Pharmaceutical UNIT 10: Validation

Analysis II Dr. Katrina Joy B. Bormate, R.Ph,PhD

AY 2023-2024 10/05/2023
1st Semester

throughout production, which establishes scientific evidence

OUTLINE that a process is capable of consistently delivering quality
products.
1. Validation
2. Process Validation Pre-requisites for Process Validation
3. Assay Validation
4. Validation (Qualification) or Manufacturing  Before process validation can be started, manufacturing
Equipments equipment and control instruments as well as the
5. Facility or Equipment Validation formulation must be qualified.
6. Installation Qualification  The information on a pharmaceutical product should be
studied in detail and qualified at the development stage,
7. Operational Qualification i.e., before an application for marketing authorization is
8. Performance Qualification submitted.
9. Validation of Existing Products  This involves studies on the compatibility of active
10. Cleaning Validation ingredients and recipients, and of final drug product and
11. Post validation packaging materials, stability studies, etc.
 Other aspects of manufacture must be validated
VALIDATION including critical services (water, air, nitrogen, power
Validation supply, etc.) and supporting operations such as
equipment cleaning and sanitation of premises. Proper
 defined as the verification, by data and analysis, that the
training and motivation of personnel are prerequisites to
design objectives of a given facility, system, apparatus, or
successful validation.
procedures are reliably fulfilled in routine operation.
 Validation is the overall expression for a sequence of
activities in order to demonstrate and document that a
ASSAY VALIDATION
specific product can be reliably manufactured by the
designed process, usually, depending on the complexity of Assay Validation
today’s pharmaceutical products, the manufacturer must Section of Administrative order no. 220, s. 1974
ensure.  “laboratory controls shall include the establishment of
Primary Goal. scientifically sound and appropriate specifications,
 Is to have documented proof that quality is part of each standards and test procedures to assure that
and every step of the manufacturing and distribution components, drug preparations in the course of
system, instead of merely testing products at the end of processing and finished products conform to appropriate
the process standards of identity, strength, quality and purity”
Important Steps in Validation ASSAY VALIDATION
1. Choosing the desired attributes of the products – method that provides an estimate of assay accuracy and
2. Determining the specifications precision
3. Selecting appropriate processes and equipment PRECISION OR REPRODUCIBILITY
4. Monitoring and testing processes, equipment and personnel – refers to the agreement among repeated measurements
while in operation ACCURACY
5. Examining test procedures themselves to ensure their accuracy – refers to the closeness of measurements to the true magnitude
and reliability concerned

By examining the preceding steps, one can visualize the scope of Reasons why Assay validation is important:
validation work to embrace: 1. It can lead the way to a scientifically sound test
 PROCESS VALIDATION procedure and is therefore fundamental to the quality
control release function
 ASSAY VALIDATION
2. It is important in the evaluation of stability and for the
 QUALIFICATION OF MANUFACTURING
establishment of expiration dates. the stability profile
 EQUIPMENTS generated should reflect the true picture of product
 VALIDATION OF EXISTING PRODUCTS BY degradation under diff. kinds of stress such as light, heat
STATISTICAL EVALUATION and humidity.
 CLEANING VALIDATION 3. The need for validated control procedures for monitoring
output and process variability cannot be
PROCESS VALIDATION overemphasized.
4. Once the validity of assay methods is proven, the
Process Validation validated assay procedures can be used for routine
 The gathering and documenting of sufficient evidence to monitoring of laboratory accuracy and training /
give reasonable assurance that the process under review evaluation of new analysts.
does what purports and is expected to do. The following steps are done to challenge the assay of
 Is the means of ensuring and providing documentary procedures:
evidence that processes (within their specified design 1. Preparation of samples
parameters) are capable of repeatedly and reliably 2. Analysis of samples
producing a finished product of the required quality. 3. Calculation of percent relative deviation
 Process Validation is defined as the collection and 4. Calculation of percent relative error
evaluation of data, from the process design stage 5. Disposition

PH ANAL II TRANSCRIBED BY: MARK HAROLD C. GONZALES 1 of 5

 Pharmaceutical UNIT 10: Validation
Analysis II Dr. Katrina Joy B. Bormate, R.Ph,PhD
AY 2023-2024 10/05/2023
1st Semester
6. Documentation amounts of pharmaceutical elements required for
compounding.
Analytical balance
 an accurate scale used in laboratories for weighing
Sample Diagram minute objects or quantities

Those certified by the National Type Evaluation Program (NTEP),

a joint program managed by the National Institute of Standards
and Technology and the National Conference on Weights and
Measures, have been tested; & their compliance with NTEP
standards and manufacturers' specifications has been verified

2. Thermometers & Temperature Probes

 general-purpose laboratory
temperature sensor.

3. In process Moisture Tester

Ohaus Moisture Balance

 is certified by testing the heat
production for a given setting
and the balance

4. Blender and Mixing Equipment’s (Rotating Speed)

High speed mixed granulator

The diagram illustrates Bias, Precision, and Accuracy.

