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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.



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.



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.



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



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.



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



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.



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



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.



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



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



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.



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



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.



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 )



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



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



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



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.



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.



Lamivudine

-

-

-

36.00

36.02

6.


Avicel PH 112

-

-

31.77

31.75

7.


Ceolus KG 802

-

-

21.00

21.00

8.


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


Quantity dispensed (kg)

1.

Opadry II white 31 k

-

-6.048

6.048

2.

Purified water

-

-

27.552

27.552


Batch Size

144.00kg

Batch No.

12LT02

S.NO




Grade

Material code

A.R. NO.


Intra granular:

1.

Tenofovir

Disoproxil

Fumarate

-

-

-

36.00

36.36

2.


Avicel PH 112

-

-

9.27

8.91

3.


AC-Di-sol

-

-

1.80

1.80



4.

Magnesium stearate

Vegetable

-

-

0.33

0.33

Extra granular :

5.

Lamivudine

-

36.00

36.02

6.


Avicel PH 112

--

-

31.77

31.75

7.


Cellulose KG 802

-

-

21.00

21.00

8.




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



1.


-

-

6.048

6.048

2.

Purified water

-

-



27.552

27.552

-


Batch Size

144.00kg

Batch No.

12LT03

S.NO


Grade

Material code

A.R. NO.


Intra granular:

1.


-

36.00

36.36

2.


Avicel PH 112

9.27

8.91

3.


AC-Di-sol

1.80

1.80

4.



Magnesium stearate

vegetable

0.33

0.33

Extra granular:

5.

Lamivudine

-

-

-36.00

36.02

6.


Avicel PH 112

-

-

31.77

31.75

7.


Cellulose KG 802

-

-

21.00

21.00

8.


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



1.


-

-

6.048

6.048

2.

Purified water

-

-

27.552



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



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



0.5 mm

2)Roll compacting the pre-mix of lot I,II,&III.

Roller speed: 12 RPM

Auger speed: 30 RPM

Time: 30mts


Auger speed: 30 RPM

Time: 30mts


Auger speed: 30 RPM

Time: 30mts

3)Roll compacting the fines collected from sifted through mesh size: #16


Auger speed: 30 RPM

Time: 30mts


Auger speed: 30 RPM

Time: 30mts


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



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



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



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



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



-

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



-

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: 2.16

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



Lot-II

Lot- III

Time taken for adding opadry II white 31k 58902 into purified water

12 minutes

14 minutes

13 minutes

-

Coating operation

-


2.5 RPM

2.5 RPM

2.5 RPM

-


3.5 kg/ cm

3.5kg/ cm

3.5 kg/ cm

-


1 mm

1 mm

1 mm

-


55 c

55 c

55 c

-




3 nos

3 nos

3 nos

-


15 RPM

15 RPM

15 RPM

-


23 cm

23 cm

23 cm

-


20 cm

20 cm

20 cm

-


57g/ min

57g/ min

57g/ min

-


Perpendicular

perpendicular

Perpendicular

-



Drying parameters: once the buildup is achieved

-

Parameters

Range

LOT-I

LOT-II

LOT-III

Pan speed


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





2.75-3.25%

3.07%


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



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

-


2.5 RPM

2.5 RPM

2.5 RPM

-


3.5 kg/ cm

3.5kg/ cm

3.5 kg/ cm

-


1 mm

1 mm

1 mm

-


55 c

55 c

55 c

-




3 nos

3 nos

3 nos

-


15 RPM

15 RPM

15 RPM

-


23 cm

23 cm

23 cm

-


20 cm

20 cm

20 cm

-


57g/ min

57g/ min

57g/ min

-


Perpendicular

perpendicular

Perpendicular



-

Drying parameters: once the buildup is achieved

LOT-III

Parameters

Range

LOT-I

LOT-II

2 RPM

Pan speed


2 RPM

2 RPM

55 c

Inlet temperature

45 C- 65 C

55 c

55 c


LOD at 800 c

NMT 2.5% w/w




2.75-3.25%

3.07%


0.86 kg

Yield reconciliation:

Stage

% Reconciliation

Pre-mix(1)



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



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



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



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



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




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



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.



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



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



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



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



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



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



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



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



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



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.



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:



All results were within the predetermined acceptance criteria. The uniformity of dosage units are met

the “readily passes” criteria.

Stage

Compression

Sampling location


Measured parameters


Acceptance criteria

Redilypassess criteria RSD≤ 4.0 %,

Mean:90.0-110.0%


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



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



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



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



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



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



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



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


Measured parameters




Acceptance criteria

Readily passes criteria RSD≤4.0 %,

Mean:90.0-110.0%


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



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



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



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



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



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



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



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


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


Lamivudine:3.0

Tenofovir:5.6

0.8

2.8



4.4

2.8


2.0


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


Lamivudine:2.8

Tenofovir:7.0

1.6

4.3

3.5

3.4




2.0


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



1205

3.

Disintegration Time(minutes)

2 minutes 07 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



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



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



Average

98

99

98

98

98




Acceptance criteria

Not less than 75% (Q) of the labelled amount of Lamivudine and Tenofovir disoproxil fumarate is


B.No. 12LT02

Lamivudine


Tablets

LOT-I

LOT- II

LOT- III

LOT- I

LOT- II

1.

99

102

101

95

101

2.

104

101

99



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



95

Maximum

105

104

104

103

101

Average

102

101

101

100

99




Acceptance criteria

Not less than 75% (Q) of the labelled amount of Lamivudine and tenofovir disoproxil fumarate is


B.No. 12LT03

Lamivudine


Tablets

LOT-I

LOT- II

LOT- III

LOT- I

LOT- II

1.

99

97



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



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



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



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



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



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


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.



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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