STORAGE CONDITIONS FOR IN-PROCESS

ST — 111
STORAGE CONDITIONS FOR IN-PROCESS


INTRODUCTION
All raw materials, packing material, semi-finished goods and finished products must be stored under suitable condition to ensure their stability and integrity.
Storage of semi finished (in-process goods) in W.I.P. area
All the in-process goods such as filled vial/ampoules waiting inspection, labelling or packing and the overprinted packing materials etc. will be stored at temperature between 2-35 ºC. Temperature record for this W.I.P area will be maintained in the following format and will be displayed conspicuously in the W.I.P. areas.

DAILY TEMPRATURE RECORD

Location: W.I.P. Area (Sterile Department)
Time of Recording Temperature: 12:30 p.m
Month


DATE
TEMPRATURE

STERILIZATION CYCLES – DRY HEAT STERILIZER

ST — 110
STERILIZATION CYCLES – DRY HEAT STERILIZER


Equipment: Double door dry heat sterilizer with mounted HEPA filter module.

Temp. required for sterilization : 220 ºC
& Depyrogenation

Time of cycle : 90 min. at 220 ºC

Set temperature : 260 ºC

Time : Validated time depending on load

PROCEDURE – (NON STERILE SIDE)

1. Remove the lock and open the pressure lock door by turning the handle anti-clockwise, till the quick throw handle could be easily pushed down.
2. Unload the carriage on the trolley provided.
3. Check working of the alarm system when the door is opened. If not, report to the supervisor or engineering department.
4. Wipe and clean the carriage and the chamber of the dry heat sterilizer with distilled water.
5. Place systematically the load to be sterilized as per the loading pattern on the carriage and put the carriage back into the chamber of the dry heat sterilizer.
6. Close the pressure lock door, by pulling up the quick throw handle and turn the handle clockwise till the door is tight and display ‘‘DO NOT OPEN’’ board on the door
7. Fill the sterilization card provided stating date, items sterilized, time, no. of units and operators.
8. Put ‘ON’ the mains and check working of the booster fan and the HEPA module.
9. Put ‘ON’ the panel switch on ‘AUTO’.
10. Affix a thermograph duly labeled on to the validated set time depending upon the load to be sterilized.
11. Set the temperature to 260 ºC on the temperature controller unit.
12. Set the timer on the temperature controller unit to the validated set time depending upon the load to be sterilized.
13. Start the ‘Heater’ switch and simultaneously start the ‘Timer’ switch. The heater timer display and the HEPA timer display should start with ‘ZERO’ readings.
14. Check the current in all the three phase of the heater with the aid of the built in ammeter switch (ammeter reading should be between 35-38 amperes for each phase).
15. Check the thermograph, the thermograph recorder and the ink flow through the thermograph recorder.
16. The temperature will gradually rise and will be indicated by the temperature indicator and the thermograph.
17. After the sterilization cycle is completed, the heater will stop and the HEPA module will start to cool the load, the starting of the HEPA module will be indicated on the Magnehelic Gauge provided and the time will be indicated on the HEPA timer.
18. Prior to unloading the charge on the sterile side check the following
a. Thermograph has recorded the desired time and temperature relationship.
b. HEPA module is operating
c. Plenum pressure on the Magnehelic gauges of the HEPA module and record the same.
d. Load is sufficiently cool to be unloaded on the sterile side.
19. Initial the sterilization card and release the load for unloading in the sterile area for filling of sterile products.
20. Indicate on the load, date of sterilization and the date before which it should be used.

CLEANING PROCEDURE FOR DISTILLED WATER STROAGE TANK

ST — 039
CLEANING PROCEDURE FOR DISTILLED WATER STROAGE TANK


INTRODUCTION

The distilled water storage tank is used to collect and store pyrogen free distilled water obtained from the distillation still. It has to a temperature of 80 ºC to keep it pyrogen free since the distilled water is used for critical operation in sterile product manufacturing like rinsing of process equipment, vessels and utensils, rinsing of rubber stoppers etc.

Apart from being pyrogen free the distilled water should also be free from any particulate matter, hence, to endure this, the distilled water storage tank is periodically cleaned thoroughly and recored maintained.

PROCEDURE

Put the heater off and drain all the distilled water in the tank from bottom drain outlet.

Now disconnect the tank from multicolumn distillation still. Title the tank on the floor and dismantle the heating element, washers and temperature-sensing element.

Clean the tank from inside using clean sponge and filtered flowing DM water. Only if required, especially 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.

Finally rinse three times with freshly collected pyrogen free distilled water, with completely draining the tank during each time of rinsing. Similarly, rinse he heating element, washer and the temperature sensor with only fresh pyrogen free distilled water thrice.

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 the tank completely.

Now freshly collect the required amount of distilled water in the tank, and keeping the heater set at 80 ºC store the water for use, keeping the set heaters ‘ON’.

Record the date of cleaning and the name of the cleaning operator.

FREQUIENCY - MONTHLY

STERILIZATION CYCLES - AUTOCLAVE

ST — 109
STERILIZATION CYCLES - AUTOCLAVE


Temperature Used: 121 ºC Time to get F0 minimum 15
Time of Cycle: Validation minutes at coolest point for
(Theoretical Cycle Temperature) all loads


Various Loads of the Autoclave

1. MEMBRANE HOLDER AND VIAL FILLING ASSEMBLY LOAD

1. Membrane Filter Holder: 142/293 mm with 0.2µ membrane filter and 2 micron fiberglass prefilter
2. 10 Liters bubble test flasks 2 N0.
3. Vial filling machine unit: 10 ml/5ml glass syringes, stainless steel syringe casing, non-returned valves, filling needles, nitrogen manifold, SS ‘T’ joints, nitrogen gas reservoir.

