validation of solid dosage forms in pharmaceutical industries factors involved in validation of solid dosage forms

1. Validation Of Solid Dosage Forms
Presented by,
Rasika.walunj
M.Pharm (QAT)
Modern college of pharmacy (for ladies), Moshi, Pune.

2. Content
• Introduction
• Types of process validation
• Validation of tablet
• Validation of capsule
• Conclusion

3. Introduction
• Validation is one of the important steps in achieving and
maintaining the quality of the final product.
• If each step of production process is validated we can assure
that the final product is of the best quality.
• Validation of the individual steps of the processes is called the
process validation. Different dosage forms have different
validation protocols.
• Here this seminar concentrates on the process validation of
solid dosage forms.
• It gives in detail the validation of each step of the
manufacturing process of solid dosage forms

4. DEFINITION
. Validation is a key process for effective
quality assurance
 “Validation is establishing documented
evidence which provides a high degree of
assurances that a specific process or
equipment will consistently produce a product
or result meeting its predetermined
specifications and quality attributes

5. • Quality assurance: Validation checks the accuracy and reliability of a
system or a process to meet the predetermined criteria. A successful
validation provides high degree of assurance that a consistent level of
quality is maintained in each unit of the finished product from one batch to
another batch.
• Economics: Due to successful validation, there is a decrease in sampling
and testing procedures and there are less number of product rejections and
retesting. This leads to cost-saving benefits.
• Compliance: For compliance to current good manufacturing practices,
validation is essential.

6. Types Of Process Validation
 Prospective validation: -
Conducted prior to market the product.
• Documented evidence which provides a high degree of assurances that a specific
process or equipment will consistently produce a product meeting its predetermined
specifications and quality attributes.
 Concurrent validation:
Based on information generated during actual implementation of
the process.
• Establishing documented evidence that the process is in a state of control during
the actual implementation of the process. This normally performed by conducing
in- process testing.

7. Type of Process Validation
 Retrospective validation:
All the processes and subsystems should be
validated ,which have been used for the
production of batches of numerical data of both
process and the end product testing of which are
included in retrospective validation

8. PRODUCT VALIDATION
• Product validation involves following steps:
Validation of raw materials and excipients.
Analytical methods of validation.
Equipment and facility validation .
 Process variables and limits.

9. VALIDATION OF RAW MATERIALS AND
EXCIPIENTS
 The validation process of solid dosage form begins with
the validation of raw materials , both API and
excipients.
 Preformulation is one of the critical step to be validated
in product validation
 Physical characters such as drug and particle size can
affect material flow and blend uniformity.
 Chemical characters like impurities can effect stability
of drug.
 The hygroscopic nature is important in both handling
and reproducibility of the manufacturing process.

10. VALIDATION OF EXCIPIENTS
 Excipients can represent less then 1% of a tablet formula
 Factors to be aware of are
I. The grade and source of the excipients
II. Particle size and shape characteristics and
 Lot-to-lot variability
• Microcrystalline cellulose(MCC) used as diluents shows
significant changes in the chemical composition, crystalinity,
particle size b/w different lots.
• Differences in particle size of MCC can effect wet
granulation/blend uniformity of tablet formulation.
• In direct compression formulations differences in particle size
distribution b/w lots can result in
• Non uniformity in initial mix
• Materials segregate during compression

11. ANALYTICAL METHODS OF
VALIDATION-
• Accuracy of method: Ability of a method to
measure the true value of a sample.
• Precision of method: Ability of a method to
estimate reproducibility of any given value.
• Specificity: Ability to accurately measure the
analyte in the presence of other components.
• Repeatability: Does the precision and accuracy
of the method change when conducted numerous
times on the same day and repeated on a
subsequent day?

12. ANALYTICAL METHOD
VALIDATION
• Reproducibility: Repeat the precision and accuracy
studies within the same lab using the same instrument
but different analysts to challenge the reproducibility
of the method.
• Precision: How will different instruments within the
same lab run by the same analyst affect the accuracy
and precision of the method.
• Ruggedness: Will the precision and accuracy of the
method be same between the development and quality
control lab

13. EQUIPMENT VALIDATION
 This can be divided into
1. Design qualification
2. Installation qualification
3. Operation qualification
4. Performance qualification
5. Maintaince (calibration, cleaning, repair)
qualification

14. PHASES OF VALIDATION-
• Design qualification (DQ): Documented
verification of the design of equipment and
manufacturing facilities.
• Installation qualification (IQ): Documented
verification of the system design and adherence to
manufacturer’s recommendations.
• Operational qualification (OQ): Documented
verification of equipment or system performance
in the target operating range.

15. Process Performance Qualification (PQ):
• Documented verification that equipment
system operates as expected under routine
production conditions.
• The operation is reproducible, reliable and in a
state of control .

