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Process Validation Of Lamivudine And
Tenofovirdesoproxil Fumarate Tablets Biology Essay
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The definition is very well thought out each word has a special significance.
Documented Evidence:
Validation requires a through documentation everything that is not documented is considered
incomplete.1
High Degree of Assurance:
This assurance is a large software package which is used in complex computerized system is rarely
free of errors. Frequently there is a perception that validation means “error free”. This assumption is
wrong. During the validation process everything realistically possible should be done to reduce errors
to a high degree.
Specific Process:
Some subparts of validation such as qualification. (Design, Installation, Operation, Performance) are
product specific and have to be done for each system.
Consistently:
Validation is not a one-time event. The performance of equipment has to be controlled during the entire
life of product.
Predetermined Specification:
Validation activities start with the definition of specifications. The performance of equipment is then
verified against these specifications. Acceptance criteria must be defined prior to testing.2
Reasons for Validation:
The three basic and most important reasons for validation are quality assurance, economics and
compliance.
1. Quality Assurance:
Product quality cannot be assured for a process by routine quality control testing because of the
limitation of statistical sampling and the limited sensitivity of finished product testing. Quality variation
among units within a batch or among, different batches is seldom detected by testing of finished
product samples.
Validation changes the adequacy and reliability of a system or process to meet predetermined criteria.
2. Economics:
The direct economic benefit of validation is a reduction in the cost associated with process monitoring,
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sampling and testing. Analysis of multiple samples would not be required in order to slow homogeneity
for a validated blending process.
The consistency and reliability of a validated process to produce a quality product provide direct cost
saving resulting from a decrease or elimination of product rejections, reworks and retesting. Final
release of the batch would be expedited and free of delays and complications caused by lengthy
investigations of process, or analytical related variances. In addition product quality complaints and
potential product recalls would be minimized.3
3. Compliance:
GMP requires that a written procedures and process controls be established to assure that the drug
products have the “Identity, Strength, Quality and Purity they purport or are represented to process.”
BENEFITS OF VALIDATION:
Reduction of Quality Cost
Through proper validation, the cost of the following process can be optimized.
1) Preventive cost is the costs incurred in order to prevent failures and reduce appraisal costs.
2) Appraisal cost of inspection, testing and quality evaluation.
3) Internal failure costs.
4) External failure costs that associated with a nonconformance condition after the product has left the
company’s ownership.4
B) Process OptimizationThe optimization of the facility, equipment system and closures etc results in a product that meets
quality requirements at the lowest costs. Trained, qualified people are the key elements in process
optimization that results in improving efficiency and productivity.
C) Assurance of Quality
Validation and process control are the heart of GMPs. Without validated and controlled process it is
impossible to achieve quality products. Hence validation is a key element in assuring the quality of the
product.5
D) Safety
Validation can also result in increased operator safety. Properly calibrated, validated Instruments and
gauges used to reduce accident and results in safety.
E) Better Customer Quality
Through proper validation, Market recall is avoided which results in better customer care and quality of
the product.
Goal of Process Validation:
To prove that the process is rugged and reproducible.
To understand the process parameters and their limits that affects the product characteristics.
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A well understood, successfully validated process reduces the dependence on intensive in process
and finished product testing.6
Types of process Validation:
Prospective validation
Concurrent validation
Retrospective validation
Revalidation.
Prospective Validation:
Prospective validation involves manufacturing, sampling, and testing of validation batches according to
a pre-approved validation protocol.
Validation batches are not released until all batches specified in the protocol have been manufactured,
all results have been reviewed, and validation reports have been written and approved.
Prospective validation should always be performed for:
New process or product
Products transferred between plants
Changes to existing processes
Concurrent Validation:
Validation batches may be released prior to the completion of the manufacture of all the batches
specified in the protocol and the final validation report approved.
More stringent testing is performed than for the normal batch approved.
An interim approval on a batch by batch by batch basis.7
Concurrent validation should only be used for existing products where the change has a low risk of
affecting critical product characteristics.
Criteria to be used to determine the acceptability of approach:
The process should be well understood, based on development information and current full-scale
commercial manufacturing experience.
There should be no recent history of recurring problems affecting critical product characteristics.
The batches are produced infrequently (e.g. limited market demand).
Retrospective Validation:
Retrospective validation establishes documented evidence that a system dose what it is supposed to
do based on a review and analysis of historical information.
It is normally conducted on a product being commercially distributed and is based on accumulated
production, testing and control data.
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Revalidation
This is nothing but the repetition of the whole validation process or a specific portion of it. It becomes
necessary in certain situations. Some of the changes are as follows.
Changes in sources of active Raw material manufacturers.
Changes in Raw materials.
Changes in Packing Materials.
Changes in process e.g. Mixing Time, Drying temperature, and Batch size etc.
Changes in Equipment.
Changes in plant Facility.
Monitoring of equipment capabilities over a period of time.
PHASES OF QUALIFICATION
The validation of facilities, equipment and services is called Qualification. The activities relating to
validation studies may be classified in to three phases.
PhaseI:
Pre-Validation Phase or 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, storage and handling of finished dosage forms.
Phase II :
Process Validation (Process Qualification Phase) designed to verify that all established limits of critical
process parameters are valid and that satisfactory products can be produced even under worst case
condition.8
Phase III :
Validation Maintaining Phase requiring frequent review of all process related documents including
validation audit reports to assure that there have been no change, deviations, failures, modifications to
production process and that all standard operating Procedures have been followed, including change
control procedures.
PARAMETERS TO BE TESTED FOR VALIDATION WORK
S.NO
Validation Work
Tested for the parameters
1
Personnel
Qualification, Responsibilities etc.
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2
Buildings
Design, Construction.
3
Services
Water, Lightings, Cleaning, Ventilation, Waste, Disposal etc.
4
Equipment
Design, Size, Location, Material of construction, Manufacturing drawing, Change parts, Maintenance,
Cleaning.
5
Raw Material and Components
Control, Testing Storage, Vendor audit.
6
Procedures
Standard Operating Procedures, Sampling, Yield calculation, Microbial contaminations etc.
7
Packaging, Labeling
Issue of labels, Expiry dating etc.
GOOD VALIDATION PRACTICES
The process of providing documented evidences that any element of technology operates as intended
and will continue to do so is called “Validation”.
Good Validation Practices are controls that furnish the basis for ensuring that appropriate technology is
developed, deployed and maintained in appropriate manner. The conceptual framework of goodvalidation practices as well as the details of the control is illustrated in the following figure.
THE PARADIGM
Technology should meet business needs
Technology should continue to meet business needs
Technology should be implemented effectively in your Environment
Documentation should be complete and current
Only qualified staffs to Develop maintain and use Technology
Appropriate level of Independent quality Control
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Controlled Technology = Validated System
Requirements prior to Validation:
The following knowledge must be available prior to starting validation:
Critical process parameters and their associated limits.
Critical product characteristics.
Process description.
Equipment and materials required
Proposed manufacturing procedures
Proposed cleaning methods
In –process and finished product testing
Validated analytical methods
Reference to development studies.
Reference to previous validation.
What is a Critical Parameter?
Operation of a critical parameter in the range immediately beyond the operating range produces
material of a significant quality.
Critical Parameters
A proven acceptable range is wider than the normal operating range and should have been established
during development in support of validation.
PAR allows flexibility for recovery from errors during routine manufacturing.
Edge of failure limits greatly help in establishing the ruggedness of process.
If operating ranges are close to edge of failure, then extensive in-process or finished product testing
may be required in addition to validation.
Planning Validation:
Study types:
A) Uniformity
B) Holding
C) Reproducibility
D) Process Capability
Acceptance Criteria:
There are typically tighter than the registered finished product specification.
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Planning process validation:
Number of batches
For most validation studies, three consecutive batches will be used.
More batches may be needed if all critical parameters cannot be tested with three batches.
Fewer batches may be applicable for changes that have a low risk of affecting critical product
characteristics.
Validation process does not end after 3 batches, it continues throughout the life cycle of the product
and must be periodically evaluated for shifts in performance
Bracketing :
A product with multiple strengths or batch sizes can be qualified using bracketing to help limit the
number of batches.