Tubing
a. 2 Silicon tubing connecting outlets of solution holding vessel to the inlet of non-return valves
b. 2 Silicon tubing connecting outlets of non-return valve to the filling nozzles
c. 6 Silicon tubing to connect manifold to nitrogen gas nozzles
d. 1 Silicon tubing to connect nitrogen source to 25 mm filter
e. One PVC tubing for connecting two nitrogen filters
f. One Silicon tubing to connect manifold to nozzle of tank for gas overlaying
4. Sponges in bags.
5. SS bucket
6. 1 PVC tubing for drainage
7. Nitrogen filter holders: 25 mm with 0.2 micron hydrophobic membrane filter 4 Nos.
8. A bin containing tubing for filtration:
a) 1 silicon tubing for solution filtration
b) 2silicon tubing for nitrogen gas overlaying during filtration
c) 1silicon tubing to connect outlet of membrane holder to inlet of solution holding vessel.
9. 15 Liters distilled water in SS bucket.
10. Empty beakers 2 Nos.
11. 1 Liter round flat bottom B.T. flask
12. Tubing for integrity testing of nitrogen filters
a. 1 PVC tubing as an inlet to nitrogen filter
b. 1 silicon tubing at outlet of nitrogen filter
13. Air sampling drum and fan
14. Parchment papers 8 Nos.
15. Aluminum foil for covering distilled water flasks
16. Millipore breather filters 1 No.
As per validation cycle, the above load is run for 30 minutes from the time the digital temperature indicator reaches 123 ºC and in this time all the items including the item in coolest location satisfy F0 = 15 minutes.

2. Holding Vessel Load
Items sterilized in this load
1. 120 Liters holding vessel
2. 4 Nos. Pegs wrapped in a parchment paper
As per validation cycle, the above load is run for 30 minutes from the time the digital temperature indicator reaches 123 ºC and in this time all the locations including the coolest location satisfy F0 = 15 minutes.

3. GARMENT AND RUBBER STOPPER LOAD

Items sterilized in this load

1. 10 Sets of garments placed in perforated baskets
2. Cotton buds for swab testing
3. Rubber stoppers (approx. 30,000) in maximum 9 large and 6 small SS pots.

As per validation cycle, the above load is run for 60 minutes from the time the digital temperature indicator reaches 123 ºC and in this time all the items including the item in the coolest location satisfy F0 = 15 minutes.


4. MEMBRANE, HOLDER, HOLDING VESSEL AND AMPOULE FILLING ASSEMBLY LOAD

Items sterilized in this Load.

1. 40 liters holding vessel
2. Membrane filter holder: 142/293 mm with 0.2µ membrane filter and 2 micron fiberglass prefilter.
3. 10 liters bubble test flask 2 Nos.
4. Ampoule filling machine unit: Ss syringes along with SS spring, filling needles, nitrogen needles, nitrogen manifold, SS‘T’ joints.

Tubing:

a. 7 silicon tubing for nitrogen line
b. 6 silicon tubing for nitrogen line
c. 8 silicon tubing for pre and post nitrogen flushing
d. 4 silicon tubing for filling of solution

5. Sponges in bag.
6. SS bucket 2 Nos.
7. 1 PVC tubing for drainage
8. Nitrogen filter holders: 25 mm with 0.2µ hydrophobic membrane filters 4 Nos.
9. A bin containing tubing for filtration:
a. 1 silicon/PVC tubing for solution filtration
b. 2 silicon tubing for nitrogen gas overlaying during filtration
c. 1 silicon tubing to connect outlet of membrane holder to inlet of solution holding vessel
10. Empty beakers 2 Nos.
11. 1 Liter round flat bottom B.T. flask
12. Tubing for integrity testing of nitrogen filters.
a. 1 PVC tubing as an inlet to nitrogen
b. 1 silicon tubing at outlet of nitrogen filter
13. Air sampling drum and fan
14. Parchment papers 8 Nos.
15. Aluminum foil for covering distilled water flask

As per validation cycle, the above load in run for 15 minutes from the time the digital temperature indicator reaches 123 ºC and in this time all the items including the items in coolest location satisfy F0 = 15 minutes.


5. EMPTY ALUMINUM CONTAINER LOAD

Items Sterilized in this Load

1. 4Nos. of empty aluminum containers for collection of filled ampoules.

As per validation cycle, the above load id run for 15 minutes from the time the time the digital temperature indicator reaches 123 ºC and in this time all the location including the coolest location satisfy F0 = 15 minutes.


6. GARMENT LOAD

Items sterilized in this load
1. 10 sets of garments placed in perforated baskets
2. Cotton buds for swab testing

As per validation cycle, the above load is run for 60 minutes from the time the digital temperature indicator reaches 123 ºC and in this time all the location including the coolest location satisfy F0 = 15 minutes.

SERVICING POLICY – CLEAN AIR SYSTEMS AND DEVICES MONITORING

ST — 106
SERVICING POLICY – CLEAN AIR SYSTEMS AND DEVICES MONITORING


The system includes:

1. HEPA Filters
2. Prefilters
3. Grils
4. Manometer/Manometer Oil
5. Light and electricals
6. Blower/Impeller
7. Motors
8. Plenum
9. Airflow velocity

Monitoring Include

1. Cleaning and checking of equipment in the systems routinely
2. Leak test/integrity test of HEPA filters
3. Maintaining records of observation and readings
4. Repairing/replacing/rectifying whenever necessary

Equipment in the System includes
1. 4 terminal HEPA filters in filling room (i.e. class 10,000 area)
2. 3 terminal HEPA filter in the three change rooms ( one terminal filter in each room)
3. 12 ft. horizontal LAF unit with 4 HEPA filters in sterile filling room
4. Gradvel down-flow laminar unit with two HEPA filters for ampoule filling in sterile filling room
5. Gradvel down-flow laminar unit for aseptic filtration in sterile filling room
6. Down-flow laminar above small right angle conveyor in filling room
7. Down-flow laminar above large turntable in filling room
8. Down-flow laminar above vial sealing machine
9. One LAF down-flow unit for rubber stopper washing in component preparation room
10. One LAF down-flow unit for component wrapping before sterilization in component preparation room
11. Gradvel down-flow laminar unit with two HEPA filters for vial/ampoule washing
12. HEPA filter module on the dry heat sterilizer
13. All prefilters of the LAF units
14. Booster fan connected to the air handling system
15. Prefilters in the booster system
16. All grill in the air handling system

Frequency of Monitoring

Clearing & checking – once in 3 months
HEPA Filter – DOP Test – once a year
Integrity Test of HEPA filter by DOP Aerosol challenge using ATI Model TDA 2E particulate detection apparatus or any other suitable instrument. Velocity: Velocity reading using Alnor Velometer 6000P series suitable or any suitable instrument.

