Validation Of Solid Dosage FormsPresented by, Rasika.walunj

M.Pharm (QAT)

Modern college of pharmacy (for ladies), Moshi, Pune.

Content

• Introduction • Types of process validation • Validation of tablet • Validation of capsule • Conclusion

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

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

The Major Reasons For Validation Are :

• 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.

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. 

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

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. 

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.

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

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?

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

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

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. 

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 .

Equipment validation

Design and development of

equipment system, or product

Installation qualification

Operational qualification

Process performance qualification

Change control

Validation Of Tablets

Some Common Variables In The Manufacture Of Tablet Products

1. Particle size of drug substance 2. Bulk density of drug substance/excipients3. 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 

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.

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.

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).

WET GRANULATION

• Two type of wet granulation to be used..1. LOW SHEAR 2. HIGH SHEARWet granulation parameters to be processing during development & validation are- 3. Binder addition- Should be added as a granulating solution 4. Binder concentration - If the binder concentration is high it is not

rejected by the spray nozzle then the binder needs to be diluted 5. Amount of binder solution- Too much binder solution can over

wet the material and prolonged drying time.6. Granulation end point- Determined by ammeter and wattmeter

equipment.

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

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

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

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

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

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.

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

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.

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

In process tests

1. Moisture content of dried granulation2. Granulation particle size distribution3. Blend uniformity4. Individual tablet/capsule weight5. Tablet hardness6. Tablet thickness7. Disintegration8. Impurity profile

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.

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

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

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.

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

IN PROCESS TESTS

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

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

Validation of capsules

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.

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.

Encapsulation Speed• The formulation should be encapsulated at a

wide range of speeds to determine the operating range of the encapsulation.

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.

Quality Control Tests Are Divided Into

PHYSICAL TEST • Disintegration test • Weight variation CHEMICAL TEST • Dissolution test• Assay • Content uniformity • Stability testing Moisture permeation test

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.

References

• http//www.pharmainfo.net/reviews/guidelines-general- principles-validation-solid-dosage.

• www.google.com

THANK YOU