16. Equipment validation
Design and
development of
equipment system,
or product
Installation
qualification
Operational
qualification
Process
performance
qualification
Change control

18. Some Common Variables In The Manufacture
Of Tablet Products
1. Particle size of drug substance
2. Bulk density of drug substance/excipients
3. Powder load in granulator
4. Amount and concentration of binder
5. Mixer speed and mixing times
6. Granulation moisture content
7. Milling conditions
8. Lubricant blending times
9. Tablet hardness
10. Coating solution spray rate

19. INDUSTRIAL PROCESS OVERVIEW OF
SOLID DOSAGE FORMS
• Steps & Process Parameter Are Following-
• MIXING OR BLENDING- Material have similar physical
properties will be easier to form a uniform mix or
blend as compare to difference in properties.
Techniques-
1. Diffusion(tumble)
2. convection(planetary or high intensity or fluid bed).
• Mixing and blending depends upon various factors-
1.Mixing speed- Mixing of drug and excipient requires
more intense mixing than adding the lubricant to the
final blend.

20. CONT…
• 2.Mixing Time- Depends on mixing technique and
speed. • If over mixed occurred at the result demixing
or segregation of the material
• 3.Drug and excipient uniformity- Handling of material
is key in obtaining valid content uniformity results.
• Sample should be equivalent to the weight of a single
tablet.
• 4.Equipment capacity - The bulk density of material
will affect the capacity of the equipment.
Undercharging or overcharging a blender can result in
poor drug or tablet lubricant distribution.

21. CONT…
• 5. Excipient uniformity-Excipient need to be uniform
in the granulation.
• Two keys excipient are-
• (A)-LUBRICANT- Lubricant needs to be distributed
uniformly in the mixture/granulation for high speed
compression operation.
• Uneven distribution of the lubricant can result in
picking & sticking problem during compression.
• B)Color-Evenly distributed in the mixture so the
tablets have a uniform appreance (color & intensity)
• Uniform dispersed in the blend prior to compression to
avoid shading(molting).

22. WET GRANULATION
• Two type of wet granulation to be used..
1. LOW SHEAR
2. HIGH SHEAR
Wet granulation parameters to be processing during development &
validation are-
1. Binder addition- Should be added as a granulating solution
2. Binder concentration - If the binder concentration is high it is not
rejected by the spray nozzle then the binder needs to be diluted
3. Amount of binder solution- Too much binder solution can over
wet the material and prolonged drying time.
4. Granulation end point- Determined by ammeter and wattmeter
equipment.

23. WET MILLING
Does the wet granulation needs to break up the
lumps and enhance the drying of granulation
factors –
• Screen size – Should be small enough to de
lump the material.
• Mill speed- Sufficient speed with out causing
any staining to the equipment.
• Feed rate- Is interrelated to screen size, mill
size and speed

24. DRYING
• Drying is a most important step in the formulation
and development of pharmaceutical product.
• It is important to keep the residual moisture low
enough to prevent product deterioration and
ensure free flowing properties.
• Type of drying technique
1. Tray dryer
2. Fluid bed
3. Microwave
• Changing dryer techniques could affect such
tablet properties such as hardness, disintegration
,dissolution & stability

25. DRYING
• High moisture content can result in-
• (1)Tablet picking or sticking to tablet punch surfaces
• 2)Poor chemical properties as a result of hydrolysis .
An over dried granulation could result in poor hardness &
friability.
• Moisture content are analyzed by following method –
(1)Near I.R
(2)Loss of drying
(3)Karl fischer

26. Factors
• Inlet/outlet temp- Should be set high enough to
maximinise drying without affecting the physical/chemical
stability.
• The outlet temp.is an indicator is an of the granulation
temp.&will increase toward the inlet temp.as the moisture
content of the granulation decreases (evaporization rate).
• Airflow- Insufficient air flow prolongs drying and affect
chemical stability .
• Moisture uniformity- Moisture content could vary in the
granulation .drying is also affect the moisture in
granulation.
• Equipment capacity- High the load high moisture should
be removed

27. Milling
• Milling operation will reduce the particle size of the dried
granulation.
• An optimal particle size/size distribution for the formulation
will need to determined .
• FACTORS-
• (a)Mill type: what mill type should be used(impact or screen)
• (b)Screen size: A smaller screen size will produce a small
particle size & a greater number of fines.
• (c)Mill speed: What is the optimal mill speed? • Higher
speed will result in a smaller particle size & possibly a wider
particle size distribution
• (D)Feed rate: Is dependent on the mill capacity ,screen size,
mill speed

28. LUBRICATION
• 1.Selection of lubricant-
• should compatible with other ingredient.
• grade of lubricant used
• 2.Amount of lubricant- too much lubrication will from
hydrophobic layer on the tablet resulting dissolution
problems.
• 3.Mixing time- Should mixing stop after the addition of
the lubricant or should additional mixing be required
• if not mixed long enough problems like chipping,
capping etc.

29. TABLET COMPRESSION
• After the preparation of granules (in case of wet
granulation) or sized slugs (in case of dry granulation)
or mixing of ingredients (in case of direct
compression), they are compressed to get final
product.
• The compression is done either by single punch
machine (stamping press) or by multi station machine
(rotary press).
• The material should readily flow from the hopper onto
the feed frame & into the dies.
• Inadequate flow can result in ‘RAT HOLING’in the
hopper.
• This can cause tablet weight &uniformity problem

30. Factors-
• Tolling: The size ,shape &concavity of the
tooling should be examined based formulation
properties &commercial specification
• compression speed- range of compression
speed to determine the operating range of the
compressor.
• compression or ejection force- determined
optimal compression force to obtain the
desired tablet hardness.