FEQUENCY: QUARTERLY

REMEDIES FOR HIGH MICROBIAL COUNTS

ST — 102
REMEDIES FOR HIGH MICROBIAL COUNTS


INTRODUCTION

It is an alarming situation to observe any microbial counts on the laminar because it is the critical area of product exposure. Hence immediate action is required when any counts are observed.

Also counts in other areas of the sterile room should be as possible to prevent any chance contamination of product. In case high microbial counts are observed, the following remedial action may be taken.

ON LAF

1. Confirm plates are taken into filling room only after they are kept under UV in the pass-through for 30 minutes.
2. Inspect each plate before exposure.
3. Plate exposure operator dose not cover plate during exposure.
4. Periodically spray benches with 70% IPA (Sterile). Sanitize LAF benches preferably before and after breaks.
5. Check for any leakages between bench and HEPA grill by smoke test.
6. Thoroughly sanitize the bench with 0.5% Aarshol after the day’s work.
7. If very high counts are observed, check the integrity of HEPA filters.

ROOM

1. Confirm the points 1 to 3 listed above.
2. Minimize the operators’ movements.
3. Thoroughly sanitize the required around the plate exposure location.
4. Clean the area periodically with sterile 70% IPA throughout the day.
5. Daily high counts will need area fumigation and change of disinfection agent.

PROCEDURE FOR ENTRY OF MAJOR EQUIPMENT INTO STREILE AREA

ST — 088
PROCEDURE FOR ENTRY OF MAJOR EQUIPMENT INTO STREILE AREA


By and large the major pieces of equipment into the sterile area such as large trolleys, ampoule filling sealing machine etc. by the very nature of the size will be moved into the sterile area either through the equipment entry door or through the change room.

Prior to moving such equipment into the sterile area, the production supervisor concerned and engineering department will ensure that it is in proper working condition. Additionally, it will be necessary to confirm that it is clean.

Just prior to the entry, the external portion of the machine will be sanitized with Sterile70% Isopropyl Alcohol and Sterile 2% Bacillocid solution (disinfectant). Initially, such a sanitized machine will be moved to the second cubical change room and retained there overnight under the UV lamp. On the following day, the machines external portion will once again be sanitized with Sterile 70% IPA and Sterile 2% Bacilloicd and then moved into the sterile area.

Should it be necessary, after the entry of the equipment, Fumigation may be carried out in the sterile room to ensure there has been no abnormal increase in Microbial Count due to the major piece of equipment.

Swab test should be taken of the equipment to confirm the proper disinfection.

MONITORING OF POSITIVE PRSSURE, AIR TEMERATURE AND RELATIVE HUMIDITY

ST — 069
MONITORING OF POSITIVE PRSSURE, AIR TEMERATURE AND RELATIVE HUMIDITY


Area under consideration: Class 100 to Class 10,000 under the same air handling units and air-conditioning plant and component preparation area (Class 10,000). Temperature Monitoring: Limit: Not to exceed 23ºC.

1. One calibrated thermometer permanently fixed on the body of 12’ LAF unit, which can be seen from the view panel in corridor.
2. The supervisor of sterile area must read and record the temperature of sterile room at any time between 11.30 hours – 14.00 hours on all filling days.
3. The chart is can annual record for the temperature in the one room.

The instrument is not calibrated semi-annually

Positive Pressure Monitoring: Daily Record

1. Filing room and change room pressure indicating manometers are mounted on a board outside the filling room in the adjoining passage.
2. the supervisor must read and record the pressure of the rooms in the ‘Daily Pressure Record’ chart at the time of recording temperature during the working hours.
3. Simultaneously, the pressure reading of each manometer mound on the LAF mentioned below should be similarly recoreded.

A. Filling Room

2 manometers mounted on one ft LAF (horizontal)

1 manometer mounted on one down-flow Gradvel laminar used for ampoule filling

1 manometer mounted on one4 ft. Gradvel down-flow laminar used for aseptic filtration

1 manometer mounted on the down-flow laminar above small right angle conveyor

1 manometer mounted on the down-flow laminar large turntable

Pressure Differential Across Terminal HEPA Filter Monitoring






The manometers indicating pressure differential across the terminal HEPA filter in the filling room and change rooms are mounted on a board outside the filling room in the adjoining passage. The pressure differential reading are recorded monthly

B. Component Preparation Area

One monometer on the vertical down-flow Gradvel laminar on the vial/ampoule washing machine.

One monometer on the vertical down-flow laminar on the final rubber stopper washing machine.

One monometer on vertical down-flow laminar above the table used for component wraping.

One manometer on vertical down-flow laminar flow hood above the vial sealing machine.

4. The filling room pressure must be grater than the adjacent 3rd change room pressure by 1.25 mm of water gauge (i.e.0.05 inches of water gauge).Similarly the 3rd change room pressure must be greater than the 2nd change room pressure by 1.25 mm water gauge. The 2nd change room pressure must be grater than 1st change room pressure by 1.25 mm water gauge and the 1st change room pressure must be grater than the outside passage by 1.25 mm water gauge.

Relative Humidity Monitoring

Sterile filling room is daily monitored for relative humidity. Dial type ‘Barigo’ brand instrument for measuring humidity is kept near the temperature indicator in the filling room. Humidity is recorded on all filling days in the prepared format. Limit not more than 55%. The instrument is calibrated semi-annually.

