Sterile products and admixtures

Presented by:Rameshwar madhariaPE/2013/313

Parenteral

Parenteral refers injectable route of

administration.

It derived from Greek words Para (Outside) and

enteron (Intestine).

So it is a route of administration other than the

oral route. This route of administration

bypasses the alimentary canal

PRIMARY PARENTERAL ROUTESRoutes Usual volume

(mL) Needle commonly used

Formulationconstraints

Types of medication administered

SVP

Sub cutaneous 0.5-2 5/8 in. , 23 gauge

Need to be isotonic Insulin, vaccines

Intra muscular 0.5-2 1.5 in. ,23 gauge

Can be solutions, emulsions, oils or suspensionsIsotonic preferably

Nearly all drug classes

Intra venous 1-100 Vein puncture1.5 in. , 20-22 gauge

Solutions, emulsions and liposomes

Nearly all drug classes

LVP 101 and larger(infusion unit)

Venoclysis 1.5 in. ,18-19 gauge

Solutions and some emulsions

Nearly all drug classes

S. No. ADVANTAGES DISVANTAGES

1. Quick onset Wrong dose or over dose can be fatal

2. Vomiting and unconscious patients can take

Pain at site

3. Prolonged action by modified formulation ( Depot)

Trained person required

4. Nutritive fluids (glucose, electrolytes) can be given

Expensive

5. Drugs with poor absorption or instability from GIT

NECESSITY OF ASEPTIC CONDITIONS IN PRODUCTION, COMPOUNDING AND ADMINISTRATION

Containers:

1. Glass:• Highly Resistant Borosilicate Glass

• Treated Soda lime Glass

• Regular Soda Lime Glass

• N.P (Non-parenteral) Glass

Type 4 is not used for parenteral packaging, others all are used for parenteral packaging.

2. Plastic:Plastic containers are used but they face following problems

• Permeation

• Sorption

• Leaching

• Softening

3. Rubber:To provide closure for multiple dose vials, IV fluid bottles, plugs for disposable syringes and bulbs for ophthalmic pipettes, rubber is the material of choice.

Problems associated with rubber closures are

• Incompatibility

• Chemical instability

• Physical instability

Closure:• Characteristics of Good Pharmaceutical rubbers

• Good ageing qualities

• Satisfactory hardness and elasticity

• Resistance to sterilization conditions

• Impermeable to moisture and air

• Examples:

• Butyl Rubbers

• Natural Rubbers

• Neoprene Rubbers

• Polyisoprene rubbers

• Silicone Rubbers

Intravenous Admixture System

• “Admixture system” refers to sterile IV solutions that are prepared by using one or more medications or electrolytes and will be administered via the parenteral route.

• It requires the measured addition of a medication to a 50 ml or larger bag or bottle of IV fluid.

• It can be provided to the patient in his/her home.

• Many hospitals involved in compounding IV solutions and medications to outpatient settings.

Methods for safe & effective use of IV admixture

• Proper training to nurses & pharmacist

• Instruction regarding labeling Information for stability & compatibility to the hospital pharmacy dept.

• Information for the formulation skills to the pharmacist.

SYSTEMCOMPONENT

PreparationArea

StorageArea

Personnel

Policies andProcedures

Admixture system

PROCESSING OF PARENTERALS

S.No. STEPS

1. Cleaning of containers, closures and equipments

2. Collection of materials

3. Preparation of parenteral products

4. Filtration

5. Filling the preparation in final containers

6. Sealing the containers

7. Sterilization

8. Evaluation of parenteral preparation

9. Labeling and packaging

Formulation of parenteral products• In the preparation of parenteral products, the following substances

are added to make a stable preparation:

The active drug

Vehicles Aqueous vehicle (e.g. water for injection, water for injection free from

CO2 )

Non-aqueous vehicle (e.g. Ethyl alcohol, propylene glycol, almond oil)

Adjuvants Solubilizing agents (e.g. Tweens & polysorbates) Stabilizers & antioxidants (e.g. thiourea, ascorbic acid, tocopherol) Buffering agents (e.g. citric acid, sodium citrate) Antibacterial agents (e.g. benzyl alcohol, metacresol, phenol) Chelating agents (e.g. EDTA) Suspending, emulsifying & wetting agents (e.g. MC, CMC) Tonicity factor (e.g. sodium chloride, dextrose)

Production facilities of parenterals

• The production area where the parenteral

preparation are manufactured can be divided

into five sections:

Clean-up area

Preparation area

Aseptic area

Quarantine area

Finishing & packaging area

Clean-up area: It is not aseptic area. All the parenteral products must be free from foreign particles &

microorganism. Clean-up area should be withstand moisture, dust & detergent. This area should be kept clean so that contaminants may not be

carried out into aseptic area.

Preparation area: In this area the ingredients of the parenteral preparation are

mixed & preparation is made for filling operation. It is not essentially aseptic area but strict precautions are

required to prevent any contamination from outside.

Aseptic area: The parenteral preparations are filtered, filled into final

container & sealed should be in aseptic area.

The entry of personnel into aseptic area should be limited &

through an air lock.

Ceiling, wall & floor of that area should be sealed & painted.

The air in the aseptic area should be free from fibers, dust

and microorganism.

The High efficiency particulate air filters (HEPA) is used for air.

UV lamps are fitted in order to maintain sterility.

Quarantine area: After filling, sealing & sterilization the parenteral product

are held up in quarantine area. Randomly samples were kept foe evaluation. The batch or product pass the evaluation tests are transfer

in to finishing or packaging area.

