D[1]

Injection Drug Description

CARNITOR®(levocarnitine) Injection 1 g per 5 mL vial

FOR INTRAVENOUS USE ONLY.

DRUG DESCRIPTION

CARNITOR® (levocarnitine) is a carrier molecule in the transport of long-chain fatty acids across the inner mitochondrial membrane.

The chemical name of levocarnitine is 3-carboxy-2(R)-hydroxy-N,N,N-trimethyl-1-propanaminium, inner salt. Levocarnitine is a white crystalline, hygroscopic powder. It is readily soluble in water, hot alcohol, and insoluble in acetone. The specific rotation of levocarnitine is between -29° and -32°. Its chemical structure is:

Empirical Formula: C7H15NO3

Molecular Weight: 161.20

CARNITOR® (levocarnitine) Injection is a sterile aqueous solution containing 1 g of levocarnitine per 5 mL vial. The pH is adjusted to 6.0 - 6.5 with hydrochloric acid or sodium hydroxide.

Last reviewed on RxList: 5/28/2009This monograph has been modified to include the generic and brand name in many instances.

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Carnitor Injection Indications & Dosage

INDICATIONS

For the acute and chronic treatment of patients with an inborn error of metabolism which results in secondary carnitine deficiency.

For the prevention and treatment of carnitine deficiency in patients with end stage renal disease who are undergoing dialysis. (US Patent Nos. 6,335,369; 6,429,230; 6,696,493)

DOSAGE AND ADMINISTRATION

CARNITOR® (levocarnitine injection) Injection is administered intravenously.

Metabolic Disorders

The recommended dose is 50 mg/kg given as a slow 2-3 minute bolus injection or by infusion. Often a loading dose is given in patients with severe metabolic crisis, followed by an equivalent dose over the following 24 hours. It should be administered q3h or q4h, and never less than q6h either by infusion or by intravenous injection. All subsequent daily doses are recommended to be in the range of 50 mg/kg or as therapy may require. The highest dose administered has been 300 mg/kg.

It is recommended that a plasma carnitine concentration be obtained prior to beginning this parenteral therapy. Weekly and monthly monitoring is recommended as well. This monitoring should include blood chemistries, vital signs, plasma carnitine concentrations (the plasma free carnitine concentration should be between 35 and 60 µmol/L) and overall clinical condition.

ESRD Patients on Hemodialysis

The recommended starting dose is 10-20 mg/kg dry body weight as a slow 2-3 minute bolus injection into the venous return line after each dialysis session. Initiation of therapy may be prompted by trough (pre-dialysis) plasma levocarnitine concentrations that are below normal

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(40-50 µmol/L). Dose adjustments should be guided by trough (pre-dialysis) levocarnitine concentrations, and downward dose adjustments (e.g. to 5 mg/kg after dialysis) may be made as early as the third or fourth week of therapy.

Parenteral drug products should be inspected visua ly for particulate matter and discoloration prior to administration, whenever solution and container permit.

Compatibility And Stability

CARNITOR® (levocarnitine injection) Injection is compatible and stable when mixed in parenteral solutions of Sodium Chloride 0.9% or Lactated Ringer's in concentrations ranging from 250 mg/500 mL (0.5 mg/mL) to 4200 mg/500 mL (8.0 mg/mL) and stored at room temperature (25°C) for up to 24 hours in PVC plastic bags.

HOW SUPPLIED

CARNITOR® (levocarnitine) Injection is available in 1 g per 5 mL single dose vials packaged 5 vials per carton (NDC 54482-147-01). CARNITOR® (levocarnitine) Injection 5 mL vial is manufactured for Sigma-Tau Pharmaceuticals, Inc. by Sigma-Tau S.p.A., 00040 Pomezia (Rome), Italy or Chesapeake Biological Laboratories, Inc. Baltimore, MD 21230-2591.

Store vials at controlled room temperature (25°C). See USP. Discard unused portion of an opened vial, as the formulation does not contain a preservative.

CARNITOR® (levocarnitine) is also available in the following dosage forms:

CARNITOR® (levocarnitine) Tablets are supplied as 330 mg tablets embossed with “CARNITOR ST” in blister packages, in boxes of 90 tablets (NDC 54482-144-07). Made in Italy.

CARNITOR® (levocarnitine) Oral Solution is supplied in 118 mL (4 FL. OZ.) multiple-unit plastic cotainers. The multiple-unit containers are packaged 24 per case (NDC 54482-145-08). CARNITOR® (levocarnitine) Oral Solution is manufactured for Sigma-Tau Pharmaceuticals, Inc. by Hi-Tech Pharmacal Co., Inc., Amityville, NY 11701.

Sigma-tau Pharmaceuticals, Inc. Gaithersburg, MD 20877. Date of Issue: 03/04


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nitor Injection Side Effects & Drug Interactions

SIDE EFFECTS

Transient nausea and vomiting have been observed. Less frequent adverse reactions are body odor, nausea, and gastritis. An incidence for these reactions is difficult to estimate due to the confounding effects of the underlying pathology.

Seizures have been reported to occur in patients, with or without pre-existing seizure activity, receiving either oral or intravenous levocarnitine. In patients with pre-existing seizure activity, an increase in seizure frequency and/or severity has been reported.

The table below lists the adverse events that have been reported in two double-blind, placebo-controlled trials in patients on chronic hemodialysis. Events occurring at ≥ 5% are reported without regard to causality.

