details of dissolution test apparatus validation

1. Presented By Prashik S Shimpi
M.Pharm (QA)
RCPIPER

2. • INTRODUCTION
• Physical and Chemical Properties of Drugs
• NEED OF DISSOLUTION TESTINGS
• THEORIES OF DISSOLUTION
• A) DIFFUSION LAYER MODEL
• B) DANCKWERT’S MODEL
• C) INTERFICIAL BARRIER MODEL
• FACTORS AFFECTING DISSOLUTION
• Dissolution Apparatus-
• VALIDATION
• EQUIPMENT VALIDATION
• CYCLE OF VALIDATION
• VALIDATION STUDY PHASES
• RE-VALIDATION
• MASTER VALIDATION PROTOCOL
• DISSOLUTION APPARATUS VALIDATION
• CONCLUSION
• REFERENCES

3. INTRODUCTION
• The dissolution process started to develop about 100 years ago as a field of pharmacy and since then important
progress has been made. Interest in drug related dissolution has grown only since the realization that dissolution is
an important factor of drug bioavailability in the 1950s. Dissolution test is required to study the drug release from
the dosage form and it’s in vivo performance. Dissolution test is used to assess the lot to lot quality of drug product.
The development and validation of dissolution procedures isofparamountimportance during development of new
formulation and in quality control.The objective of this project is to review the Validation Of the Dissolution
Apparatus.
• Defination - Dissolution is a technique in which a solid substance solubilizes in a given solvent i.e. mass transfer from
the solid surface to the liquid phase (Brahmankar et al., 1995).
• Dissolution examination is a process which is used to measure the release profile of the drugs from formulations
which are commonly solid oral dosage forms like tablets and capsules.
• Dissolution mainly takes place in two steps, 1) Liberation of the drug from the formulation,2) Dissolution of drug in
the liquid medium. (GowthamarajanK., et al., 2010).Dissolution testing of formulations was brought out in 1960s and
it was recognized through healthregulatory authorities in 1970s, and then the importance of dissolution has grown
rapidly. Modern researches lead to the development of in-vitro dissolution tests as an alternate of animal
bioequivalent studies (Rolf Rolli et al., 2003). The dissolution process needs apparatus, dissolution medium, and test
conditions that provide a method i.e. selective yet sufficiently rugged and reproducible for every day operation
andcapable of being
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• transferred between research laboratories. The basic destination of dissolution testing is to allow the measurement
of bioavailability of a dose in addition to bioequivalence of batch to batch. Hence properly organized dissolution test
is necessary for biopharmaceutical formulations. The principle for carrying these tests is that, for a product to be
therapeutically efficient, the drug must be discharged from the product and should broadly be dissolved in the fluids
of the gastrointestinal tract. The API in solution form helps the absorption of the drug from the gastrointestinal tract
into the systemic circulation to achieve its desired target area to exert its effect. The data received as a result of
dissolution examination guides the development of novel formulation and product development and also
dissolution isnecessary for regulatory approval for product marketing. (SaeedA.Qureshi, et al) In these times all solid
oral dosage forms need dissolution testing as a quality control test before brought in into market.
• Dissolution is expressed in terms of a rate process. If the rate increases, the dissolution process also increases.
Dissolution rate possibly defined as the amount of drug substance that enters solution per unit time below
standardized experimental condition. Noyes-Whitney’s equation is valuable in estimation of rate of dissolution
(SubrahmanyamC.V.S, et al., 2008).
• Equation dc / dt =KS (CS- C)

4. Physical and Chemical Properties of
Drugs
• The initiative in the development of a fresh dissolution is
the evaluation of physical and chemical information of
drug content. Knowledge ofthese information will help
the selection of dissolution medium and its volume.
Some of the physicochemical properties of API that
determine the dissolution characteristics are:
• •Ionization constants (pKa),
• •Solubility as a function of pH,
• •Solution stability as a function of pH,
• •Particle size,
• •Crystal form, and
• •Common ion, ionic strength, and buffer effects,
• •Temperature
• •Agitation

