank, using a portable meter (Limit : Not more than 150 ppm) & record the same. If the TDS is more than 150 ppm, do not proceed further.
•  Take sodium hypochlorite solution, previously analysed for free chlorine, 
•  For quantity refer " Free chlorine Percentage - Quantity of Hypochlorite required " Chart.
•  Open the inlet of underground tank.
•  Add Sodium Hypochlorite solution into the inlet pipe of the tank. Record the quantity of sodium hypochlorite solution added.

Related: Chlorination and De-chlorination of Water System

QUANTITY OF SODIUM HYPOCHLORITE (COMMERCIAL GRADE)

REQUIRED FOR DOSING 10000 LIT OF WATER.

1.  Free chlorine required is generally 1 to 3 PPM
       i.e    1 Kg in 10,00,000 L
               10 g in 10,000 L (1 tanker)
2.  Free chlorine present in sodium hypochlorite varies between 6.5% to 13% w/v
If free chlorine is 10% w/v, to maintain 1 PPM of chlorine, sodium hypochlorite required is  
            10 X 100
            -----------   =  100  ml   
                 10   
Use following charts for calculating sodium hypochlorite dosing. 
PERCENTAGE OF FREE
CHLORINE PRESENT
SODIUM HYPOCHLORITE
REQUIRED FOR DOSING
6% to 7%
7% to 8%
8% to 9%
9% to 10%
10% to 11.5%
11.5% to 13%
300 ml
275 ml
100 ml
100 ml
100 ml
100 ml
Measure the flow rate of water through the UV light chamber. This to be done by collecting water for one minute in a bucket and checking the volume in litres. Calculate the quantity of water per second by dividing with 60. This gives flow rate in liters per second (LPS).
Note the volume of UV light chamber in liters.
Calculate the residence time of water in UV light chamber by following formula…
                                   Volume of UV light Chamber in liters
Residence Time  =  ---------------------------------------------
                                                Flow rate (LPS)
Minimum dosage required (at 2538 Angstrom) for effective killing of microorganisms is 30000 microwatts sec./cm. sq.
Calculate minimum UV intensity required.
                                                               30000
Minimum UV intensity required  =      -----------------  microwatts/ cm. sq. 
                                                        Residence time
Convert microwatts in to mill watts by dividing with 1000.

Procedure :

1) Start the DM water line and check the conductivity of the DM water to be fed to the distillation still.
2) Fill the DM water surge tank completely with DM water.
3) Check that both the steam valves on the top of each column are open. 
4) Open the main steam inlet valve and let steam into the 1st column, close the drain valve.
5) Put "ON" the main switch of the distillation still panel and start the feed water pump
6) Adjust the flow of the DM feed water depending upon the inlet steam pressure and start the cooling water.
7) After some time water droplets followed by steam will start coming out from the top steam valves in the 1st column. When a continuous flow of steam comes from both the valves, close the lower valve first and then close the upper valve.
8) Similarly water droplets followed by steam will come out from the top valves of the 2nd column. When a continuous flow of steam comes, close both the valves, first the lower valve and then the upper valve.
9)  Proceed as in Step 8 for the 3rd column and then 4th column.
10)  Now distilled water will start coming out from the outlet hose.
11)  Dump off initial 10 liters of distilled water and check the conductivity of the same.
12) After the day's operation close the main steam inlet valve, open the lower drain, keep the feed water running for some time to cool the system.
13) Close the feed water and open all steam valves on the top of each of the four columns.
1. Adjust the feed water flow and the cooling water flow depending upon the inlet steam pressure such that there is full utilization of steam energy.
2. Adjust and set the dumping valve such that if the conductivity of hot distilled water goes above 1.0 micromhos, the dumping valve automatically dumps the distilled water and continues dumping the distilled water till the conductivity of the distilled water is below 1.0 micromhos.
3. Periodically clean the 18-micron SS filter on the DM water feed line so that there is a proper flow of feed water.
4. Take care to see that the DM water surge tank is never empty to prevent air entrapment in the feed water line.
5. Undertake de-scaling of the distillation still annually or when the conductivity nears the set limit or when the distillate quantity is lower than the rated quantity.
Ultraviolet rays from suitably shielded lamps have been used to reduce the number of microbes in the atmosphere.
The maximum germicidal activity of the ultraviolet light is shown at a non-ionizing wavelength of 2537 Angstroms. This wavelength produces excited molecules within the microbial cells, resulting in damaging intracellular chemical reactions, which may lead to the death of the cell. But for this a high enough intensity of ultraviolet light has to be maintained for a sufficiently long period of time in order to kill vegetative cells, bacterial spores and moulds.
The dosage of ultraviolet light is measured in microwatts seconds per square centimeter. The intensity of the ultraviolet rays obtained from the shielded lamps decreases on constant use and may fall below the required minimum level of 880 microwatts seconds per square centimeter. Thus it is necessary to monitor the intensity of the lamps/tubes at regular intervals. For the purpose of monitoring the efficiency of the ultraviolet lamps, the Black Ray Ultraviolet Intensity Meter is used.

