Validation

Introduction

Validation

Validation is a concept that has been evolving continuously since its first formal appearance in
the United States in 1978. The concept of validation has expanded through the years to
encompass a wide range of activities from analytical methods used for the quality control of the
drug substances and drug products to computerized systems for clinical trials. Validation is
therefore one element of quality assurance associated with a particular process, as the process
differs so widely, there is no universal approach to validation. Then word validation simply
means, assessment of validity' or action of proving effectiveness. According to European
community for medicinal products, validation is 'action of proving', in accordance with the
principles of Good manufacturing practices that any procedures, process, requirement, material,
activity or system actually leads to expected results.

General Concept

Assurance of product quality is derived from careful attention to number of factors including
selection of quality parts and materials, adequate product and process design, control of the
process, and in process and end product testing. Due to the complexity of today's medical
products, routine end product testing alone often is not sufficient to assure product quality for
several reasons. Some end-products tests have limited sensitivity. e.g. In some cases, where end
product testing does not several all variations that may occur in the product, which may have an
impact on safety and effectiveness, destructive testing is required to show that the manufacturing
process is adequate.

Why validation?

It would not be feasible to use the equipments without knowing whether it will produce the
product we wanted or not.

The pharmaceutical industry uses expensive materials, sophisticated facilities & equipments and
highly qualified personnel.

The efficient use of these resources is necessary for the continued success of the industry. The
cost of product failures, rejects, reworks, and recalls, complaints are the significant parts of the
total production cost.

Detailed study and control of the manufacturing process- validation is necessary if failure to be
reduced ad productivity improved.

The pharmaceutical industries are concerned about validation because of the following reasons.

i) Assurance of quality
ii) Cost reduction
iii) Government regulation

Department responsible

Site validation committee (SVC) - Develop Site master Validation plan,

Prepare/execute/approve validation

Studies Manufacturing department - Prepares the batches as a routine

Production batch Quality assurance - Ensure compliance , see that

Documentations/procedures are in place ,

Approves protocols and reports

Quality control - Perform testing and reviews protocol and report as

needed.

Responsible authorities for validation

The validation working party is convened to define, progress,, coordinate and ultimately,
approve the entire effort, including all of the documentation generated. The working party would
usually include the following staff members, preferably those with a good insight into the
company's operation.

• Head of quality assurance

• Head of engineering

• Validation manager

• Production manager

• Specialist validation discipline (s)-all areas

Department /Designation Responsibility

Manager-Production Responsible for manufacturing of batches and
review of protocol and report.
Manager – QC Responsible for analysis of samples

collected
Executive QC- Responsible for samples collection and

submission to QC
Manager-Maintenance Providing utilities and engineering

support
Executive – Production Responsible for preparation of protocol and
manufacturing of validation batches
Manager –QA Responsible for protocol authorization and
preparation of summary report.

Types Of Validation

Analytical validation

Analytical validation is the evaluation of product quality attributes through testing, to

demonstrate reliability is being maintained throughout the product life cycle and that the
precision, accuracy, strength, purity and specification has not been compromised.

Equipment validation

Validation of equipments is known as qualification. Equipment validation is divided into

installation Qualification (IQ), Operational Qualification (OQ), and Performance Qualification
(PQ).An IQ documents specific static attributes of a facility or item to prove that the installation
of the unit has been correctly performed and that the installation specifications of the
manufacturer have been met. After installation it must be ensured that the equipment can deliver
operating ranges as specified in the purchase order. This is called OQ. The PQ's are concerned
with proving that the process being investigated works as it is supposed to do.

Process validation

Process validation is "A documented program which provides a high degree of assurance that a
specific process will consistently produce a product meeting its predetermined specification and
quality attributes". Process validation is divided into different types as follows.

Ø Prospective validation: is defined as the establishment of documented evidence that a system

does what it purports to do based on pre-planned protocol. This validation is usually carried out
prior to the introduction of new drugs and their manufacturing process.

This approach to validation is normally undertaken whenever a new formula, process or facility
must be validated before routine pharmaceutical formulation commences.

Ø Retrospective validation: is defined as the establishment of documented evidence that a

system does what it purports to do based on review and analysis of historical data. This is
achieved by the review of the historical manufacturing testing data to prove that the process has
always remained in control.

Revalidation
It is the repetition of a validation process or a specific part of it. This is carried out when there is
any change or replacement in formulation, equipment, plant or site location, batch size and in the
case of sequential batches that do not meet product and process specifications.