5. NEED OF DISSOLUTION TESTINGS

6. THEORIES OF DISSOLUTION
• Several theories have been proposed to explain
the process of dissolution. Some of the
important ones are -
A) Diffusion model/film theory
B) Danckwert’s model/ surface renewal theory C)
Interfacial barrier model/limited solvation
theory

7. • A) DIFFUSION LAYER MODEL :
• Theory states that dissolution process consists of
two consecutive steps- -Solution of solid to form a
thin layer at the solid liquid interface called stagnant
layer -Diffusion of soluble solute from the
stagnant layer to the bulk of solution . The second
step is comparatively slower hence the rate limiting
steps- Equation:- dc/dt= k(Cs-Cb)
• Applying fick’s second law of absorption the
equation can be modified as following. dc/dt =
DAkw/o(Cs-Cb)/Vh…Eq No. 3
• Noyes-Whitney equation assumes that the surface
area of solid remain constant which is practically not
possible to account for the surface area change
Hixon-Crowell cubic root law is used
• Wo 1/3-W1/3= Kt …Eq. No. 4

8. • B) DANCKWERT’S MODEL : The model assumes
no stagnant layer on solid liquid interface.
Instead suggest turbulence in dissolution
medium and as a result of turbulence agitated
fluid consisting of macroscopic mass of eddies
or packets reach the interface in a random
fashion due to eddy current as a result absorbs
solute and carry it to the bulk of solution.
• Equation ,Vdc/dt = dm/dt = A(Cs-Cb)(Dγ) 1/2
…Eq. No.5

9. • C) INTERFICIAL BARRIER MODEL : Above
mentioned both theory assumes, -The rate
determining step that control dissolution is mass
transfer -Solid solution equilibrium is achieved at
solid liquid Interface According to this theory an
immediate concentration existatinterface as a
result of solvation mechanism and is function of
solubility rather than diffusion Such concept can
be given by G = Ki(Cs-Cb)eqn….(6) where, G =
dissolution rate/ unit area , Ki = effective
interface transport constant .

10. FACTORS AFFECTING DISSOLUTION
• Following factors to be considered in dissolution testing of drug are
• 1) Factors related to drug substance.
• a) Particle size
• b) Polymorphism
• c) Hydrates and solvates
• d) Surface area
• 2) Formulation factors a) Effects of diluents and disintegrants b) Effects of binder and
granulating agents c) Effects of lubricants d) Effect of processing factors.
• 3) Medium used for dissolution testing
• a) Volume
• b) Shape of dissolution vessels .
c) Co-solvents added /enzymes, surfactants
• 4) Temperature of medium
• 5) Dissolution apparatus
• 6) Hydrodynamics of dissolution
• a) agitation rate
• b) shape of dissolution vessel
• c) placement of dosage form in vessel
• d) sinkers for floating products

11. FACTORS RELATED TO DRUG
SUBSTANCE
• a) Particle size
• Particle size and surface area are inversely proportional to
each other in affecting dissolution.
• Higher dissolution rate may be achieved by reducing
particle size and hence increasing surface area.
• Polymorphism :
• DRUG
Amporphous Ploymorphic
Enantiotriphic Monotrophic

12. Dissolution Apparatus-
• USP APPARATUS 1 : Rotating Basket
• Standard 40-mesh basket.
• Other mesh size baskets are available.
• Volume ranges from 100 mL to 4L.
• A variety of vessel sizes are available.

13. USP APPARATUS 2
• Paddle :
• Standard stainless steel paddle or
Tefloncoated stainless steel paddle.
• Special Teflon and PEEK paddles are available.
• Volume ranges from 100 mL to 4L.
• A variety of vessel sizes are available.

14. USP APPARATUS 3
• Reciprocating Cylinder :
• Sequential operation for pH profiling.
• Volume ranges from 100 mL to 1L.
• 300 mL outer tubes are standard

15. USP APPARATUS 4
• Flow throught the cell
• The pump forces the Dissolution Medium
upwards through the flow-through cell
• The pump has a delivery range between 240 and
960 mL per hour, with standard flow rates of 4, 8,
and per min.
• It must deliver a constant flow(±5% of the
nominal flow rate);the flow profile is sinusoidal
with a pulsation of 120 ± 10 pulses per m

16. USP APPARATUS 5
• Paddle over Disk :
• Standard stainless steel with disposable
stainless screens.
• Used for transdermal patches in a standard
round bottom vessel.
• Volume 900 mL.