Related: Removal of Pathogens from Water Systems


PROCEDURE FOR TESTING OF LAMPS

1.  Wear safety goggles while handling the Black Ray UV Meter and while performing the tests.
2.  Connect the sensor cell to the UV meter at the corresponding polarities.
3.  Check the sensor cell window to ensure that it is clean.
4.  Install the metal reduction screen over the sensor cell window.
5.  Check the output of the UV lamp monthly in the following manner:
a.  Clean the lamp or tube with a lint-free cloth dampened with Isopropanol 70%.
b.  Place the sensor cell directly on the lamp or tube about 4 to 6 cm from either end of the light and also from the centre of the light.    
c.  Take three  readings  and  calculate  the average.
d.  Replace the lamp or tube if the average reading is below 880 microwatts per square cm .
e.  Check new lamps or tubes according to the above mentioned procedure, note the new readings and label the lamp with installation date. Check the intensity of tubes every month and record.
f.  Maintain a daily record of burning hours and efficiency of each lamp / tube in the various  production  departments.
Frequency of Measuring Intensity of UV Lamps = Monthly
Measurement of Burning Hours = Daily

POLICY FOR REPLACEMENT OF UV LAMPS:

The UV lamps are replaced if the intensity falls below 80 microwatts / sq. cm. or they are replaced after a maximum of 3000 burning hours. 

INTRODUCTION

DM water filters are periodically removed and cleaned to ensure a high quality and constant flow rate of DM water passing through it. Cleaning also prevents clogging in the filters.