Adverse Events with a Frequency ≥ 5% Regardless of Causality by Body System

DRUG INTERACTIONS

No information provided.


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Carnitor Injection - User Reviews

Carnitor Injection User Reviews

Now you can gain knowledge and insight about a drug treatment with Patient Discussions.

Here is a collection of user reviews for the medication Carnitor Injection sorted by most helpful.

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Carnitor Injection Warnings & Precautions

WARNINGS

None.

PRECAUTIONS

The safety and efficacy of oral levocarnitine has not been evaluated in patients with renal insufficiency. Chronic administration of high doses of oral levocarnitine in patients with severely compromised renal function or in ESRD patients on dialysis may result in accumulation of the potentially toxic metabolites, trimethylamine (TMA) and trimethylamine-N-oxide (TMAO), since these metabolites are normally excreted in the urine.

Carcinogenesis, mutagenesis, impairment of fertility

Mutagenicity tests performed in Salmonella typhimurium, Saccharomyces cerevisiae, and Schizosaccharomyces pombeindicate that levocarnitine is not mutagenic. No long-term animal studies have been performed to evaluate the carcinogenic potential of levocarnitine.















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Pregnancy

Pregnancy Category B.

Reproductive studies have been performed in rats and rabbits at doses up to 3.8 times the human dose on the basis of surface area and have revealed no evidence of impaired fertility or harm to the fetus due to CARNITOR® (levocarnitine injection) . There are, however, no adequate and well controlled studies in pregnant women.

Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Nursing Mothers

Levocarnitine supplementation in nursing mothers has not been specifically studied.

Studies in dairy cows indicate that the concentration of levocarnitine in milk is increased following exogenous administration of levocarnitine. In nursing mothers receiving levocarnitine, any risks to the child of excess carnitine intake need to be weighed against the benefits of levocarnitine supplementation to the mother. Consideration may be given to discontinuation of nursing or of levocarnitine treatment.

Pediatric Use

See DOSAGE AND ADMINISTRATION.



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Carnitor Injection Overdosage & Contraindications

OVERDOSE

There have been no reports of toxicity from levocarnitine overdosage. Levocarnitine is easily removed from plasma by dialysis. The intravenous LD50 of levocarnitine in rats is 5.4 g/kg and the oral LD50 of levocarnitine in mice is 19.2 g/kg. Large doses of levocarnitine may cause diarrhea.

CONTRAINDICATIONS

None known.


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Carnitor Injection Overdosage & Contraindications

OVERDOSE

There have been no reports of toxicity from levocarnitine overdosage. Levocarnitine is easily removed from plasma by dialysis. The intravenous LD50 of levocarnitine in rats is 5.4 g/kg and the oral LD50 of levocarnitine in mice is 19.2 g/kg. Large doses of levocarnitine may cause diarrhea.

CONTRAINDICATIONS

None known.



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Carnitor Injection Clinical Pharmacology

CLINICAL PHARMACOLOGY

CARNITOR® (levocarnitine) is a naturally occurring substance required in mammalian energy metabolism. It has been shown to facilitate long-chain fatty acid entry into cellular mitochondria, thereby delivering substrate for oxidation and subsequent energy production. Fatty acids are utilized as an energy substrate in all tissues except the brain. In skeletal and cardiac muscle, fatty acids are the main substrate for energy production.

Primary systemic carnitine deficiency is characterized by low concentrations of levocarnitine in plasma, RBC, and/or tissues. It has not been possible to determine which symptoms are due to carnitine deficiency and which are due to an underlying organic acidemia, as symptoms of both abnormalities may be expected to improve with CARNITOR® (levocarnitine injection) . The literature reports that carnitine can promote the excretion of excess organic or fatty acids in patients with defects in fatty acid metabolism and/or specific organic acidopathies that bioaccumulate acylCoA esters.1-6

Secondary carnitine deficiency can be a consequence of inborn errors of metabolism or iatrogenic factors such as hemodialysis. CARNITOR® (levocarnitine injection) may alleviate the metabolic abnormalities of patients with inborn errors that result in accumulation of toxic organic acids. Conditions for which this effect has been demonstrated are: glutaric aciduria II, methyl malonic aciduria, propionic acidemia, and medium chain fatty acylCoA dehydrogenase deficiency.7,8 Autointoxication occurs in these patients due to the accumulation of acylCoA compounds that disrupt intermediary metabolism. The subsequent hydrolysis of the acylCoA compound to its free acid results in acidosis which can be life-threatening. Levocarnitine clears the acylCoA compound by formation of acylcarnitine, which is quickly excreted. Carnitine deficiency is defined biochemically as abnormally low plasma concentrations of free carnitine, less than 20 µmol/L at one week post term and may be associated with low tissue and/or urine concentrations. Further, this condition may be associated with a plasma concentration ratio of acylcarnitine/levocarnitine greater than 0.4 or abnormally elevated concentrations of acylcarnitine in the urine. In premature infants and newborns, secondary deficiency is defined as plasma levocarnitine concentrations below age-related normal concentrations.

End Stage Renal Disease (ESRD) patients on maintenance hemodialysis may have low plasma carnitine concentrations and an increased ratio of acylcarnitine/carnitine because of reduced intake of meat and dairy products, reduced renal synthesis and dialytic losses. Certain clinical conditions common in hemodialysis patients such as malaise, muscle weakness, cardiomyopathy and cardiac arrhythmias may be related to abnormal carnitine metabolism.