For example: A dry product having multiple strength, which differs only in compressing weight.
Three batches each of the lowest and highest strengths could be used to bracket all intermediated
strength.
Alternatively , three batches of the lowest strength , plus one batch of each of the other strength may be
acceptable.
Identical equipment:
For pieces of equipment that have been proven to be identical during IQ / OQ , it is not required to run
three batches in each piece of equipment during validation.
For Eg: Granulator , Mixing tanks , Tableting machines.
A strategy to run at least one batch per piece of equipment would be adequate.
Stainless Steel Sampling:
Sample volume should be sufficient to perform all required analysis containers for the samples should
protect them from any degradation.Headspace in the containers should be minimum, except to allow re
–suspension when required.Sample size should be representative of the process.Take two reserve
samples in case an investigation is required.Sampling technique should be described and calibratedsampling device should be used.
Holding studies:
The holding study should be between one and three batches used .
The number of batches should be determined by the extent to which product characteristics are
affected by holding time.
Stability studies :Validation batches should be subjected to stability programme :
To meet regulatory commitment and
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To collect data to support expiration interval , formulation , new site or process .9
Protocol:
The protocol should specify the following:
The applicable batch record
A list of procedures
Tests and assays to be performed
Required data to be collected and whys
Pre – determined acceptance criteria
Description of each test method and its objective
Number of batches to be manufactured
Critical product characteristics
Samples size , location , frequency and number
Procedure for recording and evaluating results
Responsibilities.
Executing the protocol :
Prior to execution, the following must be in place:
Released raw and packaging materials
Validated analytical methods for finished product
Personnel training documented
Approved specification and batch record
Qualified utilities
Approved SOPs or draft SOPs.
Changes to protocol :
Where a change to an approved protocol is required prior to the start of execution, the protocol shall be
re – issued as the next version and shall be approved by all the same approval authorities as the
original protocol before starting the validation exercise.10
When a change is needed after protocol execution has already begin, either
1).The work shall be discontinued and re-started following approval of a new, revised protocol.
2).Supplemental documentation shall be prepared,approved, and issued that specifies the point in theprotocol execution at which the supplemental documentation becomes effective.
All protocol revision and supplemental documentation that are issued during validation must be
documented in the validation report , including change rationale.
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Failed batches:
If a batch fails acceptance criteria for a reason directly related to the process being validated , the root
cause must be determined , a change made and validation restarted.
If a batch failed for a reason unrelated to the qualification, it is not necessary to start again the rationale
must be documented.11
If the failure prevents all qualification data from being collected, the batch should be replaced.to come
If all data was collected, the batch may not be releasable to the market, but can still be considered valid
for the validation.
Example of failed batches where PV is not jeopardized :12
If a batch fails in appearance because it has physical contamination, but the contaminant was
determined to come from a raw material which is not the reason for the validation, the batch could be
used as long as the other specifications are met.13
If a spill occurs during processing which prevents all data from being collected , the batch can be
replaced in the validation series.
Failed cleaning validation the product may not be acceptable for release to the market, but the batch
may still be acceptable as a validation batch.14
No matter why the failure, all batches must be discussed in the validation
report
Validation Report:
The validation report should be approved by the same function as the protocol. The following should be
discussed in the report:15
Summary of validated parameter with ranges.
Discussion of significant deviations including failed batches.
Recommended changes to batch records or procedures.
A firm conclusion that the process is validated.
Attach executed protocol and executed batch record.
Continued evaluation :
Once the validation batches are completed , the formal validation ends.
Whether the process is operating as expected is determined by analysing day-to-day process control
data and finished product testing.16
A mechanism also should be in place to periodically review the data trends to indicate the need for re-
validation.
The periodic review should also include review of in-process and internal release specification , which
may shift with time or may need to be tightened as the process performance improves.
Certain processes for sterile products such as sterilization processes and media fills need to be
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requalified on a regular basis.1
LITERATURE REVIEW
Rajkumar P.Patil; (2011) has explored the understanding of blend uniformity in the manufacture of solid
oral dosage forms under c GMP. He concluded that testing final blend uniformity as a suitable in-
process control may evaluate and highlight the incoming ingredient batch to batch differences as well
as the physical variations in different lots of active materials.
Garg R et-al;(2008) has described guidance for validation of solid dosage forms, sterile products, oral
solutions and suspensions. They gave an overview on aspects of validation in terms of pharmaceutical
unit operations, i.e. that individual technical operation that comprises various steps involved in product
design and evaluation.
Chitlange S et-al;15 (2006) provided information on validation of granulation process which involved
validation of equipments utilized in manufacturing of granulation and validation of operation carried out
for granulation. It also validate final product for bulk density, moisture content, particle size distribution
etc. successfully validating a process may reduce the dependence upon intensive inprocess and
finished product testing.
Anurags.Rathore , joseph F.Noferi, and Edward R. Arling from pharmacia
corporation, and Gail sofer, Bioreliance; peter Watler, Amgen, Inc.; and
Rhona O’ Leary, Genentech, Inc
The trick to process validation these industry experts argue, is to understand that it is a process that
stretches through the whole product life cycle. Some secrets of success: Take a team approach; focus
on the timing of the various stages of validation; avoid some common mistakes; and build your
documentation as you go.
Thomas p. Garcia, 1,* simon j. Wilkinson, 2 and Jerry F. Scott2
This article discusses the challenges overcome during the development of a blend sampling technique
and the successful validation of the blending for a tablet dosage form containing 2% active ingredient.
Content uniformity results are discussed for three pilot- scale and seven commercial- scale batches of
tablets. Blend and core content uniformity data from the pilot- scale batch were acceptable. For the
initial commercial- scale batches, although the tablet core content uniformity results were poor. The
blend data for these batches had very high mean values, but acceptable relative standard deviation
(RSDs). This suggested that the drug was being preferentially sampled by the thief. But in a
consistent, reproducible manner. Extensive testing was performed on a commercial – scale
development batch to identify potential causes of sampling error. The results of this testing helped
define the blend- sampling technique and strategy used to validate the mixing operation.
Quality management systems – process validation guidance:
“Quality management systems – process validation guidance” ,originally finalized in 1999, is being
republished as “ GHTF/SG3/N99-10: 2004 (edition 2)” after revision due to the changes in ISO
13485:2003, which is utilized in some regulatory systems. The process validation Guidance has been
revised in section 0 through 3.4, figure 1 and Annex B. the revision can be generalized in two
categories: 1) editorial revision of terminology to be consistent with ISO 13485:2003.
Wayne A.Taylor; described the application of many statistical tools like control charts, capability studies,
designed experiments, tolerance analysis, robust design methods, failure mode and effect analysis,
sampling plans, mistake proofing in validation.
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Andrew W. Jones; (2001) discussed how to validate a process by introducing some basic statistical
concepts to use when analyzing historical data from Batch Records and Quality Control Release
documents to establish specifications and quality attributes for an existing process.
Dusel-RG et-al; (1997) performed food and drug administration requirements regarding manufacturing
process validation were discussed including examples of different types of documentation to fulfill the
requirements of minimal or extensive records.
Edwards-CM et al;(1989) have done process validation of the manufacturing of solid dosage forms wasdiscussed including protocols, records to be maintained, suitability of raw materials, equipment
performance qualification, the number of validation runs required and acceptance criteria.
AIM & OBJECTIVE
AIM
The aim of the present work is to study the prospective process validation of Lamivudine and Tenofovir
Disoproxil Fumarate tablet dosage formulation.
OBJECTIVE
To ensure product quality in each step of manufacturing
To ensure consistency of the manufacturing operation & reproducibility of the process
To demonstrate the robustness of the process
To ensure the existence of all necessary quality assurance systems within the organization
To ensure that personnel producing the drug product are properly trained and qualified to produce the
product
To fulfill the requirements of cGMP, FDA & WHO guidelines
PLAN OF WORK
Process validations to be carry out for the following drug Lamivudine and Tenofovir Disoproxil
Fumarate tablets 300/300 mg.Three consecutive batches should be manufactured for the validation
Following work have been designed according to the master manufacturing formula.
