Rahul P Gaikwad, Sameer S Sheaikh* and Dinesh Deshmukh |
Corresponding Author: Sameer S Sheaikh, Durgamata Institute of Pharmacy, Dharmapuri-Parbhani, Maharashtra, India, E-mail: [email protected]; [email protected]; [email protected] |
Received: November 30, 2018; Revised: January 17, 2019; Accepted: November 22, 2019 |
Citation: Gaikwad RP, Sheaikh SS & Deshmukh D. (2019) Review on Scale Up and Process Validation of Lacidipine Tablets. J Genomic Med Pharmacogenomics, 4(1): 364-377. |
Copyrights: © 2019 Gaikwad RP, Sheaikh SS & Deshmukh D. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
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Objective: The objective of this protocol is to define the procedure for process
validation and to establish documented evidence that the manufacturing process
is in state of control. Review the definition and types of validation.
Understand the requirements for documentation and key stages in process
validation. It is essential part of GMP. Definition of desirable attributes of
the drug product. Determination of the controls or testing parameters that will
be measured or tested.
Method: Concurrently 3 batches were taken and all critical parameters
evaluated for fixing optimum process parameters for process validation.
Results: The risk assessment was done for each step, and the critical
parameters were validated. All the tests was found to be within the limits, and
validated. Physicochemical parameter of tablets compressed with granules
obtained at final impeller amperage of 11.5 to 12.5 amps, which comply with
specification. The parameters in granulation stage are suggested for binder
addition time, kneading time and discharge time. In the coating process all the
parameters in critical steps were found within the specified limits. The sieve
analysis was done for all the three batches. The sieve used and % retains are
found to be within the specified limits. In the hopper study, all the
parameters were found to be within the specified limits and hence the critical
steps were validated. The dissolution studies for all three batches and it
complies with the specification.
Conclusion: The manufacturing of three batches of common blend for Lacidipine
tablets 6 mg was conducted for a batch size of 94.50 kg (210,000 tablets). The
study involved validating the process variables of this transferred product to
show that the process is under control. The study includes the validation of
critical steps of manufacturing such as blending, drying, granulation,
compression and coating. The process validation of Lacidipine tablets showed
that there was no significant batch-to-batch variation. Therefore it can be
concluded that the process stands validated and the data can be used in regulatory
submission for obtaining marketing authorization for the Lacidipine tablets.
INTRODUCTION
The basic principle of quality assurance is that a drug should be
produced that is fit for its intended use. In order to meet this principle, a
good understanding of process and their performance is important. Quality
should be built into the manufacturing process. These processes should be
controlled in order that the finished product meets all quality specifications
[30].
DEFINITION OF VALIDATION
WHO (World Health Organization)
The validation in the same way but elaborates considerably on the concept “Validation studies are essential part of good manufacturing practice and should be conducted in according with predefined protocols [30]. A Written report summarizing results and conclusions should be recorded, prepared and stored. Process and procedures should be established based upon the validation study and undergo periodic revalidation to ensure that they remain capable of achieve the intended results [31]. Particular attention should be accorded to the validation of processing, testing and cleaning procedures. Critical process should be validated, prospectively or retrospectively. When any new master formula or method of preparation is adopted, steps should be taken to demonstrate its stability for routine processing [2]. The defined process, using the materials and equipment specified should be shown to yield a product consistently of the required quality [3]. Significant amendments to the manufacturing process, including any change in equipment or materials, which may affect product quality and or reproducibility of the process, should be validated [7].
Why to validate the processes?
There are many reasons
in addition to the regulatory requirements for validating processes. A
manufacturer can assure through careful design of the device and packaging
careful design and validation of processes and process controls that there is a
high probability that all manufactured units will meet specifications and have
uniform quality [11]. The dependence on intensive in-process and finished
device testing can be reduced [4]. However, in-process and finished product
testing still play an important role in assuring that products meet
specifications. A properly validated and controlled process will yield little scrap
or rework resulting in increased output. Consistent conformance to
specifications is likely to result in fewer complaints and recalls. Also
whenever needed the validation file will contain data to support improvements
in the process or the development of the next generation of the process [5].
IMPORTANCE OF PROCESS VALIDATION
1) Reduction of
Quality cost 2) Process optimization 3) Assurance of quality 4) Safety
Validation protocol
Definition: A
document stating how validation will be conducted, including test parameters,
product characteristics, manufacturing equipment and decision points on what
constitutes acceptable test results [11].
