Dissolution : PVTdmsc2.dmsc.moph.go.th/webroot/drug/km/lab_analysis/Dissolution P… · Dissolution : PVT Mrs. Witinee Kongsuk ... • Provide experimental proof that the dissolution

Dissolution : PVT

Mrs. Witinee Kongsuk Bureau of Drug and Narcotic

November 27, 2015 Bureau of Drug and Narcotic

Bureau of Drug and Narcotic 2

Background

Dissolution Assembly

Mechanical Calibration

Performance Verification Test

Factors Influence Dissolution Test

FAQ

Outline

Background

Tablets and capsules are the most commonly used

dosage forms.

Their efficacy and quality depended on

* Amount of active ingredient

* Dissolution rate, absorption to blood circulation

In vivo: volunteers, samples, time consuming,

routine quality control?

3 Bureau of Drug and Narcotic

Dissolution test

- Predict the bioavailability-surrogate parameter of the

therapeutic efficacy.

- Evaluate the rate of release of a drug substance from

the dosage form.

- Quality control tool to ensure the uniformity of product

among various batches / within one batch.

- Sensitive to variations in the manufacturing process

which have critical influence on the dosage form

performance.


Apparatus 1 Basket • Vessel

- Glass or other inert transparent material

- Cylindrical with hemispherical bottom

- 1L, 2L or 4L nominal capacity

• Stirring shaft and basket

• Basket

- 40 mesh

- Gold coating of 2.5 um is allowed.

• Stirring

- rotating stirrer

- typical speeds: 50-100 rpm

• Dosage form placed in the basket


Apparatus 2 Paddle

• Vessel

- same as for Apparatus 1

• Stirring blade and shaft

- metallic or suitably inert and rigid

- may be coated

• Agitation

- rotating stirrer

- typical speeds: 50-75 rpm

• Dosage form should remain

at the bottom center of the vessel



Water bath


Visual Inspection

o Check for leaks: tubing, joints

o Circulation pump: check for leaks, trapped air, noise

o Good practice to regularly change water

o Use clean and clear water

o Keep bath clean o Ensure adequate water level

Water bath


Dissolution Assembly Vessel


Visual Inspection

Vessel

o Thorough cleaning is very important.

o Sticky residues can build up on glass surface.

o Always check the internal surface

o Irregular curvature can affect hydrodynamics.

o Check periodically during use looking for cracks,

scratches and build up of deposit or residue.





Apparatus 1 Basket



Apparatus 2 Paddle


Visual Inspection

o It is very important to carefully observe

the physical condition.

o Shaft for both apparatus must be straight.

o Loose basket clips will cause wobble.

o Basket should be right cylinders (not bent).

o Baskets that are old, distorted or frayed can give

non-reproducible results.

o Baskets should be properly cleaned and stored.

o Ensure vent hole in basket head is clear.

o Baskets should be attached carefully to the shaft.

o Paddles: smooth coating, if coated

Baskets and Paddles


The USP defines the sampling position as “A zone midway between the surface of the dissolution

medium and the top of the rotating basket or blade, not

less than 1 cm from the vessel wall"

Canular



• Calibrated thermometer • Calibrated stopwatch

Other related tools


History: USP Dissolution test USP XVIII

(1970)

Dissolution test became official in USP

USP XX

(1980)

Apparatus Suitability Test

USP 30

(2007)

Apparatus Suitability:

Performance Verification Test (PVT)

USP 32

(Dec 1, 2009)

- The PVT using Salicylic acid tablets RS

is no longer required for USP App 1 and 2

- USP move from acceptance criteria for

individual tablet results to a new set of

acceptance criteria using the GM and %CV

obtained from the dissolution results

USP 34 to ..

(2011)

Prednisone Tablets RS for App 1 and 2

17

The new testing procedure and the acceptance criteria will be provided

in the Technical Data Sheet accompanying the new lot of the reference material.

Bureau of Drug and Narcotic

Collaboration with USP

Training:

• 24 June, 2010

Ms. Barbara B. Hubert

Mr. Paul J. Crown

• 27-28 Aug, 2015

Mr. Paul J. Crown

Mr. Joseph Eaton

Collaborative study to establish

acceptance range for the next lot

USP Prednisone Tablets for

dissolution App 1 and App 2:

Since June, 2009 18


Calibration

• Evaluation of dimensional and functional conformance to specification


• Confirmation the acceptable operation of the equipment

Performance Verification Test

(PVT)


References: - USP 38: <711> Dissolution

- USP Prednisone Tablets RS Certificate

- Dissolution Toolkit Version 2.0

o Conformance to USP specification

o Position designation in the assembly

- Stirring elements

* Shafts

* Blade or baskets

- Vessels

o Recommendation:

Maintain the same position for vessels / stirring

elements within the assembly throughout a PVT cycle




Apparatus level



Shaft verticality

o Deviations of greater than 1.5º

can result in change in

dissolution results

o Can be checked using

a digital protractor

o Check at two planes perpendicular

to each other o Recommendation: <0.5º



Vessel verticality


Mechanical Calibration Shaft centering

o The shaft is positioned so that its axis is < 2 mm

at any point from the vertical axis of the vessel o Use a centering gauge



Wobble

- Rotates smoothly

without significant wobble

that could affect the results - Recommendation: + 0.5 mm



Rotation speed

o Usually checked with a tachometer

(rotation speed gauge)

- or check manually using a timer

o Measure each spindle for until

a stable reading is obtained

- USP specification: + 4%

o Recommendation:

all measured speeds should be within + 1 rpm of the set value.