Design Qualification (DQ)

The design qualification outline the key features of the system designed to address the user
requirement regulatory compliance and selection rationale of a particular supplier. Caution
should be taken when putting together a design qualification since it will have a major impact on
installation, operation and performance qualifications

The following are the key considerations for design qualifications: -

1. Physical dimensions of the equipment and accessories

2. Suitable operating environment of the instrument

3. Health and safety requirement

Installation Qualification (IQ)

Simply IQ means is it correctly installed? It further consist of documented verifications that all
key aspects of equipment are in working condition and have been properly installed in
accordance with manufacturers specification and placed in an environment suitable for its
intended use.

The installation qualification of equipment may include, but not limited to the following
verifications:

Preventive maintenance

Equipment information

Verification of components and equipments

Utilities and environmental conditions

Operational qualification (OQ)

OQ is a series of tests that measure the performance capability of the equipment .OQ focuses on
the equipment, rather than demonstrating performance capabilities relating to producing a
particular product.

Process performance qualification (PQ)

PQ is defined as “the process to verify that the system is repeatable and consistently producing a
quality product” or in other words the “the process to demonstrate that the instrument can fulfill
requirement outlined in the DQ”

Process/Product validation

Validation is establishing documented evidence, which provides a high degree of assurance that
a specific system will consistently produce a product meeting its predetermined specifications
and quality attributes.

Qualification and Process Validation

Phases in Process validation

The activities relating to validation studies may be classified into three:

Phase I:this is the Pre-validation Qualification Phase which covers all activities relating to
product research and development, formulation pilot batch studies, scale-up studies, transfer of
technology to commercial scale batches, establishing stability conditions and storage, and
handling of in-process and finished dosage forms, equipment qualification, installation
qualification master production document, operational qualification and process capacity
Fig. Schematic diagram of processing steps and respective in-process variables during
tablet manufacture

Phase 2:this is the process validation phase. It is designed to verify that all established limits of
the critical process parameter are valid and that satisfactory. Products can be produced even
under the worst conditions.

Phase 3: Known as the validation maintenance Phase, it requires frequent review of all process
related documents, including validation of audit reports, to assure that there have been no
changes, deviations failures and modifications to the production process and that all standard
operating procedures (SOPs), including change control procedures, have been followed. At this
stage, the validation team comprising of individuals representing all major departments also
assures that there have been no changes/deviations that should have resulted in requalification
and revalidation. A careful design and validation of systems and process controls can establish a
high degree of confidence that all lots or batches produced will meet their intended
specifications. It is assumed that throughout manufacturing and control, operations are conducted
in accordance with the principle of good manufacturing practice (GMP) both in general and in
specific reference to sterile product manufacture.

Guide To Inspections Solid Dosage Forms

The objective is to present an overview and to discuss aspects of validation in terms of

Pharmaceutical unit operations, i.e., those individual technical operations that comprise

the various steps involved in product design and evaluation. The key elements that form

the basis of a prospective process validation program is:

 1. Definition of the desirable attributes of the drug product or components thereof as well as
those characteristics that are not desired
2. Establishment of limitations or constants for these attributes
3. Determination of the controls or testing parameters that will be measured or tested
4. Initiation of studies to establish control or boundary limits for those key attributes that
influence the product, process, quality, and performance

There are several important reasons for validating a product and /or process. First, manufacturers
are required by law to confirm to GMP regulations. Second, good business dictates that a
manufacture avoids the possibility of rejected or recalled batches. third, validation helps to
ensure product uniformity, reproducibility, and quality .All pharmaceutical scientists, whether in
development, quality assurance, production.

Process overview

1. Dispensing

i) Check and ensure dispensing booth is clean and line check is given as per current Standard
operating procedure.

ii) Check and ensure that balance is not due for calibration. Check for zero error in the balance.
2.Sifting

i) Check and record the temperature and relative humidity in processing area temperature

ii) should be 25 ±2.0° C & RH 45±5%.

iii)Check and ensure visually all the equipment and equipment parts are cleaned.

iv) Record remarks if any. Check and record the integrity of the sieves before and after sifting
through out the processing activity.

3. Granulation

Control Parameters
Fixed Variable (Monitor) Response (Test)
Equipment Mixing speeds Drug distribution

Amount of granulation Water/ solvent

Fluid feed rate granulation Appearance (size)

Time Load Power consumption

(amp/torque)

i) Add ingredient into vessel then Dissolve.

ii) Add the other ingredients into saizoner and mix of 5 minutes using impeller at slow
speed.
iii) Collect, samples at 3,5 and 7 minutes at 5 different places and subject it to analysis for
uniformity in content.

iv) Add granulating solution and homogenize at slow speed for about 10 minutes.

iv) After granulation is over check the Loss of drying the wet granules.