Preparation of flow chart
2. Preparing the validation protocol which include
Review of qualification status of equipment and facility
Identification of CPPs and CQAs
Preparation of sampling plan
Acceptance criteria
3.Execution of validation
4. Compliance and evaluation of the results
DRUG PROFILE
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VIREAD is the brand name for Tenofovir disoproxil fumarate (a prodrug of tenofovir) which is a fumaric
acid salt of bis-isopropoxycarbonyloxymethyl ester derivative of tenofovir. In vivo Tenofovir disoproxil
fumarate is converted to tenofovir, an acyclic nucleoside phosphonate (nucleotide) analog of adenosine
5'-monophosphate. Tenofovir exhibits activity against HIV-1 reverse transcriptase.
IUPAC Name
9[(R)2[[bis[[(isopropoxycarbonyl)oxy]methoxy]phosphinyl]methoxy]propyl]adenine fumarate (1:1).
Molecular formula:
C19H30N5O10P • C4H4O4
Molecular weight:
635.52.
Structural formula:
VIREAD® (tenofovir disoproxil fumarate) Structural Formula Illustration
Tenofovir compound
Colour:
White to off-white crystalline powder.
Solubility:
13.4 mg/mL in distilled water at 25 °C. It has an octanol/phosphate buffer (pH 6.5) partition coefficient(log p) of 1.25 at 25 °C.
Mechanism of action:
Tenofovir disoproxil fumarate is an acyclic nucleoside phosphonate diester analog of adenosine
monophosphate. Tenofovir disoproxil fumarate requires initial diester hydrolysis for conversion to
tenofovir and subsequent phosphorylation’s by cellular enzymes to form tenofovirdiphosphate, an
obligate chain terminator. Tenofovirdiphosphate inhibits the activity of HIV-1 reverse transcriptase and
HBV polymers by competing with the natural substrate deoxyadenosine 5’-triphosphate and, after
incorporation into DNA, by DNA chain termination. Tenofovir is a weak inhibitor of mammalian DNApolymerases α, β, and mitochondrial DNA polymerase γ.
Pharmacokinetics
The pharmacokinetics of Lamivudine have been evaluated in healthy volunteers and HIV-1 infected
individuals. Tenofovir pharmacokinetics are similar between these population.
Absorption:
VIREAD is a water soluble diesterprodrug of the active ingredient tenofovir. The oral bioavailability of
tenofovir from VIRED in fasted patients is approximately 25% following oral administration of a single
dose of VIRED 300mg to HIV-1 infected patients in the fasted state, maximum serum concentration
(Cmax) are achieved in 1.0 ±0.4 hrs.Cmax and AUC values are 0.30 ± 0.09 µg.hr/ml, respectively.
The pharmacokinetics of tenofovirare dose proportional over a VIRED dose range of 75 to 600mg and
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are not affected by repeated dosing.
Distribution:
In vitro binding of tenofovir to human plasma or serum proteins is less than 0.7 and 7.2%, respectively,
over the tenofovir concentration range 0.01 to 25 µg/ml. the volume of distribution at steady – state is
1.3 ± 0.6 L/kg and 1.2 ± 0.4 L/kg, following intravenous administration of tenofovir 1.0 mg/ kg and 3.0
mg / kg.
Metabolism and elimination:
Lamivudine structure formula:
G:\pk\ss2.png
Mechanism of action:
It exerts virustatic effect against retroviruses by competitively inhibiting HIV – RT after intracellular
conversion of the drug to its action form.
Pharmacodynamics of Lamivudine
Lamivudine, commonly called 3TC) is a potent nucleoside analog reverse transcriptase inhibitor
(nRTI). It is marketed by GlaxoSmithKline with the brand names Zeffix, Heptovir, Epivir, and Epivir-
HBV. Lamivudine has been used for treatment of chronic hepatitis B at a lower dose than for treatment
of HIV. It improves the seroconversion of e-antigen positive hepatitis B and also improves histology
staging of the liver. Long term use of lamivudine unfortunately leads to emergence of a resistant
hepatitis B virus (YMDD) mutant. Despite this, lamivudine is still used widely as it is well tolerated.
Pharmacokinetics:
Absorption
C max is approximately 1.28 mcg/mL (single dose of 100 mg). T max is 0.5 to 2 h. Absolute
bioavailability is approximately 87%.
Distribution Less than 36% protein bound. Vd is approximately 1.3 L/kg.
Metabolism
Metabolism of lamivudine is a minor route of elimination. The metabolite is trans-sulfoxide metabolite.
Elimination
The majority is eliminated unchanged in the urine. Mean half-life is 5 to 7 h. Cl is approximately 398.5
mL/min.
Lamivudine Adverse Reactions / Lamivudine Side Effects:
Abdominal pain, nausea, vomiting, diarrhoea, insomnia, cough, nasal symptoms, arthralgia, muscle
pain, headache, fever, rash, alopecia, malaise, increased creatininephospholinase, & alanine
aminotransferase, peripheral neuropathy. Rarely rhabdomyolysis, pancreatitis, hepatitis.neutropenia&
anaemia,(in combination with zidovudine)thrombocytopenia, increases in LFTs> Paronychia.
Angioedema, utricaria&anaphylactiod reaction. Lactic acidosis associated wth severe hepatomegaly &
hepatic steatosis.
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Precautions:
Warnings Lactic acidosis with hepatomegaly and steatosis (including fatal cases) has been reported
with the use of lamivudine alone or in combination. Severe acute exacerbations of hepatitis B have
been reported in patients who have discontinued Lamivudine.
MATERIALS AND METHODS
A. LIST OF EQUIPMENTS USED:
The major equipment’s listed in the process validation protocol revision was used and given in the
below table.
S.No
Name of equipment’s
Size/ capacity
1.
Multimill
-
2.
Vibrosifter
-
3.
Roll compactor
-
4.
V-blender
75 lit
5.
V-blender
500 lit
6.
Tablet compression machine
30 station single rotary
7.
Tablet coating machine
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Neocoata
B.BATCH DETAILS:
Label claim : Each film coated tablets contains LAMIVUDINE AND TENOFOVIR DISOPROXIL
FUMARATE tablets 300mg/ 3oomg.
No. of batches : Three
Batch size : The proposed batch size of all the three batch is 1,20000 tablets.
C.LIST OF RAW MATERIALS USED:
Raw materials:
Tenofovir disoproxil fumarate.
Lamivudine USP.
Microcrystalline cellulose NF.
Croscarmellose sodium EP/BP/NF.
Magnesium stearate NF.
Coating materials:
Opadry II white 31 K 58902.
Purified water USP
PROCESS FLOW DIAGRAM:
The sequence of manufacturing operation was carried out as per the below process flow diagram.
Step 1: sifting
1.1)Co-sift Tenofovir disoproxil fumarate, microcrystalline cellulose and Croscarmellose sodium
through ASTM #25 mesh and collect in a labelled HDPE drum lined with two poly bags
1.2)Sift the magnesium stearate through ASTM# 60 mesh and collect in a labelled HDPE drum lined
with two poly bags.
Step 2 : pre-mixing
2.1) Load the step 1.1 materials into 75 L v-blender and blend for 20 minutes at slow speed (14 rpm).
2.2) Load the step 1.2 materials into 75 L v-blender and mix for 7 minutes at slow speed(14rpm)
2.3) Unload the pre-mix of 2.1 and 2.2 into labelled HDPE container having double lined polythene
bags.
Step 3: compaction and milling
3.1) Roll compaction the pre-mix (lot 1, 2, and 3) into the roller compactor at roller speed 12 ± 1 (11-13)
rpm and auger speed 30 ±10 (20-40) rpm.
3.2) Remove the fines from compacts by through mesh size: # 16.
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3.3) Roll compact the fines collected from sifted through mesh size: # 16 into the roller compactor at
roller speed 12 ± 1 (11-13) RPM and auger speed 30 ±10 (20-40) rpm.
3.4) Mill the step 3.3 compacts through multimill equipped with 1.5mm screen with knives in forward
direction at medium slow speed (1500 rpm ).
