Validation

Throughout today’s class…

Please post in the chat box… or e-raise
your hand for discussion…
-Your experiences with any Validation
work
-…Cleaning Validation/or CSV
-Your challenges with Validation
Would love to hear!
Validation
Objectives

• To review the definition and types of validation

• To understand the requirements for documentation
and key stages in the process of validation
• To consider models for process validation
Validation
Definition:

The documented act of proving that any

procedure, process, equipment,
material, activity or system leads to the
expected result.
Types of Validation
•Process Validation
 Manufacturing process
 Sterilization process
•Cleaning Validation
•Method Validation
 API, finished product and stability
analysis
Validation
Basic Requirements

• Studies are conducted against pre-determined

protocols.

• Written reports summarizing results and conclusions

are prepared, evaluated, approved and maintained.

• Changes to processes, operating parameters,

equipment or materials that may affect product
quality/reproducibility are validated before
implementation.
Validation
Stages of Validation

• Design qualification (DQ)

• Installation qualification (IQ)

• Operational qualification (OQ)

• Performance qualification (PQ)

Validation
Installation Qualification: the documented act of
demonstrating that a process equipment and ancillary
systems are appropriately selected and correctly
installed.
 All equipment, gauges and services should be adequately
identified and given a reference number.
 IQ is a formal and systematic check against the supplier’s
specifications and any additional criteria.
 Should be repeated a sufficient number of times to
produce meaningful results
 At this stage the preventive maintenance requirements
should be identified and documented.
Validation
Operational Qualification: the documented act of
demonstrating that process equipment and ancillary
systems work correctly and operate consistently in
accordance with established specifications.

 OQ should follow an authorized protocol and the critical

equipment/system parameters should be identified.
 Critical variable studies should include “worst-case”
conditions .
 Information gained during OQ should be used to develop
operating procedures and instructions.
Validation
Process Qualification: the phase of validation
dealing with sampling and testing at various
stages in
the manufacturing process to ensure that
product
specifications are met.

• All of the different types of process validation

fall under this category.
• Process qualification cannot be performed
Validation
Types of Process Validation

• Experimental approach
 Prospective validation
 Concurrent validation
• Analysis of historical data
 Retrospective validation
• Re-validation
 Periodic re-validation
 Re-validation after change
Validation
Prospective Validation – the validation protocol is
executed before the process is used commercially.
• All equipment and methods used should be fully
qualified and validated.
• The number of batches produced should be
sufficient to experience a normal variation for
accurate, real-world data to evaluate.
• Normally data from 3 batches is sufficient to
consider a process validated.
 Different lots of raw materials and excipients should
be used.
Validation
Prospective Validation (continued)
• Extensive sampling and testing should be
performed at various stages and documented.
 Detailed testing should also be carried out on the
finished product
 Once the data from the validation is reviewed, any
recommendations should be made on the extent of
in-process controls required for routine production.
• A matrix approach can be used for process
validation of different strengths of the same
products.
Validation
Concurrent Validation: current production
batches
are used to monitor process parameters.

▫ Provides limited assurance of consistency.

▫ Risk of modification of process parameters or
specifications over time and questions
dispositions of batches already released.
▫ Not encouraged except in special
circumstances.
Validation
Retrospective Validation: conducted for a product that
is already marketed, based on extensive historical data.

 Only acceptable for well-established processes.

 Data is required from a minimum of 10 consecutive
production batches.
 A list of process deviations, corrective actions, any
changes to the manufacturing process, stability data for
several batches and trend analysis should be included
with the validation study to provide additional
information.
Validation
Process Re-validation: required when there
is a
change to a critical process parameter,
formulation,
primary packaging component, raw material
manufacturer, major equipment or premises.

▫ Documentation requirements are identical to

the initial validation
▫ Changes could be planned or unplanned.
Validation
Process Validation

• New products:
 Every process needs to be validated before
approval.

