Stability of drug substances

Stability studies :

Define stability  :

To study on how the product quality changes with time under the influence of temperature, humidity and light ti establish its shelf life or retest.

Why stability  ?

• To provide storage condition
• To provide retest or expiry.

How to establish retest/expiry date :

Pack the material into tiny packs simulated to marketing conditions and keep in stability chamber.

withdraw as per the scheduled intervals and test it. Compare the results against initial results and draw trend chart.

what is long-term or real time storage condition :

The condition at which the material is stored.

 what is Accelerated storage condition :

The condition at which the material is stored about 15 degrees above to the long term storage temperature to know the potential degradation of the substance.

For every real time storage condition, one accelerated storage condition study for a period of 6 months is essential to extrapolate the retest or expiry.

Product intended to store at 25°C:

Retest/Expiry= available long term study period + 12 months

OR 

available long term study period X 2

apply both the formula and report whichever is  lower value, as the retest.

In short we can remember in more way:

1. If the available long term data is more than 1 year, then the retest is +12 month to the long term period. 

2. If the available long term data is less than 1 year, then the retest is twice to the  long term period. 

Product intended to store at 5°C:

Retest/Expiry= available long term study period + 6 months

OR 

available long term study period X 1.5

apply both the formula and report whichever is  lower value, as the retest.

In shout we can remember in more way:

1. If the available long term data is more than 1 year, then the retest is +6 month to the long term period. 

2. If the available long term data is less than 1 year, then the retest is 1.5 times to the  long term period. 

ICH Q1(A) and Q1(E) guidance are  more useful for stability studies.

Tips to remember :

1. The stability chambers are calibrated once in year.
2. frequent preventive maintenance shall be done the chamber, specially heater tanks maintenance.
3. Standby chamber shall be in place.
4. Within 24 hours, the samples shall be shifted to standby chamber when the current chamber is failed to run.
5. Excursions in the chamber shall be monitored and acknowledged once in a day minimum.
6. Prefer purified water as a source of  water supply to the stability chamber heater tank.
7. yearly once the  chamber uniform distribution of temp and humidity shall be verified .
8. if the accelerated condition study has no variance during, there is no extrapolation study required to establish retest or expiry. use the formulas as given above.
9. if there are changes or variance in the accelerated condition, the retst and expiry shall be less the proposed extension period.
10. Forced degradation study shall be done as a part of stability indicative nature of analytical method and to know the degradation pathways.

Regards,

Bujji Reddy Kanchi.

Quality-Pharmaceuticals

9676749937

Data Backup procedure Chromatography software

Empower Chromatography software backup and Restoration verification

1. Backup
2.Restoration
3.Deletion
4.System audit trail archival
5. Disaster management

Empower Backup procedure into Empower server(Monthly Manual backup)

1.                       Select the project view from the context menu in the configuration manager.

2.                       Expand the projects node in the tree pane. The list of projects is displayed under this node in the tree pane and in the view table.

3.                       Ensure that the required project is in read only lock status before backup.

4.                       Select and right-click on the required project, then click on backup, the backup project wizard – comment Entry page appears. Enter or choose appropriate audit trail comment and click on next.

5.                       Ensure that the correct project is selected for backup and click on next. Enter a path for destination of backup or use browse button to locate the destination and then click on next.

6.                       When the export process is finished click on next button, the backup project wizard start page appears. Then click on finish.

7.                        SYSTEM AUDIT TRAIL BACKUP

8.                       Configure System > Configuration Manager > System Audit trail, select the

9.                        required month audit trails either manually or using a view filter.

10.                   Go to Records > System Audit trail >Archive > Binary

11.                   Select the path and type the file name then click on save button, the audit trail archive and binary file is saved in the selected folder.

12.                   RESTORATION OF PROJECTS

13.                   Create a project ‘Restore’ in respective year.

14.                   Insert the respective CD/DVD into the drive.

15.                   Go to Pro > Configure System > Configuration Manager > Projects, right click on the project and click on Restore Projects.

16.                   Choose a directory to restore from (i.e where the CD/DVD is located in the drive) and click on next, select the parent project ‘Restore’ and click on next.Finish button will be enabled after successful data restoration, click on finish to

17.                               complete.

18.                   report shall be raised and concluded.

19.                   Take print out of report and and check against original record.

20.                   DELETION OF PROJECTS

21.                    Configure System > Configuration Manager > Projects, select the required project to delete.

22.                   Right click on the project and click on Delete, provide the audit trail comment and password and then click on OK.

23.                   Three calendar years projects shall be available in Empower and older than three years shall be deleted or based on capacity and performance of the server disk drives shall be assessed and the deletion of projects shall be decided as required or initial verification or based on need.

24.                   ARCHIVE AND REMOVAL OF SYSTEM AUDIT TRAIL

25.                   Go to Pro > Configure System > Configuration Manager > Records > System Audit trail > Archive and Remove.

26.                   Once the System audit trail ‘archive and remove’ screen is opened,  click on OK button.

27.                   Three calendar years projects shall be available in Empower and older than three years shall be deleted or based on capacity and performance of the server disk drives shall be assessed and the deletion of projects shall be decided as required or initial verification or based on need.

28.                   ARCHIVE AND REMOVAL OF SYSTEM AUDIT TRAIL

29.                   Go to Pro > Configure System > Configuration Manager > Records > System Audit trail > Archive and Remove.

30.                   Once the System audit trail ‘archive and remove’ screen is opened,  click on OK button.

31.                   Disaster management :

32.                   Daily(Hot) and weekly backup –Automatic backup

33.                   Monthly Backup is happening

34.                   The server room is maintained with controlled temperature.

35.                   The server room shall be maintained with fire alarm.

36.                   The server room shall be equipped with Commercial Sprinkler.

37.                   Daily hot backup is taken from all analytical instruments.

38.                   Hot backup in the secondary tapes is archived at QA daily.

39.                   The backup tapes are kept in Fire proof cabinets.

Chromatography Software backup and Restoration verification-Disaster management

Empower Chromatography software backup and Restoration verification

1. Backup
2.Restoration
3.Deletion
4.system audit trail archival
5. Disaster management

Empower Backup procedure into Empower server(Monthly Manual backup)

1.                       Select the project view from the context menu in the configuration manager.

2.                       Expand the projects node in the tree pane. The list of projects is displayed under this node in the tree pane and in the view table.

3.                       Ensure that the required project is in read only lock status before backup.

4.                       Select and right-click on the required project, then click on backup, the backup project wizard – comment Entry page appears. Enter or choose appropriate audit trail comment and click on next.

5.                       Ensure that the correct project is selected for backup and click on next. Enter a path for destination of backup or use browse button to locate the destination and then click on next.

6.                       When the export process is finished click on next button, the backup project wizard start page appears. Then click on finish.

7.                        SYSTEM AUDIT TRAIL BACKUP

8.                       Configure System > Configuration Manager > System Audit trail, select the

9.                        required month audit trails either manually or using a view filter.

10.                   Go to Records > System Audit trail >Archive > Binary

11.                   Select the path and type the file name then click on save button, the audit trail archive and binary file is saved in the selected folder.

12.                   RESTORATION OF PROJECTS

13.                   Create a project ‘Restore’ in respective year.

14.                   Insert the respective CD/DVD into the drive.

15.                   Go to Pro > Configure System > Configuration Manager > Projects, right click on the project and click on Restore Projects.

16.                   Choose a directory to restore from (i.e where the CD/DVD is located in the drive) and click on next, select the parent project ‘Restore’ and click on next.Finish button will be enabled after successful data restoration, click on finish to

17.                               complete.

18.                   report shall be raised and concluded.

19.                   Take print out of report and and check against original record.

20.                   DELETION OF PROJECTS

21.                    Configure System > Configuration Manager > Projects, select the required project to delete.

22.                   Right click on the project and click on Delete, provide the audit trail comment and password and then click on OK.

23.                   Three calendar years projects shall be available in Empower and older than three years shall be deleted or based on capacity and performance of the server disk drives shall be assessed and the deletion of projects shall be decided as required or initial verification or based on need.

24.                   ARCHIVE AND REMOVAL OF SYSTEM AUDIT TRAIL

25.                   Go to Pro > Configure System > Configuration Manager > Records > System Audit trail > Archive and Remove.

26.                   Once the System audit trail ‘archive and remove’ screen is opened,  click on OK button.

27.                   Three calendar years projects shall be available in Empower and older than three years shall be deleted or based on capacity and performance of the server disk drives shall be assessed and the deletion of projects shall be decided as required or initial verification or based on need.

28.                   ARCHIVE AND REMOVAL OF SYSTEM AUDIT TRAIL

29.                   Go to Pro > Configure System > Configuration Manager > Records > System Audit trail > Archive and Remove.

30.                   Once the System audit trail ‘archive and remove’ screen is opened,  click on OK button.

31.                   Disaster management :

32.                   Daily(Hot) and weekly backup –Automatic backup

33.                   Monthly Backup is happening

34.                   The server room is maintained with controlled temperature.

35.                   The server room shall be maintained with fire alarm.

36.                   The server room shall be equipped with Commercial Sprinkler.

37.                   Daily hot backup is taken from all analytical instruments.

38.                   Hot backup in the secondary tapes is archived at QA daily.

39.                   The backup tapes are kept in Fire proof cabinets.

Purified water system validation

     

Purified Water system validation

water system validation shall be done in three phases.