T1 - Top right

T2- Top left

B3- Bottom left

B4 - Bottom right

M5 – Middle

4. Drying and sizing

Fixed Variable (Monitor) Response (Test)

Bowl charge Inlet/ exhaust air Particle size
temperature distribution
Porosity of filter Product temperature Densities
bags
Bowl sieve Drying time Loss on drying

Air volume Assay (for heat

sensitive materials)
Humidity of incoming air
(dew point)

Humidity of exhaust air

i) Check and ensure the integrity of the Fluidized bed drying bag.
ii) Initially dry the wet granules with air for 10 minutes, Dry the granules are per batch
process report instruction.
iii) Check the Loss of drying of granules; it should not be not more than 1% at 70°C for 15
minutes.
iv) Check and ensure the dried granules are not stored above 25°C before the milling is
started.
v) Check and ensure the integrity of the sieves before and after sieving.
vi) Pass the granules through 16 mm mesh sieve, break the oversize granules using mill
fitted with 2mm screen.
vii) Collect the granules in poly bags, and check for flow properties
viii) Check the weight of sifted and dried granules.

5. Milling

Variable Response

Screen size Particle size distribution

Milling speed Loose/ tapped densities

Feed rate
6.Powder blending

Variable Response

Blending time Content uniformity

Blender speed Assay

Intensifier bar Particle size distribution

Powder flow

7.Lubrications

Variable Response
Blending speed Particle size distribution

Blending time Loose / tapped densities

Method of addition Flow properties

Tabletting characteristics

(Friability, hardness)

i) Perform the pre mixing and final mixing as per Batch process report instruction
ii) During the final mixing before i.e., before adding the remaining quantity of
iii) the lubricant mix for 15 minutes.
iv) Collects sample at 5,10,15 minute's intervals form top, middle, bottom and
v) Composite and subject it to analysis for assay.
vi) After adding the remaining quantity of lubricant mix for 5 minutes.
vii) Collects sample at 3,5,7 minutes interval form top, middle, bottom and
viii) Composite and subject it to analysis for assay and content uniformity.
ix) Check the weight of the final blend and record.

8.Compression

i) Check and ensure the temperature and relative humidity of the compression room is not more
than 25°C and Relative Humidity not more than 50%.

ii) Check and ensure the compression machine is cleaned

iv) Collect 40 tablets and inspect for Appearance, weight, thickness, friability and hardness
every 1 hour.

iv) Tablets weight variation shall be XX mg. hardness shall be (IP) kg/cm2, thickness.

v) Collect 40 tablets by "Bracketign" i.e. by increasing this speed of the compression

machine form the target speed and by reducing from the targeted speed.

vi) Collect 10 tablets during initial, middle and end of the compression process and subjective
it to analysis for content uniformity and perform the assay also.

9. Coating

i) Check and ensure the coating pan and other equipment's are cleaned.

ii) Check and ensure that the tablets is deducted, the speed of the coating pan inlet and
exhaust air temperature, spray rate, spray type, temperature of the coating solution.

iii) After coating is completed, samples are collected for dissolution testing and weight
variation.

10. Labelling and packing

Check and record the temperature air the heating roller and sealing roller Check and record that
the over printing instructions on labels and cartons.

Check and verify that price overprinted on label and carton is as per current price list.

After ensuring the proper labeling of tablets, check, for correctness of cartons packing for the
same.

11.Finished product analysis and release

Finished product needs to be analyzed as per in-house specification product released only
after predetermined specifications and quality attributes. Needs to be released only after pre-
determined specifications
Guide To Inspections Sterile Products

Sterile products have several unique dosage form properties, such as freedom from
microorganism, freedom from pyrogens, freedom from particulates, and extremely high
standards of purity and quality; however the ultimate goal in the manufacture of a sterile product
is absolute absence of microbial contamination. The most obvious limitation is the nature of the
sterility test .It is a destructive test; thus it depends on the statistical selection of a random sample
of the whole lot. If microbial growth is detected in a sterility test, this may reflect a false
positive reading because of the problem of accidental contamination of the culture media while
performing the sterility test. Three principles are involved in the validation process for sterile
product:

1. To build sterility into a product

2. To demonstrate to a certain maximum level of probability that the processing and sterilization
methods have established sterility to all units of a product batch

3. To provide greater assurance and support of the end product sterility test.

Steam sterilization validation

In steam sterilization validation, we care mainly concerned with autoclaving. Before discussing
all this lets discuss some important terms, which are repeatedly used in such discussion. These
are D value value &F values.

D-Value or decimal point reduction time

It is used to express the rate of killing of microorganisms during sterilization.

