Patel Hiren Popatbhai et al. / Int. Res J Pharm. App Sci.

, 2012; 2(4): 1-16 ISSN-2277-4149

International Research Journal of Pharmaceutical and Applied Sciences

Available online at www.irjpas.com
Int. Res J Pharm. App Sci., 2012; 2(4):1-16

Research Article

Process Validation of Benazepril HCl 5 mg Tablet

2
Patel Hiren Popatbhai1, Shrivastava AK , Jindal Dinesh 3
1
Department of Quality Assurance, Nims Institute of Pharmacy, Nims University, Jaipur, India.
2
Department of Quality Assurance, Nims Institute of Pharmacy, Nims University, Jaipur, India.
3
Department of Pharmaceutical Chemistry, Nims Institute of Pharmacy, Nims University, Jaipur, India.
(Received: 08 July, 2012; Accepted: 10 August, 2012; Published: 29 August, 2012)
*Corresponding Author: Email: [email protected]

ABSTRACT
The purpose of research was to study prospective process validation Benazepril HCl 5 mg tablet dosage
formulation. The critical process parameter was identified with the help of process capability
and evaluated by challenging its lower & upper release specification. O n e initial process validation
batches size, method, equipment & validation criteria were taken. The critical parameter involved in
sifting, Blending ,compression stages were identified and evaluated as per validation master plan. The
outcome indicated that this process validation data provides high degree of assurance that
manufacturing process produces product meeting its predetermined specifications and quality attributes.
Key words: process validation parameters, Quality assurance, Tablet dosage form.

INTRODUCTION

According to Indian GMP vali dati on study is high degree of assurance that a specific process (such
essential part of GMP. Those required to be done as the manufacturing of pharmaceutical dosage
as per predetermined protocols. Prospective process forms) will consistently produce a product meeting
validation is carried out during the development its predetermined specifications and quality
stage by means of risk analysis of the production characteristics.”
process which is broken down into individual As per USFDA (2008) “Process validation is the
steps1. Validation is a concept that has been evolving collection and evaluation of data, from the process
continuously since its first formal appearance in the design stage throughout the production, which
United States in 1978. Validation as it is known today establish scientific evidence that a process is capable
has developed from the need to maintain quality, of consistently delivering quality products.”
consistency, and above all public safety. Validation is The definition is very well thought out and each word
a rapidly growing and evolving concept. This has a special significance
evolution stems from technology’s growth rate. It is
responsible for providing higher degree of assurance Principle Elements of Validation:
for the product. The foundation of validation, the Documented Evidence:
methodology behind validation, and the need for Validation requires a through documentation
validation will likely remain a key aspect of the everything that is not documented is considered
industry. The present project reflects the current incomplete.
trends and serves as an educational tool in our High degree of Assurance:
progressive industry. Validation is the confirmation The assurance is that a large software package as
by examination and the provision of objective used in complex computerized systems is rarely free
evidence that the particular requirements for a of errors. Frequently there is a perception that
specific intended use are fulfilled. validation means “error free”. This assumption is
wrong. During the validation process everything
Definition of Validation1-3 realistically possible should be done to reduce errors
As per ISO 17025 Validation is the confirmation by to a high degree.
examination and the provision of objective evidence Specific process:
that the particular requirements for a specific Same subparts of validation such as qualification.
intended use are fulfilled. (Installation, Operation, Performance) are product
As per USFDA (1987) “Process validation is specific and have to be done for each system.
establishing documented evidence which provides a Consistently:

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Validation is not a one-time event. The performance

of equipment has to be controlled during the entire Benefits of Validation:
life of product. Reduction of Quality Cost:
Predetermined Specifications: Through proper validation, the cost of the following
Validation activities start with the definition of process can be optimized.
specifications. The performance of equipment is then 1) Preventive costs are costs incurred in order to
verified against these specifications. Acceptance prevent failures and reduce appraisal costs
Criteria must be defined prior to testing. 2) Appraisal costs of inspection, testing and
quality evaluation.
Reasons for Validation4 3) Internal failure costs
The three basic and most important reasons for 4) External failure costs that associated with a
validation are quality assurance, non-conformance condition after the product
has left the company’s ownership.
Quality assurance:
Product quality cannot be assured for a process by Process Optimization:
routine quality control testing because of the The optimization of the facility, equipment system
limitation of statistical sampling and the limited and closures etc. results in a product that meets
sensitivity of finished product testing. Quality quality requirements at the lowest costs. Trained,
variations among units within a batch or among qualified people are the key elements in process
different batches are seldom detected by testing of optimization that results in improving efficiency and
finished product samples. Validation changes the productivity.
adequacy and reliability of a system or process to
meet predetermined criteria. Assurance of Quality:
Validation and process control are the heart of
Economics: GMPs. Without Validated and controlled process it is
The direct economic benefit of validation is a impossible to achieve quality products. Hence
reduction in the cost associated with process validation is a key element in assuring the quality of
monitoring, sampling and testing. Analysis of the product.
multiple samples would not be required in order to
slow homogeneity for a validated blending process. Safety:
The consistency and reliability of a validated process Validation can also result in increased operator
to produce a quality product provide direct cost safety. Properly calibrated, validated instruments and
savings resulting from a decrease or elimination of gauges used to reduce accident and results in safety.
product rejections, reworks and retesting. Final Better Customer Quality:
release of the batch would be expedited and freed of Through Proper validation, Market recall is avoided
delays and complications caused by lengthy which result in better customer care and quality of the
investigations of process, or analytical related product.
variances. In addition product quality complaints and
potential product recalls would be minimized. Elements of Validation5, 6