 The shots on targets (1) and (2) are biased: in both cases the 5. Tablet Hardness Tester
shots cluster away from the bull’s eye.
 The clusters on targets (3) and (4) are both unbiased. Tablet hardness - sometimes
 The shots on targets (1) and (3) are precise: both set are also referred to as tablet break
bunched together. force - measures the mechanical
 The shots on targets (2) and (4) are widely scattered, hence integrity of a tablet
imprecise.
 Only the shots on target (3) are accurate

On the course of an analysis, duplicate values are obtained and

should agree closely. The best estimate is the average value.

VALIDATION (QUALIFICATION) OR 6. Disintegration Apparatus

MANUFACTURING EQUIPMENTS
1. Scales and Balances
Electronic balance
 an essential weighing
instrument in most
modern pharmacies, is
often used to measure
extremely fine
Ex: “Cycle” rates and Water Bath Temperature

PH ANAL II TRANSCRIBED BY: MARK HAROLD C. GONZALES 2 of 5

 Pharmaceutical UNIT 10: Validation
Analysis II Dr. Katrina Joy B. Bormate, R.Ph,PhD
AY 2023-2024 10/05/2023
1st Semester
Disintegration testing determines whether tablets or capsules
disintegrate within a defined period of time when placed in a liquid
medium 10. Mill
Ex: Mill speed
7. Tablet Friabilator
 Milling is the most common form of machining, a
material removal process, which can create a variety of
features on a part by cutting away the unwanted material.
 The milling process requires a milling
machine,workpiece, fixture, and cutter.
 The workpiece is a piece of pre-shaped material that is
secured to the fixture, which itself is attached to a
platform inside the milling machine.
 The cutter is a cutting tool with sharp teeth that is also
secured in the milling machine and rotates at high
speeds. By feeding the workpiece into the rotating cutter,
material is cut away from this workpiece in the form of
small chips to create the desired shape.
 The ball mill is a key
8. Dissolution Apparatus
equipment to grind the crushed
materials, and the ball mill is
Ex: Water Bath Temperature, Agitator
widely used in powder-making
Speed, Analytical Equipment required for
production
assay

An agitator is a type of mixer used for

substances with low viscosities in low
shear application
11. Homogenizer
Dissolution is a test used by the
A homogenizer is
Pharmaceutical industry to characterize
a piece of
the dissolution properties of the active
laboratory or
drug, the active drug's release and the dissolution from a dosage
industrial
formulation. Dissolution testing is used to formulate the drug
equipment used for
dosage form and to develop quality control specifications for its
the homogenizatio
manufacturing process.
n of various types
of material, such as
tissue, plant, food,
soil, and many others.
Homogenization
is a very common sample preparation step prior to the
analysis of nucleic acids, proteins, cells, metabolism,
pathogens, and many other targets.
 requires the ingredients to be processed until of a
uniform globule or particle size. For most products,
including creams, ointments, sauces, flavoring emulsions
and pharmaceutical suspensions, this requires a globule
or droplet size in the range of 2 – 5 microns.
9. Dryer 12. Filters
A. Hot Air Oven A. Normal Clarification
are electrical devices which use dry B. Sterilization filters
heat to sterilize. They were originally  manufacturer’s
developed by Pasteur.[1] Generally, they certification and bubble
can be operated from 50 to 300 °C, testing
using a thermostat to control the C. HEPA Filters
temperature.  High-efficiency
particulate
arrestance (HEPA) also
sometimes called high-
efficiency particulate
B. Fluid bed dryer arresting or high-
efficiency particulate air,
is a type of air filter.

PH ANAL II TRANSCRIBED BY: MARK HAROLD C. GONZALES 3 of 5

 Pharmaceutical UNIT 10: Validation
Analysis II Dr. Katrina Joy B. Bormate, R.Ph,PhD
AY 2023-2024 10/05/2023
1st Semester
 HEPA filters are composed of a mat of randomly For example, if we specified 316 stainless, we’ll test to verify it is in
arranged fibres. fact 316 stainless. Sometimes stainless steel is passivated and
 HEPA filters are composed of a mat of randomly you can test to verify there are no further residues from the
arranged fibres. passivation process.