• Sterile products:
 all processes affecting the sterility, manufacturing
environment (including the sterilization stage) need
to be validated.
• Non-sterile products:
 mixing, granulation, content uniformity and other
parameters need to be validated.
Validation
Types of Documentation

• Validation Master Plan (VMP)

• Validation protocols (VP)
• Validation reports (VR)
Validation
Validation Master Plan: a document that
summarizes the company’s overall philosophy,
intentions and approaches to validation.
• Should comprise all prospective, concurrent,
retrospective and re-validations.
• Should be brief, concise and clear. References to
existing/additional documents should be included.
• Provides an overview of the entire validation
operation, its organizational structure, its content
and planning.
 All validation activities for critical operations should
be included.
Validation
Validation Master Plan Content:
• Introduction (scope, policy, etc)
• Organizational structure and responsibilities
• Facility and process description
• Personnel, planning and scheduling
• Any specific process considerations
• Equipment, apparatus, processes and systems to
be validated
• Key acceptance criteria
• Documentation format
• References to SOPs
• Any training requirements
Validation
Validation Protocol: a written plan stating how
validation will be conducted (test parameters, equipment,
characteristics) with details of critical steps, the range of
variability, and how the system/process will be tested.
 This document provides a synopsis of what the validation
hopes to accomplish.
 Lists the selected process and control parameters, the
number of batches to be included and how the data will be
analyzed.
 The protocol needs to be approved and any changes post-
approval must be documented.
Validation
Validation Protocol Content:
• Objectives and scope of the validation study
• Site of the study, type of validation and number of
batches
• Personnel and their responsibilities/qualifications
• Description of the equipment (including IQ, OQ
outcomes)
• Description of processing steps
• Sampling details
• Critical process parameters (and their tolerances)
• Any specifications and test methods to be used
• Forms and charts to document results
Validation
Process Validation: Critical Control Points
for
Tablet Granulation

• Particle size distribution of active

• Blending time
• Granulating time and speed
• Drying time, moisture content
• Granule active content, homogeneity
Validation
Process Validation: Critical Control Points
for
Tablet Compression
• Mass
• Hardness
• Thickness
• Friability
• Disintegration
• Dissolution
• Moisture
Validation
Process Validation: Critical Control Points
for
Solutions
• pH
• Homogeneity (assay)
• Mixing time, speed
• Bioburden
• Density
Validation
Validation Report Content:
▫ Title
▫ Objective of the study
▫ Reference to the protocol
▫ Details of material
▫ Equipment, programs and cycles used
▫ Details of procedure and test methods
▫ Comparison of results against acceptance criteria
▫ Recommendations on limits and criteria for production
batches
▫ Approval
Validation
Cleaning Validation : the documented act of
demonstrating that cleaning procedures for the
equipment
used in fabricating/packaging will reduce to an acceptable
level all residues and to demonstrate that routine cleaning
and storage of equipment does not allow microbial
proliferation
• Appropriate cleaning procedures must be developed for
all product-contact equipment used in the production
process.
• At least 3 consecutive applications of cleaning procedure
should be successful to prove the method is validated.
Validation
Cleaning Validation (continued)
• Validation of cleaning processes should be based
on worst-case scenarios.
• Cleaning procedures for similar products and
processes do not need to be individually
validated.
 A “worst case” study can be performed that take
into account similarities of products, the
formulations and other factors.
 Bracketing can be performed for biologics
(including vaccines) for similar products based on
scientific justification.
Validation
Cleaning Validation (continued)
• Cleaning procedures must follow established
and validated methods
• Clean-in-Place (CIP): automatic procedures
used when machinery cannot be
disassembled.
• There should be documented evidence that
routine storage or cleaning of equipment does
not allow microbial growth
 Equipment should be dried before storage
 No standing water should remain post-cleaning
Validation
Cleaning Validation: Analytical Methods

• Analytical methods used to detect residuals

should be substance or class of substance
specific and validated before use.
• These methods should be:
• Specific
• Adequately sensitive
• Challenged in combination with proposed
sampling methods
Validation
Cleaning Validation Protocol Content:
• Objective
• Responsibilities
• Description of equipment to be used
• Intervals
• Cleaning procedures to be used
• Number of consecutive cleaning cycles
• Routine monitoring requirements
• Sampling details
• Analytical methods to be used
• Acceptance criteria
• Bracketing (if applicable)
Validation
Cleaning Validation: Sampling

• Direct Surface Sampling (swab method)

 Suitability of material to be used for sampling
and sampling medium determined
• Indirect Sampling (rinse solutions)
 Allow sampling of large surface area,
inaccessible areas
 Must consider solubility of contaminant
 Used in conjunction with direct sampling
during validation
Validation
Cleaning Validation: Detergents

• Must evaluate removal of detergent residues

and define acceptable limits.