Compliance: Design Qualification (DQ):

GMP requires that written procedures and process It is documented review of the design, at an
controls be established to assure that the drug appropriate stage of stages in the project, for
products have the “identity, strength, quality and conformance to operational and regulatory
purity they purport or are represented to possess.” expectations.
1. GMPs and regulatory requirements
Regulatory Requirements: 2. Performance criteria
Fourth, and certainly foremost, among the reasons for 3. Facility air flow, movement flow &
validation is that it is a regulatory requirement for pressure regimes
virtually every process in the global health care 4. Reliability& efficiency
industry-for pharmaceuticals, biologics, and medical 5. Commissioning requirements
devices. Regulatory agencies across the world expect 6.Construct ability & installation of equipment
firms to validate their processes. The continuing 7. Maintenance& access to critical equipment
trend toward harmonization of requirements will & instrumentation
eventually result in a common level of expectation 8. Safety& environment impact
for validations worldwide. Utility for validation
beyond compliance is certainly available. The Installation Qualification (IQ):
emphasis placed on compliance as a rationale has It is documented verification that all aspects of a
reduced the visibility of the other advantages a firm facility, utility or equipment that can affect product
gleans from having a sound validation program.

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quality adhere to approved specifications and are manufacturing process from the development
correctly installed. Important IQ considerations are: function to production.
1. Installation conditions (wiring, utilities, Prospective validation includes those considerations
and functionality) that should be made before an entirely new product is
2. Calibration, preventative maintenance, introduced by a firm or when there is a change in the
cleaning schedules manufacturing process which may affect the
3. Safety features product's characteristics, such as uniformity and
4. Supplier documentation, prints, drawings identity.
and manuals The following are considered as key elements of
5. Software documentation prospective validation.
6. Spare parts list
7. Environmental conditions (such as clean Equipment and Process
room requirements, temperature and a. Equipment: Installation Qualification
Humidity) b. Process: Performance Qualification
8. Equipment design features (i.e. materials c. Product: Performance Qualification:
of construction clean ability)
Retrospective Validation
Operational Qualification (OQ): Retrospective Validation involves the examination of
It is documented verification that all aspects of a past experience of production on the assumption that
facility, utility or equipment that can affect product composition, procedures, and equipment remain
quality operate to Intend throughout all anticipated unchanged; such experience and the results of in-
ranges. OQ considerations include: process and final control tests are then evaluated.
1. Process control limits (time, temperature, Recorded difficulties and failures in production are
pressure, line speed and setup conditions) analyzed to determine the limits of process
2. Software parameters parameters. Retrospective validation is obviously not
3. Raw material specifications a quality assurance measure in itself, and should
4. Process operating procedures never be applied to new processes or products. It may
5. Material handling requirements be considered in special circumstances only, e.g.
6. Process change control when validation requirements are first introduced in a
7. Training company. Retrospective validation may then be
8. Short term stability and capability of the useful in establishing the priorities for the validation
process. program. If the results of a retrospective validation
9. Potential failure modes, action levels and are positive, this indicates that the process is not in
worst-case conditions. need of immediate attention and may be validated in
accordance with the normal schedule. For tablets
Performance Qualification (PQ): which have been compressed under individual
It is documented verification that all aspects of a pressure-sensitive cells, and with qualified
facility, utility or equipment perform as intended in equipment, retrospective validation is the most
meeting predetermined acceptance criteria. comprehensive test of the overall manufacturing
PQ considerations include: process of this dosage form.
1. Actual product and process parameters
and procedures established in OQ Using either data-based computer systems or manual
2. Acceptability of the product methods, retrospective validation may be conducted
3. Assurance of process capability as in the following manner:
established in OQ 1. Gather the numerical data from the
4. Process repeatability, long term process completed batch record and include
stability assay values, End product test
results and in-process data.
Types of Validation7 2. Organize these data in a
Prospective Validation chronological sequence according to
Establishing documented evidence prior to process batch manufacturing data, using a
implementation that a system does what it proposed spread sheet format.
to do based on preplanned protocols. This approach 3. Include data from at least the last
to validation is normally undertaken whenever the 20–30 manufactured batches for
process for a new formula (or within a new facility) analysis. If the number of batches is
must be validated before routine pharmaceutical less than 20, then include all
production commences. This is a preplanned manufactured batches and commit
scientific approach and includes initial stages of to obtain the required number for
equipment validation. In fact, validation of a process analysis.
by this approach often leads to transfer of the