Pharmacokinetic and clinical studies with CARNITOR® have shown that administration of levocarnitine to ESRD patients on hemodialysis results in increased plasma levocarnitine concentrations.


















Pharmacokinetics

In a relative bioavailability study in 15 healthy adult male volunteers, CARNITOR® (levocarnitine injection) Tablets were found to be bio-equivalent to CARNITOR® (levocarnitine injection) Oral Solution. Following 4 days of dosing with 6 tablets of CARNITOR® (levocarnitine injection) 330 mg b.i.d. or 2 g of CARNITOR® (levocarnitine injection) oral solution b.i.d., the maximum plasma concentration (Cmax) was about 80 µmol/L and the time to maximum plasma concentration (Tmax) occurred at 3.3 hours.

The plasma concentration profiles of levocarnitine after a slow 3 minute intravenous bolus dose of 20 mg/kg of CARNITOR® (levocarnitine injection) were described by a two-compartment model. Following a single i.v. administration, approximately 76% of the levocarnitine dose was excreted in the urine during the 0-24h interval. Using plasma concentrations uncorrected for endogenous levocarnitine, the mean distribution half life was 0.585 hours and the mean apparent terminal elimination half life was 17.4 hours.

The absolute bioavailability of levocarnitine from the two oral formulations of CARNITOR® (levocarnitine injection) , calculated after correction for circulating endogenous plasma concentrations of levocarnitine, was 15.1 ± 5.3% for CARNITOR® (levocarnitine injection) Tablets and 15.9 ± 4.9% for CARNITOR® Oral Solution.

Total body clearance of levocarnitine (Dose/AUC including endogenous baseline concentrations) was a mean of 4.00 L/h.

Levocarnitine was not bound to plasma protein or albumin when tested at any concentration or with any species including the human.9

In a 9-week study, 12 ESRD patients undergoing hemodialysis for at least 6 months received CARNITOR® (levocarnitine injection) 20 mg/kg three times per week after dialysis. Prior to initiation of CARNITOR® therapy, mean plasma levocarnitine concentrations were approximately 20 µmol/L pre-dialysis and 6 µmol/L post-dialysis. The table summarizes the pharmacokinetic data (mean ± SD µmol/L) after the first dose of CARNITOR® (levocarnitine injection) and after 8 weeks of CARNITOR® (levocarnitine injection) therapy.

After one week of CARNITOR® (levocarnitine injection) therapy (3 doses), all patients had trough concentrations between 54 and 180 µmol/L (normal 40-50 µmol/L) and concentrations remained relatively stable or increased over the course of the study.

In a similar study in ESRD patients also receiving 20 mg/kg CARNITOR® (levocarnitine injection) 3 times per week after hemodialysis, 12- and 24-week mean pre-dialysis (trough) levocarnitine concentrations were 189 (N=25) and 243 (N=23) µmol/L, respectively.

In a dose-ranging study in ESRD patients undergoing hemodialysis, patients received 10, 20, or 40 mg/kg CARNITOR® (levocarnitine injection) 3 times per week following dialysis (N~30 for each dose group). Mean ± SD trough levocarnitine concentrations (µmol/L) by dose after 12 and 24 weeks of therapy are summarized in the table.


12 weeks 24 weeks10 mg/kg 116 ± 69 148 ± 5020 mg/kg 210 ± 58 240 ± 6040 mg/kg 371 ± 111 456 ± 162

While the efficacy of CARNITOR® (levocarnitine injection) to increase carnitine concentrations in patients with ESRD undergoing dialysis has been demonstrated, the effects of supplemental carnitine on the signs and symptoms of carnitine deficiency and on clinical outcomes in this population have not been determined.

Metabolism And Excretion

In a pharmacokinetic study where five normal adult male volunteers received an oral dose of [3H-methyl]-L-carnitine following 15 days of a high carnitine diet and additional carnitine supplement, 58 to 65% of the administered radioactive dose was recovered in the urine and feces in 5 to 11 days. Maximum concentration of [3H-methyl]-L-carnitine in serum occurred from 2.0 to 4.5 hr after drug administration. Major metabolites found were trimethylamine N-oxide, primarily in urine (8% to 49% of the administered dose) and [3H]-γ-butyrobetaine, primarily in feces (0.44% to 45% of the administered dose). Urinary excretion of levocarnitine was about 4 to 8% of the dose. Fecal excretion of total carnitine was less than 1% of the administered dose.10

After attainment of steady state following 4 days of oral administration of CARNITOR® (levocarnitine injection) Tablets (1980 mg q12h) or Oral Solution (2000 mg q12h) to 15 healthy male volunteers, the mean urinary excretion of levocarnitine during a single dosing interval (12h) was about 9% of the orally administered dose (uncorrected for endogenous urinary excretion).

REFERENCES

1. Bohmer, T., Rydning, A. and Solberg, H.E. 1974. Carnitine levels in human serum in health and disease. Clin. Chim. Acta57:55-61.

2. Brooks, H., Goldberg, L., Holland, R. et al. 1977. Carnitine-induced effects on cardiac and peripheral hemodynamics. J. Clin. Pharmacol.17:561-568.

3. Christiansen, R., Bremer, J. 1976. Active transport of butyrobetaine and carnitine into isolated liver cells. Biochim. Biophys. Acta448:562-577.

4. Lindstedt, S. and Lindstedt, G. 1961. Distribution and excretion of carnitine in the rat. Acta Chem. Scand.15:701-702.