31. CONT…
• The following in-process tests should be
examined during the compression stage-
• Appearance
• Hardness
• Tablet weight
• Friability-0.5-1%
• Disintegration
• Weight uniformity 35

32. In process tests
1. Moisture content of dried granulation
2. Granulation particle size distribution
3. Blend uniformity
4. Individual tablet/capsule weight
5. Tablet hardness
6. Tablet thickness
7. Disintegration
8. Impurity profile

33. THE TABLET COATING PROCESS
• Tablet coating can occur by different techniques
• (e.g. -sugar, film or compression)
• Key area to consider for tablet coating include the following-
• (a)Tablet properties –The tablet needs to be enough to
withstand the coating process.
• If tablet attrition occurs ,the tablets will have rough surface
appearance
• Round shape easily coated than multiple sides.
• (b) Equipment type- Coater will need to be selected.
• Conventional or perforated pan & fluid bed coaters are potential.
• (c)Coater load- Too high load at the result attrition occurred.

34. THE TABLET COATING PROCESS
(d)Pan speed-
It is interrelated to coating parameter such as inlet
temp,spray rate & flow rate.
(e)Spray guns- Number & types of guns should be
determined in order to efficiently coat the tablet.
Size of spray nozzle properly to ensure even distribution
over the tablet bed & to prevent clogging of the nozzles.
(f)Spray rate-
Spraying too fast will cause the tablets to become over wet,
resulting in clumping of the tablets & possible dissolution
of the tablet surface.
Spray too slowly will cause the coating material to prior to
adhesion to the tablets, result in rough & poor coating
efficiency

35. THE TABLET COATING PROCESS
g)Tablet flow-flow of the tablets in the coater
should be examined to ensure proper flow.• The
addition of baffles may be required adequate
movement of the tablet for coating.
h) Inlet/outlet temp &air flow-parameter should
be set to ensure that the atomized coating solution
reaches the tablet surface & then is quickly dried.
• (i)Coating solution- The conc. & viscosity of the
coating solution will need to be determined

36. CONTI…
ii)The stability of the coating solution should be
investigated to establish its shelf life.
(j)Coating weight- A min. & max. coating
weight should be established for the tablet
(k)Residual solvent level- If solvents are used
for tablet coating ,the residual solvent level will
need to be determined.

37. APPERANCE TEST FOR TABLET
COATING-
1. Cracking or peeling of the tablet
2. Intagliation fill-in
3. Color uniformity
4. Coating efficiency should be determined for
the coating operation

38. IN PROCESS TESTS
1. Appearance
2. Assay
3. content uniformity
4. Tablet hardness
5. Tablet thickness
6. Impurity profile
7. Dissolution

39. FINISHED PRODUCT TESTS
1. Moisture content of dried granulation- usually
less then 2%
2. Granulation particle size distribution
3. Blend uniformity
4. Individual tablet weight
5. Tablet hardness
6. Tablet thickness
7. Disintegration
8. Impurity profile

41. CAPSULE COMPOSITION-
• Capsule shell provide :
• The reason for the presence of each ingredient in the capsule
formulae.
• Justify the level and grade of each ingredient .
• Explain the selection of the capsule size and shape
• Discuss the need for capsule identification(color).
• Capsule shell contents-
• Establish the compatibility of the capsule shell and the capsule
contents.
• Determine the hygroscopic nature of the capsule formulation
• For example : A hygroscopic formulation(API /excipients)can
pull water from the capsule shell, which could effect the API
stability.

42. PROCESS EVALUATION AND
SELECTION
• The process to manufacture the contents of a
hard gelatin capsule is the same as the tablet.
• It may required only a blending step, such as a
direct compression tablet, or several unit
operations, such as a wet granulation tablet
(e.g. mixing, wet milling, drying, dry milling
and blending).
• In either case, the materials are then
encapsulated in a capsule shell.

43. Encapsulation Speed
• The formulation should be encapsulated at a
wide range of speeds to determine the
operating range of the encapsulation.

44. ENCAPSULATION
• Encapsulation is a critical step in the
production of capsules, similar to the
compression for tablet dosage forms.
• The materials to be encapsulated will need to
have good flow properties and a consistent
density.

45. Quality Control Tests Are Divided
Into
 PHYSICAL TEST
• Disintegration test
• Weight variation
 CHEMICAL TEST
• Dissolution test
• Assay
• Content uniformity
• Stability testing Moisture permeation test

46. CONCLUSION
• Solid dosage form validation should be part of
comprehensive validation program within an
industry.
• The multidisplinary validation team must identify
the product and process characteristics that must
be studied and incorporate specific validation
tests to ensure that product will meet all quality,
manufacturing and regulatory requirements.
• Continuous awareness of validation will produce
reproducibility.

47. References
• http//www.pharmainfo.net/reviews/guideline
s-general- principles-validation-solid-dosage.
• www.google.com