MONITORING OF HEPA FILTERS

ST — 068
MONITORING OF HEPA FILTERS


Air supply to the sterile area must be appropriately filtered to minimize the potential contamination by both viable and nonviable particulate matter. HEPA filters are used to filter the air, both at terminal points of blowers and in laminar flows where product will be expressed. The HEPA Filter fixtures are to be monitored periodically by the following tests to check that they maintain their rated efficiency.

1. Air velocity
2. Pressure drop across HEPA filters
3. Checking integrity of HEPA filter using cold DOP
4. Air direction

In addition to monitoring the filter surface, the seal of each filter element to its frame and the seal between the filter frame and the filter housing must be verify that particles are not escaping around the filter.

1. Air Velocity Measurement of HEPA Filters

Air velocity of laminar flow hoods is measured to assure an acceptable level airflow in the sterile area, component preparation area, and all terminal HEPA filters are to be monitored.

Equipment Used: Alnor Velometer no. 600 P

PROCEDURE

In case of laminar flow hoods, measure the air velocity by positioning the velometer probe at a distance of one foot above the work surface. Read velocity directly from the meter and record. Six reading should be taken and the average calculated.

In case of terminal HEPA filters, the velocity should be taken six inches away from the grill and six readings should be taken and averaged and these reading should be taken for calculating air changes in the room.

ACEPTANCE CRITERA
A minimum air velocity at work surface of 0.3 meters/second (i.e. 60.0 ft/minute) for vertical laminar flow hoods and a minimum velocity of 0.45 meters/second (i.e. ft/minute) for horizontal laminar flow hoods.

*If velocity drops below the acceptable criteria, replace the filters

Frequency of test: Quarterly

2. Procedure For Measuring Pressure Drop Across HEPA Filter

The amount of pressure drop across terminally mounted or laminar flow hood HEPA filter is related to the particulate loading of the filter or the amount of blocking of the filter output. The life of HEPA filter can be improved by cleaning the pre-filters in air handling units frequently. When the pressure drop across the HEPA filter reaches above the limit, the filter must be changed. Limit: 2’’ of water gauge (i.e. 50.8 mm of water gauge)

PROCEDURE

EQUIPMENT

1. Two sampling tubes, one upstream of the filter and one downstream.
2. Calibrated Magnehelic gauges or inclined manometer (zero adjusted)

Place one end of the sampling tube in the upstream of the filter under test, and connect the other end to the inlet of the calibrated Megnehelic or inclined manometer. Place one end of the other sampling tube downstream of the HEPA filter and the other end to the outlet of the Megnehelic gauge or inclined manometer, and record the reading directly from the Megnehelic gauge manometer.

Frequency of Testing: Quarterly

Limit = pressure drop not more than 2 inches of water gauge (i.e. 50.8 mm of water gauge). If the pressure drop is more than the limit, the filter has to be replaced.

3. 3. Procedure For Checking Integrity Of HEPA Filter Using DOP

Air supply to the sterile area must be appropriately filtered to minimize the potential contamination by both viable and nonviable particulate matter. HEPA filters are used to filter the air, both at terminal points of blows and in laminar flow where product will be exposed. To check the efficiency of particulate retention, the HEPA filter fixtures are to be monitored. The porosity of HWPA filter is 0.3 micron. Therefore, aerosol of DOP can be used to check the efficiency of retention since it has an average particle size of 0.45.

PROCEDURE
Start the system and introduce DOP in the upstream of the HEPA filter. Scan the down stream flow with suitable light scattering photometer which detects the DOP particles. Whole of filter surface and filter frame/housing to be scanned. Any leakages if observed, to be mentioned in a diagram and can be rectified, if leaks are within limit.

Frequency of integrity testing DOP of HEPA filters using DOP is at least once a year or when there is any replacement of filter, gasket housing etc.

Acceptance Limit is = 99.997% retention of particles.

Direction of Air-flow

Direction of air-flow of all terminal HEPA filters and HEPA filters of all laminar flow hoods are also monitored using smoke stick Titanium Tetrachloride (TiCl4). The smoke sticks are moved in front of the HEPA filters to note the direction of the airflow to confirm that the movement is in straight line and that there is not turbulence at critical areas of operation.

CONTROL AND PLACEMENT PLANS OF BIOLOGICL MONITORS

ST — 043
CONTROL AND PLACEMENT PLANS OF BIOLOGICL MONITORS


INTRODUCTION

Monitoring and controlling of vial micro-organism is as important as the controlling of non-viable particulate matter which often transport viable micro-organism, because there are chances that these viable micro-organism may find their way into the product and contaminate the product.

The most common method of monitoring the air in the sterile area is by the use of settling plates containing soybean casein digest agar.

1. Soybean casein digest agar medium is used to identify the presence of microbial organisms in containing soybean digest agar.
2. Petridishes containing soybean casein digest agar medium suitably prepared and provided by QC are marked with numbers that correspond to the locations where plates are to be exposed.
3. Plates should be exposed at work height, on tabletops or carts positioned to collect representative sample.
4. Sterile room must be monitored whether or not there is activity on every working day.
5. Plates should be exposed during each shift working.
6. One plate should be exposed upto 100 sq. ft of floor area and one additional plate for each additional 100 sq. ft of floor area.
7. Expose one plate at the location of highest particle count determined by long count.
8. All LAF hoods must be monitored in unmanned state.
9. One plate is kept as negative control; on this plate the time at which plates are to be exposed is marked.
10. All the plates are kept in pass box under UV lamp in lid sown position half an before the exposure commences.
11. Plates are exposed for minimum 60 minutes during working hours and then kept back in the pass box to be taken for incubation.
12. Plates are incubated at 30 ºC to 35 ºC for 48 hours and then 20 ºC to 25 ºC for further 72 hours.
13. At the end of 48 hours, total number of colonies of bacteria and fungus are down in plate count of sterile area from by equality control microbiologist and second reading taken after 72 hours for fungus.
14. Area disinfection procedure is reviewed and attention is paid to the area where high counts are observed consistently.
15. 5% Copper Sulphate treatment or 2% Bacillocid treatment is carried out when fungus presence is observed in the area consistently for two-three days.