5. Rebouche, C.J. and Engel, A.G. 1983. Carnitine metabolism and deficiency syndromes. Mayo Clin. Proc.58:533-540.

6. Rebouche, C.J. and Paulson, D.J. 1986. Carnitine metabolism and function in humans. Ann. Rev. Nutr.6:41-66.

7. Scriver, C.R., Beaudet, A.L., Sly, W.S. and Valle, D. 1989. The Metabolic Basis of Inherited Disease. New York: McGraw-Hill.

8. Schaub, J., Van Hoof, F. and Vis, H.L. 1991. Inborn Errors of Metabolism. New York: Raven Press.

9. Marzo, A., Arrigoni Martelli, E., Mancinelli, A., Cardace, G., Corbelletta, C., Bassani, E. and Solbiati, M.1991. Protein binding of L-carnitine family components. Eur. J. Drug Met. Pharmacokin., Special Issue III: 364-368.

10. Rebouche, C.J. 1991. Quantitative estimation of absorption and degradation of a carnitine supplement by human adults. Metabolism 40:1305-1310.



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Carnitor Injection Medication Guide

PATIENT INFORMATION

No information provided. Please refer to the WARNINGS and PRECAUTIONS sections.



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Carnitor Injection Consumer

IMPORTANT: HOW TO USE THIS INFORMATION: This is a summary and does NOT have all possible information about this product. This information does not assure that this product is safe, effective, or appropriate for you. This information is not individual medical advice and does not substitute for the advice of your health care professional. Always ask your health care professional for complete information about this product and your specific health needs.

LEVOCARNITINE - INJECTION

(lee-voh-KAR-nih-teen)

COMMON BRAND NAME(S): Carnitor

USES: This medication is used to prevent and treat low blood levels of carnitine. Carnitine is a substance made in the body from meat and dairy products. It helps the body use certain chemicals (long-chain fatty acids) for energy and to keep you in good health. Low blood levels of carnitine may occur in people whose bodies cannot properly use carnitine from their diets, people on dialysis due to serious kidney disease, and people being treated with certain drugs (e.g., valproic acid, zidovudine). Carnitine levels that are too low can cause liver, heart, and muscle problems.

The injectable form of this drug is recommended if you have serious kidney disease (e.g., ESRD/dialysis) because high doses of the form taken by mouth may increase the risk of serious side effects. Consult your doctor or pharmacist for details.

HOW TO USE: This medication is given into a vein by slow injection or through an IV, as directed by your doctor. The dosage is based on your weight, medical condition, and response to therapy.

If you are giving this medication to yourself at home, learn all preparation and usage instructions from your health care professional. Before using, check this product visually for





particles or discoloration. If either is present, do not use the liquid. Learn how to store and discard medical supplies safely.

Inform your doctor if your condition persists or worsens.


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LEVOCARNITINE DRUG

ON

“Process Validation of Levofloxacin Tablet as a Oral Dosage Form””

Submitted in partial fulfillment of theRequirements for 2nd semester of

Master of PharmacyIn

Pharmaceutics

Supervised by: Submitted by:

Mr.Amit Upadhay SABNISH Lecturer M.Pharm. IInd Sem.

M.Pharm. ROLL No. -05900756010

SHIVDAN SINGH INSTITUTE

OF

TECHNOLOGY & MANAGEMENT(Department of Pharmaceutical Sciences).

Aligarh, (U P)

Affiliated to

GAUTAM BUDDHA TECHNICAL UNIVERSITYLUCKNOW (U.P.)

INDEX

Sr. No. Contents Page No.

1.0Introduction

2-5

2.0 Objective 6-7

3.0 Drug Profile 8-10

4.0Review of literature

11-13

5.0 Proposed Methodology During Research 14

6.0 List of abbreviations 15

7.0 References 16-18

INTRODUCTION

Validation is documentary evidence which demonstration that ongoing process is working on

pre determine specification it is of following type.

Prospective validation is conducted before a new product is released for distribution or,

where the revisions may affect the product’s characteristics, before a product made under

a revised manufacturing process is released for distribution.

Concurrent validation is subset of prospective validation and is conducted with the

intention of ultimately distributing product manufactured during the validation study.

Retrospective Validation is the validation of a process based on accumulated historical

production, testing, control and other information for a product already in production and

distribution.

Validation of equipment is divided in four phases. (Design qualification, installation

qualification, operational qualification and performance qualification). Design qualification

defines the functional & operational requirement and specification of the instrument and

details the conscious decision in the selection of supplier. Design qualification ensures that

instrument has all the necessary function and performance criteria that will enable them to be

successfully implemented for the intended application to met business requirements.

Operational qualification is the process of demonstrating that an instrument will function

according to its operational specification in the selected environment. Performance

qualification is the process of demonstrating that an instrument consistently performs

according to a specification appropriate for its routine use. This establishes confidence that

process is effective and reproducible. In process validation studies each and every process

related to manufacturing and analysis of raw material to finished product is validated as per

recommended guidelines like USFDA, ISO, and ICH. All equipment used in manufacturing and

analysis must be validated as per recommended guidelines like USFDA, ISO, ICH, WHO.

The FDA interprets sub part F section 211.100(a) of the current good manufacturing regulation

for drug product to mean that pharmaceutical process must be validated these two section of the

regulation are presented following:

Section 211.100(a) - “there shall be written procedure for production and process control

designed to assure that the drug product have the identity, strength, quality and purity they

represented to posses. Such procedure shall include all requirements in the subpart. These

written procedure including any changes, shall be drafted, review and approved by the

appropriate organizational units and reviewed and approved by the quality control unit.”