3.5) Sift the milled granules through ASTM # 16 mesh.
3.6) Mill the step 3.5 (#16 mesh) retains through multimill equipped with 1.5mm screen with knives in
forward direction at medium slow speed (1500rpm).
3.7) Repeat 3.6 step till there is no retains on # 16 mesh.
3.8) Sift the materials step 3.7 through # 60 mesh and collect # 60 meshes above retained granules
and # 60 meshes below passed fines separately in a container and record the weight.
Note: If the weight of fines (below # 60 mesh) is more than 28.44kg ( 60% of the total intra granular
weight ) carry out one more cycle of compaction and mill it.
Step 4: sifting of extra granular materials
Sift together lamivudine, microcrystalline cellulose (avicel), microcrystalline cellulose ( ceolus) and
croscarmellose sodium through ASTM # 25 mesh.
Step 5: Blending
Load the decompacted granules of step 3 and sifted materials of step 4 into 500L V- blender and blend
for 20 minutes at fast speed (10 rpm).
Step 6 : Lubrication
Sift the magnesium stearate through ASTM #60 mesh and load into 500L V-blender and mix for 7minutes at fast speed (10rpm).
Unload the blend into labelled HDPE containers lined with two clear polythene bags .
Step 7 : Compression
Rotatory press with “D”tooling with
Upper punch :20mm × 9.5mm, modified capsule shape , standard concave with bevelled edge with
‘RH80’
Lower punch :20mm×905mm, modified capsule shape , standard concave with bevelled edge,Plain
punch .
Step 8: In process parameters
1.Average weight (30 tablets):1200mg ±30mg (1170-1230mg)
2.Uniformity of weight :1200mg ±4.0% (1152 -1248mg)
3.Hardness : 190-370N
4.Thickness: 7.00±0.30mm(6.70-7.30mm)
5.Disintergration time : NMT 25 min
6.Friability: NMT 0.8%(On 6.5gm of tablet 100 rotations )
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Coating
1. Opadry II white 31 k58902-36 mg /tablet
2. Purified water USP qs
Coating parameters
1.Inlet temperature 45- 65 ºC, exhaust:40 -50ºC
2.Weight of average tablet weight gain 3.0% w/w
RATIONALE FOR SELECTION OF NON-CRITICAL & CRITICAL STEPS &
ITS PROCESS PARAMETERS FOR VALIDATION
DISPENSING
Check and ensure dispensing booth is clean & line clearance is given as per current version of
standard operating procedures
Check & ensure that balance is calibrated
Check for zero error in the balance & ensure that Lamivudine and Tenofovir disoproxil fumarate drug
and all the materials i.e., Excipients are issued as per Batch Manufacturing Record
PRE-BLENDING
Check & record the temperature and relative humidity in processing area
Check & ensure visually all the equipment & equipment parts are cleaned and record remarks if any
Check and record the integrity of the sieves before & after sifting and throughout the processing activity
Carry out sifting and dry mixing as per the Batch Manufacturing Record instructions
This step involves blending of deagglomeration materials. The purpose of blending is to get uniform mix
LUBRICATION
This step involves blending of materials along with the lubricating agent (Magnesium stearate)
The purpose of lubrication is to ensure the proper lubrication of the granules and to facilitate easy flow
of the granules
In this step blending is done for 5mins at 10rpm to get proper mix of lubricant
GRANULES BLENDING
This process involves blending of granules. The purpose of blending is to get uniform mixing
The content of uniformity of Lamivudine and Tenofovir disoproxil fumarate in the granules shall be
tested with blend respectively
Sampling shall be performed in the blender & in the unloaded container to check the content uniformity
COMPRESSION
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This process involves compression of lubricated granule into tablets
Speed of the machine is a critical process variable and also following parameters are proposed to be
studied at different machine speed at different hardness levels to validate the compression process like
weight variation, thickness, hardness, friability, disintegration & content uniformity
Hopper study shall be carried out at target speed to evaluate uniformity of blend throughout the
compression process & to prove that no segregation takes place due to centrifugal force caused by
agitation of turret and also by flow of materials from feed time
COATING
This process involves coating of the compressed tablets
In this process the critical steps to be monitored are Inlet air temperature, spray rate, tablet bed
temperature & pan rotational speed
Description, Coating weight gain, Assay, Related substances & Dissolution were monitored for the
changes of the process parameters
5.9. VALIDATION PROCEDURE
Three batches are taken for validation which had to be manufactured as described in the Master
Production Document
Record the process observation stage by stage & batch wise
Yield to be recorded at appropriate stages of the process as per Master Production Document
Current versions of standard operating procedure to be followed
PROCESS TO BE VALIDATED:
INFLUENCE MATRIX
The Processes to be validated are decided using influence matrix. The effects of process variables on
product characteristics are studied and assessed as having medium, weak and strong influence. The
variables having strong and medium are chosen for validation.
Table 3: The effects of process variables on product characteristics
Product Characteristics
Process variables
Avg.Wt
Hardness
D.T
Content
Uniformity
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Dissolution
Friability
Water content / LOD
Sizing /Milling
NA
NA
NA
NA
NA
NA
NA
Pre-lubrication
NA
NA
NA
S
NA
NA
M
Blending
NA
NA
NA
S
NA
NA
M
Compression
S
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S
S
S
M
S
M
Coating
S
W
M
W
S
W
M
Strong – S, Medium – M, Weak – W, Not Applicable – NA
Avg. Wt- Average Weight, D.T- Disintegration Time
RESULTS AND DISCUSSION
DISPENSING OF RAW MATERIALS: Batch No. 12LT01
Batch Size
144.00kg
Batch No.
12LT01
S.NO
Ingredients/ specification
Grade
Material code
A.R. NO.
Theoretical qty (kg)
Intra granular:
1.
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Tenofovir disoproxil fumarate
-
-
-
36.00
36.36
2.
Microcrystalline cellulose
Avicel PH 112
-
-
9.27
8.91
3.
Croscarmellose sodium
AC-Di-sol
-
-
1.80
1.80
4.
Magnesium stearate
vegetable
-
-
0.33
0.33
Extra granular :
5.
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Lamivudine
-
-
-
36.00
36.02
6.
Microcrystalline cellulose
Avicel PH 112
-
-
31.77
31.75
7.
Microcrystalline cellulose
Ceolus KG 802
-
-
21.00
21.00
8.
Croscarmellose sodium
AC-di-sol
-
-
6.84
6.84
9.
Magnesium stearate
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Vegetable
-
-
0.99
0.99
Coating materials
S.No
Ingredients
Material code
A.R. NO
Theoretical qty (kg)
Quantity dispensed (kg)
1.
Opadry II white 31 k
-
-6.048
6.048
2.
Purified water
-
-
27.552
27.552
DISPENSING OF RAW MATERIALS: Batch No. 12LT02
Batch Size
144.00kg
Batch No.
12LT02
S.NO
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Ingredients/ specification
Grade
Material code
A.R. NO.
Theoretical qty (kg)
Intra granular:
1.
Tenofovir
Disoproxil
Fumarate
-
-
-
36.00
36.36
2.
Microcrystalline cellulose
Avicel PH 112
-
-
9.27
8.91
3.
Croscarmellose sodium
AC-Di-sol
-
-
1.80
1.80
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4.
Magnesium stearate
Vegetable
-
-
0.33
0.33
Extra granular :
5.
Lamivudine
-
36.00
36.02
6.
Microcrystalline cellulose
Avicel PH 112
--
-
31.77
31.75
7.
Microcrystalline cellulose
Cellulose KG 802
-
-
21.00
21.00
8.
Croscarmellose sodium
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AC-di-sol
-
-
6.84
6.84
9.
Magnesium stearate
Vegetable
-
-
0.99
0.99
Coating materials
S.No
Ingredients
Material code
A.R. NO
Theoretical qty (kg)
Quantity dispensed (kg)
1.
Opadry II white 31 k
-
-
6.048
6.048
2.
Purified water
-
-
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27.552
27.552
-
DISPENSING OF RAW MATERIALS: Batch No. 12LT03
Batch Size
144.00kg
Batch No.