PROCEDURE

A. NORMAL CLEANING
1.  Remove the DM water filters from the housing.
2.  Unscrew the cartridge and remove the rubber washers if any at both ends of the cartridge.
3.  Clean the washers and the cartridge thoroughly with distilled water.
4.  Back flush for 10 minutes with hot pre-filled distilled water.
5.  Flush if possible for 10 minutes with hot pre-filled distilled water and fix it back to the housing for use.
6.  Flush the housing for 3 to 4 minutes with water before using the water and check the flow rate.
If the above procedure is not adequate to give a good flow rate and some amount of clogging still persists then, soak the cartridge for 2 to 4 hours in 2% Nitric Acid solution. After soaking in acid, wash the cartridge in free-flowing DM water till free from traces of acid. Back flush for 10 minutes with filtered hot distilled water. Forward flush if possible for 10 minutes with filtered hot distilled water and fit it back to the housing for use.           
Frequency of cleaning: Fortnightly
Various SS filters on the DM water line which are cleaned as follows:
1.  Two 10 microns filters on the vial/ampoule washing machine.
2.  One 20 microns filter on rubber stopper washing line.
3.  One 18 microns filter on the feed water for multicolumn distillation still.
4.  One 40 microns filter and one 20 micron filter on DM line prior to the UV disinfection bank.
5.  One SS disc filter for tray washing and one for rubber stopper washing (both 10 microns ).
6.  One 40 microns filter after mix bed of DM plant. 
INTRODUCTION
The DM water line is incorporated with a UV bank comprising of six tubes in series for the purpose of reduction of microbial load in the DM water before it is finally used for the purpose of container washing. For the effective functioning of the bank, the tubes have to be cleaned every day before and after operations.
PROCEDURE
1. Before starting the DM water line, clean each and every tube on the six UV bank by manually operating the built in brushes forward and backward ten times.
2. Now start the DM water line and discard the first five liters of water that flows through the bank.
3. Again clean each and every tube by moving the brush forward and backward thrice as the water continues to flow through the bank. Discard about 3 liters of this water also.
4. Now start the UV bank and use the water for operation.
5. After the day's operation, close the UV bank and clean the tubes by moving the brushes forward and backward and flush out some water.
NOTE:
1. Check the intensity of the UV tubes in the bank and maintain a record and/or maintain a burning hours record (monthly).
2. The cleaning brushes should be periodically serviced so that they are not jammed.
3. UV tubes should be changed after 3000 burning hours or when the intensity goes below (8.8 x 100) microwatts/cm2, whichever is earlier.
1st BED-CATION BED
•  Cation bed is regenerated with Hydrochloric Acid
[Quantity of acid solution - 48 Lt. HCl + 55 Lt. DM water (strength solution = 14%)].
Step : open specific valves of cation bed container to introduce acid by down-flow. (In certain equipment there is arrangement to introduce acid by suction, which is obtained by venturi effect). The flow is adjusted by adjusting the valve. After the HCl solution addition/ suction is complete, close the suction valve and open respective valves completely to drain and rinse the cation bed.
•  Rinsing of the bed is done for 15 minutes to 20 minutes and this rinse is down-flow rinse.
•  For the up-flow washing of anion bed close the respective valves and open the specific valves  to drain till the pH of outlet water is 3.5 to 4.5 .
2nd BED ANION BED
•  Anion bed is regenerated using alkali.
[Quantity of alkali solution - 13.6 kg Sodium hydroxide + 136 Lt. DM water
(strength solution = 14%)].                    
Step : open specific valves to introduce alkali solution to anion bed. (In certain equipment there  is arrangement to introduce acid by suction, which is obtained by venturi effect). Control the suction of alkali with specific valve such that the addition / suction of the alkali take place in 20 minutes to 30 minutes. After the addition / suction is over, close suction valve and open respective valve  completely for the flow-down rinse of anion bed; the down-flow rinse is given for 15 to 20 minutes.
•  After down-flow rinsing is complete give up-flow rinse to the anion bed.
•  For the up-flow washing of anion bed close the respective valves and open the specific valves to drain. After up-flow washing is complete, check pH of drain water should be around 9 to 9.5 and continue rinsing the bed till the conductivity of the water is adequate.  
MIXED BED:
•  Firstly backwash has to be given to the mixed bed for the purpose of separating cation and  anion resins. The backwash is given for 30 minutes.
•  For Back Wash : open the respective valves and also open air release valve at the top; after backwash cation resin will settle at the bottom and anion resin will remain at the top. This separation can be observed on the lower view panel on the bed.
•  For the mixed bed, first regenerate the anion portion of the bed i.e. the top portion using alkali.
•  Quantity of alkali to be used = 2.5 kg  NaOH + 25 Lt. Water (10%).
•  Close all the valves; inlet and other valves on mixed bed for settling of resin on mixed bed.
•  Now start the addition / suction of alkali in mixed bed by opening respective valves. 
•  Now for rinsing of the alkali, keep the same valves open except keep suction valve and rinse  for 30 minutes.
•  To regenerate the cation portion of the bed i.e. the bottom portion using acid.
•  For acid treatment of mixed bed, close all valves. Open suction valve .
•  Quantity of acid to be used = 6 Lt. Of HCl + 12 Lt. Of water.
•  Open respective valves adjusting the flow such that the acid is added or sucked in 20 min.  approximately.
•  After all the acid has been added or sucked, close suction valve and fully open valves  to rinse the lower cation area of the mixed bed for 20 min. to 30 min.
Note that introduction of acid/alkali on all beds is from top to bottom. After acid treatment and  rinsing of mixed bed go in for air mixing of mixed bed.
AIR MIXING
•  Close all valves.
•  Open respective valves. Open the air valve on top of mixed bed. 
•  Open the drain valve and bring the water level in the mixed bed to half. [Observe from the view glass of the container].
•  Open the air inlet valve and open vent valve and observe thorough mixing of resins from view  glass.
•  After air mixing is complete, close all valves.
•  Open air vent valve for some time to remove air entrapped and completely fill the mixed bed  with water and wait till the water comes out from the air vent. Let water flow from the air vent for 10 to 15 minutes. After 15 min. open the drain, valve and wash all the beds and check the pH  of the final water, continue washing the beds till the pH of the final water is 5.5 to 7.5 and the conductivity is within limits.
CARBON BED:
•  Close the valve feeding water to cation column and then turn the re-circulation pump to  switch off position.
•  Open respective valves and allow to drain for 2 minutes. Valves should be opened to the extent that a pressure of 10lb/in is shown on the main pressure gauge.
•  Open respective valves and allow backwash for 5 minutes. Ensure complete air removal by  back-washing further if required.
•  Open specific valve to remove air from carbon bed.
•  Open and close respective valves for normal operation of carbon bed.
•  Allow to drain for 1 minute.
•  Close & open respective valves for normal operation.
•  Open conductivity meter valves to give a flow rate of 500ml/min. and check conductivity.
         The limits are as follows :
         For Cation                       NMT  30 microsiemens/cm2.    
         For Mix Bed                    NMT   3 microsiemens/cm2.    
If the conductivity is found to be within limits, open all valves supplying water to the point of use. Check the conductivity again after 2 hours and record.
Alert limits for Regeneration are as follows :
         For Cation                       NMT  20 microsiemens/cm2.    
         For Mix Bed                    NMT  2.5 microsiemens/cm2.
INTRODUCTION
Sometimes vial/ampoule washing machine is equipped with a header tank, which is a DM water reservoir, which provides continuous DM water for every washing cycle of the vials and ampoules. As per GMP it is necessary to periodically dismantle the tank and clean it thoroughly.
PROCEDURE
1. Disconnect the electric supply to the solenoid valve.
2. Remove the flexible water supply hose.
3. Dismantle the header tank from the washing machine and take it near the distillation still.
4. Remove the side lid of the tank by unscrewing the stainless steel nuts with the help of the spanner and also remove the rubber gasket.
5. Flush the inner portion of the tank with hot (80°C) distilled water for 5 min.
6. Scrub the inside of the tank, the lid and the gasket with a clean sponge and again rinse the tank, lid and gasket three times with hot distilled water.
7. Clean the water level indicator by passing hot distilled water through it 3 times.