Section 211.110(a) – “to assure batch uniformity and integrity of drug product, written

procedure shall be established and followed that describe the in process control, and test or

examination to be conducted on appropriate sample of in process material of each batch. Such

control procedure shall be established to monitor the output and to validate the performance

these manufacturing process that may be responsible for causing variability in the

characteristics of in process material.

Levofloxacin hemihydrate tablet 750mg shall be manufactured using the Wet Granulation

Technology. The dissolution profile of the Exhibit batches shall be compared with the

dissolution profile of the innovator batch of this product. The batches manufactured during

the validation shall be setup for the stability study and other parameters monitored

periodically and shall be reviewed by the validation task force.

Types Of Process Validation 1: Depending on when it is performed in relation to production,

validation can be prospective, concurrent, and retrospective or revalidation (repeated

validation).Prospective validation is carried out during the development stage by means of a

risk analysis of the production process, which is broken down into individual steps: these are

then evaluated on the basis of past experience to determine whether they might lead to

critical situations. Where possible critical situations are identified, the risk is evaluated, the

potential causes are investigated and assessed for probability and extent, the trial plans are

drawn up, and the priorities set. The trials are then performed and evaluated, and an overall

assessment is made. If, at the end, the results are acceptable, the process is satisfactory.

Unsatisfactory processes must be modified and improved until a validation exercise proves

them to be satisfactory. This form of validation is essential in order to limit the risk of errors

occurring on the production scale, e.g. in the preparation of inject able products.

Concurrent validation is carried out during normal production. This method is effective only if

the development stage has resulted in a proper understanding of the fundamentals of the

process. The first three production-scale batches must be monitored as comprehensively as

possible. The nature and specifications of subsequent in-process and final tests are based on

the evaluation of the results of such monitoring. This careful monitoring of the first three

production batches is sometimes regarded as prospective validation. Concurrent validation

together with a trend analysis including stability should be carried out to an appropriate

extent throughout the life of the product.

Retrospective validation involves the examination of past experience of production on the

assumption that composition, procedures, and equipment remain unchanged; such

experience and the results of in-process and final control tests are then evaluated. Recorded

difficulties and failures in production are analyzed to determine the limits of process

parameters. A trend analysis may be conducted to determine the extent to which the process

parameters are within the permissible range.

Retrospective validation is obviously not a quality assurance measure in itself, and should

never be applied to new processes or products. It may be considered in special circumstances

only, e.g. when validation requirements are first introduced in a company. Retrospective

validation may then be useful in establishing the priorities for the validation programmer. If

the results of a retrospective validation are positive, this indicates that the process is not in

need of immediate attention and may be validated in accordance with the normal schedule.

For tablets which have been compressed under individual pressure-sensitive cells, and with

qualified equipment, retrospective validation is the most comprehensive test of the overall

manufacturing process of this dosage form. On the other hand, it should not be applied in the

manufacture of sterile products.

Revalidation is needed to ensure that changes in the process and/or in the process

environment, whether intentional or unintentional, do not adversely affect process

characteristics and product quality. Revalidation may be divided into two broad categories:

• Revalidation after any change having a bearing on product quality.

• Periodic revalidation carried out at scheduled intervals.

Revalidation after changes Revalidation must be performed on introduction of any changes

affecting a manufacturing and/or standard procedure having a bearing on the established

product performance characteristics. Such changes may include those in starting material,

packaging material, manufacturing processes, equipment, in-process controls, manufacturing

areas, or support systems (water, steam, etc.). Every such change requested should be

reviewed by a qualified validation group, which will decide whether it is significant enough to

justify revalidation and, if so, its extent.

Revalidation after changes may be based on the performance of the same tests and activities

as those used during the original validation, including tests on sub processes and on the

equipment concerned. Some typical changes which require revalidation include the following:

• Changes in the starting material(s). Changes in the physical properties, such as density,

viscosity, particle size distribution, and crystal type and modification, of the active ingredients

or excipients may affect the mechanical properties of the material; as a consequence, they

may adversely affect the process or the product.

• Changes in the packaging material, e.g. replacing plastics by glass, may require changes in

the packaging procedure and therefore affect product stability.

• Changes in the process, e.g. changes in mixing time, drying temperature and cooling regime,

may affect subsequent process steps and product quality.

• Changes in equipment, including measuring instruments, may affect both the process and

the product; repair and maintenance work, such as the replacement of major equipment

components, may affect the process.

• Changes in the production area and support system, e.g. the rearrangement of

manufacturing areas and/or support systems, may result in changes in the process. The repair

and maintenance of support systems, such as ventilation, may change the environmental

conditions and, as a consequence, revalidation/requalification may be necessary, mainly in the

manufacture of sterile products.

• Unexpected changes and deviations may be observed during self-inspection or audit, or

during the continuous trend analysis of process data. Periodic revalidation it is well known

that process changes may occur gradually even if experienced operators work correctly

according to established methods. Similarly, equipment wear may also cause gradual changes.

Consequently, revalidation at scheduled times is advisable even if no changes have been

deliberately made.