17. USP APPARATUS 6
• Rotating Cylinder :
• Two-piece assembly for testing transdermal
patches using Apparatus 1 and 2 dissolution
testers.
• Volume 900 mL.

18. USP APPARATUS 7
• Reciprocating Holder:
• Utilizes sequential operationand a variety of
dosage holders.
• Volume ranges from 20 mL to275 mL.
• Useful for transdermal patches,osmotic pump
delivery systemsas well as other non-
disintegrating dosage forms.

19. VALIDATION
• WHAT IS VALIDATION?
Establishing documented evidence which provides a high degree
ofassurance that a specific process will consistently produce a
product meeting its pre-determined specifications and quality
attributes.
MORE WAYS TO DESCRIBE VALIDATION…
• A state of being, which if unchanged, assures that a pharmaceutical
manufacturing system will consistently produce quality medicines.
• Part of the lifecycle of pharmaceutical manufacturing systems
starting withthe conceptual elements of process design and
ending with the cessation of production.
•A sequence of complementary activities that include verifications,
tests, and documentation.
• An extension of Good Engineering Practices that includes review
and approval by an independent quality organization.
• A mindset that assures that systems are designed, constructed, and
can be robustly operated to produce quality medicines

20. WHY IS VALIDATION DONE?
• We validate the production process because, in
part, the process definesthe product and assures
its quality attributes.
• SIDEBAR: WHAT IS THE PRODUCT?
• What are the “pre-determined specifications
andquality attributes”?
• • Safety • Efficacy • Identity • Potency • Purity

21. EQUIPMENT VALIDATION
• A validation programme involves various
components inpharmaceutical organisation
related to process, equipment and product.
• It is a regulatory requirement for pharmaceutical
companies toperform Instrument Validation on
all new instruments.
• Instrument Validation requires detailed
knowledge of theinstrumentation system being
validated and is therefore usuallyperformed by
the company supplying the instrument.

22. Definition (US-FDA):-
• Definition (US-FDA):- Validation is the
establishment of documentary evidence which
provide a high degreeassurance of specified
processwill consistently produce the product
meeting with predetermined specification and
quality attributes.
• Validation studies are performed for analytical
equipment, tests, facility systems such as air,
water, steam, the manufacturing, cleaning,
sterilization processes.

23. CYCLE OF VALIDATION

24. VALIDATION STUDY PHASES
• Phase 1: Pre-Validation Phase (Qualification
Phase).
• Phase 2: Process Validation Phase (Process
Qualification phase).
• Phase 3: Validation Maintenance Phase.

25. VALIDATION PLAN

26. PHASE-1(QUALIFICATION)
• DESIGN QUALIFICATION:
“A documented review of the design, at an appropriate
stageor stages in the project, for conformance to
operational and regulatory expectations.”
Specification of requirements for facilities, plants
andequipment, mainly in connection with
purchase/modificationof equipment.
DQ REVIEW DOCUMENTS :
 User Requirement Specification (URS)
 Functional Specification (FS)
 Tender Specifications and Drawings
 Vendor Quality procedures and documents
 Purchase Specification

27. • INSTALLATION QUALIFICATION :
• IQ verifies that the equipment has been installed
in accordance with the manufacturer’s
recommendation in a proper manner and that all
of the devices are placed in an environment
suitable for their intended purpose.
COMPUTER AND SOFTWARE IQ :
• SoftwareRequirements and Specifications should
be clear, written down, and approved by the
appropriate personnel prior to creating the
software package.
• Software Installation should be recorded, when
made, so that theproper model numbers, serial
numbers, installationdateetc.