The death of microbes during sterilization follows first order kinetics. That is regardless of the
type of treatment given i.e. whether heat, chemical or radiation, microbes die according to a
logarithmic relationship between concentration or population of living cells the time of exposure
or radiation dose. So the term „D‟ refers to the time or dose required to reduce the microbial
population by one decimal point or for 90% reduction or one log reduction under a given set of
conditions

Importance of D-value

It is a specific kinetic expression for each microorganism in a specific environment subjected to

specific sterilization agent on condition.

D- value can be used to calculate Z value.

D- value can also be used to calculate biological F value.

Factors affecting D value

Type of microorganism used as biological indicator

Formulation components &characteristics like pH

Surface on which microorganism is exposed like glass, steel, plastic, rubber etc.

Temperature, gas concentration, or radiation dose during sterilization

2) Z value

In heat sterilization, D value only refers to the resistance of m-gm at a particulate. Z value refers
to the influence of temperature changes on resistance of m -gm to heat.Z value can be defined as
the increase in temperature required decreasing the D-value of an organism up to 10th fold or by
90%(1 log cycle reduction)

Mathematically value can be expressed as

Z= T2-T1

------------------------

Log D1-logD2

3) F value

F value is a unit of lethality used to compare the relative sterilizing capacities of different heat
processes.F value is a measure of total process lethality It indicates the equivalent amount of
time delivered by a heat process at a particular temperature i.e. a reference temperature & a
specific z- value .

4) F0Value

F0 value is nothing; just the F value when Z is 100 C & T is 1210 C

So, the equation becomes

This term has a great application in steam sterilization.

Steam Sterilization by autoclaving

Here we are mainly concerned with autoclaving.

General considerations: -

The main term or expression used here is F valueThe time period used in this equation is not the
clock time units. But F0 time is a complete summary or summation of the time spent by
Biological Indicator during entire cycle at a temperature of 121.1C a fraction of times spent at
temperature below 121.1C. A multiple of times spent at temperature above 121.1c.

Qualification &Calibrations

Mechanical checking, upgrading qualifying the sterilization unit.

Autoclave should be checked for quality, dependability, proper installation, lack

of contamination etc. The main concern is steam. So the temperature &pressure instruments used
to study autoclave must be calibrated.

Selection &calibrations of thermocouples

Thermocouple is used, as temperature indications in autoclave therefore must be durable for

repeated use. Accuracy of the thermocouple should be ±0.5c.An error of just0.1c in temperature
measurement might produce a 2.3% error in F value. Thermocouple should be calibrated before
&after validation experiment. New devices are available now which can automatically correct
the temperature or slight errors in thermocouple calibration

Selection & Calibrations of Biological Indicator

Most heat resistant bacterial spores, B. Stearothermophilus is used as biotin so as to assume that
a minimum F value has been achieved in coolest location of autoclave load. Proper storage
conditions should be provided for biological indicators. Freeze storing provides a more stable
resistant profile for biological indicators shelf life.

Heat Distribution Studies:

Heat distribution studies can be carried out

In empty autoclave chamber.

In loaded autoclave chamber.

Teflon tape should be used to secure thermocouples. Two thermocouples are taken as references.
One is placed in ice-bath and other in increase temperature oil bath during each cycle. The main
concern is to identify the coolest spot and the effect of load size and configuration on cool spot
location. Difference in temperature between coolest spot and mean chamber temperature should
not be more than ± 2.5°C.

Heat Penetration Studies:

This is the most critical step of the whole validation process. Determination of Fvalue of cold
spot is very important. The cold spot for containers ³100ml is determined using container
mapping studies. Thermocouple probes are inserted within a container. The cycle is repeated to
establish the coldest point. Minimum and Maximum loading configurations should be studied.
Thermocouples are placed both inside and outside the container at the cool spot, in steam exhaust
line and in constant temperature bath outside the chamber. F0 value at cool spot is calculated.
After attaining the desired temperature, the cycles are repeated until the user is satisfied with the
aspects of validation. F=8 is the realistic minimum value. The sterilization cycle design must be
based on heating characteristics of load and of containers located in lowest heating zone of load.
The variation in heating rate of slowest heating zone must be determined under full load .The
effect of load to load variation on temperature-time profiles must be determined.

Finally a monitoring program is established to ensure that validated cycle remains unchanged in
future. For this purpose, thermocouples are used to measure heat penetration at cool spots and it
is verified that designed F value has been attained.

If there is any change in load size, load configuration or container characteristics, repeated
validation studies must be carried out to prove that cool spot has not changed. If it has changed,
it must be confirmed that it receives the designed F time exposure from sterilization cycle use.

References

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