OBJECTIVE

The objective of this exercise is to develop a process validation protocol to validate the

process and have documented evidence to ensure that Critical process variables are checked

during validation. Also to demonstrate the process Capability of the product meets it’s

predetermined specifications and quality Attributes. This protocol for the process validation

of Levofloxacin hemi hydrate tablets 750 mg formulation defines the procedural aspects to be

followed while carrying out Process validation activity that includes prerequisites before

commencing the actual work like, Master formula and process, approved vendors and

characteristics of raw materials. Also it defines the acceptance criteria, re-validation criteria

and justification for critical process parameters.

Process validation is used to confirm that the resulting product from a specified process

consistently conforms to product requirements. A risk-based approach to process validation

provides a rational framework for developing an appropriate scope for validation activities,

focusing on processes that have the greatest potential risk to product quality. This article

presents a case study in which a risk-based approach was used to

Evaluate a typical mammalian cell culture and purification process. This risk assessment used a

Failure Modes and Effects Analysis (FMEA) to evaluate the impact of potential failures and the

likelihood of their occurrence for each unit operation. Unit operations included in the process

validation required a risk priority number greater than or equal to a specified threshold value.

Unit operations that fell below the threshold were evaluated for secondary criteria such as

regulatory expectations or historical commitments. The risk assessment covered the entire

process and a portion of the assessment is reviewed here.

Process validation is a requirement defined in the ICH Q7A guideline, Good Manufacturing

Practice Guidance for Active Pharmaceutical Ingredients as "the documented evidence that

the process, operated within established parameters, can perform effectively and reproducibly

to produce an intermediate or API meeting its predetermined specifications and quality

attributes." A similar requirement is specified in The Code of Federal Regulations, Title 21—

Food and Drugs; Part 820: Quality Systems regulation, which states that a "process shall be

validated with a high degree of assurance

Because these requirements focus on ensuring safe and effective product for use, validating

processes or unit operations that have direct effect on product quality is critical. For processes

or unit operations that do not directly affect product quality, there is an opportunity to apply

risk management principles to make risk-based decisions about whether to include non-critical

processes in a formal validation package. This risk-based approach is supported in the FDA's

concept paper, "Pharmaceutical cGMPs for the Twenty-First Century: A Risk-Based Approach.

To make risk-based decisions, a systematic approach is essential. The ICH Q9 guideline, Quality

Risk Management, provides a structure to initiate and follow a risk management process.

Drug profile

Levofloxacin, (-) S-9- fluoro-2, 3-dihydro-3-methyl-10-(4-methyl-1-piperazinly)-7-oxo-7H-pyrido

[1, 2, 3,-de]-1,4-benzoxazine-6-carboxylic acid hemihydrates. Levofloxacin is a chiral

fluorinated carboxyquinolone, A Racemate of Ofloxacin. It is S-(-) isomer of the

fluoroquinolone antibacterial Ofloxacin and have broad-spectrum antimicrobial 1, 2 activity

and penetrates well into cerebrospinal fluid (CSF), bone tissue, bronchial mucosa, and

subcutaneous adipose tissues. Levofloxacin is very effective against both gram negative and

gram positive bacteria. Levofloxacin is given as the hemihydrate, but doses are expressed in

terms of the base; Levofloxacin Hemihydrate 750 mg is equivalent to about 750 mg of the

base. Levofloxacin is given by mouth or intravenously to treat susceptible infections.

Structure:

C18H20FN3O4 1/2H2O Mol Wt 370.38

Figure No .1

Structure: Levofloxacin hemihydrate

Mechanism of action:

Levofloxacin inhibits bacterial type II topoisomerases, topoisomerase IV and DNA gyrase.

Levofloxacin, like other fluoroquinolones, inhibits the A subunits of DNA gyrase, two subunits

encoded by the gyrA gene. This results in strand breakage on a bacterialv chromosome,

super coiling, and resealing; DNA replication and transcription.

Figure No.2

Mechanism of action of levofloxacin hemihydrate

Pharmacokinetics:

1) Absorption: Orally administered Levofloxacin is rapidly and almost completely absorbed

with peak plasma concentrations being obtained within 1 h. The absolute bioavailability is

approximately 100 %. Levofloxacin obeys linear pharmacokinetics over a range of 50 to600

mg. Food has little effect on the absorption of Levofloxacin.2) Distribution: Approximately 30 - 40 % of Levofloxacin is bound to serum protein.500mgonce

daily multiple dosing with Levofloxacin showed negligible accumulation. There is modest but

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predictable accumulation of Levofloxacin after doses of 500 mg twice daily. Steady-state is

achieved within 3 days.

3) Metabolism & Elimination: Levofloxacin is metabolized to a very small extent, the

metabolites being desmethyl Levofloxacin and Levofloxacin N-oxide. These metabolites

account for < 5 % of the dose excreted in urine. Levofloxacin is stereo chemically stable and

does not undergo chiral inversion. Following oral and intravenous administration of

Levofloxacin, it is eliminated relatively slowly from the plasma (t½: 6 - 8 h). Excretion is

primarily by the renal route > 85 % of the administered dose).There are no major differences

in the pharmacokinetics of Levofloxacin following intravenous and oral administration,

suggesting that the oral and intravenous routes are interchangeable.