28. PHASE2 (Process qualification phase)
• OPERATIONAL QUALIFICATION : The documented
action of demonstrating that processequipment
and ancillary systems work correctly and
operateconsistently in accordance with
established specifications.
Operation Qualification (OQ) for testing the
equipments in theselected user environment is to
ensure that it meets the previouslydefined
functional and performance specifications.

29. How may runs are to be performed
during Operational Qualification (OQ)
testing?
• Guidelines stress the importance of equipment
qualification simulating actual production
conditions, including 'worst case' situations and
that "tests and challenges should be repeated a
sufficient number of times to assure reliable and
meaningfulresults. Three consecutive batchesare
recommended for process validation rather than
for equipment qualification. No specific number
of "runs" for equipment qualification, but
multiple tests to simulate actual operating ranges
and to establish consistency are expected.

30. PERFOMANCE QUALIFICATION
• Assurance that the process continues to comply with
established requirements. Performance Qualification
(PQ) for testing that thesystem consistently performs as
intended for the selected application.
• Purpose- To define testing requirements in a
product/process/performance/qualification/validation
protocol.
• Principle- Performance qualification validation testing
plan are usually process or product specific but will
include the following background and result for the plan,
testing method used, and a predetermined and general
and/or specific acceptance criteria.

31. RE-VALIDATION
• Re-validation is required when the operating
equipment or system has been changed in
some way. It is carried out when:
• Major mechanical equipment has been
replaced
• Computer systems have been replaced
• New products have to be run on the system.
• Critical items have been replaced or repaired.

32. RETRO-VALIDATIONS
• Retrospective validation must be done on
equipment that records
• have either been lost or validation was not
provided for in the initial
• life of the machine. Retrospective validations
get more difficult the
• older the machine.

33. PHASE-3 (VALIDATION MAINTENANCE
PHASE)
• It is the maintenance of the validation which
has been alreadyestablished.

34. MASTER VALIDATION PROTOCOL
• The Master Validation Protocol (MVP) is the outline of
the validation for a facility. MVP: Identifies which items
are subjects to validation. Defines the nature
• and extent of testing expected to be done on each
item.Outlines the
• test procedures and protocols to be followed to
accomplish
• validation.
• Describes functional responsibilities and requirements
to document
• the work carried out and the results obtained.

35. INSTALLATION QUALIFICATION
• Installation qualification consists of
documented verification that all
• key aspects of the dissolution apparatus are in
working condition and
• have been properly installed in accordance
with manufacturer’s
• specifications in the proper operating
environment.

36. CALIBRATION
• The installation qualification should document that specific devices
• contained within the dissolution apparatus (e.g., speed, time, and
temperature displays) have been calibrated to traceable standards.
• INSTALLATION QUALIFICATION-
• Environmental Conditions
• Computerized System
• Equipment Information
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• Preventive maintenance
• SOP
• Utilities

37. DISSOLUTION APPARATUS VALIDATION
• Dissolution is defined as the process by which a known
amount of drug substance goes into solution per unit
of time under standardized conditions.
• The primary goal of dissolution testing is to be used as
a qualitative tool to provide measurements of the
bioavailability of a drug as well as to demonstrate
bioequivalence from batch-to-batch.
• Validation is achieved by performing a series of
validation activities; for a dissolution apparatus,
validation is obtained through installation qualification
and operational qualification.

38. APPARATUS 1 Vessel:
• APPARATUS 1 Vessel: cylindrical, 160-210 mm
height, inside diameter 98-106 mm, nominal
capacity is 1000 mL; sides are flanged at the top.
Shaft: positioned so that its axis is not more than
2 mm at any point from the vertical axis of the
vessel and rotates smoothly and without
significant wobble. Materials of Construction:
Shaft and basket components are stainless steel,
type 316 or equivalent. Basket position: the
distance between the inside bottom of the vessel
and the basket is maintained at 25 +/- 2 mm
during the test.