Phase -1

Phase -2

Phase -3

Phase -1

A test period of 2-4 weeks should be spent for monitoring the system intensively. During this period the system should operate continuously without failure or performance deviation.Water cannot be used for pharmaceutical manufacturing in this phase.The following should be included in testing approach.

·       Under take chemical & microbiological testing in accordance with a defined plan.

·       Sample incoming feed water daily to verify its quality.

·       Sample each step of purification process daily.

·       Sample each point of use daily.

·       Develop appropriate operating ranges.

·       Demonstrate production and delivery of product water of required quantity and quality.

·       Use and refine the SOP’s for operation,maintenance,sanitization and trouble shooting.

·       Verify provisional alert and action levels.

·       Develop and refine test failure procedure.

Phase -2

A further test period of 2-4 weeks. Sampling scheme will be same as  Phase – 1.Water can be used for manufacturing process in this phase.

Approach should also

·       Demonstrate consistent operation within established ranges.

·       Demonstrate consistent production & delivery of water of required quality and quantity.

Phase - 3

Phase 3 runs for one year after satisfactory completion of phase-2.Water can be used for manufacturing process during this process.

Objectives & Features of Phase -3

·       Demonstrate extensive reliable performance.

·       Ensure that seasonal variations are evaluated.

·       The sample locations, sampling frequencies and test should be reduced to the normal routine pattern based on established procedures proven during Phase -1 & phase - 2.

Specification :

Test	Specification
Description	A clear colourless odourless liquid.
pH	Between 5.0 and 7.0.
Conductivity	Stage-1: Not more than 1.3 µS/cm (online).                             ( or) Stage-2: Not more than 2.1 µS/cm(off-line). Stage-3: If the conductivity result is greater than 2.1 µS/cm, then proceed as in table - pH and conductivity requirements.
Total Organic Carbon	Not more than 500 ppb
Nitrates	Not more than 0.2 ppm
Heavy Metals	Not more than 0.l ppm
Total Aerobic Microbial  Count	Not more than 100 CFU/mL
Specified Pathogens
Test for Escherichia coli	Shall be absent.
Test for Salmonella species	Shall be absent.
Test for Staphylococcus aureus	Shall be absent.
Pseudomonas aeruginosa	Shall be absent.

Air handling unit (AHU) Qualilfication and Clean room classification

Air handling unit (AHU) Qualilfication  and clean room Classification : 

 Ensure the AHU is in switch ON.

 Switch ON the anemometer and allow it to some time for stabilization.

  Ensure that anemometer measuring unit is in FPM mode.

 To change the measuring unit mode, press the UNIT button till display shows FPM.

Take the readings at five locations at each filter as per below mentioned diagram.

           

V1                                    V2                      V5 V3                                    V4

•  Position the probe pointing towards airflow. Locate the probe approximately 1/6 diagonal distance and measure velocities from each corner.For clean room measurement shall be taken at a distance of 150 mm from the filter face. Take the readings after stabilization or take the average reading of oscillating value shown in the display.

Procedure to Calculate the Air changes

  Calculate the supply grill area A= Length (in ft) x Width (in ft).

Calculate the supply grill Average velocity V= (V1+V2+V3+V4+V5 ) /5.( in ft/min) .

Calculate the air flow delivered by each supply grill in CFM   = A x V (in CFM).

Find the total quantity of supply air delivered in to the room in CFM by adding all             supply grills air flow CFM.

Calculate the air changes by below given formula.

                    Air changes per hour = Total supply air flow rate (CFM) in the clean room x 60

                                                                        Volume of the clean room (cu. ft)          

Example :

Air velocity =  100 feet per min

Air Flow =  Velocity Ft/ min x grill area(Ft²⁾

                              =  100 x 4 =400 Cubic feet per min(CFM)

If room has two supply grills, sum the two air flows = 400+ 400= 800 CFM

Air changes = Air flow x 60

Room volume(Ft³ )

=800 Ft³x 60 min

  1000 Ft³

= 48 Air changes per hour (Limit : Not less than 25 air changes per hour for ISO 8)

There are 5 tests during AHU Qualification.

S.NO	Test	Frequency	Instruments used	Acceptance criteria
1	Air Changes	For every six months (on or before 7 days)	Anemometer for Velocity of air	Not less than 25 air changes per hour
2	Particle count “At Rest Condition”		Particle counter	Not more than 3520000 for ISO 8 There is an equation to estimate particle limit.
3	HEPA Filter Integrity Test (Leak Test)		Aerosol Photometer and Aerosol generator using compressed air	No leak should be observed Not more than 0.01% leak
4	Recovery test	For every one year (on or before 15 days)	Particle counter	Recovered within 15 minutes, after polluting the room with aerosols
5	Air flow pattern		Dry ice in hot water to generate SMOKE	Uni-directional and positive and negative pressure should be indicative.

Regards,
Bujji Reddy.
9676749937