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4. Trim the data by eliminating test Revalidation

results from noncritical processing Revalidation means repeating the original validation
steps and delete all gratuitous effort or any part of it, and includes investigative
numerical information. review of existing performance data. This approach is
5. Subject the resultant data to essential to maintain the validated status of the plant,
statistical analysis and evaluation. equipment, manufacturing processes and computer
6. Draw conclusions as to the state of systems. Possible reasons for starting the revalidation
control of the manufacturing process include:
process based on the analysis of  The transfer of a product from one
retrospective validation data. plant to another
7. Issue a report of your findings  Changes to the product, the plant,
(documented evidence). the manufacturing process, the
cleaning process, or other changes
Concurrent Validation: that could affect product quality
It is establishing documented evidence that a process  The necessity of periodic checking
does what it purports to do, based On information of the validation results
generated during actual implementation of the  Significant (usually order of
process. It may be Practical Approach under certain magnitude) increase or decrease in
circumstances. Examples of these may be as follows batch size.
 When a previously validated  Sequential batches that fail to meet
process is being transferred to a product and process specifications.
third party contract manufacturer or  The scope of revalidation
to another manufacturing site procedures depends on the extent
 Where product is a different of the changes and the effect upon
strength of a previously validated the product.
product with same ratio of active  Changes in source of active Raw
ingredients. material Manufacturers
 When number of lots evaluated  Changes in Raw Materials
under retrospective validation was  Changes in Packaging Materials
not sufficient to obtain a high  Changes in process e.g. Mixing
degree of assurance demonstrating Time, Drying Temperature, and
that process is fully under control. Batch Size etc.
 Changes in Equipment
 Changes in Plant Facility

RESULTS AND DISCUSSION

Formulation

Ingredients Use of Quantity required/ Quantity

Ingredients Tablet (mg) required/Batch (mg)
Blending
Benazepril Hydrochloride Active Ingredient 5.000 1.000
Lactose monohydrate Diluent 149.000 29.800
Microcrystalline Cellulose Diluent 25.000 5.000
Pregelatinised Starch Disintegrating agent 5.000 1.000
Crospovidone Disintegrating agent 3.000 0.600
Colloidal Hydrated Glidant 8.000 1.600
Silica Syloid 244 FP
Lubrication
Talc Glidant 2.000 0.400
Hydrogenated Castor Oil Lubricant 5.000 1.000
Film Coating
Hypromellose E5 Film former, 3.600 0.936
polymer
Polysorbate 80 Plasticizer 0.600 0.156
Titanium dioxide Opacifier, 0.900 0.234
Pigment

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Talc Glidant 0.870 0.226

Ferric oxide yellow Pigment 0.030 7.800 g
Purified Water Solvent q.s 14.000
TOTAL 208.000 -----

BLENDING

Tests Results Acceptance criteria

After adding Co-Sifted Benazepril Hydrochloride (DMF), Lactose Monohydrate (DCL 11),
Microcrystalline Cellulose (Avicel PH 112), Pregelatinised Starch (Starch 1500), Crospovidone
(PolyplasdoneXL-10), Colloidal Hydrated Silica Syloid 244 FP
RPM of blender 16 16 ± 1 RPM
Mixing time 20 minutes 20 minutes
After adding Co-Sifted Talc & Hydrogenated Castor Oil
RPM of blender 16 16 ± 1 RPM
Mixing time 5 minutes 5 minutes
Sieve analysis
Above 30 # 0.00 % To be recorded
Above 40 # 0.00 % To be recorded
Above 60 # 1.45 % To be recorded
Above 100 # 18.95 % To be recorded
Untapped BD 0.59 g/ml To be recorded
Tapped BD 0.78 g/ml To be recorded

Blending stage yield reconciliation

% Yield of blend (Practical) 100.04 % To be recorded

Compression Process
various parameters like description, average weight,
The blend obtained was run on the 55 station DR uniformity of weight, thickness, hardness, friability,
compression machine. The Speed of compression in disintegration time and dissolution to assure the
RPM was optimized and the tablets was tested for reproducibility of the compressed tablets.