FREQUENCY - DAILY

CHECK LIST OF JOBS START UP AND AFTER SHUTDOWN

ST — 016
CHECK LIST OF JOBS START UP AND AFTER SHUTDOWN


A. WASHING AREA

1. Cleaning of compresses air filters. (Shavo-Norgren)
2. Cleaning of DM water storage tank.
3. Setting of vials washing machine.
4. Fixing of filter of down-flow unit and to check working. Adjust manometer oil to zero. If HEPA is removed, check DOS test and air velocity.
5. Keep SS boxes washed with DM water.
6. Fix cleaned DM water filters in respective housings.
7. Check all tubing, if required, changed them.
8. Cleaning of split AC filters.

B. RUBBER STOPPERS TREATMENT

1. Get the washing machine cleaned thoroughly.
2. Check connections of steam and DM water line.
3. Clean SS Pall filters, GS filter and in-line.
4. Clean SS pots and lids.
5. Clean distilled water storage tanks and 20 Lt. capacity pressure unit.
6. Keep in the area, plastic containers required to soak the stoppers.
7. Clean membrane holder assembly and refill it.
8. Fix filter of air down-flow unit and check working. If HEPA is removed check DOS test and air velocity.
9. Set manometer oil level upto zero.
10. Check availability of Benzalkonium Chloride & Hydrochloric Acid in washing area.

C. STERILZATION

1. Clean, dry and connect distilled water storage tank.
2. Check working of thermostatic control.
3. Run distilled water plant for 2-3 hours and discard the collection.
4. Check leakages if any during run of distilled water plant. Check water conductivity.
5. Get chemical analysis of distilled water done.
6. Check rate of distilled water collection per hour.
7. Check cleaned SS Pall filter is fixed to the DM water inlet before running the plant.
8. Check working of autoclave thermograph. Check inkbottle for sufficient quantity of link. If possible, calibrate thermograph.
9. Normal servicing of autoclave is done by vendor.
10. Run autoclave for 30 minutes and observe any leakages through steam valves, door gasket and joint. Check working of dial thermometer.
11. Check fixing and conditions of air in-let filter.
12. Check working of pressure gagues.
13. Clean the autoclave with distilled water and Benzalkonium Chloride solution before operating.
14. Clean carriage of sterilizer chamber with vacuum cleaner and then with distilled water and sponge.
15. Cleaning carriage of sterilizer with diluted Hydrochloric Acid and then with water.
16. DOP test of HEPA filter module and air velocity.
17. Run dry sterilizer empty at 300 ºC for 1 hour to check its heating and cooling functions.
18. Check working of thermograph for temperature and time and working of HEPA filter after heating cycle.
19. Checks working of inter locking system of autoclave and dry sterilizer.
20. Check hot air leakages through door gasket.

D. COMPOUDING ROOM

1. Check working of homogenizer.
2. Replace N2 25 mm filter.
3. Connect N2 line for sparging and filtration.
4. Remove unwanted material from tables in compounding room.
5. Keep back material removed from sterile area.
6. Replace all UV tubes after noting intensity.
7. Provide new sippers for operators.
8. Check working of conveyer & filling machine.
9. Check grease in filing machine.
10. Check all nitrogen, oxygen and LPG gas lines for working and leakages. Check all gas liners are correctly identified.
11. Check the pressure of room and change rooms.
12. Check temperature of filling room.
13. Replace old sponge used for wiping foot soles change room.
14. Calculate air change per hour from velocity of air through each terminal HEPA filters.
15. Open all return air riser dampers.
16. Check working of fumigation switch and plate.
17. Get area cleaned with 0.5 % Aarshol again before starting fumigation.
18. Check working of down-flow unit, portable laminar including DOP test and air velocity.
19. Check working of ampoules filling machine if required.

E. SEALING ROOM

1. Run machine without vials for few minutes. Observe any abnormal sound.
2. Take trial of 2 ml vials sealing.
3. Lubricate the machine and keep ready for use.
4. Thoroughly wipe and clean vibrator with 70 % IPA.

F. INSPECTION ROOM

1. Keep batch ready in inspection room.
2. Remove labels of the product other than those that are under inspection.
3. Take trial of machine without vials.

G. LABELLING ROOM

1. Keep batch and labels ready for labeling on the first day of the start up.
2. Keep about 3.0 kg. Gum Acacia in container.
3. Remove previously labelled products from area.
4. Check al accessories required for labeling.

H. PACKING ROOM

1. Keep packing materials, batch ready for packing.
2. Check all accessories required for packing.
3. Confirm line clearance before packing start up.

I. DM WATER PLANT

1. Formaldehyde treatment and double regeneration of DM water plant. Formaldehyde treatment should be given only if viable counts are high.
2. Check DM water free from acid, alkali, formaldehyde traces for pH.
3. Clean SS storage tank used for multicolumn distillation still.

Data Control

1. Purpose :
§ To establish a procedure for writing, approval, issuance, controlling and distribution of documents and data control.
§ To ensure that only the most recent revisions of documents are available at point of use.
§ To ensure that any change in a document is recorded and that all appropriate documentation is updated to reflect the change.