39. APPARATUS 2 Vessel:
• APPARATUS 2 Vessel: cylindrical, 160-210 mm height,
inside diameter 98-106 mm, nominal capacity is 1000
mL; sides are flanged at the top. Shaft: positioned so
that its axis is not more than 2 mm at any point from the
vertical axis of the vessel and rotates smoothly and
without significant wobble.
• MATERIALS OF CONSTRUCTION: Shaft and blade are a
single entity that may be coated with a suitable inert
coating. Blade position:The distance between the inside
bottom of the vessel and the blade is maintained at 25
+/- 2 mm during the test. The blade passes through the
diameter of the shaft so that the bottom of the blade is
flush with the bottom of the shaft

40. Cont…
• OPERATIONAL QUALIFICATION Operational Qualification consists
of documented evidence that the equipment operates as
intended and is capable of consistent operation within
established specifications. The operational qualification of a
dissolution apparatus should include the following verifications:
• TEMPRATURE DISTRIBUTION STUDY: A temperature distribution
study should be conducted during the operational qualification.
The study should include temperature mapping of each vessel
contained within the dissolution apparatus. Temperature should
be mapped using a data system for a minimum time that is
based on the monograph or 1 hour, whichever is greater. The
temperature must remain at 37°C ± 0.5°C;
• ROTATIONAL SPEED STUDY : A rotation speed study should be
conducted during the operational qualification. The study
should include a measurement of the speed of the shaft
rotation for each vessel contained within the dissolution
apparatus.

41. SYSTEM SUITABILITY :
• SYSTEM SUITABILITY : A system suitability test using USP
calibrators should be conducted during operational
qualification testing. The procedure fordissolution and
sampling is outlined in the Certificates supplied with each
USP Calibrator tablet for each apparatus. The calibrators
used for the test are disintegrating tablets (Prednisone) and
non-disintegrating tablets (Salicylic Acid). The test is
successful if the percent of drug released at 30 minutes
falls within a pre-established range.
• The ranges for each combination of apparatus and
calibrators at 50 or 100 RPM are established by the USP and
are different for each lot of calibrators.
• PERFORMANCE QUALIFICATION: In Performance
qualification different types of dosage form are used.

42. CONCLUSION
• Validation provides the good quality product
and the equipment. Validation gives the
surety that equipment having the good
qualification like design, operation,
installation, and performance qualification
which have pre-determined. Validation data
should be generated for the all types of the
product and the equipment to demonstrate
the adequacy of the manufacturing process.

43. REFERENCES
• 1. PotdarManohar A. “Pharmaceutical quality assurance” 2ndEdition, NiraliPrakashan, p-8.1-
8.7
• 2. Nash Robert A. “Pharmaceutical Process Validation”3rd Edition, Marcel Dekker Inc, p-442
• 3. Cole Graham C. ‘Pharmaceutical Production Facilities” 2nd Edition, CRC Press, p-199
• 4. Despautz Joseph F. “Automation And Validation Of Information In Pharmaceutical
Processing” Vol-90, Marcel Dekker Inc, p-221
• 5. Berry And Harpaz“ Validation Of Active Pharmaceutical Ingredient”2nd Edition, CRC Press,
p-429
• 6. Sharon M.Averell Frost, “ Introduction to the Validation of a Dissolution Apparatus.”p-19.
• 7.http://www.pharmainfo.net/ (equipment-validation-articles) (laboratory-equipment-
qualification)
• 8. Encyclopedia of pharmaceutical technology; James swarbrick, James C. Boylan; 2nd edition;
volume-I,p-718-724
• 9. Pharmaceutical dissolution testing,BanakarUmesh V;volume-49,p94-96,p-174-179
• 10. Biopharmaceutics and pharmacokinetics; D.M.Brahmankar, Sunil B. Jaiswal; vallabh
prakashan,p-20-25
• 11. USP asian edition,2005,p-2303-2310
• 12. European pharmacopoeia-1997,p-128-132 13. www.dissolutiontech.com (Need of
dissolution testing)
• 13. www.dissolutiontech.com (Need of dissolution testing)
• 14. The Theory and Practice of Industrial Pharmacy, Leon Lachman, Herbert A. Lieberman,
Joseph L. Kanig, 3rdedition, Varghese Publishing House, p-303
• 15. Text Book of Physical Pharmaceutics, C.V.S.Subrahmanyam,p-97