Observations Description
8.0 mm , standard concave, Round 8.0 mm , standard concave, Round
Upper punch
embossed with ‘5’ embossed with ‘5’
8.0 mm , standard concave, Round
Lower punch 8.0 mm , standard concave, Round Plain
Plain
Dies 8.0 mm, round 8.0 mm, round
Tooling B Type B Type
No. of Upper
55 To be recorded
punches
No. of lower
55 To be recorded
punches
No. of dies 55 To be recorded
Compression
CPD IV 55 B (Cadmach) To be recorded
machine

Machine speed challenge study

Following table represent the summarized details of process parameters for machine speed challenge

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Process parameters

Parameters Observations Acceptance Criteria

Minimum speed challenge:
Machine speed 12 RPM To be recorded
in RPM
Description White, round, biconvex uncoated tablets White to off white, round, biconvex uncoated
debossed with ‘5’ on one side and plain on tablets debossed with ‘5’ on one side and plain
other side. on other side.

Average weight LHS: 200.2 202.0 mg ± 5.0% (191.9 mg to 212.1 mg)

( in mg)
RHS: 199.5
Uniformity of LHS RHS 202.0 mg ± 7.5% (186.9 mg to 217.1 mg)
weight (in mg) Min. : 197.8 196.4
Max.: 202.6 201.6

Breaking force LHS RHS 25N-150N( Target 110N)

(Hardness) Min. : 85 73
Max.: 104 106

Thickness ( mm) LHS RHS 3.80 mm ±0.20 mm (3.60 mm to 4.00 mm)

Min. : 3.69 3.68
Max.: 3.72 3.73

Friability LHS RHS NMT 1.0 % w/w (Weight: around 6.5 g)

(% w/w)
0.01% NIL

Disintegration LHS RHS NMT 15 minutes

time (minutes) Min. : 1’20” 1’25”
Max.: 1’40” 1’40”

Uniformity of The acceptance value of the first 10 tablets The acceptance value of the first 10 tablets
dosage units should be 3.3 should be less than or equal to 15.0. If the
(by content acceptance value is greater than 15.0, test next
uniformity) 20 tablets and calculate the acceptance value.
The final acceptance value of the 30 tablets
should be less than or equal to 15.0 and no
individual content of the dosage unit should be
less than (1-25.0x0.01)M or more than
(1+25.0x0.01)M.

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Machine speed challenge study

Observations
Parameters Maximum speed challenge: Acceptance Criteria
Machine speed in
60 RPM To be recorded
RPM
White, round, biconvex uncoated tablets
debossed with ‘5’ on one side and plain on White to off white, round, biconvex
Description other side. uncoated tablets debossed with ‘5’ on one
side and plain on other side.

LHS: 201.3
Average weight
202.0 mg ± 5.0% (191.9 mg to 212.1 mg)
( in mg)
RHS: 200.4
LHS RHS
Uniformity of
Min. : 198.7 198.0 202.0 mg ± 7.5% (186.9 mg to 217.1 mg)
weight (in mg)
Max.: 204.6 203.0
LHS RHS
Breaking force 25N-150N( Target 110N)*
Min. : 93 92
(Hardness)
Max.: 120 106
LHS RHS
3.80 mm ±0.20 mm (3.60 mm to 4.00
Thickness ( mm) Min. : 3.67 3.67
mm)*
Max.: 3.80 3.81

LHS RHS
Friability
NMT 1.0 % w/w (Weight: around 6.5 g)
(% w/w)
NIL 0.02%

LHS RHS
Disintegration
Min. : 1’17” 1’27” NMT 15 minutes
time (minutes)
Max.: 1’39” 1’40”

Uniformity of The acceptance value of the first 10 tablets

The acceptance value of the first 10
dosage units should be 3.3
tablets should be less than or equal to
(by content
15.0. If the acceptance value is greater
uniformity)
than 15.0, test next 20 tablets and
calculate the acceptance value. The final
acceptance value of the 30 tablets should
be less than or equal to 15.0 and no
individual content of the dosage unit
should be less than (1-25.0x0.01)M or
more than (1+25.0x0.01)M.