Contents of validation protocol: 1) General information; 2) Objective, Label claim; 3) List of equipment and their qualification status; 4) Facilities qualification; 5) Process flow charts; 6) Manufacturing procedure narrative; 7) List of critical processing parameters and critical recipients; 8) Sampling, tests and specifications; 9) Acceptance criteria [17].
Process validation lifecycle
Process design: GMP,
requirements for process design: 1) Design of facility; 2) Design of equipment;
3) Design of production and control procedures; 4) Design of laboratory
controls; 5) Propose process steps (unit operations) and process variables
(operating parameters) that need to be studied; 6) Identify sources of
variability each unit operation is likely to encounter; 7) Consider possible
range of variability for each input into the operation; 8) Evaluate process
steps and variables for potential criticality; 9) Select process steps and
variables for test in representative models; 10) Development studies to
identify critical operation parameters and operating ranges; 11) Designed
experiments; 12) Lab scale, pilot scale and/or full scale experimental batches
to gain process understanding; 13) Establish mechanisms to limit or control
variability based on experimental data; 14) Aim for a “robust process”, i.e.,
one that can tolerate input variability and still produce consistent acceptable
output [12].
Confirmation of process: 1) Transfer developmental knowledge to Production, i.e., technology
transfer; 2) Batch record and operating SOPs in place, equipment and facilities
equivalency established; 3) Raw materials approved; 4) Measurement systems
qualified (QC lab as well as production floor test instrumentation); 5)
Personnel training completed; 6) Environment controlled as necessary; 7)
Execution of confirmed batches with appropriate sampling points and sampling
level; 8) First evidence that process can function at commercial scale by
production personnel; 9) Demonstrates reproducibility [8].
Types of process validation
A) Prospective Validation
B) Concurrent Validation
C) Retrospective Validation
D) Revalidation
E) Periodic revalidation
Phases in process validation
A) Phase 1. (Pre-validation phase)
B) Phases 2 (Pre-validation phase)
C) Phase 3 (Process validation phase/Process
qualification phase)
D) Phase 4 (Validation maintenance phase)
In-process quality control test includes
1) Uniformity of
weight 2) Uniformity of content 3) Disintegration time 4) Friability
PROCESS PARAMETERS FOR STANADARDIZATION
Granulation
These variables affect
the: 1. Granule strength; 2. Bulk density of blend; 3. Flow characteristics of
granules [26].
Semi-drying and milling
1) Dust free; 2)
Round, uniform shape; 3) Good flow behavior; 4) Easy to dose; 5) Good
dispersibility; 6) Good solubility; 7) Compact structure; 8) Low
hygroscopicity; 9) High bulk density; 10) Dense surface; 11) Narrow grain size
distribution; 12) Low abrasion; 13) Visual attractiveness [9].
Drying
Moisture content in
granules which determined in terms of LOD is important factor. If moisture
content is more in granules it will lead to poor flow and sticking problem. If
moisture is less it will lead to capping, high friability and chipping. During
drying the desired LOD will be maintained in the granules which will influence
the quality parameters like flow properties of granules, physical properties
during compression like tablet hardness. Inlet temperature of FBD is most
critical variable for the same. LOD is checked periodically to establish the
same during drying [12].
Blending
1. Bulk Density; 2.
Angle of Repose; 3. Sieve analysis; 4. Compressibility Index.
Compression
Following physical
parameters are to be checked to establish the above-mentioned variables at
regular intervals. 1. Appearance; 2. Individual Weight variation; 3.Group
Weight variation; 4. Hardness; 5. Thickness; 6. Friability [16].
Film coating
The Eight Critical Parameters
for film Coating: 1. Gun geometry; 2. Automising/pattern air; 3. Pan pressure;
4. Pan speed; 5. Spray rate; 6. Inlet outlet air temperature; 7. Total air
volume; 8. Adhesion of particles to the gun surface [13].
Packing
Following parameters
influences speed of the machine: 1. Proper forming of blister pockets; 2.
Proper sealing of blister pack; 3. Configuration of blister pack.
MATERIALS AND METHODS
Materials
Name: LACIDIPINE
Classification:
Belongs to the class of dihydropyridine derivative selective calcium-channel
blockers with mainly vascular effects.
Categories: Calcium
antagonist.
