Process Validation of Liquid Orals

PROCESS VALIDATION OF LIQUID ORALS Presented By:

Aasawaree Jeevan YadavF.Y.M. Pharmacy (Pharmaceutics)

Guided By:Dr. (Mrs.) Snehalatha Boddu

VALIDATION

Documented program

Pre-determined specifications and quality attributes

WHO - Validation is documented act of providing that any procedure,

process, equipment, material, activity or system actually leads to the

expected results

Aasawaree Jeevan Yadav

SCOPE OF VALIDATION1. Instrument calibration

2. Process utility services (support services)

3. Raw materials and Packaging materials (Stage 1 & 2)

4. Equipment

5. Manufacturing

6. Product design

7. Cleaning

8. Operators (knowledge, skills, attitude)

9. Analytical test methods

i. Accuracyii. Precision

a. Repeatabilityb. Reproducibilityc. Intermediate precision

iii. Linearityiv. Rangev. Limit of detection (LOD)vi. Limit of quantification

(LOQ)vii. Ruggednessviii. Robustness

knowledge

attitude

skills


1. Manufacturing process control (raw material)2. Pre-formulation evaluation3. Stability studies4. Environmental control/checks5. Cleaning controls (contamination)

APPLICATIONS OF VALIDATION


PROCESS VALIDATION


USFDA - establishing documented evidence which provides a

high degree of assurance that a specific process (such as the

manufacture of pharmaceutical dosage forms) will

consistently produce a product meeting its predetermined

specifications and quality characteristics.


OBJECTIVE OF PROCESS VALIDATION1. Reduces variation between various batches.2. Assurance of quality of the product. 3. Decreases the risk of regulatory noncompliance.4. Ensure the consistency of the manufacturing operation and reproducibility of the process.5. Ensure the existence of all necessary quality assurance system within

organization.6. More rapid and reliable start-up of new equipment.7. Easier scale-up from development work.8. Easier maintenance of equipment.9. Improve employee awareness for processes.


REASONS FOR PROCESS VALIDATIONChanges in:1. New product or existing products as per

SUPAC (Scale-Up and Post Approval Changes)

2. Site of manufacturing.3. Batch size.4. Equipment.5. Process existing products.6. Composition or components.7. Critical control parameters.8. Vendor of API or critical excipient.


ADVANTAGES OF PROCESS VALIDATION

1. Simple process 2. Moisture sensitive and heat sensitive products 3. Consistent through output.4. Reduction in rejections and reworks.5. Fewer complaints about process related failure.6. Reduced testing in process and finished goods.7. Easier scale-up from development work.8. Easier maintenance of equipment.9. More rapid and accurate investigations process deviation.10. Increased confidence about process reproducibility and product

quality.11. Improve employee awareness of processes.


STRATEGY FOR VALIDATION METHODS1. Define the application purpose

and scope of the method2. Define the performance

parameters and acceptance criteria

3. Define validation experiments4. Develop SOPs for executing the

method routinely5. Define criteria for revalidation6. Document validation

experiments and results in the validation report


STAGES OF PROCESS VALIDATION


PHASES OF PROCESS VALIDATION

1. Pre-validation Qualification

2. Process Validation

3. Validation Maintenance


expected or expecting to be thespecified thing in the future

existing, happening, or done at the same time

looking back on or dealing with past events or situations

repetition of a validation process

TYPES OF PROCESS VALIDATION


PRINCIPLES OF VALIDATION Installation Qualification (IQ) Operational Qualification (OQ) Performance Qualification (PQ)

CRITICAL FACTORS OF PROCESS VALIDATION

1. All the critical point of the process should be clearly identified.2. The process should run using the extremes of the system at the

critical points.3. The quality system should support the validation effort by way of

document control, preventive maintenance, calibration, etc.4. Adequate data are required to provide statistical support to

demonstrate product consistency. Aasawaree Jeevan Yadav

1. Validation Master Plan (VMP)

2. Validation Protocol (VP)

3. Validation Reports (VR)

4. Standard Operating Processes (SOPs)

DOCUMENTATION IN VALIDATION PROCESS


LIQUID ORALS


LIQUID DOSAGE FORMS CAN BE ADMINISTERED

1. Topically

2. Orally (per oral)

3. Parenterally (S.C., I.M., I.V.)


Liquid orals

MonophasicSolutionsLinctuses

ElixirsSyrups

Liquid drops

Biphasic

SuspensionEmulsion


LIQUID DOSAGE FORMS CAN BE PREPARED1. By dissolving the active drug substance(s) in an aqueous or