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Hardness challenge study

Following table represent the summarized details of process parameters for machine speed challenge

Process parameters
Observations
Parameters Acceptance Criteria
Minimum Hardness challenge:
Machine speed in
30 RPM To be recorded
RPM

White, round, biconvex uncoated

White to off white, round, biconvex uncoated
tablets debossed with ‘5’ on one
Description tablets debossed with ‘5’ on one side and plain
side and plain on other side.
on other side.

LHS RHS
Average weight
202.0 mg ± 5.0% (191.9 mg to 212.1 mg)
( in mg)
199.6 201.4

LHS RHS
Uniformity of
Min. : 197.2 199.5 202.0 mg ± 7.5% (186.9 mg to 217.1 mg)
weight (in mg)
Max.: 201.8 205.1
LHS RHS
Breaking force 25N-150N( Target 110N)*
Min. : 31 32
(Hardness)
Max.: 40 41
LHS RHS
Thickness (
Min. : 3.98 3.99 3.80 mm ±0.20 mm (3.60 mm to 4.00 mm)*
mm)
Max.: 4.02 4.03

Friability LHS RHS

NMT 1.0 % w/w (Weight: around 6.5 g)
(% w/w) 0.20 % 0.12 %

LHS RHS
Disintegration
Min. : 0’17” 0’14” NMT 15 minutes
time (minutes)
Max.: 0’21” 0’23”

Min. : 86 %
Dissolution Max.: 91 % Not less than 80% (Q) in 30 minutes.
Avg.: 88 %

Hardness challenge study

Observation
Parameters Maximum Hardness challenge: Acceptance Criteria

Machine speed
30 RPM To be recorded
in RPM

White, round, biconvex uncoated White to off white, round, biconvex uncoated
Description tablets debossed with ‘5’ on one side tablets debossed with ‘5’ on one side and plain
and plain on other side. on other side.

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Average LHS RHS

weight 202.0 mg ± 5.0% (191.9 mg to 212.1 mg)
( in mg) 200.1 204.1
LHS RHS
Uniformity of
Min. : 196.6 200.1 202.0 mg ± 7.5% (186.9 mg to 217.1 mg)
weight (in mg)
Max.: 202.8 208.2
LHS RHS
Breaking force 25N-150N( Target 110N)*
Min. : 133 148
(Hardness)
Max.: 164 167
LHS RHS
Thickness (
Min. : 3.55 3.59 3.80 mm ±0.20 mm (3.60 mm to 4.00 mm)*
mm)
Max.: 3.61 3.65

Friability LHS RHS

NMT 1.0 % w/w (Weight: around 6.5 g)
(% w/w) 0.04 % 0.03 %

LHS RHS
Disintegration
Min. : 4’17” 4’20” NMT 15 minutes
time (minutes)
Max.: 4’49” 4’47”

Min. : 87 %
Dissolution Max.: 96 % Not less than 80% (Q) in 30 minutes.
Avg.: 91 %

DIFFERENT STAGES OF THE COMPRESSION PROCESS

Following table represent the summarized details of process parameter for different stages of compression
process in the manufacturing of Pre- Process validation batches.

Parameters Observations
Acceptance
Initial stage Middle stage End stage Criteria
Machine
speed in 30 RPM 30 RPM 30 RPM To be recorded
RPM White to off
white, round,
White, round, White, round, biconvex White, round, biconvex biconvex
biconvex uncoated uncoated tablets uncoated tablets uncoated
Description tablets debossed with debossed with ‘5’ on debossed with ‘5’ on tablets
‘5’ on one side and one side and plain on one side and plain on debossed with
plain on other side. other side. other side. ‘5’ on one side
and plain on
other
202.0 side.
mg ±
Average
LHS RHS LHS RHS LHS RHS 5.0% (191.9
weight
203.3 200.8 202.5 203.3 201.0 202.6 mg to 212.1
( in mg)
mg)
202.0 mg ±
Uniformity of LHS RHS LHS RHS LHS RHS
7.5% (186.9
weight (in Min.: 146.5 196.5 Min.:198.3 199.1 Min: 193.0 197.9
mg to 217.1
mg) Max. 206.6 206.7 Max.:206.7 206.2 Max: 204.7 205.6
mg)

LHS RHS LHS RHS LHS RHS 25N-150N(

Hardness (N) Min. : 93 85 Min. : 103 105 Min. : 75 68 Target 110N)*
Max.: 130 109 Max.: 119 130 Max.: 94 90

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LHS RHS LHS RHS LHS RHS 3.80 mm ±0.20