OPERATIONAL QUALIFICATION

Operational Qualification (OQ)

 is Essential In Challenging Your Equipment Parameters
 At this stage, if you’ve specified that your equipment is
13. Viscometer going to run in a range of 50-150 RPM and will draw a
 Viscometers measure specific amount of power, you want to verify that the
the viscosity and flow equipment is achieving those operational requirements.
properties of fluids. So, review those parameters and challenge them. Again,
Viscosity arises from the make sure your equipment actually runs the way it’s
internal friction of a fluid supposed to run.
and is defined as a  Objective of operation qualification
liquid’s resistance to flow o is to obtain adequate assurance that the
or shear stress. equipment when operated by the approved
 Viscosity is a very useful SOP’s does perform its assigned limits.
indirect measure of Items covered by Operational Qualification
material properties 1. APPLICABLE SOP’S (ex: operation of equipment,
including molecular sanitation)
weight and density, both of which affect flow behavior. 2. UTILIZATION LIST (ex: product to be sterilized,
 Viscometers can therefore be used to monitor batch temperature)
consistency and quality control. 3. PROCESS DESCRIPTION
a. Rotor Speed vs. Setting 4. KEY PROCESS VARIABLES (ex: heat cycle, cycle
b. Thermometer certification length)
5. TEST FUNCTIONS – the items to be tested are indicated
(ex: cycle timer, air velocity, instrument air, empty
chamber distribution)
6. TEST INSTRUMENTS – indicate instruments used to
conduct test ( pressure gauges, recorder, velocity
FACILITY OR EQUIPMENT VALIDATION meters, etc.) Document serial numbers, calibration
 Is the confirmation that the specified process conditions numbers, calibration dates and any other pertinent
are reliably fulfilled in a given apparatus. information.
 Based on current government regulations, new facility 7. TEST INSTRUMENT CALIBRATION – indicate
construction, and internal policies, validation priorities frequency of any deviations etc.
were established to reflect:
1. STERILE PRODUCTS
2.SOLID DOSAGE FORMS PERFORMANCE QUALIFICATION
3. LIQUID PRODUCTS Performance Qualification (PQ)
4. PACKAGING FACILITIES  Puts Your Equipment To The Final Test
 In the PQ - performance qualification – phase, we like to
The validation program consists of several phases such as: challenge the equipment, much like in the OQ phase, but
* Installation Qualification now under load. While it’s great that it runs at 50 RPM or
* Operational Qualification 150 RPM when it’s empty, what happens when there’s
* Actual Qualification 300 kilos of material in it? Can it still achieve those speed
ranges? That’s the essence and focus of the PQ phase.
INSTALLATION QUALIFICATION Once you’ve completed these three phases, the
equipment is available for use in whatever process you
Installation Qualification (IQ) intended for it.
 Evaluates Means of Accommodating New Equipment 3rd phase validation (Actual Validation) steps:
and Testing Its Materials 1. State objective
The Installation Qualification (IQ) execution; 2. Indicate procedure
 verifies that the equipment, and its ancillary systems or 3. Perform tests
sub-systems have been installed in accordance with 4. Evaluate data and draw conclusions
installation drawings and or specifications.
 It further details a list of all the cGMP requirements that VALIDATION OF EXISTING PRODUCTS
are applicable to this particular installation qualification. Historical data considered appropriate for retention and
 These requirements must all be satisfied before the IQ evaluation:
can be completed and the qualification process is 1. Those data that are directly related to the efficiency of the
allowed to progress to the execution of the (OQ). product, such as:
a) Potency
b) Content uniformity
c) Dissolution ( bioavailability )
PH ANAL II TRANSCRIBED BY: MARK HAROLD C. GONZALES 4 of 5
 Pharmaceutical UNIT 10: Validation
Analysis II Dr. Katrina Joy B. Bormate, R.Ph,PhD
AY 2023-2024 10/05/2023
1st Semester
2. Those data concerned in the processing characteristics, such
as:
a) Moisture content
b) Weight variation

Statistical tools that have been found to be useful in evaluating

historical data are:
1. Graphical presentations
a) Control charts for averages and variability
b) Cumulative difference charts

2. Quantitative techniques
a) Analysis of variance
b) Tolerance limits

CLEANING VALIDATION
Cleaning validation is documented proof that one can
consistently and effectively clean a system or equipment items.
Cleaning validation program consists of 3 phases:
1. Pre-validation – to evaluate the cleaning, sampling and
analytical testing procedures
2. Validation – to establish that the cleaning results are
repeatedly acceptable
3. Re-validation – to ensure continuing validity of the
cleaning procedures

Some approaches to validation of cleaning procedures:

1. PRODUCT LINE
- Which is based on the assumption that the active ingredient is the
most deleterious contaminant and that the mix ratio of active to
excipient residue levels.
2. DETERGENT RESIDUE LEVELS
- Which are assumed to be independent of the product
and are validated by equipment piece and detergent.
 Cleaning SOP’s must exist for every piece of equipment.
 Thin layer chromatography (TLC), High performance
liquid chromatography (HPLC), Ultraviolet
spectrophotometry and Infrared spectroscopy are
suitable for this purpose.

POST VALIDATION
 Post validation efforts are required whenever there is a
change in formulation, processing conditions, analytical
methods, cleaning procedures or materials

REFERENCES
 Dr. Bormate’s PPT
 PH ANAL BOOK

PH ANAL II TRANSCRIBED BY: MARK HAROLD C. GONZALES 5 of 5