2. Scope :
All quality system documents and records.

3. Responsibilities
3.1. Management representative
3.1.1 Oversees the control of all documents, by keeping a master list of the location of all documents.
3.1.2 Responsible for reviewing the change proposal form (MR/4/003), and informing the originator in case of rejection / approval of change proposal.
3.1.3 Ensures the availability of the documents at proper location.
3.1.4 Provides the document change control training.
3.2. document users
3.2.1 To verify that document / data being used is current by consulting the control documents master list (MR/4/001).
3.2.2 Any user of the document can request a change to a document.
3.3 Plant Engineer, HR Manager, Production Manager ,QA Manager are Functional Authorities for Maintenance Department, HR Department, Production Department and QA/QC Department respectively While Director Finance & Administration will be Functional Authority for Sales Section, Purchase Department and M.R.
4. procedure
4.1. document hierarachy
4.1.1 The documents of the Quality System are categorized into four levels:
4.1.1.1 Level 1: Quality Manual, Quality Policy, Quality Objectives and Organizational Chart.
4.1.1.2 Level 2: Job Descriptions, Quality Procedures, and Standard Operating Procedures.
4.1.1.3 Level 3: Specifications, Testing Methods, Operating Instructions, and Flow Charts, etc.
4.1.1.4 Level4: Formats and Quality Records.

4.2. document Identification (level i, ii, and iii)
4.2.1 Documents of Level I, II and III, excluding the Quality Policy, Validation Protocol and Validation Report will be uniquely identified using the following format:
Medicraft Pharmaceuticals (Pvt) Ltd. Peshawar
ISO No.
MR/2/001

Title: Mention title of Document
Issue
2
Supersedes
Issue 1 of MR/2/001
Effective Date
August 2004
Revision Date
July 2006
Page No.
1 of 10

*AAA = Deptt. code.
BBB = Section Code (Section code is applicable to a document whose scope is section- wide. eg, if a procedure is applicable to Injectable section only, its ISO No., must include its section code (AAA-BBB/C/DDD). But if a document is applicable to whole production deptt., then its ISO No. (AAA/C/DDD) will include only deptt. code.)
C = Level of the document, ie., 1,2,3, and 4.
DDD = Document Number.
Approved codes of deptt./section are:
S.No.
Department/Section
Abbreviation
1
Management Representative
MRC
2
Production
PRD
3
Injectable
INJ
4
Tablet
TAB
5
Liquid
LIQ
6
Dry Syrup
DSS


S.No.
Department/Section
Abbreviation
7
Capsule
CAP
8
Human Resource
HRD
9
Research and Development
RDD
10
Store
STR
11
Raw Material Store
RMS
12
Packing Material Store
PMS
13
Finished Goods Store
FGS
14
Quality Assurance
QAD
15
Quality Control
QCD
16
Sales and Marketing
SAL
17
Maintenance
MNT
18
Purchase
PUR
19
Printing
PNT

4.2.2 Quality manual, Job Descriptions, Validation Protocols, Validation Reports and Validation Master Plan are exceptions to the coding rule of 4.2.1, whose ISO No. will be as:
QM/1
JD/2/DDD
VMP/2
VR – AAA/3/DDD
VP – AAA/3/DDD

Where AAA is Deptt./Section Code, as mentioned in the above table, and DDD is the document number.
4.3. document structure (Level I, ii and iii)
4.3.1 Level II and III documents, except Job Descriptions, specification and Testing Methods, Validation Master Plan, Validation Protocol, and Validation Report will contain the following headings, with accompanying detail necessary, to perform the related procedure:
4.3.1.1 Purpose
4.3.1.2 Scope
4.3.1.3 Responsibilities
4.3.1.4 Definitions (Optional)
4.3.1.5 Procedure
4.3.1.6 References (Optional)
4.3.1.7 Related Documents
4.3.1.8 Annexure
4.3.1.9 Change Control History
4.3.1.10 Distribution List
4.3.2 All the pages of Level I, II, and III documents will bear following additional information duly signed by an authorized persons:
4.3.2.1 Written By
4.3.2.2 Reviewed By
4.3.2.3 Checked By (Not applicable for MR Documents)
4.3.2.4 Approved By (Applicable for Q.A, Q.C, Production and Maintenance Department’s documents)
4.3.2.5 Authorized By ( Not applicable for Quality Assurance and Quality Control
department’s documents).
4.4. document prepartation (Level i, ii, iii and iv)
4.4.1. Management Representative, in consultation with Plant Manager and senior management, will prepare Quality Policy and Quality Objectives for the organization.
4.4.2. Deptt. / Section Head will develop a document, although he / she can assign this task, by consulting concerned Manager, to other person who has the competency to perform the task.
4.5. document review, checking, approval and authorization
4.5.1. Documents related to Production Deptt., M.R., Maintenance Deptt., Human Resource Deptt., QA Deptt., QC Deptt., Purchase Deptt., and Sales Deptt., will be reviewed by the Manager Production, Management Representative, Plant Engineer, HR Manager, QA Manager, QC Manager, Finance Manager and Distribution Manager respectively.
4.5.2. MR will check all the documents for its compliance to QMS requirements.
4.5.3. QA Manager will have the authority to approve the technical documents of the Production, Maintenance, QA and QC Deptt.
4.5.4. Plant Manager/designee will authorize the documents approved by QA Manager.
4.5.5. Authorization of documents related to MR, HRM, Purchase Deptt., and Sale Deptt, will be given by Director Finance& Administration/ Director Marketing.
4.6 issuance of documents
4.6.1 Management Representative will keep a copy of all the documents in a Central Quality File and will distribute controlled copies to the concerned deptt./section, in according with distribute list.
4.6.2 All the original documents are printed, preferably, on white A4/Legal Size Paper.
4.6.3 Controlled documents are stamped in red as “Controlled Copy” by Management Representative for identification.
4.6.4 Uncontrolled copies are allowed only for use by external parties, e.g. customers, auditors, consultants etc. These are stamped in red on the front page as “Uncontrolled Copy”. MR will have the authority to issue Uncontrolled Copies.
4.6.5 MR centrally controls the issuance of documents by maintaining a controlled documents Master list, MR/4/001.