12LT03
S.NO
Ingredients/ specification
Grade
Material code
A.R. NO.
Theoretical qty (kg)
Intra granular:
1.
Tenofovir disoproxil fumarate
-
36.00
36.36
2.
Microcrystalline cellulose
Avicel PH 112
9.27
8.91
3.
Croscarmellose sodium
AC-Di-sol
1.80
1.80
4.
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Magnesium stearate
vegetable
0.33
0.33
Extra granular:
5.
Lamivudine
-
-
-36.00
36.02
6.
Microcrystalline cellulose
Avicel PH 112
-
-
31.77
31.75
7.
Microcrystalline cellulose
Cellulose KG 802
-
-
21.00
21.00
8.
Croscarmellose sodium
AC-di-sol
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-
-
6.84
6.84
9.
Magnesium stearate
Vegetable
-
-
0.99
0.99
Coating materials
S.No
Ingredients
Material code
A.R. NO
Theoretical qty (kg)
Quantity dispensed (kg)
1.
Opadry II white 31 k
-
-
6.048
6.048
2.
Purified water
-
-
27.552
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27.552
PROCESS CHECKS:
Sifting:
Operation
Lots
12LT01
12LT02
12LT03
Time taken to sift the Tenoforvir disproxil fumarate, microcrystalline cellulose &croscarmellose sodium
through mesh size:#25 mesh
No: a0046 and magnesium stearate through mesh size:#60 mesh no:A0049
I
12 minutes
20 minutes
12 minutes
II
11 minutes
19 minutes
16 minutes
III
11 minutes
18 minutes
15 minutes
Pre-mixing:
Operation
Lot
Mixing time
12LT01
12LT02
12LT03
Blending of sifted materials of s.no:1,2&3 from raw material table into 75 L. V-blender at 14 RPM
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Blending of magnesium stearate in to the above mixture.
I
II
III
20 minutes
7 minutes
20 Minutes
7 minutes
20 Minutes
7 minutes
20 minutes
7 minutes
20 minutes
7 minutes
20 Minutes
7 minutes
20 minutes
7 minutes
20 minutes
7 minutes
20 Minutes
7 minutes
Compaction and milling operation:
Operation
12 LT01
12LT02
12LT03
1)Gap between compaction rollers
0.5 mm
0.5 mm
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0.5 mm
2)Roll compacting the pre-mix of lot I,II,&III.
Roller speed: 12 RPM
Auger speed: 30 RPM
Time: 30mts
Roller speed: 12 RPM
Auger speed: 30 RPM
Time: 30mts
Roller speed: 12 RPM
Auger speed: 30 RPM
Time: 30mts
3)Roll compacting the fines collected from sifted through mesh size: #16
Roller speed: 12 RPM
Auger speed: 30 RPM
Time: 30mts
Roller speed: 12 RPM
Auger speed: 30 RPM
Time: 30mts
Roller speed: 12 RPM
Auger speed: 30 RPM
Time: 30mts
4)Milling of the compacted materials in the s.no.2&3 of the above operation by the multimill
Speed:1500 RPM
Screen size:1.5 mm
Time: 55 minutes
Speed:1500 RPM
Screen size:1.5 mm
Time:10 minutes
Speed:1500 RPM
Screen size:1.5 mm
Time:10 minutes
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5)Sifted the above step through mesh
Size:# 16
Size:# 16
Size:# 16
6)Milling the #16 retains through the multimill of the above operation
Speed:1500RPM
Screen size:1.5 mm
Time:10 minutes
Speed:1500RPM
Screen size:1.5 mm
Time:10 minutes
Speed:1500RPM
Screen size:1.5 mm
Time:10 minutes
7)a) weight of #60 mesh retained granules
b)weight of #60 mesh passed granules
26.34 kg
20.60 kg
26.78 kg
20.20 kg
27.04kg
19.93kg
Shifting and blending operation:
Operation
12 LT01
12LT02
12LT03
Mixing time for the screened material (extra granular) and decompacted intra granular material in the
500 L v-blender
20 minutes,
Speed: high
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20 minutes,
Speed: high
20 minutes,
Speed: high
Mixing time for the sifted magnesium stearate and the above materials in to v- blender at a speed of 10
RPM
7 minutes,
Speed: high
7 minutes,
Speed: high
7 minutes,
Speed: high
Remarks:
The sifting pre-mixing, compaction & milling and sifting & blending process were excuted as per the
approved BMR. No deviation and incident was observed during the execution of process.
STAGE- Compression:
The compression process are executed as per the approved BMR. The ideal speed for 30 station,
single rotary compression machine throughout the compression was slow (20±5 RPM), where all the inprocess parameters were within the limit. No deviation and incident was occurred during the
compression stage.
Physical parameters of Core Tablets
Parameters
Limit
12LT01
12LT02
12LT03
Description
White to off white, oval shaped tablets debossed with ‘RH80” on one side and plain on the other side.
Complies
Complies
Complies
Average weight
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1200 ± 30 mg(1170-1230mg)
1206.6 mg
1214.9 mg
1205.8 mg
Uniformity of weight
1200 mg 4.0 % (1152 – 1248 mg)
1180.2 – 1227.7 mg
1199.8 – 1229.6 mg
1180.9 - 1228.4 mg
Hardness
190-370 N
187.0 – 206.0 N
238.0 – 276.0 N
391.0 – 427.0 N
Thickness
7.00 ± 0.30 mm (6.70 - 7.30 mm)
7.31 – 7.38 mm
7.09 – 7.21 mm
6.64 -6.75 mm
D.T
NMT 25 minutes
1.45 – 2.02 min
2.21 min – 3.02 min
3.45 – 4.12 min
Friability
NMT 0.8 %
0.12 %
0.09 %
0.049 %
1)Film Coating- Batch No. 12 LT001
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Lot- I
OBSERVATION
Lot-II
Lot- III
Time taken for adding Opadry II white 31k 58902 into purified water
12 minutes
14 minutes
13 minutes
-
Coating operation
-
Speed of stain less steel coating pan(1 to 10 RPM)
2.5 RPM
2.5 RPM
2.5 RPM
-
Atomizing air pressure (2.0 to 6.0 kg/ cm
3.5 kg/ cm
3.5kg/ cm
3.5 kg/ cm
-
Nozzle size should be 1mm
1 mm
1 mm
1 mm
-
Inlet temperature 45 c- 65 c
55 c
55 c
55 c
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-
No of guns used – 3 nos
3 nos
3 nos
3 nos
-
Peristaltic pump (8 to 40 RPM)
15 RPM
15 RPM
15 RPM
-
Spray nozzles distance from tablet bed (20 to 25 cm)
23 cm
23 cm
23 cm
-
Distance between each gun (17 to 24 cm)
20 cm
20 cm
20 cm
-
Spray rate (40-100 g/ min)
57g/ min
57g/ min
57g/ min
-
Spray nozzles must be perpendicular to rolling bed of tablets
perpendicular
perpendicular
Perpendicular
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-
Parameters
Range
LOT-I
LOT-II
LOT-III
Pan speed
Jogging ever 1-2 minutes at 2 RPM
2 RPM
2 RPM
2 RPM
Inlet temperature
45 C- 65 C
55 c
55 c
55 c
LOD at 800 c
NMT 2.5% w/w
After 10 minutes drying:2.31
After 15 minutes drying:2.03
After 15 minutes drying: 2.16
Desired weight build up
2.75-3.25%
3.07%
Rejection quantity after inspection in kg
0.86 kg
Remark: the coating process was executed as per the approved BMR. No deviation and incident was
observed during the execution of coating process.
2)Film Coating- Batch No. 12 LT002
Lot- I
OBSERVATION
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Lot-II
Lot- III
Time taken for adding opadry II white 31k 58902 into purified water
12 minutes
14 minutes
13 minutes
-
Coating operation
-
Speed of stain less steel coating pan(1 to 10 RPM)
2.5 RPM
2.5 RPM
2.5 RPM
-
Atomizing air pressure (2.0 to 6.0 kg/ cm
3.5 kg/ cm
3.5kg/ cm
3.5 kg/ cm
-
Nozzle size should be 1mm
1 mm
1 mm
1 mm
-
Inlet temperature 45 c- 65 c
55 c
55 c
55 c
-
No of guns used – 3 nos
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3 nos
3 nos
3 nos
-
Peristaltic pump (8 to 40 RPM)
15 RPM
15 RPM
15 RPM
-
Spray nozzles distance from tablet bed (20 to 25 cm)
23 cm
23 cm
23 cm
-
Distance between each gun (17 to 24 cm)
20 cm
20 cm
20 cm
-
Spray rate (40-100 g/ min)
57g/ min
57g/ min
57g/ min
-
Spray nozzles must be perpendicular to rolling bed of tablets
Perpendicular
perpendicular
Perpendicular
-
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Drying parameters: once the buildup is achieved
-
Parameters
Range
LOT-I
LOT-II
LOT-III
Pan speed
Jogging ever 1-2 minutes at 2 RPM
2 RPM
2 RPM
2 RPM
Inlet temperature
45 C- 65 C
55 c
55 c
55 c
LOD at 800 c
NMT 2.5% w/w
After 10 minutes drying:2.31
After 15 minutes drying:2.03
After 15 minutes drying: 2.16
Desired weight build up
2.75-3.25%
3.07%
Rejection quantity after inspection in kg
0.86 kg
Remark: the coating process was executed as per the approved BMR. No deviation and incident was
observed during the execution of coating process.
3)Film coating Batch No. 12 LT003
Lot- I
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OBSERVATION
Lot-II
Lot- III
Time taken for adding opadry II white 31k 58902 into purified water
12 minutes
14 minutes
13 minutes
-
Coating operation
-
Speed of stain less steel coating pan(1 to 10 RPM)
2.5 RPM
2.5 RPM
2.5 RPM
-
Atomizing air pressure (2.0 to 6.0 kg/ cm
3.5 kg/ cm
3.5kg/ cm
3.5 kg/ cm
-
Nozzle size should be 1mm
1 mm
1 mm
1 mm
-
Inlet temperature 45 c- 65 c
55 c
55 c
55 c
-
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No of guns used – 3 nos
3 nos
3 nos
3 nos
-
Peristaltic pump (8 to 40 RPM)
15 RPM
15 RPM
15 RPM
-
Spray nozzles distance from tablet bed (20 to 25 cm)
23 cm
23 cm
23 cm
-
Distance between each gun (17 to 24 cm)
20 cm
20 cm
20 cm
-
Spray rate (40-100 g/ min)
57g/ min
57g/ min
57g/ min
-
Spray nozzles must be perpendicular to rolling bed of tablets
Perpendicular
perpendicular
Perpendicular
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-
Drying parameters: once the buildup is achieved
LOT-III
Parameters
Range
LOT-I
LOT-II
2 RPM
Pan speed
Jogging ever 1-2 minutes at 2 RPM
2 RPM
2 RPM
55 c
Inlet temperature
45 C- 65 C
55 c
55 c
After 15 minutes drying: 2.16
LOD at 800 c
NMT 2.5% w/w
After 10 minutes drying:2.31
After 15 minutes drying:2.03
Desired weight build up
2.75-3.25%
3.07%
Rejection quantity after inspection in kg
0.86 kg
Yield reconciliation:
Stage
% Reconciliation
Pre-mix(1)
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Limit: 95% to 100%
B.NO.
12LT01
12LT02
12LT03
Stage
% yield
Blending
Limit: 95% to 100%
12LT01
12LT02
12LT03
Compression
Limit: 94.0% to 101.0%
12LT01
12LT02
12LT03
Coating(stage yield)
12LT01
12LT02
12LT03
Coating (over all yield)
Limit: 93.0- 100.0%
12LT01
12LT02
12LT03
Remark: the yield was in the specified limit
Stage: Lubrication (blend uniformity)
Acceptance criteria
All individual results are within 90.0 – 110.0% from the absolute mean
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RSD-NMT 5.0%
Batch no.
12LT01
12LT02
12LT03
Sampling location
Lamivudine
Tenofovir
Lamivudine
Tenofovir
Lamivudine
1.
99.1
103.9
102.2
100.6
100.5
2.
100.5
100.8
101.0
99.6
100.6
3.
100.5
101.3
101.2
99.5
100.3
4.
100.1
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99.4
99.5
98.5
100.9
5.
99.2
101.6
102.1
98.8
100.8
6.
100.3
98.6
99.7
98.5
100.3
7.
100.6
97.3
101.0
99.4
100.3
8.
99.5
99.1
102.3
99.6
99.9
9.
99.9
99.2
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102.5
100.6
101.2
10.
100.2
100.0
102.6
99.0
99.4
11.
98.3
99.5
102.3
100.4
100.8
Minimum %
98.3
97.3
99.5
98.5
99.4
Maximum %
100.6
103.9
102.6
100.6
101.2
Average %
99.8
100.1
101.4
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99.5
100.5
Remarks: all individual results are within 90.0-110.0% from the absolute mean and %RSD:NMT 5.0%
Stage: Blending Pooled
Batch No.
12LT01
12LT02
12LT03
S.No
Test
Results
Results
Result
1
Description
Complies
complies
Complies
2
Identification by HPLC
Complies
Complies
Complies
3
Water content(by kf)
1.4
2.2
1.7
4
Assay by HPLC each 1200mg granular powder contains
Lamivudine
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Tenofovir disoproxil fumarate
299.6
99.9
299.2
99.7
305.6
101.9
308.1
102.7
305.6
101.9
2)308.4
102.8
Remarks:
The above results of validation batches shows that the blending process meets the acceptance criteria
and blending parameters are suitable
Stage: Lubrication (blend uniformity for pooled )
Acceptance criteria
All individual results are within 90.0 – 110.0% from the absolute mean
RSD-NMT 5.0%
Batch No.
12LT01
12LT02
12LT03
Sampling location
Lamivudine
Tenofovir
Lamivudine
Tenofovir
Lamivudine
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1.
99.1
103.9
102.2
100.6
100.5
2.
100.5
100.8
101.0
99.6
100.6
3.
100.5
101.3
101.2
99.5
100.3
4.
100.1
99.4
99.5
98.5
100.9
5.
99.2
101.6
102.1
98.8
100.8
6.
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100.3
98.6
99.7
98.5
100.3
7.
100.6
97.3
101.0
99.4
100.3
8.
99.5
99.1
102.3
99.6
99.9
9.
99.9
99.2
102.5
100.6
101.2
10.
100.2
100.0
102.6
99.0
99.4
11.
98.3
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99.5
102.3
100.4
100.8
Minimum %
98.3
97.3
99.5
98.5
99.4
Maximum %
100.6
103.9
102.6
100.6
101.2
Average %
99.8
100.1
101.4
99.5
100.5
% RSD
0.7
1.76
1.06
0.77
0.51
STAGE: BLENDIG POOLED
Batch no.
12LT01
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12LT02
12LT03
S.No
Test
results
Results
Result
1.0
Description
Complies
complies
Complies
2.0
Identification by HPLC
Complies
Complies
Complies
3.0
Water content(by kf)
1.4
2.2
1.7
4.0
Assay by HPLC each 1200mg granular powder contains
lamivudine
tenoforvirdisoproxilfumarate
299.6
99.9
299.2
99.7
305.6
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101.9
308.1
102.7
305.6
101.9
2)308.4
102.8
Remark:
The above results of validation batches shows that the blending process meets the Acceptance criteria
and blending parameters are suitable.
STAGE: COMPRESSION
Stage
compression
Sampling location
Samples at every 10 minutes
Measured parameters
Uniformity of dosage units via content uniformity
Acceptance criteria
Redilypassess criteria RSD≤ 4.0 %,
Mean:90.0-110.0%
All individual results: 75.0- 125.0%
B.NO 12LT01
Lamivudine
Tenofovir
Time Interval
Sample No.
Sample No.
1
2
3
Average
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RSD
1
2
3
Average
1.
97.2
99.9
101.2
99.4
2.1
96.1
102.7
102.7
100.5
2.
100.1
99.5
100.5
100.
0.5
101.8
98.4
101.4
100.5
3.