Thickness
Min. : 3.66 3.69 Min. : 3.70 3.69 Min: 3.66 3.74 mm (3.60 mm
( mm)
Max.: 3.74 3.78 Max.: 3.79 3.75 Max:3.72 3.78 to 4.00 mm)*
Disintegration LHS RHS LHS RHS LHS RHS
NMT 15
time Min. :1’30” 1’26” Min. :1’30” 1’26” Min:1’27” 1’30”
minutes
(minutes) Max.:1’44” 1’40” Max.:1’44” 1’40” Max:1’40” 1’40”
NMT 1.0 %
Friability LHS RHS LHS RHS LHS RHS
w/w (Weight:
( % w/w) 0.02% NIL NIL NIL NIL NIL
around 6.5 g)

Min. : 93 % Min. : 88 % Min. : 91 % Not less than

Dissolution
Max.: 95 % Max.: 95 % Max.: 96 % 80% (Q) in 30
(%)
Avg.: 94 % Avg.: 91 % Avg.: 95 % minute

compression stage yield reconciliation

% Yield of 92.64 % To be recorded
compression
(Practical)

COMPOSITE SAMPLE AFTER COMPLETION OF COMPRESSION PROCESS:

Following table represent the summarized results of composite sample analysis.

Parameters Observations Acceptance Criteria

White, round, biconvex uncoated tablets White to off white, round, biconvex
Description debossed with ‘5’ on one side and plain uncoated tablets debossed with ‘5’ on
on other side. one side and plain on other side.

Average weight 202.0 mg ± 5.0% (191.9 mg to 212.1

201.8
( in mg) mg)
Friability
NIL NMT 1.0 % w/w (Weight: around 6.5 g)
( % w/w)

Tablet breaking force Min: 63

Max: 78 25 N to 150 N
Hardness (N)*

The acceptance value of the first 10

Uniformity of dosage tablets should be less than or equal to
units (by content The acceptance value of the first 10
15.0. If the acceptance value is greater
uniformity) tablets should be 5.3
than 15.0, test next 20 tablets and
calculate the acceptance value. The final
acceptance value of the 30 tablets
should be less than or equal to 15.0 and
no individual content of the dosage unit
should be less than (1-25.0x0.01)M or
more than (1+25.0x0.01)M.

Assay 100.1% 95.0% to 105.0% of label claim

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COATING
Coating solution preparation

Following table represent the summarized details of process parameter for samples of coating solution in the
manufacturing of Pre-Process validation batches.

Parameters Observations Acceptance Criteria

Initial After 48 hrs

Stirring time 10 Minutes 10 Minutes To be recorded

Light yellow viscous Light yellow viscous

Description To be recorded
solution solution

Viscosity 102 cp 105 cp To be recorded

Weight/mL 0.92 g/ml 0.94 g/ml To be recorded

TAMC: 60 CFU/g TAMC: 45 CFU/g

Bioburden TYMC: <10 CFU/g TYMC: < 10 CFU/g To be recorded

Coating stage
Following table represent the summarized details of process parameter for coating stage in the manufacturing of
Pre-Process validation batches.

Parameters Observations Acceptance criteria

No.of Guns@ 2 2
Inlet air temperature@ Min: 62.5 C Max: 65.0 C 60 C + 5 C
Exhaust air temperature@ 40 C 40 C + 5 C

Product bed temperature@ Min: 36.5 C Max: 40 C 35 C + 5 C

Atomizing air pressure@ 0.4 Mpa 0.4 + 0.1 Mpa

Pan RPM@ Min: 1.3 Max: 3.5 3.0 – 14.0
Peristaltic pump RPM@ Min: 6 Max: 8 To be recorded
Min: 78.1 ml/min. Max: 104.8 To be recorded
Spray rate of solution@
ml/min.
Coating Time 1 hr 29 minute To be recorded
Gun to bed distance 8” 6-10’’
Qty. of Coating solution
22.32 kg To be recorded
consumed
Target Coat weight build up 3.04 %
Approx. 2.97% (1.97% to
3.97% w/w)
Description Light yellow colored, round biconvex, Light yellow colored, round
film coated tablets debossed with biconvex, film coated tablets
‘5’on one side and plain on other side. debossed with ‘5’on one side
and plain on other side.

208.0 mg + 5%
Average Weight in mg. 208.32
(197.6 mg to 218.4 mg).