Finishing & packaging area: Parenteral products are properly labelled and packed. Properly packing is essential to provide protection against

physical damage. The labelled container should be packed in cardboard or

plastic container. Ampoules should be packed in partitioned boxes

EVALUATION OF PARENTERAL PREPARATIONS

• The finished parenteral products are subjected to the following tests, in order to maintain quality control:

• A) sterility test• B)clarity test• C)leakage test• D)pyrogen test• E)assay

A) sterility test

• It is a procedure carried out to detect and conform absence of any viable form of microbes in or on pharmacopeia preparation or product.

1) Method of sterility testing

i ) METHOD 1 Membrane filtration method

ii) METHOD 2 Direct inoculation method

Membrane filtration method (METHOD 1):

Membrane filtration Appropriate for : (advantage)

• Filterable aqueous preparations

• Alcoholic preparations

• Oily preparations

• Preparations miscible with or soluble in aqueous or

oily (solvents with no antimicrobial effect)

All steps of this procedure are performed aseptically in a

Class 100 Laminar Flow Hood

Membrane filter 0.45μ porosity

Filter the test solution

After filtration remove the filter

Cut the filter in to two halves

First halves (For Bacteria) Second halves (For Fungi)

Transfer in 100 ml culture media(Fluid Thioglycollate medium)

Incubate at 30-350 C for not less then 7 days

Transfer in 100 ml culture media(Soyabeans-Casein Digest medium)

Incubate at 20-250 C for not less then 7 days

Observe the growth in the media Observe the growth in the media

Direct inoculation method (METHOD 2):

Suitable for samples with small volumes

volume of the product is not more than 10% of the volume of the medium

suitable method for aqueous solutions, oily liquids, ointments and creams

Direct inoculation of the culture medium suitable quantity of the preparation to be examined is transferred directly into the appropriate culture medium & incubate for not less than 14 days.

Observation and results

Culture media is examined during and after at the end of incubation. The

following observations are possible:

1) No evidence of growth Pass the test for sterility.

2) There is evidence of growth Re-testing is performed same

no. of sample, volume & media as in original test No

evidence of growth Pass the test for sterility.

3) There is evidence of growth isolate & identify the organism.

Re-testing is performed with twice no. of sample if:

No evidence of growth Pass the test for sterility.

B)clarity test

• Particulate matter is defined as unwanted mobile insoluble matter other than gas bubble present in the product.

• If the particle size of foreign matter is larger than the size of R.B.C.. It can block the blood vessel.

• The permit limits of particulate matter as per I.P. are follows:

Methods for monitoring particulate matter contamination:

1) Visual method

2) Coulter counter method

3) Filtration method

4) Light blockage method

C)leakage test

• The sealed ampoules are subjected to small cracks which occur due to rapid temperature changes or due to mechanical shocks.

Filled & sealed ampoules

Dipped in 1% Methylene blue solutionUnder negative pressure in vacuum chamber

Vacuum released colored solution enter into the ampoule

Defective sealing

Vials & bottles are not suitable for this test because the sealing material used is not rigid

D)pyrogen test

Pyrogen = “Pyro” (Greek = Fire) + “gen” (Greek = beginning).

Fever producing, metabolic by-products of microbial growth and death.

Bacterial pyrogens are called “Endotoxins”. Gram negative bacteria produce more potent endotoxins than gram + bacteria and fungi.

Endotoxins are heat stable lipopolysaccharides (LPS) present in bacterial cell walls, not present in cell-free bacterial filtrates

Method Dissolve the subs being examined in, or dilute it with a pyrogen free

saline solution

Warm the liquid being examined to approx. 38.5o C temp before injection

The volume of injection is NLT 0.5ml/kg & NMT 10ml/kg of body weight

Withhold water during test

Clinical thermometer is inserted into the rectum of rabbit to record body temp

2 normal reading of rectal temp are should be taken prior to the test injection at an interval of half an hr & its mean is calculated- initial temp

The solution under test is injected through an ear vein

Record the temp of each rabbit in an interval of 30 min for 3 hrs

The difference between initial temp & maximum temp is recorded- taken as response

Interpretation of results

Limulus amebocyte lysate [LAL] test

• Limulus amebocyte lysate [LAL] test another method for the determination of pyrogenic endotoxins

• In this method the test solution is combined with a cell lysate from the ameabocyte [blood celels] of horse shoe crab

• Any endo toxin that might be present will be coagulated with protien fraction of the ameabocytes and results in the formation of a gel

• This consider to be simple,rapid and of greater sensitivity that the rabbit test

E)assay

• Assay is performed according to method given In the monograph of that parental preperation in the pharmacopoeia

• Assay is done to check the quantity of medicament present in the parenteral preperation

References• Encyclopedia of pharmaceutical technology by James

Swarbrick pg.no.1266-1299

• Pharmaceutical product development by N.K.JAIN

• Chemical Incompatibility of Parenteral Drug Admixtures; T. J. Mccarthy; S.A. Medical journal 2

• The theory & pratice of “Industrial Pharmacy” Leon Lachman ,Herbert A. Liberman.special Indian Edition 2009 Pg. No.693-680.

• Modern Pharmaceutics Fourth Edition, Revised and Expanded, Edited By G.S.Banker & C.T.Rhodes, Marcel Dekker pg387-389.

• The Science & practice of Pharmacy, By Remington, Vol-01, Edi.21st, Lippincott Publication, pg-838-840.

Thank You……..