Renal impairment: The pharmacokinetics of Levofloxacin is affected by renal impairment. With

decreasing renal function renal elimination and clearance are decreased, and elimination half-

lives increased as shown in the table below:

ClCR [ml/min] < 20 20 - 40 50 - 80

ClR [ml/min] 13 26 57

T1/2 [h] 35 27 9

4) Indications And Usage: This drug is recommended for use against a wide variety of

infections when susceptibility is demonstrated. This May be safe for use for patients taking

theophylline, warfarin, or cyclosporin. Specific dosage regimes are at the discretion of the

attending physician acting on information from the manufacturer and the national authority

for drug safety and use. Suggested dosages for specific agents may be on the individual agent

pages

REVIEW OF LITERATURE

1.Gupta Vivek, Bonde C.G. have reported5 the Statistical Assurance of Process Validation By

Analytical Method Development and Validation for Levofloxacin IR Tablets and Blend A new

simple, rapid and reliable UV Spectrophotometric method was developed and validated for

the estimation of Levofloxacin Hemi hydrate in blend & tablets formulations. The method was

based on simple UV estimation in cost effective manner for regular laboratory analysis. The

instrument used was Perkin Elmer, UV Spectrophotometer (Lambda 25) and using 0.1 N HCl as

solvent system. Sample was analyzed using UV Win Lab 5.2.0 Software and matched quartz

cells 1 cm and was monitored at 293.7 nm. Levofloxacin was used as an internal standard.

Linearity was obtained in the concentration range of 2 - 10 mg mL–1 for Levofloxacin

hemihydrates. The validation parameters, tested in accordance with the requirements of ICH

guidelines, prove the suitability of this method. Spectrophotometric interferences from the

tablet excipients were not found. Statically tools of ANNOVA and Boneforri’s multiple tests

were implemented on results of blend uniformity and content uniformity, done on process

validation batches samples, Vol.1, No.3, pp 921-924, July-Sept 2009.

2.Guidance for Industry Process Validation:6 General Principles and Practices For purposes of

this guidance, process validation is defined as the collection and evaluation of data, from the

process design stage throughout production, which establishes scientific evidence that a

process is capable of consistently delivering quality products. Process validation involves a

series of activities taking place over the lifecycle of the product and process. This guidance

describes the process validation activities in three stages.

Stage 1 – Process Design : the commercial process is defined during this stage based on

knowledge gained through development and scale-up technology

Stage 2 – Process Qualification : during this stage, the process design is confirmed as being

capable of reproducible commercial manufacturing.

Stage 3 – Continued Process Verification : ongoing assurance is gained during routine

production that the process remain in state of control

November 2008 Current Good Manufacturing Practices (CGMP), United state Food and drug

administration

4. MHRA, 2007, (sixth edition in 2002.)7 Rules and Guidance for Pharmaceutical Manufacturers

and Distributors, (“Orange Guide”) Compiled by the Inspection and Standards Division of the

Medicines and Healthcare products Regulatory Agency, The principles and guidelines of GMP

are adopted by the European Commission. The objective of GMP is to ensure that products

are consistently produced and controlled to particular quality standards.

5) Guide to Good Manufacturing Practice for Medicinal Products, (8) Part II. PIC/s

Pharmaceutical Inspection Convention Pharmaceutical Inspection Co-Operation Scheme

Contain text about the requirement of the Good Manufacturing Practice as per the updated

version of the GMP PIC guide. The updated version has the Incorporation of PE 007 and

contains the text about the Active Pharmaceutical Ingredients adopted from the ICH APIs guide

Q7A, as per the guide the source of the Active Pharmaceutical Ingredients should be approved

because the Active Pharmaceutical Ingredients are not considered as the approval things, and

this information is adopted in the guide PE 009-6 (Part II). Geneva; p 1-555 April 2007.

6) USFDA, Assessor checklist (9) Current Good Manufacturing Practices (cGMP), this check list

present the criteria to be used in evaluating the facility as per regulatory cGMP requirements.

The company’s policies and procedures must meet these requirements. Requirements that

include the need for a process validation study , procedure or arrangement because Correct

completion of this checklist may save a significant amount of assessment time and cost of the

audit, a well prepared checklist which cover all the important criteria to be evaluated is

beneficial to the auditor because while auditing the auditor will not invest extra time in the

minor issue and cover all the critical issue needed for the audit of the company, the checklist

have the space for writing the comment about particular issue which in turn help to discuss

with the management and to prepare the audit report at the end of the audit21 CFR Part 210

and 211: (2006.

7).USFDA, September 2004,10 Guidance for Industry Quality Systems Approach to

Pharmaceutical Current Good Manufacturing Practice Regulations, This draft guidance is

intended to help manufacturers that are implementing modern quality systems and risk

management approaches to meet the requirements of the Agency's current good

manufacturing practice (CGMP) regulations (2l CFR parts 210 and 211) September 2004.

8.) Leonard Steinborn, GMP/ISO Quality Audit Manual for Health care Manufacturers and

Their Suppliers, 2003, (11) Sixth Edition, volume – 1, CRC press Boca Raton London New York

Washington, D.C., contain text about the purpose and objective of the audit, a detail

information about different type of the audit, the requirements and the basic tools for the

structuring and planning of the various validation study like process validation study ,analytical

method validation study, cleaning validation study.

9.) ICH Harmonized Tripartite Guideline, (2003) ,(12) International Conference on

Harmonization Of Technical Requirements For Registration Of Pharmaceuticals For Human

Use, stability testing of New drug substances and products Q1A(R2),This Guideline gives the

important information about the stability testing of the Drug substance and product at different

conditions of temperature and relative humidity, these studies will helpful to identify the shelf

life of the product and its package requirement for the distribution and sell in the market of

different climatic condition in the world and also provide the information about the storing

temperature of the product while shipment and during the use of the product to prevent the

degradation of the product, Guideline, (2003).