S. No.
Level
Document Type
Issuance Detail
1
Level I
Quality Manual
Restricted only to MR, and users authorized by the CEO or MR.
Quality Policy and Organizational Objectives
Issued to all Departments.
2
Level II
Quality Procedures and SOPs
Issued to concerned Department/Personnel.
Job Descriptions
3
Level III
Operating Instructions
Issued to concerned Department/Personnel.
Testing Procedures and Specifications, Specifications, etc.
4
Level IV
Quality Records and formats
Issued to concerned Department/Personnel.
Documents of external origin
4.7 Quality records and formats (level iv)
4.7.1 Quality records have a limited extent of control, only their format is controlled.
4.7.2 Quality records are uniquely identified by their name and ISO No.
4.7.3 In cases where it is feasible, the format of the level IV documents, except log books and registers ,will be as:

Medicraft Pharmaceuticals (Pvt) Ltd. Peshawar
Page No.
x of y
Title: Mention Title of the Document
ISO No.
AAA-BBB/C/DDD
Issue
1
Effective Date
April 2004

4.7.4 MR maintains a Quality Record List which describes the following information:
4.7.4.1 Record Name
4.7.4.2 Keeper and Location
4.7.4.3 Retention Period
4.7.4.4 Issue No.
4.8 amending documents and records
4.8.1 For amending documents procedure for change control is followed.
4.9 Withdrawl of obsolete documents
4.9.1 Obsolete documents are identified by MR and are duly stamped in red as “Obsolete Document”.
4.9.2 All copies of obsolete documents are withdrawn by MR. One copy of the obsolete document, along with its Circulation Record (MR/4/002) is kept for reference purposes, in an Obsolete Document File, MR/4/004. All remaining copies are destroyed by MR.
4.10 documents of external origin
4.10.1 Documents of external origin are stamped in red as “For Reference Only” and is issued to concerned deptt. and person only.
S. No.
Document of External Origin
Document Type
1
Guidelines
Layout Standards, Reference Templates, Guidelines on GMP,
Quality Auditing, Guidelines for Objectives
2
ISO Standards
ISO 9001:2000
3
Official Reference Books
BP, USP, and other official books etc.
5 related documents
Nil
5 related records
5.1 Controlled Documents Master List, MR/4/001.
5.2 Circulation Record, MR/4/002.
5.3 Change Proposal Form, MR/4/003.
5.4 Obsolete Document File, MR/4/004.
5.5 Amendment Sheet, MR/4/017.


6 annexure
6.1 Flow Chart for Amending Document


ANNEXURE 7.1
Flowchart for Amending the Document

4.8.1
Start
Originator

Identifies and initiates need for changing documents through CPF.







4.8.3

MR and Concerned Deptt./ Section head review CPF

Accepts ?
MR and Concerned Deptt./Section Head

Identifies reason CPF was not approved

No 4.8.2






Yes


Author of Document evaluates the Change Proposal

Approves ?
Author of Document

Informs MR for reason of CPF rejection. 4.8.5 4.8.4

No





Yes



4.8.6
MR

Revises his copy of document manually and informs the originator and all concerned section/deptt. head.







4.8.9 4.8.7
MR

Notifies the Originator
Concerned Deptt./Section Head

Manually amends the document.







MR

Verifies amended changes after about 1 week. 4.8.8





End






Note: In this flow chart document means Level I, II, III, and IV documents, and number written on a rectangle shows the section no. of this procedure.

5.6.1 For Permanent change:
5.6.1.1 Changes required are raised on a Change Proposal form (MR/4/003) along with a copy of suggested changes (if required) and is submitted to Management Representative.
5.6.1.2 Management Representative will discuss and evaluate proposed changes, in consultation with concerned deptt./section head.
5.6.1.3 If they reject proposed changes, MR will notify the originator about rejection of CPF along with the reason of rejection.
5.6.1.4 In case Change Proposal is accepted, MR will forward the proposal for final approval to functional authority who has written the document or holds the authority to approve the concerned document.
5.6.1.5 If change proposal was rejected by functional authority, he will inform MR about the reason of rejection of CPF.
5.6.1.6 Once the change proposal is approved, MR will:
5.6.1.6.1 In case of a major change whole document will be revised with the new issue number by following guidelines given in section 4.4 and 4.5.
5.6.1.6.2 For minor changes M.R. will amend the document in his control, and will inform the originator and concerned deptt./section head about the changes.
5.6.1.6.2.1 Concerned deptt./section head after getting information from Management Representative will make the proposed changes in the document manually.
5.6.1.6.2.2 After about one week, MR will verify the proposed changes by visiting the deptt./section using the amended document.
5.6.1.6.2.3 The newly amended document will carry the new revision no., i.e., revision 1 will become revision 2. In case of level IV documents instead of revision no., issue number will change.
5.6.1.6.2.4 After three revisions next issue of the document will be issued.
5.6.2 FOR TEMPORARY CHANGE
5.6.2.1 For temporary change procedure for change control is followed.
5.6.2.1.1.1

ENVIRONMENTAL

Medicraft Pharmaceuticals (Pvt) Ltd. Peshawar	Page No.	1 of 4
Job Descriptions	ISO No.	JD/1/024
	Issue	2

Part 1

Designation: Manager Research and Development

Department: Research and Development

Reports to: Production Manager

Part 2

Broad Functions:

1. Responsible for supervising all the activities in his area of responsibilities such as launching of new products according to latest research, improving and economizing the existing formulations.

2. Responsible for supervision and control of staff reporting to him as per company’s policies and procedures maintaining high level of GMP, safety and housekeeping requirements in R&D Section.

Part 3

Principal Responsibilities:

Responsible for supervision and control of work related activities in his area of responsibilities as described below:

1. Supervise the development of formulations for newly discovered drugs in light of modern research.

2. Pinpoint the defect in the existing formulations in consultation with the production manager and supervise the manufacturing of the trial batch.

3. Discuss with production manager suggestion for the economizing of the productivity improvement and improving the quality of the product.

5. Ensure that all the precautions are practiced before starting, during and after the completion of the trial batch, e.g. cleanliness of equipment and area, humidity and temperature control, etc.

