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: 5/28/2009

This 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
(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

Last reviewed on RxList: 5/28/2009

This monograph has been modified to include the generic and brand name in many instances.

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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.

Last reviewed on RxList: 5/28/2009

This monograph has been modified to include the generic and brand name in many instances.

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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.

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.

Last reviewed on RxList: 5/28/2009

This monograph has been modified to include the generic and brand name in many instances.

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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.

Last reviewed on RxList: 5/28/2009

This monograph has been modified to include the generic and brand name in many instances.

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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.

Last reviewed on RxList: 5/28/2009

This monograph has been modified to include the generic and brand name in many instances.

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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 weeks
10 mg/kg 116 ± 69 148 ± 50
20 mg/kg 210 ± 58 240 ± 60
40 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.

Last reviewed on RxList: 5/28/2009

This monograph has been modified to include the generic and brand name in many instances.

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Carnitor Injection Medication Guide

PATIENT INFORMATION

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

Last reviewed on RxList: 5/28/2009

This monograph has been modified to include the generic and brand name in many instances.

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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 the

Requirements for 2nd semester of

Master of Pharmacy
In
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 UNIVERSITY

LUCKNOW (U.P.)

INDEX

Sr. No. Contents Page No.

1.0 2-5
Introduction

2.0 Objective 6-7

3.0 Drug Profile 8-10

4.0 11-13
Review of literature
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:
 O
F COOH

N N
H
N O
1/ 2 H 2O
H3C CH3

Levofloxacin hemihydrate

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 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.
(8)
5) Guide to Good Manufacturing Practice for Medicinal Products, 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.