nonaqueous (e.g. alcohol, ether, glycerin) solvent

2. By suspending the drug in appropriate medium

3. By incorporating the drug substance into an oil or water phases


MANUFACTURING OF MONOPHASIC LIQUIDS Process Flow

Mixing

Addition of Raw MaterialsActiveExcipients

Mixing timeRPMTemperatureFinal volume

Measured ResponsesControl Variables

ClarityViscosityAssay

ClarityMesh sizeFilter integrity

Filtration

VolumeFilling machine speedFillingAasawaree Jeevan Yadav

MANUFACTURING OF BIPHASIC LIQUIDS

Water

Continuous Phase

Other helping agents

Mixing

Aqueous solution

Dispersed Phase

For suspension

Preservatives

Surfactants

Drug solution in oil

Grinding of Drug and

other solids

Dissolved drug in oil

For emulsion

Milled drug


Continuous Phase

Dispersed Phase

Pre-mix or crude Dispersion

Fine Dispersed Delivery System

pH adjustment

Other additives (flavors and coloring agents)

Volume adjustment

Homogenize


VALIDATION OF

LIQUID ORALSAasawaree Jeevan Yadav

OBJECTIVES OF PROCESS VALIDATION FOR LIQUIDS

To do the process

systematically to assure the

quality of the product

Ensures that the product meet

the predetermined

specifications


VALIDATION OF LIQUID ORALS1. Equipment

2. Raw materials

3. Compounding

4. Microbiological quality

5. Oral suspension uniformity

6. Product specifications

7. Stability

8. Packaging


NUMBER OF VALIDATION TRIALS For New Product, Product Transfer or Having Major Changes

generally at least three consecutive successful batches are required:1. One Right = Accident2. Two Right = Coincidence3. Three Right = Validated

SAMPLING FOR VALIDATION For Solution, take at least 2 samples at top and bottom of the bulk For Suspension, take at least 2 samples at top, Middle and Bottom of

the bulk Finished Product Testing (Net content, Microbiology, Content

Uniformity)Aasawaree Jeevan Yadav

CRITICAL PARAMETERS

Equipment

Mixing speedHomogenizing speed

Mixing timeHeating/ cooling time

Flow rate

ManufacturingDissolving step

Melting stepHomogenizing step

Processing

Mixing speedMixing timeCooling time

Homogenizing speedHomogenizing timeAasawaree Jeevan Yadav

ACCEPTANCE CRITERIADissolved

active ingredient

Clear solution

Filtration No residue on filter

pH adjustment pH within specification

Final mixingpH, viscometer,

appearance, assay content


TEST PARAMETERS FOR SUSPENSIONS AND EMULSIONS

TEST PARAMETER SUSPENSION EMULSION

Appearance √ √

Viscosity √ √

pH √ √

Content uniformity √ √

Sedimentation √ ˟Re-suspendability √ ˟

Particle size √ √

Release rate √ √Aasawaree Jeevan Yadav

OPERATIONS IN PROCESS VALIDATION Raw material validation

1. Particle size and size distribution2. Particle shape or morphology3. Microbial count4. pH of the solvent or vehicle

Monitoring outputs1. Appearance2. pH value and Viscosity3. Microbial count4. Content uniformity5. Dissolution testing


OPERATIONS IN PROCESS VALIDATION Filling and Packaging

Operation Validation

1. Leakage test for filled

bottle

2. Cap sealing test

3. Fill volume

determination


VALIDATION REPORT Validation Team must prepare

the report Report must be reviewed and

approved by QA. Written Notification or either

successful completion or failure of the process validation must be issued to top management.

In case of failure, an investigation must be completed and documented prior to repeat the validation study.


CHANGES AND REVALIDATION Change of any of the following may need revalidation

1. Formula Composition2. Raw Material Source3. Manufacturing Process4. Manufacturing Location5. Equipments6. Batch Size

1. Minor2. Intermediate3. Major

CHANGES


accurate and reliable method of

estimation

quality, identity, strength, purity,

stability, effectiveness and safety

better acceptability of the drug


Process Validation of Liquid Orals

Science

Transcript of Process Validation of Liquid Orals