6. Ensure proper housekeeping and cleaning as per relevant SOPs.

7. Assign daily jobs to R & D officer.

8. Ensure to fulfill the daily production target in the assigned area.

9. Notify the Production Manager / maintenance department any breakdown of process / service equipment and any subsequent delay in production.

10. Inform, persuade and convince staff reporting to him of the benefits of GMP, Safety, Quality and ensure that our products maintain best quality.

11. Ensure that the manufacturing sections are complying with the standard procedures related to GMP / SH&E set by the company.

12. Carry out audit of manufacturing and pinpoint violation GMP/SH&E standards to the person responsible for it and arrange for its rectification on priority basis.

13. Responsible for proper outfit, cleanliness and hygiene of the staff reporting to him.

14. Ensure the security and safety of equipment/ products and personnel in the section.

15. Pinpoint any safety hazard/unsafe practices and take an appropriate action for its rectification.

16. Check late comings, and act of indiscipline of the staff reporting to him by taking immediate action.

17. Training / development of the new colleagues including management and non–management staff.

18. Recommend increment of the staff reporting to him.

19. Follow and implement all the policies and procedure of the company as communicated from time to time in his section, permanently or temporarily.

20. Attend courses / meeting as and when required.

21. Bring about improvement in the working of the section through creative and innovative ideas.

22. He is authorized to recommend leave of his subordinate.

23. He will perform any other work assigned by production manager / factory manager / director(s) from time to time as per business requirement.

24. He is responsible to supervise and manage the work of his sub – ordinates and authorize to:

    1. Recommend overtime, leave etc.

    2. Transfer, promotion, demotion etc.

25. Staff reporting to him:

    1. Section Incharge.

    2. Supervisors.

    3. Workers.

26. Area of responsibilty:

    1. Production Deptt.

Part 4

Principal Relation:

1. Contacts Inside the company:

   1. Frequently remains in contact with Production Manager, Incharge RMS/PMS, Supervisor Printing Section, Supervisor Finished Goods Store, Tablet Section Incharge, Supervisors and workers in his section.

2. Outside the company:

   1. Nil

Part 5

Supplementary Information:

Education: B. Pharmacy / Equivalent Degree.

Experience: Minimum 2 to 3 year but not necessary.

Skills: Computer literate but not necessary.

a system and instructions and to assign responsibilities

3Medicraft Pharmaceuticals (Pvt) Ltd. Peshawar	Page No.	1 of 1
Title: Procedure for Training and Skill Development.	ISO No.	HRD/2/001
	Issue	1
	Supercedes	Issue 2 of HRD/2/001
	Effective Date	October, 2005
	Revision Date	October, 2006

1. Purpose :

• To ensure that all employees receive adequate training in approved procedures, manufacturing skills, and safety to meet or exceed customer expectations.

• To provide for a system and instructions and to assign responsibilities for determining training needs, providing the training, and keeping training records.

2. Scope :

• This procedure applies to all training activities at Medicraft Pharmaceuticals.

3. Responsibilities

• Human Resource Department is responsible for all new or transferred employees to meet the minimum requirements for the position being filled, by initiating and ensuring all the necessary trainings on time, with the coordination of MR.

• Human Resource Manager identifies with the coordination of MR ensures that all necessary training is received by the staff.

• HRM with the coordination of MR is responsible for making the necessary arrangement regarding the training session, such as arranging a training instructor, etc.

4. procedure

   1. orientation to new employees AND OTHER TRAININGS TO ALL THE CONCERNED EMPLOYEES.

1. Orientation to new employees includes orientation on administration policies (e.g., working hours, leaves, medical, disciplinary policies etc.), understanding of Quality Policy, Job description, and on – job training.

2. HR Manager initiates the planning of the training by maintaining the format of Training Plan for the Year 200X.(HRD/4/004) and coordinate with MR in case if any alteration is required to be made in the planning,

3. The training plan is made for a particular time period, tentatively for 3 months.

4. All the section/ department heads also plan and maintain the format of Training Plan for the Year 200A(HRD/4/004) and send them with MR in case if alteration is required to be done.

5. MR after analyzing the Training Plans duly adjusted for the dates and times, sends copies of all to HRM and concerned copies to each section with one copy of HRD Training Plan.

6. Training Request Form (HRD/4/001) is used if an external training is required.

7. Training Form (HRD/4/002) is maintained during training by the trainer. The Training Form (HRD/4/002) is then sent to HRD to update the Individual Employees Training Record(HRD/4/003). During the training session, performance of each trainee is evaluated.

8. In case of departmental / sectional training the Training Form (HRD/4/002) is maintained, the data from which is transferred to Individual Employee Training Record (HRD/4/003) within the section, and the Training Form is sent to HRD for updating of Central folder for Individual Employee Training Record (HRD/4/003).

9. All the departments updates the Individual Employees Training Record(HRD/4/003) from time to time by keeping liaison with Central Folder for Individual Employee Training Record (HRD/4/003)

10. Unplanned training if required to be done, then MR and HRD is communicated via Internal Memo (MR/4/006).

11. Individual Training Record Forms are maintained at the relevant department/sections.

2. EVALUATION OF EMPLOYEES.

Employees are evaluated by the head / Incharge of each section / department by maintaining the Form Employees Performance Evaluation form (HRD/4/005) and is communicated to HRD.

5. related documents

Nil

5. related records

1. Training Request Form, HRD/4/001

2. Training Form, HRD/4/002.

3. Individual employee training record HRD/4/003.

4. Training Plan for the year 200A HRD/4/004.

5. Employees performance evaluation form HRD/4/005

7. ANNEXURE

Nil.

7. CHANGE CONTROL HISTORY

Procedure for Training and Skill Development was revised in the month of November 2005 and it has replaced issue 2 of the document HR/2/01 with issue 1 of HRD/2/001

Written By	Reviewed By	Authorized by:
Aman Shah	Farooq Khan	Ashfaq Ahmad
HRM	MR	Director Admin./ Acct.
Date:	Date:	Date: