Astoria Plaza

Mario Carlo A. Soliven Pasig City

20 March 2015
DIRECTOR
QUALITY ASSURANCE AND PRODUCT DEVELOPMENT
Pascual Laboratories, Inc.
TRADITIONAL APPROACH
Development

Scale-up/ Tech Transfer

Typically 3 PV batches

Change Control/
Annual Review

Process Validation
VALIDATION LIFE CYCLE
Risk Analysis VALIDATION MASTER PLAN
DESIGN Process Validation
QUALIFICATION
REVALIDATION

INSTALLATION Cleaning Validation

QUALIFICATION

OPERATIONAL Computer Validation MONITORING

QUALIFICATION MAINTENANCE
Analytical Method CHANGE CONTROL
PERFORMANCE
QUALIFICATION Validation

QUALIFICATION PROCESS VALIDATION VALIDATION

PHASE PHASE MAINTENANCE PHASE

Process Validation
PURPOSE OF PV
• Process Validation (PV) ensures and
provides documented evidence that
processes within their specified design
parameters are capable of repeatedly
and reliably producing a finished product
of predetermined quality.

Process Validation
 SCOPE
• All critical production processes
with direct impact on product
quality must be validated, with
emphasis on critical process steps,
parameters and equipment
involved.

Process Validation
 SCOPE
New Products
• Process validation should be conducted
for all new products prior to commercial
production.
Existing Products
• Process validation should be conducted
for all existing products with significant
changes which may affect product quality,
directly or indirectly, depending on risk
assessment
Process Validation
 SCOPE
Existing Products
• Change in master formula
• Change in manufacturing and
packaging processes and parameters
• Change in batch size
• Change in process equipment

Process Validation
 SCOPE
Existing Products
• Change in raw material (source/
supplier; material form or
characteristics; material specifications)
• Change in primary packaging material
(material composition, critical material
specifications, source/supplier
• Site transfer

Process Validation
 APPROACH
• Prospective
• Concurrent
• Retrospective

Process Validation
NUMBER OF BATCHES
• Depends on the complexity of the process,
the magnitude of the process change, and
the reliability of the process controls
employed.
• For prospective and concurrent
validation, three (3) consecutive successful
production batches should be used, as
minimum. Additional process runs may be
required to further evaluate process
reproducibility and consistency.
Process Validation
NUMBER OF BATCHES
• For product families/groups, use of matrix
or bracketing approach may be justified.
• For retrospective validation, data from
ten (10) to thirty (30) consecutive batches
should be evaluated to assess process
reproducibility and consistency. The
evaluation of processes based on fewer
batches may be conducted, if justified.

Process Validation
MATRIXING AND
BRACKETING
• A single validation exercise may be used to
represent a family or group of similar
products when justified and approved by
Quality Assurance.
• Appropriate rationale for matrixing or
bracketing should be based on scientific
evidence and/or risk assessment and must
be documented as part of the validation
package.
Process Validation
PRE-REQUISITES
• Approval of change control document
• Approval of process validation protocol
• Approval of master manufacturing and
packaging instructions
• Facilities, equipment and utility systems
have been qualified and calibrated.

Process Validation
PRE-REQUISITES
• Analytical methods have been validated.
• Raw and packaging materials including
their suppliers have been qualified and
approved.
• All personnel involved in the validation
have been trained in the relevant SOPs.

Process Validation
 MATERIAL
QUALIFICATION
• Prior to the conduct of validation due to
change in material (grade,
specifications or source), three (3)
representative lots of the material
should first undergo material
qualification, to be conducted by
Quality Control laboratory.

Process Validation
MATERIAL
QUALIFICATION
• In cases where the source is changed,
the assessment of the suitability of the
source, including vendor accreditation,
shall be handled by QA under the
standard vendor qualification
procedures.

Process Validation
PROCESS FLOW
Product
Product/ Process
Characterization
Development Validation
Master
Plan

Product Characterization Characterization

Development Protocol Report
Report

Change
Control

Validation Scheduling
Periodic Review
Protocol

Commercial Validation Validation

Revalidation
Production Report Runs

Process Validation
CRITICAL PROCESS
PARAMETERS
OPERATION Process Product Attributes
Parameters
Wet Granulation Loading Capacity Granule size
Granulating solution distribution
addition rate
Impeller / chopper
speed
Wet massing time
Oven Drying Powder bed thickness Moisture content
Temperature Solvent residue
%RH of drying air
Drying time
Process Validation
CRITICAL PROCESS
PARAMETERS
OPERATION Process Product
Parameters Attributes
Fluid Bed Drying Load Moisture Content
Inlet/Outlet temperature
Bed temperature
% RH of drying air
Airflow rate
Milling / sieving Screen size Particle size
Blade Setting Bulk / tap density
Blade Speed
Feed rate

Process Validation
CRITICAL PROCESS
PARAMETERS
OPERATION Process Product Attributes
Parameters
Blending Blender capacity Blend content uniformity
Mixing time (in mixer and in drums)
Speed of mixing Particle size and bulk/
tapped density of final blend
Compression Tablet press speed Tablet weight, thickness,
Compression force hardness and friability
Weight and Content uniformity
compaction force Dissolution / disintegration
Powder feed rate Assay
into dies
Process Validation
CRITICAL PROCESS
PARAMETERS
OPERATION Process Parameters Product Attributes
Encapsulation Fill volume Capsule weight/ length
Tamper setting Content uniformity
Encapsulation speed Dissolution
Aspiration setting Assay
Film coating Spray rate Weight variation
Pan speed Assay
Airflow rate Dissolution /
Pan loading disintegration
Inlet / exhaust temperatures Appearance: mottling
Spray guns nozzle and or specking
assembly

Process Validation
CRITICAL PROCESS
PARAMETERS
OPERATION Process Parameters Product Attributes
Powder Filling Machine speed Fill Weight
(bottle/ sachet) Dosator setting Assay and content
Sealing temperature uniformity
Seal integrity
Strip Packaging Sealing temperature Seal integrity
Machine speed

Blister Forming Temperature Seal integrity

Packaging Sealing temperature
Machine speed

Process Validation
CRITICAL PROCESS
PARAMETERS
OPERATION Process Parameters Product Attributes
Dispersion of Homogenization time Homogeneity
APIs/ Homogenization speed Potency
preservatives Mixing time
Mixing speed
Temperature

Process Validation
CRITICAL PROCESS
PARAMETERS
OPERATION Process Parameters Product Attributes
Dissolution of Homogenization time Homogeneity
APIs/ Homogenization speed Potency
preservatives Mixing time
Mixing speed
Temperature
Dissolution of Homogenization time Homogeneity
non-active Homogenization speed Viscosity
compounds Mixing time Specific Gravity
Mixing speed pH
Temperature

Process Validation
CRITICAL PROCESS
PARAMETERS
OPERATION Process Parameters Product Attributes
pH Adjustment Mixing time pH
Mixing speed Homogeneity
Homogenization time
Homogenization speed
Temperature
Viscosity Mixing time Viscosity
Adjustment Mixing speed Homogeneity
Homogenization time
Homogenization speed
Temperature

Process Validation
CRITICAL PROCESS
PARAMETERS
OPERATION Process Parameters Product Attributes
Filling process Equipment settings Fill volume/weight
Filling speed Content Homogeneity
Filling temperature Degradation products
Filling time Torque/seal integrity
Micro

Process Validation
CRITICAL PROCESS
PARAMETERS
OPERATION Process Parameters Product Attributes
Holding process Storage time Potency
Mixing time Degradation products
Mixing speed Homogeneity
Micro
pH
Viscosity
Standstills Equipment settings Potency
Duration of standstill Degradation products
Mixing time Micro
Mixing speed

Process Validation
 PROCESS
VALIDATION-
SOLIDS

Process Validation
SAMPLING PLAN- SOLIDS

Twin Shell Blender

Process Validation
 POCKET SAMPLER
• Multilevel Sampler for taking
discrete samples

Process Validation
 SLOT SAMPLER
• Multilevel Sampler gives a single
composite sample

Process Validation
 TABLET FORMULATION
Process Step Sampling/Testing Acceptance Criteria

Dry Mixing (w/API) Content Homogeneity RSD <6.0%

85%-115% LC
Wet Granulation Homogeneity Check Compressible Mass;
Visually Homogeneous
Drying Moisture Content Meets MC Specs

Sizing Particle Size As per Development

Distribution Data

Final Blending Content Homogeneity RSD <6.0%; Meets

Assay Specs
Bulk Unloading Content Homogeneity RSD <6.0%; Meets
Assay Specs

Process Validation
 TABLET FORMULATION
Process Step Sampling/Testing Acceptance Criteria

Compression Physical Tests Meets Specs

- Appearance
- Hardness
- Thickness
- Weight Variation
Chemical Tests (assay, Meets Specs
dissolution, content
uniformity,
degradation limits)
Micro Tests Meets USP

Process Validation
 TABLET FORMULATION
Process Step Sampling/Testing Acceptance Criteria

Coating Physical Tests Meets Specs

- Appearance
- Hardness
- Thickness
- Weight Variation
Chemical Tests (assay, Meets Specs
dissolution, content
uniformity,
degradation limits)
Micro Tests Meets USP

Process Validation
 TABLET FORMULATION
Process Step Sampling/Testing Acceptance Criteria

Blister Packaging Leaker’s Test No colored tablets

observed
Peel-Off Test Not possible by hand
and using knife

Process Validation
 PROCESS
VALIDATION-
LIQUID

Process Validation
SAMPLING PLAN- LIQUIDS
Main Mixing Tank

Top View

Front View

Process Validation
 CUP SAMPLER
- LIQUID DOSAGE FORM
- Suitability: High and low viscosity
liquids and suspensions

Process Validation
ACCEPTANCE CRITERIA
Process Step Sampling/ Testing Acceptance Criteria
Dissolution of Visual Dissolution No undissolved
Raw Material Check materials observed
Final Mixing Content 95%-105% LC
Homogeneity Check RSD<6.0%
Degradation Within limits
compounds
Preservative assay 90%-110%
pH and Viscosity Within limits
Micro Meets USP

Process Validation
 ACCEPTANCE CRITERIA
Process Step Sampling/ Testing Acceptance Criteria
Filling Verification of Cap Within limits
Sealing
Verification of Fill Within limits
Volume

Process Validation
 PROCESS
VALIDATION-
SEMI-SOLIDS

Process Validation
 SAMPLING PLAN

1 2 3
Top

4
Middle

5 6 7
Bottom
Top View
Left Right
Center
Front View

Process Validation
 VISCOUS SAMPLER
Suitability: Medium viscosity
materials (Creams)

Process Validation
 ACCEPTANCE CRITERIA
Process Step Sampling/ Testing Acceptance Criteria
Melting of Visual Check Homogeneous; no
Raw Material lumps materials
observed
Dispersion of Visual Check No undispersed
Raw Material materials observed
Emulsification Bulk homogeneity Meets specs
Degradation
compounds
pH
Viscosity
Micro
Process Validation
 ACCEPTANCE CRITERIA
Process Step Sampling/ Testing Acceptance Criteria
Tube Filling Content Meets assay spec
Homogeneity; RSD <6.0%
Preservative assay
Degradation Within limits
Compounds
Fill Weight Within limits

Viscosity Within specs

Micro Meets USP

Process Validation
 -END-

Process Validation