8. Clean the flexible water supplying hose by passing through it hot distilled water and steam  directly from the distillation still.
9. Fix the lid back to the tank along with the gasket. Tighten the nuts and assemble the tank back to the washing machine.
10. Re-connect the electric supply to the solenoid valve, and fix back to the cleaned flexible water supply hose to the tank.
Note : Everyday at the end of the days operation on the machine, drain the water from the header tank completely, as stagnant water is a source of microbial proliferation.
Frequency of cleaning: Weekly
In case of high microbial counts or presence of Pseudomonas and E Coli
1)  Proceed as in Step 1 to Step 5.
2)  Steam the tank from the inside for 10 minutes ensuring that the steam passes through the  glass level indicator also.
3)  Wash the lid, nuts, bolts and gasket with hot distilled water and then steam them 5 minutes.
INTRODUCTION
The distilled water storage tank is used to collect and store pyrogen free distilled water obtained from the distillation still. It has to be stored at a temperature of 80°C to keep it pyrogen free.
Apart from being pyrogen free the distilled water should also be free from any particulate matter, hence, to ensure this, the distilled water storage tank is periodically cleaned thoroughly and record maintained.
PROCEDURE
1  Put the heaters off and drain all the distilled water in the tank from the bottom drain outlet. Now disconnect the tank from the multicolumn distillation still. Tilt the tank on the floor and dismantle the heating elements, washers and temperature-sensing element.
2  Clean the tank from inside using clean sponge and filtered flowing DM water. If any sticky particles are observed, use a nylon scrubber and 0.05% Benzalkonium Chloride solution (50%) for cleaning and then thoroughly rinse with flowing DM water.
3  Finally rinse three times with freshly collected pyrogen free distilled water. Similarly, rinse the heating element, washers and the temperature sensor with only fresh pyrogen free distilled water thrice.
4  Fix the heating elements with washers, and the temperature sensor to the tank and put the tank upright. Close the tank with the lid and connect it to the multicolumn distillation plant. Start the multicolumn distillation plant and collect about 50 liters of distilled water in the tank and then bottom drain completely.
5 Now collect the required amount of distilled water in the tank, and maintain it at 80°C untill use.
FREQUENCY - MONTHLY
INTRODUCTION
The DM water surge tank acts as a reservoir of DM water for the purpose of supplying feed water to the multi-column distillation still. It is also a reservoir for the purpose of running the overnight DM water re-circulation loop via the DM water resin beds to keep the bio-burden of the DM water low.
The surge tank receives the DM water from the final mixed bed after it is passed through a UV disinfection system. Since this tank stores water for critical operations, the tank has to be periodically cleaned to get rid of the resin fines from the DM bed and other particulate matter. These may find its way from the DM bed into the tank as well as to reduce the bio-burden of the DM water. To the surge tank, two pumps are connected; one is the feed water pump which pumps this water to the multi-column distillation still and the second pump is for the overnight DM water re-circulation.
PROCEDURE
1.  Open the lid of the tank and drain the water completely from the tank by opening the bottom drain.
2.  Disconnect the pipes connecting the tank to the feed water pump and the re-circulation pump.
3.  Remove the ball float, if there is float valve in the tank.
4.  Clean the tank from inside thoroughly by using a clean sponge and filtered flowing DM water  keeping the bottom drain open throughout the washing.
5.  If any sticky particulate matter is observed on the sides or bottom of the tank, use a nylon scrubber with 0.05% Benzalkonium Chloride solution for cleaning and then thoroughly rinse with filtered flowing DM water keeping the bottom drain outlet open.
6.  Finally rinse three times with hot distilled water. Drain the tank during each time of rinsing.
7.  Similarly clean the lid and the ball float.
8.  Reconnect all the disconnected pipelines.
9. Close the bottom drain outlet and collect fresh DM water from the DM water plant and close the lid and clamps. 
FREQUENCY OF CLEANING: WEEKLY
DISTILLED WATER:
1.  Fresh distilled water is collected every week from the distillation still for the following analysis:
a.  For chemical analysis as per IP in a clean stoppered flask.
b.  Microbial count comprising of total microbial count and test for the absence of E. Coli and    Pseudomonas species in a clean pre-sterilized stoppered flask.
c.  For pyrogen testing in a clean pre-sterilized stoppered flask.
2.  After analysis, a copy of the test report is submitted to the sterile department along with alert remarks in case of adverse results.
3.  The distilled water used for the rinsing of containers, rubber stoppers and equipment is stored at 80°C.
Demineralized Water
1.  DM water is collected from pre-fixed locations for the following analysis.
a.  For chemical analysis as per IP it is collected in a clean stoppered flask from the point of       use on the vial/ampoule washing machine. (every week)
b.  For microbial analysis, which comprises of total microbial count and test for the absence of E. coli and Pseudomonas species it is collected in clean pre-sterilized stoppered flasks from the following points and tested separately. (every week)
i.  After in line UV manifold.
ii.  From vial/ampoule washing machine storage tank (header). While collecting extreme precautions are taken to prevent chance microbial contamination.
c.  Conductivity of the DM Water in use is checked everyday and record maintained in the  sterile department.
Acceptance Criteria
         Chemical Analysis
         DM water                                          :        As per Pharmacopeia
         Distilled water                                    :        As per Pharmacopeia
         Microbial Limits:
         DM water total T.M.C. limit             =       Not more than 50 cfu/ml.
         Distilled water total T.M.C. limit       =       Not more than 10 cfu/ml.
         Conductivity Limits:
         DM water                                        =       Not more than 3.0 microsiemens
         Distilled  water                                 =       Not more than 1.0 microsiemens
The microbial count of the DM water should be low. The DM plant beds are the main source of potential growth of microorganisms and stagnant water in DM beds leads to microbial proliferation. Flowing water through the beds keeps the microbial count low. Hence it is necessary to keep a continuous flow of water through the beds at the end of the day when the plant is not in use. Hence this continuous flow of water can be achieved with the help of re-circulation loop which is kept 'ON' throughout the night and also when plant is not in use.
PROCEDURE:
1.  Close the valve between the mixed bed and surge tank to present draining of water in the beds.
2.  Then close the valve between carbon bed and cation bed.
3.  Then start the re-circulation pump and open the valve between the surge tank and the cation bed.
4.  Then open the valve between the mixed bed and surge tank.
5.  Now the pumps will take water from surge tank and pump into cation bed, anion bed and then to the mixed bed and water will be back to surge tank, after passing through UV disinfection tube and 40 micron SS filter, thus completing the re-circulation loop.
A.  PURPOSE
This calibration is performed to determine the actual UV sensitivity of the Bacillus subtilis and /or Saccharomyces cerevisiae challenges used in the performance test methods leading to actual log reduction obtained at doses of 38000 mW-sec/cm2 for B. subtilis & 16000 mW-sec/cm2 for S. cerevisiae.
B.  APPARATUS
Assemble an apparatus in which a small stirred sample can be irradiated in a nearly collimated beam. The radiometer can then be used to measure the intensity (I0).
A UV lamp (not the unit under study) equivalent to pressure to the lamp to be used in the system shall be wired to a ballast and a voltage regulator (Figure). Suspend the lamp over the tube painted flat black. Use a solution contained in a small dish equal to or smaller in diameter than that of collimated tube with sufficient solution to give a 1 cm depth. Measure I0 at the surface of the liquid by removing the dish and stirrer and placing the radiometer at the corresponding position.
C.  CALCULATION
Calculate the average intensity in the stirred solutions by using the radiometer I0 measurement and following the equation. The calculation requires use of the absorbance that is irradiated at 254 nm.
                                                       I0 ( 1- e–aeL )
                                    I ave =     ————————
                                                            aeL
ae   = absorbance per cm to the base e
L     = depth of the solution irradiated in collimated beam (cm)
I0    = measured intensity  (mW/cm2 )
I ave = intensity average  (mW/cm2 )

Related: Difference Between Purified Water and De-mineralized Water


D.  GROWTH MEDIUM
1.  Formula for nutrient agar
            Ingredients per liter of distilled or deionized water
            Beef extract      3   g.
            Peptone             5   g.
            Agar                   15 g. 
2.  Formula for YM Medium (Yeast)
•  Broth
         Ingredients per litre of distilled or deionized water  
         Yeast extract                  3   g.
         Malt extract                   3   g.
         Peptone                         5   g.
         Dextrose                        10 g.
•  Agar
Same as for broth plus Agar 15 g.
•  Antibiotic stock solution 2ml/100ml agar.
(Do not autoclave antibiotic stock solution. Add aseptically after autoclaved YM agar had  cooled to approximately 45 - 50 ° C)
•  Antibiotic stock solution ingredients per 100 ml of distilled or deionized water……
         Chlortetracycline  0.5 g.
         Chloramphenicol  0.5 g.
3.  Sterilize media solutions in an autoclave (steam sterilizer) for 15 minutes at 15 lbs. Pressure  (121°C).
4.  Buffered dilution water

E.  CULTURE OF BACILLUS SUBTILIS SPORES AND SACCHAROMYCES CEREVISIAE

         Obtain cultures from American Type Culture Collection and revive according to instructions.
         Use the following ATCC cultures:
         Bacillus subtilis ATCC #6633
         Saccharomyces cerevisiae ATCC # 18824

F.  CALIBRATION OF CHALLENGE ORGANISM SENSITIVITY

1.  B. subtilis (spore) sensitivity
Inoculate a 10 ml slant of nutrient agar and incubate at 35° C for 24 hours (±2 hours)
•  Perform this initial passing of the culture for three successive passes, each 24 hours transferring to a fresh slant.
•  After incubation time has elapsed on the third transfer, wash the slant with 2 ml of buffered water.
•  Transfer the 2 ml of organisms to a tube containing 10 ml of buffered water. Mix the suspension.
•  Transfer 1 ml of the suspension to each of 12 french square bottles of nutrient agar. Incubate inoculated bottles at 35°C for 24 hours
•  Wash all 12 slants using 5 ml of buffered water and 20-30 glass beads until all visible growth has been removed from the slant.
•  Pool all 12 slants together into one flask. Heat shock the suspension in a 65°C water bath for 15 minutes, with intermediate swirling of the flask for even heating.
•  Centrifuge the suspension at 2500 rpm for 15 minutes. Carefully remove the supernatant.
•  Wash the cells three times using 99 ml aliquots of buffered water for each wash. Centrifuge in between washes to remove supernatant while keeping the spores.
•  After removal of the supernatant on third wash, re-suspend the spores in 50 mL of buffered water.
•  Filter the suspension through Whatman # 1 filter. It may be necessary to use several filters if clogging becomes excessive.
•  The final filtered spores suspension will be used for UV exposures in calibration and testing of the treatment units.
•  Determine the final concentration of spores using pour plate technique at appropriate dilutions (except 107 -108 spores/ml). Incubate plates at 35°C for 48 hours prior to reading.
•  Suspension can be stored at 2-4°C indefinitely; however, enumeration should be performed prior to each use to ensure proper concentration. In addition, a spore strain test should be performed prior to each use to ensure spore predominance.
•  Dilute aliquots of the spore suspension stock to yield a concentration of 5 x 104 to 1 x 10spore/ml
•  Measure the UV lamp output of the collimated beam at the level of the top of the suspension  (I0)
•  Add sufficient diluted spore suspension to a petri dish (recommended maximum of 60 mm  diameter) and a small magnetic stirrer (recommended 10 mm length x 3 mm diameter). Irradiate the samples at specific recorded time intervals so as to provide a graph of organism survival versus total UV dose for that time span.
•  Handle irradiated samples aseptically and analyze within 30 minutes of exposure.  Prior to analysis, store the samples in dark. Use pore plate technique to analyse samples. Plate each sample in triplicate using nutrient agar and incubate at 35° C for 48 hours. Take counts of plate at 48 hours, then re-incubate for an additional 72 hours, taking reading every 24 hours. The final reading shall be used. If overgrowth occurs, the reading immediately preceding the overgrowth shall be used.
•  Prepare a spore calibration curve of log Ns/No versus measured dose. From the graph, determine the inactivation for UV dose of 38000 mW-sec/cm2.
No =  initial spore concentration
Ns  = mean value of three plate counts on each exposed sample
2.      S. cerevisiae (yeast) sensitivity
•  Inoculate a 10 ml tube of YM broth  and incubate on shaker water bath at 25°C and  sufficient speed to aerate the culture (approximately 225 rpm) for 24 hours (+ 2 hours)
•  Perform this initial passing of the culture for three successive passes, each 24 hours transferring to a fresh broth tube.
•  After incubation time has elapsed on the third transfer, uniformly suspend the yeast cells in a tube and pipet 5 ml each to two 2 liter flasks containing 1 liter of YM broth in each. Incubate on shaker water bath at 25°C and sufficient speed to aerate the culture(approximately 225 rpm) for 24 hours. 
•  Centrifuge the suspension at 2500 rpm for 15 minutes. Carefully remove the supernatant.
Pool all the cells from the 2 liters of centrifuged suspension.
•  Wash the cells three times using 99 ml aliquots of buffered water for each wash. Centrifuge in between washes to remove supernatant while keeping the cells.
•  After removal of the supernatant on third wash, suspend the cells in 50 mL of buffered water.
•  The final suspension will be used for UV exposures in calibration and testing of the treatment  units. These cells must be used within 24 hours of harvest and stored at room temperature during this time.
•  Determine the final concentration of spores using pour plate technique at appropriate dilutions (except 107 -108 cells/ml). Incubate plates at 25°C for 48 to 72 hours prior to reading.
•  Dilute aliquots of the yeast suspension stock to yield a concentration of 104 to 105 cells/ml
•  Measure the UV lamp output of the collimated beam at the level of the top of the suspension  (I0)
•  Add sufficient diluted yeast suspension to a petri dish ( recommended maximum of 60 mm diameter) and a small magnetic stirrer (recommended 10 mm length x 3 mm diameter). Irradiate the samples at specific recorded time intervals so as to provide a graph of organism survival verses total UV dose for that time span.
•  Handle irradiated samples aseptically and analyze within 30 minutes of exposure.  Prior to analysis, store the samples in dark. Use pore plate technique to analyse samples. Plate each sample in triplicate using YM agar and incubate at 25°C for 5 days. Take counts of plate at 48 hours, then re-incubate for an additional 72 hours, taking reading every 24 hours. The final reading shall be used. If overgrowth occurs, the reading immediately preceding the overgrowth shall be used.
•  Prepare a yeast calibration curve of log Ns/No versus measured dose. From the graph, determine the inactivation for UV dose of 16000 mW-sec/cm2.
                 No =  initial cells  concentration
                 Ns  = mean value of three plate counts on each exposed sample
Special Note :
Irradiation's are done to give duplicate data at 8 intervals up to 4 logs inactivation.
Calculation of the doses is made by assuming the 4% of the measured I0 is reflected from the water surface. The average intensity times exposure time is used as the dose. The concentration of spores or yeast is such that the UV absorbance of the solution is very small and hence any error in calculation of absorbance is almost negligible.
Notes :
1.  The collimating tube shall be a minimum of 53 cm. (21 inches) in length and the interior shall be painted flat black.
2.  The support stand shall be adjustable to raise or lower the collimating tube to the surface of the petri dish.
3.  Measurement of the UV dose must be done at the same point at which the petri dish surface is exposed. 
Following additional documents are required from the manufacturer / supplier of the system
1.  Structural integrity performance (These test are performed to evaluate the basic design, materials and fabrication quality of the complete systems, rigid and disposable treatment chambers and flexible tubing units subject to line pressure.
The documents include -
a.  Hydrostatic pressure test - Complete assembly
b.  Hydrostatic pressure test - Metallic pressure vessels
c.  Burst test non metallic pressure vessels
d.  Cycle test -nonmetallic disposable pressure vessels, valves and controls and open discharge  units.
2.  UV alarm performance test certificate. 

PQ FOR WATER USED IN PRODUCTION OF API

INTRODUCTION :-

The purified water is used for the manufacturing of API. The raw water is generally
(i)  Treated with Alum to remove colloidal matter.
(ii)  Filtered through Sand filter, cartridge filter to remove particulate matter
(iii)  Treated with Charcoal to remove coloring matter.
(iv)  Passed through resins to remove soluble salts.
The entire process is carefully designed & validated to convert the raw water into purified water meeting pharmacopoeial requirements.
The performance of the purification process is checked as per the following.


Test
Requirement
Remarks
Description
It should be clear, colourless, odorless and  tasteless  liquid.

Acidity  or  Alkalinity
To 10 ml. Freshly boiled and cooled water in a borosilicate  glass flask, add 0.05 ml of methyl red solution, the resulting solution should not be red. To 10 ml of water add 0.1 ml of bromothymol blue solution; the resulting solution should not be blue.

Ammonium
To 20 ml of water add 1ml of alkaline potassium mercuri - iodide reagent and allow to stand for 5 minutes. When viewed  vertically the solution should not be more intensely colored than a solution prepared at the same time by adding 1 ml of alkaline potassium mercuric-iodide solution to a mixture of 4  ml of ammonium standard (1 ppm NH4) and 16 ml of ammonia-free water (0.2 ppm ).

Calcium  and
To 100 ml of water add 2 ml of ammonia Magnesium buffer pH 10.0, 50 mg of mordant black II mixture and 0.5 ml of 0.1 M disodium edetate. A blue colour should not be produced.

Heavy  Metals
In a glass evaporating dish evaporate 150 ml to 15 ml  on a water bath.12 ml of the resulting solution complies with limit test for heavy metals, (limit 0.1 ppm). Use lead standard solution  (limit 1 ppm Pb)  to  prepare the standard.

Chloride
To 10 ml of water add 1 ml of 2M nitric acid & 0.2  ml  of 0.1 M silver nitrate. The appearance of the solution does not change within 15 minutes.