Temperature control

Calibrated thermometer

37 + 0.5 ˚C

Distance between the inside bottom of the vessel

and the bottom of the basket or paddle is maintained

at 25 + 2 mm during the test use a spacing gauge or ball


USP Performance Verification Test (PVT)

• Provide experimental proof that the dissolution test

assembly is suitable for dissolution testing

• Confirms the acceptable operation of the equipment

• The result must conform to range given in the

certificate for the specification lot of reference material.

• PVT is a prerequisite for a proper performance

qualification of the dissolution assembly.


Reference Standards for PVT

Always use the current lot

Follow the instructions on the label concerning storage and handling


Prednisone USP RS

Check

• Current lot • Validity

Current Lot: O0G356

Previous Lot: N0E330 (Valid Use Date: 31-May-2009) 30 Bureau of Drug and Narcotic

Prednisone USP RS

Certificate

Label


USP Prednisone Tablets RS

Check

• Current lot • Validity

Current Lot: R031Y0 (Valid Use Date: 30-Sep-2016)

Previous Lot: R001B1 (Valid Use Date: 31-Dec-2015)



Certificate & Label



Do not push tablets through foil backing.

To remove tablets from blister, peel foil.

Use only whole tablets.

Store in a dry place.

Store at controlled room temperature

Not exceeding 25 ºC

Unused or unopened blister strips should be kept in the secondary package.

Certificate & Label



Information:

- Calculation value

- Expiration

- Instruction of use

- Legal notice

Certificate & Label

Expiration!!!

It is the responsibility of each user to determine that

this lot is current or valid when used.



- Store in a dry place.

- Store the tablets at controlled room temperature

not exceeding 25º



Dissolution medium:

- Steps to prepare the medium “deaerated water”


USP Deaeration Technique

Note: - Vacuum should be less than 100 mbar - Temperature of medium should not fall below 37°C

Heat water while stirring gently

to about 41 – 45 C

Filter under vacuum through 0.45 um porosity filter

(HVLP type or equivalent) into a filtering flask with a stirring device

Seal the flask,

continue to apply vacuum

while stirring for an additional 5 min


Procedure

alcohol < 5% of total volume of standard solution (If used)

Deaeration step

Weight and carefully introduce dissolution medium

to the vessel 499 g (correspond to 500 ml)

Allow media in each vessel to reach

37 + 0.5 ºC and use immediately

Perform dissolution test : single or two stage (each apparatus at 50-rpm)

Determine the quantity of prednisone dissolved

at 30 minutes in each vessel (uv at 242 nm)



Result:

• GM • %CV

App # of vessels

Single-Stage

Two-Stage

1st Stage of Two Stages

2nd Stage of Two Stages

GM* %CV GM* %CV GM* %CV

1

6

51-80

11

55-74

8.2

51-80

11 7

8

12 na

14 na

2

6

27-41

6.4 29-38

4.7 27-41

6.3 7 6.3

8 6.2 4.8 6.2

12 6.3 na

14 6.2 na

*Percent of the labeled amount of prednisone dissolved at 30 minutes at 50-rpm

Lot R031Y0

40


“passed the PVT”



Criteria for PVT

• must not fall outside the limit GM

• must not be greater than the limit %CV

meet the criteria

meet the criteria


Futility Factor

%CV at or above value given,

second stage testing will not produce passing result


www.usp.org

Search for

PVT calculation tool

Select “Begin using the tool”

PVT Calculation Toolkit



44














Data of 6 vessels

with 3 decimals



Submit data



Result & Report


53


Recommendations for PVT

- Designated vessels and shaft for each position

in dissolution instrument

- Rigorous mechanical calibration

- Proper deaeration of dissolution medium

- Test should be started as soon as possible

after media deaeration

- Always handle tablets with

* gloves (not cotton)

* forceps or tweezers which will not scratch or

damage the surface of the tablets


• Do not use chipped, cracked or capped tablets

• For Apparatus 2 Paddle

- Drop tablets into non-rotating apparatus

- Tablets must settle to the bottom of the vessel

before rotation of the shaft begins.