Weight: 422.911
g/mol
Chemical formula: C26H33NO6
IUPAC name:
3,5-diethyl4-{2-[(1E)-3-(tert-butoxy)-3-oxoprop-1-en-1-yl]phenyl}-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate
Absorption: Well
absorbed, the systemic bioavailability of Lacidipine is approximately 33%.
Protein binding:
>95%
Metabolism:
Extensive first pass metabolism.
Route of elimination:
The metabolites are mainly eliminated by the biliary route and excreted via the
feces.
Half-life: 13 to 19
h.
Plasma concentration:
1.6 to 5.7 μg/L
Toxicity:
Hypotension and tachycardia; Bradycardia could occur from parasympathetic
(vagal) stimulation, LD50=1000 mg/kg (orally in rat).
Bioavailability: 2
to 52%
Melting point:
183.5-184.5°C
State: Solid
Water solubility:
0.82 mg/L
Methods
Procurement and
authentication of drug Lacidipine under study: Evaluation of three batches considering parameters listed below for
I.P.Q.C tests.
1. Optimization
of granulation end points
2. Evaluation
of granules
3. Compression
of granules into tablet
4. Evaluation
of Tablet
5. Film
coating of compressed tablets
6. Evaluation
of coated tablets
7. Sampling
of strips
8. Preparation of the validation report.
RESULTS (FIGURES 1 AND 2 AND TABLES 1-15)
Finished product report
The finished product report for all the three batches was collected.
All the tests for finished product were passed as per the specification (Figure 3 and Tables 16-19).
DISCUSSION
The common blend 94.50
kg was divided into three different strengths viz. 19.50/130,000 tab for 2 mg
strength 30.00 kg/100,000 tab for 4 mg and 45.00 kg/100,000 tab for 6 mg tab.
Dry mixing and granulation
Dry mix was done for 5
min at impeller slow speed (75 rpm) to match Froude number with tablet batches.
Granulation was carried out at slow speed of impeller and chopper slow speed
with addition of granulating solution as per manufacturing instruction which
produced satisfactory granules so the binder addition time and kneading time is
recommended as mentioned in manufacturing instructions.
Wet milling
Wet milling was done
in Quadro co-mill using 250Q screen to break wet mass and facilitate uniform
drying to keep residual solvents within specified limits.
Drying
Drying was carried out
at controlled inlet temperature of 55°C and desired loss on drying of NMT 2.0%
w/w at 105°C achieved. LOD of dried granules achieved between NMT 2.0% w/w.
Hence the drying process was found to comply the predefined specification for 3
batches
Pre lubrication and lubrication
The pre lubrication
time of 25 min is to match number of revolution with that of tablet batches and
found satisfactory at blender fast speed. The blend uniformity results were
found to comply with the predefined specification. Lubrication time of 5 min at
blender fast speed shows satisfactory results. Blend uniformity results found
to be complied with predefined specification for all three batches. The process
validation of Lacidipine tablets 6 mg was conducted for a batch size of 45.00
kg (100,000 tab) which included the validation of critical steps of
manufacturing such as compression and film coating which were found
satisfactory.
Compression
Compression was
carried out on 30 station Fette press. All physical parameter such as
individual weight variation, thickness, friability, disintegration time are
well within the acceptance limit at full hopper, middle hopper and end hopper.
Hopper study data shows no segregation during compression and uniformity of
dosage unit at full hopper; middle hopper and end hopper are found
satisfactory. On the basis of all analytical and physical parameter data found
that compression stands validated.
Film coating
Coating had been
performed with the parameters as mentioned in manufacturing instructions in
order to obtain the desired film coating buildup of 3.0 ± 0.5% w/w. Film
coating inlet temperature is recommended as 65°C-75°C. Finished product report
shows that final product meets the finished product specification.
Deviation and incidents: Nil.
Compression:
Stands validated as per parameters specified in manufacturing instructions.
Film coating:
Stands validated as per parameter specification in manufacturing instructions.
CONCLUSION
The manufacturing of
three batches of common blend for Lacidipine tablets 6 mg was conducted for a
batch size of 94.50 kg (210,000 tablets). The study involved validating the
process variables of this transferred product to show that the process is under
control. The study includes the validation of critical steps of manufacturing
such as blending, drying, granulation, compression and coating. The Process
validation of Lacidipine tablets showed that there was no significant
batch-to-batch variation. Therefore it can be concluded that the process stands
validated and the data can be used in regulatory submission for obtaining
marketing authorization for the Lacidipine tablets.
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