100.3
100.1
99.6
100.00
0.4
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101.4
100.8
100
100.6
4.
99.9
100.6
99.4
100
0.6
100.3
102.3
99.6
100.7
5.
96.7
100.1
99.7
98.8
1.9
95.9
102.6
100
99.3
6.
99.9
100.1
99.9
100
0.1
98.5
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100
100.2
99.6
7.
99.1
99.1
99.1
99.1
0.00
97.6
100.3
100.3
99.6
8.
96.6
100.8
101.0
99.5
2.5
95.0
100.7
101.7
99.0
9.
99.9
99.9
96.7
98.8
1.9
102.0
9802
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95.6
98.6
10.
100.1
99.8
99.7
99.9
0.2
100.0
100.5
100.9
100.5
11.
101.0
100.4
100.6
100.7
0.3
100.7
100.4
100.2
100.3
12
99.0
98.7
102.4
100.0
2.1
100.00
96.5
102.7
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99.7
.13
98.9
98.2
98.2
99.0
0.8
98.8
101.4
101.7
100.6
14.
97.7
100.3
101.7
99.9
2.0
95.9
101.9
102.0
99.1
15.
100.3
99.9
97.1
99.1
1.8
101.8
99.2
95.0
98.7
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16.
97.2
98.4
99.4
98.3
1.1
98.6
98.8
100.4
99.3
17.
100.3
100.4
100.8
100.5
0.3
98.0
99.4
99.9
99.1
18.
96.9
101.3
101.3
99.8
2.5
95.2
100.5
100.3
98.7
19.
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99.7
100.6
99.6
100.0
0.6
97.6
99.7
101.2
99.5
20.
98.4
100.5
100.0
99.6
1.1
101.2
101.8
101.4
101.5
21.
100.9
100.8
100.2
100.6
0.4
100.3
100.1
99.3
99.9
Tenofovir = Tenofovir Disoproxil fumarate.
Remark:
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All results were within the predetermined acceptance criteria. The uniformity of dosage units are met
the “readily passes” criteria.
Stage
Compression
Sampling location
Samples at every 10 minutes
Measured parameters
Uniformity of dosage units via content uniformity
Acceptance criteria
Redilypassess criteria RSD≤ 4.0 %,
Mean:90.0-110.0%
All individual results: 75.0- 125.0%
B.NO 12LT02
Lamivudine
Tenofovir
Time Interval
Sample No.
Sample No.
1
2
3
Average
RSD
1
2
3
Average
RSD
1.
101.3
99.4
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98.8
99.8
1.3
100.3
103.6
98.8
100.9
2.
99.4
99.0
99.0
99.1
0.3
99.7
99.7
99.4
99.6
3.
99.1
99.5
99.7
99.4
0.3
99.2
99.1
103.8
100.7
4.
100.0
100.1
100.1
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100.1
0.1
99.5
99.6
99.5
99.5
5.
99.3
100.9
98.4
99.5
1.3
99.3
99.8
98.2
99.1
6.
98.4
98.7
99.4
98.9
0.5
98.9
100.3
99.7
99.6
7.
98.8
99.5
98.4
98.9
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0.5
98.8
102.0
99.0
99.2
8.
99.9
100.1
100.0
100.0
0.1
99.7
99.6
102.2
100.5
9.
99.4
99.3
99.0
99.2
0.3
101.8
101.5
101.4
101.5
10.
99.0
99.3
99.0
99.1
0.2
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98.7
98.9
98.6
98.8
11.
100.4
100.1
101.2
100.6
0.6
99.8
99.5
99.8
99.7
12
101.3
101.4
100.7
101.1
0.4
99.9
104.0
99.5
101.1
.13
101.0
100.5
100.4
100.6
0.3
99.7
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100.0
100.1
99.9
14.
100.7
101.0
99.7
100.5
0.7
100.0
99.8
99.3
99.7
15.
101.4
100.6
100.2
100.8
0.6
101.4
99.9
99.2
100.2
16.
100.9
102.6
100.5
101.3
1.1
104.1
100.6
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101.3
102.0
17.
101.1
100.1
100.5
100.6
0.5
100.5
99.6
99.7
100.0
18.
100.9
100.5
100.6
100.7
0.2
99.8
99.5
102.3
100.6
19.
100.9
100.9
102.5
101.4
0.9
102.3
102.7
100.7
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101.9
20.
98.9
99.3
100.6
99.6
0.9
97.3
97.2
99.8
98.1
21.
100.4
99.8
101.2
100.5
0.7
99.5
99.7
99.9
99.7
Tenofovir = Tenofovir disoproxil fumarate
Remark:
All results were with predetermined acceptance criteria the uniformity of dosage units are met the
“readily passes” criteria.
Stage
Compression
Sampling location
Samples at every 10 minutes
Measured parameters
Uniformity of dosage units via content uniformity
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Acceptance criteria
Readily passes criteria RSD≤4.0 %,
Mean:90.0-110.0%
All individual results: 75.0- 125.0%
B.NO 12LT03
Lamivudine
Tenofovir
Time interval
Sample No.
Sample No.
1
2
3
average
RSD
1
2
3
average
1.
97.1
97.5
97.3
97.3
0.2
98.0
99.8
97.1
98.3
2.
99.3
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97.6
97.7
98.2
1.0
101.3
97.4
100.0
99.6
3.
97.5
96.9
99.5
98.0
1.4
98.2
96.7
100.5
98.4
4.
99.2
97.5
99.7
98.8
1.2
101.1
99.8
98.1
99.7
5.
99.7
97.3
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97.6
98.2
1.3
98.3
98.4
97.3
98.0
6.
100.0
97.7
97.8
98.5
1.3
99.9
99.9
97.4
99.1
7.
97.1
97.3
100.0
98.1
1.6
96.8
97.9
98.4
97.7
8.
100.0
97.8
97.6
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98.5
1.4
98.4
97.4
98.5
98.1
9.
99.5
97.6
98.4
98.5
1.0
101.2
98.8
98.7
99.5
10.
97.5
97.6
97.9
97.7
0.2
97.2
97.2
100.0
98.1
11.
101.5
101.5
100.9
101.3
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0.3
105.9
102.5
98.7
102.4
12
102.6
104.0
101.7
102.7
1.1
103.9
101.4
102.6
102.7
.13
101.8
102.7
101.0
101.8
0.8
102.4
103.8
98.7
101.7
14.
101.7
100.9
101.3
101.3
0.4
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103.6
101.2
100.7
101.9
15.
102.1
102.2
101.8
102.0
0.2
101.4
103.0
101.8
101.2
16.
101.5
102.o
102.4
102.0
0.5
100.3
106.2
103.2
103.2
17.
101.1
101.8
103.3
102.1
1.1
98.6
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100.9
101.8
21.
104.4
101.7
101.9
102.7
1.5
101.6
105.2
104.3
103.7
Tenofovir = Tenofovir disoproxil fumarate.
Remark:
All results were within the predetermined acceptance criteria. The uniformity of dosage units are met
the “readily passes” criteria.
STAGE: COMPRESSION (INITIAL)Batch No.
12LT01
12LT02
12LT03
S.No
Test
Test
Results
Results
Acceptance criteria
1.0
Uniformity of dosage unit
Lamivudine:3.3
Tenofovir:5.55
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3.3
4.3
0.7
3.8
Acceptance value of first 10 dosage unit is less than or equal to LI(LI is 15.0)
2.0
Uniformity of dosage unit
Lamivudine:1.4
Tenofovir:2.0
0.5
1.8
0.3
1.6
RSD is NMT 4.0%
STAGE: COMPRESSION (MIDDLE):
Batch No.
12LT01
12LT02
12LT03
S.No
Test
Test
Results
Results
Acceptance criteria
1.0
Uniformity of dosage unit
Lamivudine:3.0
Tenofovir:5.6
0.8
2.8
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4.4
2.8
Acceptance value of first 10 dosage unit is less than or equal to LI(LI is 15.0)
2.0
Uniformity of dosage unit
Lamivudine:1.2
Tenofovir:2.0
0.4
0.9
1.8
1.11
RSD is NMT 4.0%
STAGE : COMPRESSION (END)
Batch No.