Nitrate
To 5 ml of water in a test tube immersed in ice add  0.4 ml of a 10% w/v solution of potassium chloride, 0.1 ml of diphenylamine solution and, drop-wise with shaking 5 ml of sulphuric acid. Transfer the tube  to a


cotdwater-bath at 50°C and allow to stand for 15 minutes. Any blue color in the solution should not be more intense than that in a solution prepared at the same time and in the same manner using a mixture of 4.5 ml of nitrate  free water and 0.5 ml of nitrate standard solution (2 ppm  NO3)  (0.2 ppm).       

Sulphate
To  10 ml of water add 0.1 ml of 2M  hydrochloric acid and 0.1 ml of 0.25 M Barium Chloride. The solution should show no change in appearance for at least one hour.

Oxidisable Substances
To 100 ml of water add 10 ml of 1M Sulphuric Acid and  0.1 ml of 0.02 M Potassium Permanganate VS and boil for 5 minutes. The pink colour should be completely discharged.      

Non - Volatile  Matter
100 ml of water is evaporated to dryness on a water bath and dried at 100°C to 105°C. Leaves not more than 0.001% w/v  of  residue.          

Aluminium
If the water intended for use in the manufacture of dialysis solutions, it complies with the test for aluminium. To 400 ml add 10 ml of acetate buffer solution pH 6.0 R and 100 ml of distilled water R. The solution complies with the limit test for aluminium  (10 µg/l). Use as the reference solution a mixture of 2 ml of aluminium standard solution (2 ppm Al) R, 10 ml of acetate buffer  solution pH 6.0 R and 98 ml of distilled water R.  To prepare the blank, use a mixture of 10 ml of acetate buffer solution pH 6.0 R and 100 ml of distilled water R.

Microbial contamination
Total viable aerobic count should not be more than 100 micro-organisms per millilitre, determined by membrane filtration, using agar medium B.




POUR-PLATE METHOD  :- 
Using Petri dishes 9 cm in diameter, add to each  dish 1 ml of the sample prepared as described  and 15 ml to 20 ml of a liquefied agar medium  suitable for  the cultivation of bacteria  (such as  medium B), prepare  for each medium at least two  Petri dishes for each level of dilution. Incubate the  plates at 30°C to 35°C (20°C to 25°C for fungi) for five  days, unless a reliable count is obtained in a  shorter time. Select the plates responding to  one dilution and showing the highest number of  colonies less than 300 (100 colonies for fungi).
Take the arithmetic average of the counts and  calculate the number of colony-forming units per   gram or millilitre.           

1)  Test  For  E. Coli
Aseptically  transfer 1 ml  of  water  sample  in  sterile  screw  capped  container,  add  100  ml  Nutrient  broth,  shake,  allow  it to  stand  for  1  hour,  and  shake  again.  Loosen  the  cap  and  incubate  at  37°C  for   18  to  24  hours.

Primary  Test
Aseptically transfer 1 ml of  enriched  culture  prepared as above to the tubes containing positive and negative controls and to the tube containing sterile 5 ml  Maconkey's broth with inverted Durham's tube.   Incubate for 48 hours at 37°C. Acid  formation (change  in colour from red to yellow) and gas liberation (gas  bubbles in inverted Durham's tube) should not be seen. 

Secondary  Test :
Add 1 ml of contents of the tube showing acid and gas  to each of two tubes containing (a) 5 ml of sterile  Maconkey's broth, and (b) 5  ml of sterile peptone water. Incubate for 24 hours and examine tube  (a)  for  acid  and gas formation, and tube (b) for presence of indole formation. To test for  presence of indole add 0.5 ml of Kovac's reagent. Shake well and allow  to  stand for 1 minute. If a red colour is produced in the reagent  layer, indole is present.  The presence of acid, gas and indole in the secondary test indicates the  presence of Escheriuchia Coli.        



2) Test for Salmonellae
Preparation of Media :
Aseptically  transfer 1 ml of water sample in sterile screw capped container,  add  100  ml  Nutrient broth,   shake, allow to stand for 1 hour, and shake again.  Loosen the cap and incubate at 37°C for 18 to 24  hours.

Primary Test :
Add  1.0  ml  of  the  enriched  culture  prepared  as  above  to  each  of  two  tubes  containing  (a)  10  ml  of  salenite  F  broth  and  (b)  10  ml  of  Tetrathionate  Broth  and  incubate  at  36°C  to  38°C  for  48  hours.  From  each  of  these  two  culture  inoculate  three  plates  containing  a  layer  of  (i)  Brilliant  Green  Agar,  (ii)  Desoxycholate  Citrate  Agar,  and  (iii)  Bismuth  Sulphate  Agar.  Incubate  the  plates  at  36°C  to  38°C  for  18 to 24 hours. Colonies confirming to following description shall be absent:
1. Brilliant  Green Agar:  Small, transparent & colorless, or opaque, pinkish or white (frequently surrounded by a pink or red zone )
2. Deoxycholate Citrate:  Colourless and opaque, with Agar or without black centres
3. Bismuth Sulphite Agar:  Black or green

Secondary  Test :
Perform this test as secondary /confirmatory test:  
Subculture  any  colonies showing  the  characteristics  given  in  Table  1  in  Triple  Sugar  Iron  Agar,  by  first  inoculating  the  surface  of  the  slope  and  then  making  a  stab  culture  with  the  same  inoculating  needle  and  at  the  same  time  inoculate  a  tube  of  Urea  Broth.  Incubate  at  36°C  to  38°C  for  18  to  24  hours.  The  formation  of  acid  and  gas  in  the  stab  culture  ( with  or  without  concomitant  blackening )  and  the  absence  of  acidity  from  the  surface  growth  in  the  triple  sugar,  iron  agar,  together  with  absence  of  a  red  colour  in  the  urea  broth,  indicates  the  presence  of  Salmonellae.  If  acid  but  no  gas  is  produced  in  the  stab  culture,  the  identity  of  the  organisms  should  be  confirmed  by  agglutination  tests.      