• Manufacturer must know the composition of

detergents
Validation
Cleaning Validation: Establishing Limits

• Based on:
 Materials (contaminants) involved
 Therapeutic dose
• Approach:
 Product specific
 Product families – “worse case” is chosen
 Risk groups
Validation

Analytical Validation
• Objective: demonstrate that the procedure it
suitable for its intended purpose.

• Types of procedures to be validated

 Testing for impurities
 Assay of API in a drug product
 Dissolution testing
 Sterility/BET
Validation
Analytical Validation – Critical Characteristics
• Accuracy
• Precision
▫ Repeatability
▫ Intermediate Precision
• Specificity
• Limit of Detection (LOD)
• Limit of Quantitation (LOQ)
• Linearity
• Range
Validation
Analytical Validation: Specificity

Conducted for:
• Identification Tests
 Able to discriminate between compounds likely to be present
 Positive results compared to known reference material
• Assay and Impurity Test(s)
 Chromatographic resolution between
 Closely eluting components
 Components or impurities that elute near API
 Methods:
 Spike API or drug product with known impurity levels
 Forced degradation (expose to stress conditions)
Validation
Analytical Validation: Linearity

• Evaluate across range of the procedure

 Dilution of standard stock solution of API
 Multiple replicates of synthetic mixtures of
drug product components
• Determine linear relationship via appropriate
statistical methods
• Perform across minimum of 5 concentrations
Validation
Analytical Validation: Range

• Depends on intended application

• Derived from linearity studies
• Minimum specified ranges:
 Assay of drug substance or product: 80-120%
 Content uniformity: 70 – 130%
 Dissolution: +/- 20% over the specified range
 Determination of impurity: reporting level to 120%
of specification
Validation
Analytical Validation: Accuracy

• Established across specified range

• Assay – Drug Substance
 Application of analytical procedure to an analyte of known
purity (reference material)
• Assay – Drug Product
 Application of analytical procedure to synthetic mixture of drug
product components with known quantities of drug substance
• Impurities
 Assessed on samples spiked with known amounts
• Recommended Data:
 Minimum 9 determinations over at least 3 concentration levels
 Reported as % recovery
Validation
Analytical Validation: Precision

• Repeatability
 3 concentrations/3 replicates each over
specified range, or
 Minimum of 6 determinations at 100% of [test]
• Intermediate Precision:
 Vary days, analysts, equipment
• Recommended Data:
 Standard deviation, RSD, confidence interval
Validation
Analytical Validation: Detection Limit

• Approaches:
 Visual Evaluation
 Signal-to-Noise (3:1)
 Standard deviation of response and the slope
 Calibration curve
Validation
Analytical Validation: Quantitation Limit

• Approaches:
 Visual evaluation
 Signal-to-Noise (10:1)
 Standard deviation of response and slope
 Calibration curve
Validation

Analytical Validation: Robustness

• Ensure validity of procedure is maintained
• System suitability testing
• Assess stability of analytical solutions
• Assess effect(s) of variation:
 Mobile phase (pH, composition)
 Column
 Temperature
 Flow rate
Validation
Validation vs. Verification
• Verification of compendial (USP, etc.) methods
is required for drug substance and drug
product analysis.
• Proves method is suitable for its intended
purpose under actual conditions of use.
• Verification usually entails the following
parameters:
▫ Specificity
▫ Limit of detection
▫ Limit of quantitation
Validation
Possible Issues during Validation
• Lack of time
• Lack of personnel
• Lack of experience and knowledge
• Changes to the process
• Prospective vs. retrospective validation
• Lack of documentation infrastructure
• Lack of implementation of validation
• Poorly designed documents