12LT01
12LT02
12LT03
S.No
Test
Test
Results
Results
Acceptance criteria
1.0
Uniformity of dosage unit
Lamivudine:2.8
Tenofovir:7.0
1.6
4.3
3.5
3.4
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Acceptance value of first 10 dosage unit is less than or equal to LI(LI is 15.0)
2.0
Uniformity of dosage unit
Lamivudine:1.2
Tenofovir:1.0
0.7
1.7
1.5
1.4
RSD is NMT 4.0%
Remark:
The above results of validation batches shows that the Initial, Middle, End sample from compression
stage meets the acceptance criteria.
STAGE-COMPRESSION: Pooled samples
Product name
Lamivudine and Tenofovir disoproxil fumarate tablets.
Sampling location
S.No
Test
12LT001
12LT002
12LT003
1.
Description
Complies
Complies
Complies
2.
Average weight(mg)
1209
1208
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1205
3.
Disintegration Time(minutes)
2 minutes 07 seconds
3 minutes 56 seconds
4 minutes 01 seconds
4.
Friability (%)
0.0
0.04
0.04
5.0
Assay by HPLC (each core tablets contains).
Lamivudine
295.1mg
98.4%
302.6mg
100.9%
300.0mg
100.0%
Tenofovir Disoproxil Fumarate
292.3mg
97.4%
299.2mg
99.7%
304.0mg
101.3%
REMARK:
The above results of validation batch shows that, the compression process meets the acceptancecriteria.
STAGE- DISSOLUTION OF B.No. 12LT01
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Pooled samples from each lot
Dissolution:(single time point with 6 units)
Acceptance criteria
Not less than 75% (Q) of the labelled amount of Lamivudine and Tenofovir Disoproxil Fumarate is
dissolved in 30 minutes.
B.No. 12LT01
Lamivudine
Tenofovir Disoproxil Fumarate
Tablets
LOT-I
LOT- II
LOT- III
LOT- I
LOT- II
1.
97
98
101
95
99
2.
100
100
97
100
100
3.
97
100
97
99
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100
4.
100
100
97
97
97
5.
101
101
98
100
99
6.
96
97
97
95
94
Minimum
96
97
97
95
94
Maximum
101
101
101
100
100
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Average
98
99
98
98
98
STAGE- DISSOLUTION OF B.No. 12LT02
Pooled samples from each lot
Dissolution:(single time point with 6 units)
Acceptance criteria
Not less than 75% (Q) of the labelled amount of Lamivudine and Tenofovir disoproxil fumarate is
dissolved in 30 minutes.
B.No. 12LT02
Lamivudine
Tenofovir disoproxil fumarate
Tablets
LOT-I
LOT- II
LOT- III
LOT- I
LOT- II
1.
99
102
101
95
101
2.
104
101
99
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101
98
3.
105
101
104
103
101
4.
101
101
102
100
97
5.
101
104
101
98
101
6.
102
99
101
101
95
Minimum
99
99
99
95
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95
Maximum
105
104
104
103
101
Average
102
101
101
100
99
STAGE- DISSOLUTION OF B.No. 12LT03
Pooled samples from each lot
Dissolution:(single time point with 6 units)
Acceptance criteria
Not less than 75% (Q) of the labelled amount of Lamivudine and tenofovir disoproxil fumarate is
dissolved in 30 minutes.
B.No. 12LT03
Lamivudine
Tenofovir disoproxil fumarate
Tablets
LOT-I
LOT- II
LOT- III
LOT- I
LOT- II
1.
99
97
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98
99
96
2.
97
100
98
98
97
3.
96
97
100
95
98
4.
101
101
101
99
100
5.
99
101
101
96
100
6.
98
100
99
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99
100
Minimum
97
97
98
95
96
Maximum
101
101
101
99
100
Average
98
99
100
98
98
Remarks:
The above results of validation batches shows that the coating process meets the acceptance criteria.
The quality control results were reviewed and results are well within the acceptable limit. The validation
samples were collected as per the protocol and no deviation observed against the process validation
protocol.
STAGE- COATED TABLETS: pooled samples
Batch no.
12LT01
12LT02
12LT03
No
Test
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Results
results
results
Acceptance criteria
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
Description
Identification
A)by HBLC
b)By TLC
Average weight.
Uniformity of dosage units by content uniformity(By HPLC).
Dissolution (by HPLC) medium:0.1N hydrochloric acid:900ml at 37.0 ± 0.5ºC apparatus :USP type II
rotational speed:75 RPM
Water content (By KF)
Related substances (By HPLC) impurities of lamivudine any impurity
Impurities of tenofovirdisoproxilfumarate mono – POC PMPA
Mixed dimer
Dimer
Any unknown impurity
Any other unknown impurity
Total impurity
Assay (By HPLC) each film coated tablets contains lamivudine USP
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Tenofovirdisoproxilfumarate
Residual solvents
Microbial test a) total aerobic microbial count
b) total combined yeast and moldscount
c) Escherichia coli
A.R. NO
complies
complies
complies
1245
Lamivudine:2.9
Tenofovir : 6.2
Lami
vudine:- minimum: 100 maximum: 104 average : 101 tenofovir :- minimum : 95 maximum : 105 average
: 99
2.6
0.56
0.45
0.032
Below qualification limit
0.044
0.027
0.74
302.92 mg 101.0
301.5mg100.5%
---
Less than 10
Less than 10
Absent
Complies
Complies
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Complies
1241
Lamivudine:4.1
Tenofovir :1.9.
Lami
vudine:-minimum : 101 maximum : 105 average : 102 tenofovir :- minimum :100 maximum : 104
average : 102.
2.5
Not detected
0.39
0.034
0.047
0.077
0.051
0.89
298.7 mg 99.6%
295.7mg 98.6%
---
Less than 10
Less than 10
Absent
Complies
Complies
Complies
1245
Lamivudine:1.8
Tenofovir:4.9.
Lami
vudine:- minimum: 100 maximum: 104 average: 102 tenofovir:- minimum: 98 maximum: 102 average:99
2.7
Not detected
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0.41
0.033
0.033
0.060
0.065
0.73
301.7 mg 100.6%
303.1mg101.0%
---
Less than 10
Less than 10
Absent
white to off white, oval shaped, film coated tablets debossed with ‘RH80’’ on one side and plain on the
other.
The retention time of the major peak in the chromatogram of sample solution should corresponds to
that in the chromatogram obtained from the standard solution as directed under assay.
The position of the spots corresponding to tenofovir disoproxil fumarate, Lamivudine obtained in the
chromatogram of the respective standard solution should correspond to that of the spots obtained inthe chromatogram of the sample solution.
1236mg ± 35mg (1201mg to 1271mg).
Meets the requirement of USP<905>
Not less than 75% (Q) of the labelled amount of lamivudine and tenofovirdisoproxilfumarate is
dissolved in 30 minutes.
Not more than 4.0% w/w
Not more than 0.20%
Not more than 1.0%
Not more than 0.20%
Not more than 0.45%
Not more than 0.20%
Not more than 0.25%
Not less than 279.0mg to not more than 321.0mg (not less than 93.0% and not more than 107.0%
Not less than 279.0mg to not more than 321.0mg (not less than 93.0% to not more than 107.0%)
Complies with USP <467> criteria as per option 1.
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NMT 1000 CFU/g
NMT 100 CFU/g
Should be absent
SUMMARY
The process validation of the Lamivudine and Tenofovir disoproxil fumarate tablets of batch no were12LT01, 12LT02 and 12LT03was carried out and the process was challenged at certain stages like
sifting,granulation,mixing and drying and compression stages and it was found to satisfactory. It has
met the all predetermined specifications respectively as per the protocol mentioned.
CONCLUSION
The validation data results were evaluated and found to be satisfactory .The control variable, critical
steps and manufacturing process were reviewed and found to be satisfactory.
Overall it is evident that the process followed is capable of producing consistent result within the
predefined acceptance criteria for the batch 12LT01, 12LT02, 12LT03.The process validation werevalidated as per protocol.
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