Control Test :
Carry  out  a  control  test  by  repeating  the  primary  and  secondary  test  using  1.0  ml  of  the  enriched  culture  and  a  column  of  broth  containing  10  to  50  Salmonellas  Abony  ( NCTC  6017 ),  prepared  from  a  twenty  four  hour  culture  in  Nutrient  Broth,  for  the  inoculation  of  tubes  (a)  and  (b).  The  test  is  invalid  if  the  results  do  not  indicates  that  the  control  contains  Salmonellae. 

3) Test for Pseudomonas
Place  1  ml  of water  in  sterile  screw - capped  jar  containing  100  ml  of  Centrimide  Broth,  and  incubate  at  30°C  to  32°C  for  72  hours.  Subculture  on  a  plate  containing  a  layer  of  Cetrimide  Agar  and  incubate  at  30°C  to  32°C  for  48  hours.  Examine  the  resulting  growth  by  Gram's  stain .  Gram  negative  bacilli  shall be absent.

Oxidase  test  :
Place 2 or 3 drops of a freshly prepared 1%w/v  solution of N,N,N,N'- tetramethyl-P Phynylendediammonium dichloride  on  a  piece  of  filter  paper.  (Whatman No.  1 is suitable) and  smear  with  the  suspect  colony   The purple  colour  shall not be obtained within  5  to  10  seconds.          

Control Test :
Carry out a control test by repeating the test adding the prescribed quantity and a volume of broth  containing 10 to 50  Pseudomonas Aeruginosa (NCTC 6750 ), prepared  from  twenty  four  hour  culture  in  Nutrient  Broth, to  a  sterile,  screwcapped  jar  containing  100  ml  of  Cetrimide  Broth.  The test must show Gram negative Bacilli and must also show purple colour when treated with 1.0 % w/v  solution  of  N,N,N,N'-tetramethyl-P-Phynylendediammonium  dichloride  on  a  piece  of  filter  paper.  

4) Test  for Staphylococcus aureus
Place  1  ml  of  Water  sample  in  a  sterile  screw capped  jar  containing  100  ml  of  fluid  Soyabean  Casein  digest  medium  and  incubate  at  30°C  to  32°C  for  72  hours.  Subculture  on  a  plate  containing  a  layer  of  Mannitol  Salt  Agar  medium  or  Vogel  Johnson  Agar  medium  and  incubate  at  30°C  to  32°C  for  48  hours.  Examine  the  resulting  growth  by  Gram's  stain .  Gram  positive  cocci ( in  clusters )  in  yellow  colonies  ( in  mannitol  salt  agar  medium )  should be absent.  Gram positive cocci Black colonies surrounded  by  yellow  zones  ( in  Vogel  Johnson  agar  medium ) shall be absent.



Coagulase Test  :
Transfer  representative  suspect  colonies  from  the  agar  surfaces  of  the  mannitol  salt  agar  medium  or  Vogel  Johnson  agar  medium  to   individual  tubes,  each  containing  0.5  ml  of  mammalian,  preferably  rabbit  or  horse  plasma  with  or  without  suitable  additives.  Incubate  in  a  water  bath  at  37°C  examining  the  tubes  at  three  hours  and  subsequently  at  suitable  intervals  upto  24  hours.  The coagulation to any degree shall be absent.

Positive Control:
Carry  out  a  control  test  by  repeating  the  test,  adding  the  prescribed  quantity  and  a  volume  of  broth  containing  10  to  50  Staphylococcus  aureus  ( ATCC  6538,  NCTC  10788 ),  prepared  from  a  twenty  four  hour  culture  in  fluid  Soyabean - Casein  digest  medium  to  a  sterile  screw  capped  jar  containing  100  ml  of  fluid  Soyabean  Casein  digest  medium.  The  test  shall show the evidence of Staphyllococcus arues



DESIGN QUALIFICATION FOR DISTRIBUTION AND HANDLING OF WATER USED IN THE MANUFACTURING OF API

Water used for API manufacturing shall be properly stored & distributed to avoid chemical/microbiological contamination which can adversely affect the reactions or quality of the intermediate/Bulk drug.
For the safe storage & proper handling following Design Qualification shall be considered.
1.  Water should be transported through Heated recirculating system only.
2.  Water should be stored at 75 - 80°C.
3.  Total system involving the storage tank, Piping, etc should be heated at 75°C periodically.
4.  Dead legs should be avoided in transporting.
5.  Material of construction used for storage tanks, Pipings should be examined critically. Special care should be taken for the use of MOC in case where the bulk drug is very sensitive to metal content.
6.  316L Stainless Steel. type pipings & fitting should be preferred.
7.  In the transporting piping the screw fittings should be avoided.
8.  Microretantive filters should be used to protect Outlets/Vents.
9.  Pipings should be fumigated periodically
10.  Storage tanks should be sterilized from time to time.
Ankur Choudhary is India's first professional pharmaceutical blogger, author and founder of Pharmaceutical Guidelines, a widely-read pharmaceutical blog since 2008. Sign-up for the free email updates for your daily dose of pharmaceutical tips.
Email: .moc.enilediugamrahp@ofni Need Help: Ask Question


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