Yield (%) of Coated Tablets 100 % To be recorded

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FINISHED PRODUCT ANALYSIS

Tests Observations Acceptance Criteria

Light yellow colored, round Light yellow colored, round biconvex,
biconvex, film coated tablets film coated tablets debossed with ‘5’on
Description
debossed with ‘5’on one side and one side and plain on other side.
plain on other side.
Average weight of 208.0 mg + 5%
208.8
tablets (mg) (197.6 mg to 218.4 mg).
A) By TLC: The Rf value of the A) By TLC: The Rf value of the principle
principle spot obtained from the spot obtained from the test solution under
test solution under test corresponds test corresponds to that obtained from the
to that obtained from the standard standard solution.
solution. B) By HPLC: The retention time of the
B) By HPLC: The retention time of major peak in the chromatogram of the
Identification
the major peak in the assay preparation should correspond to
chromatogram of the assay that in the chromatogram of the standard
preparation should correspond to preparation as obtained in the assay.
that in the chromatogram of the
standard preparation as obtained in
the assay.
Tablet breaking force
(Hardness) 110 25 to 150 N

Loss on drying 1.2 % Not more than 5.0%

Uniformity of dosage The acceptance value of the first 10
units (By Content tablets should be less than or equal The acceptance value of the first 10
Uniformity) to 4.4 tablets should be less than or equal to
15.0. If the acceptance value is greater
than 15.0, test next 20 tablets and
calculate the acceptance value. The final
acceptance value of the 30 tablets should
be less than or equal to 15.0 and no
individual content of the dosage unit
should be less than (1-25.0x0.01)M or
more than (1+25.0x0.01)M.

Dissolution Min. : 95 % Not less than 80% (Q) in 30 minutes.

Max. : 101 %
Mean.: 98 %

Assay (By HPLC) 101.3 % 95.0 % to 105.0% of label claim.

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Tests Observations Acceptance Criteria

Microbial examination
A) Microbial enumeration
tests 2.5 CFU/g Not more than 103 cfu /g
i) Total Aerobic microbial
count
ii) Total combined Less than 10 CFU/g
Yeasts / Moulds Not more than 102 cfu /g
count Absent
B) Test for specified
microorganism Should be absent
i) Escherichia coli

Related compound
(By HPLC)
Related compound E Below Quantification limit
Related compound F ND Not more than 1.0%
Related compound C 0.07 %
Related compound B 0.06 % Not more than 1.0%
Related compound D Below Quantification limit Not more than 3.0%
0.1% Not more than 1.0%
Related compound G Not more than 1.0%
Single maximum unknown 0.07 %
impurity Not more than 1.0%
Total impurities 0.3 %
(Excluding Related Not more than 0.2%
compound C)
Not more than 2.0%

Residual solvents** Meet USP <467> Meet USP <467> option-1 requirements.

Table.1 Process Variables

Processing Equipment Process Variables Quality Attributes

Stage
Sifting Vibro sifter Sieve Size Particle size

Blending Blender Load Untapped Bulk Density

Mixing time
Mixing Speed
Compression Compression Machine Compression Speed  Description
Compression Force  Average Wt. of 20 tablets
 Uniformity of Wt.
 Hardness
 Thickness
 Disintegration time
 Friability
 Dissolution
 Uniformity of dosage units (By
content Uniformity)
 Assay

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Coating Stirrer Time  Description

Solution Stirrer speed  Viscosity
 Weight/ml
 Bio burden
Coating Auto Coater  Coating  Description
 Pan load (kg)  Average Wt. of 20 tablets
 No. of guns  LOD
 Distance of  Uniformity of weight
guns from bed
pan speed
 Peristaltic pump
speed
 Inlet air
temperature
 Exhaust air
temperature
 Atomization air
pressure
 Tablet bed
temperature
 Coating time
 Coating
solution

Figure.1 sampling location from Blender Bin after Blending

T
T T

M M
2

B2
B1

D1

SUMMARY

Process validation is a fundamental concept of batch size 200,000 Tablets and same manufacturing
cGMP. Benazepril Hydrochloride 5 mg used in process and formula. The entire manufacturing and
treatment of hypertension. The main objective of sampling procedure was done with the approved
presented work was to carry out Prospective Pre- validation protocol and sampling plan. The Critical
process validation of one batch of having same process parameters was studied for validation of