PROPOSED METHODOLOGY DURING RESEARCH

Proposed Methodology during the research work outlines are as follows

Designing of SOP during the research work

Identification of product to be validated

Determination of critical Parameter during the validation

Designing Process Validation Protocol including sampling Plan

Environmental monitoring

Compilation of data

Preparation of Validation Report

Result and discussion

Summary and conclusion

These are so many critical parameter during the validation like

Temperature control

Humidity control

Time of process eg Granulation, shifting, missing time .drying , Blending , compression coating

Machine RPM etc.

LIST OF ABBREVIATIONS

USFDA: United State Food Drug Application;

CFR: Code of Federal Regulations;

GMP: Good Manufacturing Practices;

GCP: Good Clinical Practices;

CDSCO: Central Drug Standard Control Organization:

CDER: Center for Drug Evaluation and Research

WHO: World Health Organization

REFERENCES

1) Types of validation from WHO expert committee on specification for pharmaceutical

preparation-WHO technical report series, no. 863-34th report (1996- 200pages)

2) A WHO guide to good manufacturing practice (GMP) requirements Part 2: Validation This

guidance document has been prepared to aid vaccine manufacturers in the preparation and

performance of the validation studies required by Good Manufacturing Practices (GMP) of the

World Health Organization (WHO). The Guide presents a review of the types and extent of

validations required by GMP, the preparation of a Master Validation Plan, formats for the

equipment and systems qualifications and process and analytical assay validation protocols,

and examples of the typical requirements for various validation studies. Validation of

computerized systems is not covered in this Validation Guide.

3) Canada guideline for phase of process validation in which process validation is distributed

indifferent phase’s pre validation phases, process qualification phases, maintenance phases.

4) Statutory and Regulatory Requirements for Process Validation is taken from guideline for

industry process validation: general principle and practice this draft guidance, when finalized,

will represent the Food and Drug Administration's (FDA's) current thinking on this topic. It

does not create or confer any rights for or on any person and does not operate to bind FDA or

the public. You can use an alternative approach if the approach satisfies the requirements of the

applicable statutes and regulations. If you want to discuss an alternative approach, contact the

FDA staff responsible for implementing this guidance. If you cannot identify the appropriate

FDA staff, call the appropriate number listed on the title page of this guidance.

5) Gupta Vivek, Bonde C.G. has reported the Statistical Assurance of Process Validation by

Analytical Method Development and Validation for Levofloxacin IR Tablets, Vol.1, No.3, pp

921-924, July-Sept 2009.

6) Guidance for Industry Process Validation: General Principles and Practices For purposes of

this guidance, process validation November 2008 Current Good Manufacturing Practices

(CGMP), United state Food and drug administration.

7) MHRA, 2007, (sixth edition in 2002.) Rules and Guidance for Pharmaceutical Manufacturers

and Distributors, (“Orange Guide”) Compiled by the Inspection and Standards Division of the

Medicines and Healthcare products Regulatory Agency

8) Guide to Good Manufacturing Practice for Medicinal Products, 5 April 2007, Part II. PIC/s

Pharmaceutical Inspection Convention, Pharmaceutical Inspection Co-Operation Scheme; PE

009-6 (Part II). Geneva; p 1-55;. The updated version has the Incorporation of PE 007 and

contains the text about the Active Pharmaceutical Ingredients adopted from the ICH APIs

guide Q7A.

9) Pharmaceutical Inspection Convention, 1 August 2006, Pharmaceutical Inspection Co-

Operation Scheme; PE 009-5. Geneva, Guide to Good Manufacturing Practice for Medicinal

Products, This Guideline gives the important information about the quality management,

personnel, premises, documents and production etc. this guide is very important for the

preparation of the site master file of the company.

10) USFDA, September 2004, Guidance for Industry Quality Systems Approach to

Pharmaceutical Current Good Manufacturing Practice Regulations USFDA, September 2004,

Guidance for Industry Quality Systems Approach to Pharmaceutical Current Good

Manufacturing Practice Regulations.

11) Leonard Steinborn, 2003, GMP/ISO Quality Audit Manual for Health care Manufacturers

and Their Suppliers, Sixth Edition, volume – 1, CRC press Boca Raton London New York

Washington, D.C., contain text about the purpose and objective of the audit, a detail

information about different type of the audit, the requirements and the basic tools for the

structuring and planning of the audit and performing a quality audit by using a well prepared

audit checklist

12) ICH Harmonised Tripartite Guideline, 6 February 2003, International Conference on

Harmonisation Of Technical Requirements For Registration Of Pharmaceuticals For Human

Use, stability testing of New drug substances and products Q1A(R2),This Guideline gives the

important information about the stability testing of the Drug substance and product at different

conditions of temperature and relative humidity.

13) ICH Harmonised Tripartite Guideline, 6 February 2003, International Conference on

Harmonisation for validation of analytical procedure (Q2B), This Guideline gives the important

information about the validation of the analytical procedure which are used in the assessment

and analyses of the drugs and sample of the cleaning validation because before conducting the

analyses and cleaning validation all the analytical procedure will be validated.

14) Pharmaceutical Inspection Convention, 3 August 2001, recommendations on validation

master plan, installation and operational qualification, non-sterile process validation, cleaning

validation, This Guideline gives the important information about the validation program

carried out in the pharmaceutical industries, which include the validation of the different

equipments and process and also the qualification of the equipments, also gives the steps and

acceptance criteria for various operation.