• Samples should remain at the bottom center

of the vessel

• Visually inspect and record any unusual observations

• Filter samples immediately after withdrawing

samples from each vessel


Recommendations for PVT


Tablet should be stored in original container,

according to description on label

Remove tablets from package immediately

prior to testing

Do not put tablet RS next to water bath

while waiting for bath to equilibrate

Avoid exposure to excess humidity

Prednisone Tablets RS will give low results

Do not dry Prednisone Tablets RS in an oven

No need to weigh Tablets RS beforehand (Weight is for information and investigation purposes)

56


Sources of factors influence dissolution

Note: instrument and analyst are qualified 57


Laboratory environment

Medium

Filtration

Quantitative method

USP specification:

“ No part of the assembly, including the environment

in which the assembly is placed, contributes significant

motion, agitation, or vibration beyond that due to the

smoothly rotating stirring element.”

Source of vibration:

* Apparatus

- Tension or dirt on the drive chain or belt

- Worn parts

- Alignment of belt guide plates

- Surging of individual spindles

- Turbulence in the water bath


Laboratory Environment: Vibration

Laboratory Environment

Has anything changed in the lab environment?

- New equipment added to the immediate area

- Other changes (e.g. construction)

Vibration transfer

- Be careful how many testers put on the same bench

- Is bench suitable?

- What else is on the bench or nearby?

shaker, mixer, centrifuge

- consider use of vibration damping pads


Medium

Using deaerated media

- use immediately after deaeration

- transfer media carefully to minimize re-aeration

of the media

Air bubbles can attach to particles

- decreasing dissolution by reducing surface area

- Increasing dissolution by

# lifting and moving particles

# bubble clogging the meshes of the basket

and retaining particles in a zone of higher

shear stress compare to the vessel bottom


Filtration

Removal of undissolved particles

i.e. drug or excipients in the sample solution

Filtration should occur concomitantly with or

immediately after sampling.

Unfiltered sample can continue drug dissolution

before filtration.

Use Individual, clean syringes and filters

for sampling each vessel, each time.


Filtration Precautions:

- Prewetting may be necessary.

- Adsorption of the drug onto the filter has to be

evaluated.

- Chemical compatibility and extractable impurities

should be considered by the selection of

the proper (inert) filter material.

- Important to perform filter check / validation.

*** PVDF membrane filter is recommended for PVT.


Quantitative Method Standard Preparation

- Prednisone USP RS

- Alcohol < 5% of total volume of Standard solution

(If used)

- Prepared Working and Control Standard

- Calculated absorptivity (AU per mg/ml) values of

working and control standards should be

in agreement with historic values and

within 1% of each other.

UV Spectrophotometry

- Calibrated UV-Vis spectrophotometer

- λmax at 242 nm

- 1.0 cm path-length quartz cell 63


When to perform PVT ?

Installation of new apparatus

Movement or relocation of apparatus

Equipment maintenance

- Adjustment of drive mechanism

- Replacement of drive belt

- Replacement of circulator

- Replacement of vessels, baskets, paddle etc

Routine test schedule

If only one apparatus, basket or paddle, is used,

then only that apparatus needs to be tested.



FAQ

Q: How many runs have to be performed for the PVT?

A: Current approach for PVT

Single stage: Performance of two consecutive runs

including all positions of dissolution instrument.

The combined results for both runs will be evaluated

and compared with the acceptance criteria.

Two-stage: allow the analyst to evaluate the results

of the 1st run and compare it with the acceptance criteria

If the results are within the 1st stage acceptance criteria,

the PVT test can be stopped at this stage.

For 12 or 14 positioned assembly: a single run is required


FAQ

Q: Did the method to perform the PVT using the current

lot change from the previous lot?

A: The method to perform the PVT has not changed from

the previous lot. USP provided some recommendations

to help customers achieve a successful PVT in the

Dissolution Toolkit. The procedure for the PVT is given in

the USP Certificate.


FAQ

Q: What is the storage condition for

USP Prednisone Tablets RS catalog#1559505?

A: USP Prednisone Tablets RS should be stored as per

the label. Please refer to General Chapter <659> for

storage and handling definitions.


FAQ

Q: When does a particular lot of USP Prednisone

Tablets RS catalog # 1559505 expired?

A: Unlike other USP Reference Standards, a period of validity

is proven on the USP Certificate of USP Prednisone

Tablets RS. This date is final and will not be extended.

A specific lot should not be used after its assigned valid

use date.


FAQ

Q: What should I do if the PVT for Apparatus 1 passes

and then fails for Apparatus 2?

A: If nothing but stirring elements are changed when

switching from Apparatus 1 to Apparatus 2, then the PVT

for Apparatus 1 is considered to be successful.

The cause of failure should be investigated and

any adjustments made.

If the cause is paddle stirring elements and

no other changes are made, the PVT has to be repeated

for Apparatus 2 only.

If any changes are made other than the replacement

of the paddle stirring elements, the PVT should be

repeated for both Apparatus 1 and 2.

Bureau of Drug and Narcotic 70

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