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one batch were validation of Sifting, blending & pressure, peristaltic pump speed, coating time and
lubrication, compression, film coating and finished spray rate. After completion of coating, coated
product testing was done. tablet were tested for various parameters like
description, average weight, uniformity of weight,
Validation of sifting process disintegration time, and % LOD to assure the
The Vibrosifter 36” & Vibrosifter 20” was used for reproducibility of the coated tablets.
the process set with different process parameters  Speed of pan: 1.3 – 3.5 RPM (Limit: 3.0 –
such as Particle size, sieve size. Sifting process was 14.0 RPM)
carried out as per BPCR and 40# sieves used. And  Inlet air temperature: 62.5ºC – 65.0ºC
observe that No Materials should be retained. (Limit: 60ºC + 5 ºC)
 Exhaust air temperature: 40ºC (Limit:
Validation of Blending 40ºC + 5 ºC)
The lubrication was done in cage bin by adding the  Product bed temperature: 36.5ºC – 40ºC
lubricants and blending it at 16 RPM for 20 (Limit: 35ºC + 5 ºC)
minutes followed by 5 minutes after addition of  Peristaltic pump speed: 6 - 8 RPM (To be
Talc & Hydrogenated Castor Oil. The variables recorded)
studied after lubrication was blend uniformity,  Atomizing air pressure: 0.4 Mpa (Limit:
composite assay and % LOD. 0.4 + 0.1Mpa)
 Results for Blend uniformity: 97.8 % to  Spray rate: 78.1 – 104.8 ml/min. (To be
102.0 % (Limit: 95.00 % to 105.00 % of recorded)
the target value (i.e. label claim) of active  Coating Time: 89 min. (To be recorded)
ingredient.)  Average weight: 208.32 mg (Limit: 208.0
 RSD value for was found between 1.5 % mg + 5% )
(Limit: NMT 5 %)  % Yield: 100.0 % ( To be recorded)
 Assay: 101.4 % (Limit: 95.0 % – 105.0 %  Quantity of Coating solution consumed:
of labeled amount) 22.32 kg ( To be recorded)
 % LOD: 1.08 % w/w (Limit: Not more
than 4.0%w/w at 105ºC) Validation of Finished Product
 % Yield: 100.04 % (Limit: To be  Average weight: 208.8 mg (Limit:
recorded). 208.0 mg + 5%)
 Assay: 101.3% (Limit: 95.0 % –
Validation of Compression: 105.0 % of labeled amount)
The blend obtained was run on the 55 station DR  Dissolution: 95 % – 101 % (Limit:
compression machine. The Speed of compression NLT 80 (Q) % in 30 minutes)
in RPM was optimized and the tablets was tested  % LOD: 1.2 % (Limit: NMT 5.0 %)
for various parameters like description, average  Hardness: 110 N (Limit: 25N – 150
weight, uniformity of weight, thickness, hardness, N)
friability, disintegration time and dissolution to
assure the reproducibility of the compressed Based on the data, various physicochemical test
tablets. parameters it was summarized that the process,
 Average weight: 198.0 – 204.6 mg (Limit: parameters, specifications and controls have been
191.9 mg – 212.0 mg) adequate to show the total conformance of the
 Thickness: 3.55 mm – 4.03 mm (Limit: product to specifications. So presented study show
3.60 mm – 4.00 mm) that the set process parameters of the Benazepril
 Hardness: 7-8 (Limit: 25N – 150 N) Hydrochloride 5 mg could be reproduced during
 Friability: 0.01 % – 0.20 %(Limit: NMT the process resulting in the product meeting the
1.0 % w/w) specifications.
 Disintegration time: 0 minute, 14 sec – 4
minute, 49 sec (Limit: NMT 10 minutes)
 Dissolution: 86 % – 96 % (Limit: NLT 80 CONCLUSION
(Q) % 30 minutes)
 Assay: 100.1 % (Limit: 95.0 % – 105.0 % Process validation study on one Batch of
of labeled amount) Benazepril Hydrochloride Tablet 5 mg having
 % Yield: 92.64 % (Limit: To be recorded) batch size of 200,000 tablets was successfully
completed and the manufacturing critical process
Validation of Film Coating parameters were validated in this process validation
The Automatic Coating Machine used for the study.
process was set with different process parameters
such as pan speed, inlet air temperature, outlet air Based on the review of critical process parameters
temperature, tablet bed temperature, compressed air and analytical results as detailed in this summary

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report, for critical process parameters are specified The data presented in this validated summary
below in this Process Validation Summary Report report indicates that the manufacturing process
for “BENAZEPRIL HYDROCHLORIDE with above recommended limit(s)/range(s) of
TABLET 5 mg” having batch size of 200,000 critical process parameters for “Benazepril
tablets. Hydrochloride Tablet 5 mg” as described in batch
manufacturing record having batch size of 200,000
The manufacturing critical process parameters for tablets is validated and consistently produce the
“BENAZEPRIL HYDROCHLORIDE TABLET 5 finished product of “Benazepril Hydrochloride
mg” having batch size of 200,000 tablets Tablet 5 mg” meeting all pre-determine
mentioned in process validation protocol. specification and quality attributes.

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