Process Validation Of Lamivudine And Tenofovirdesoproxil Fumarate Tablets Biology Essay

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Process validation is establishing documented evidence which provides a high degree of assurance that a specific process (such as the manufacture of pharmaceutical dosage form) will consistently produce a product meeting its predetermined specifications and quality characteristics.

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:

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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, 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 Optimization

The 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:

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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 good validation 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

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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 calibrated sampling 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 the protocol 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 was discussed 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 DNA polymerases 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:

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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 7 minutes 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 Ã- 9.5mm, modified capsule shape , standard concave with bevelled edge with 'RH80'

Lower punch :20mmÃ-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 °C, exhaust:40 -50°C

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.

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

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

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.

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

-

-

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

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.

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

-

-

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

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

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

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 in process 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:2.03

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

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

-

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

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

-

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)

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

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

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