Definitions related to the topic: Parenteral Products Sterilization & Sterile Product Pyrogen SVP LVP Light Resistant Containers Well closed containers Tightly closed containers Single dose container Multiple dose container Hermetically sealed container

PARENTERALSpara: outsideenteron: intestine (i.e. beside the intestine)These are the preparations which are given

other than oral routes. Injections:These are Sterile, Pyrogen free preparations intended to be

administered parenterally (outside alimentary tract).

Why Parenteral? Parenteral Route Is Used bcoz 1) Rapid action2) Oral route can not be used3) Not effective except as injection4) Many new drugs particularly those

derived from new development in biotechnologically can only be given by parenteral coz they are inactivated in GIT if given orally.

5) New drugs require to maintain potency & specificity sodium that they are given by parenteral.

Advantages:Quick onset of actionSuitable for the drugs which are not

administered by oral routeUseful for unconscious or vomiting patients.Duration of action can be prolonged by

modifying formulation.Suitable for nutritive like glucose &

electrolyte.Suitable for the drugs which are inactivated in

GIT or HCl (GI fluid)

Disadvantages: Once injected cannot be controlled (retreat)Injections may cause pain at the site of

injectionOnly trained person is requiredIf given by wrong route, difficult to control

adverse effectDifficult to save patient if overdoseSensitivity or allergic reaction at the site of

injectionRequires strict control of sterility & non

pyrogenicity than other formulation.

Necessities of Parenteral preparations: Sterility (must)Pyrogen (must)Free from particulate matter (must) Clarity (must)Stability (must)Isotonicity (should)Solvents or vehicles used must meet special purity and

other standards. Restrictions on buffers, stabilizers, antimicrobial

preservative. Do not use coloring agents.Must be prepared under aseptic conditions.Specific and high quality packaging.

Parental Routes of Administration: Most Common: 1. Subcutaneous (SC; SQ ;Sub

Q) 2. Intramuscular (IM) 3. Intravenous (IV)Others: 4. Intra-arterial (IA) 5. Intrathecal 6. Intraarticular 7. Intrapleural

8. Intracardial 9. Intradermal (Diagnostic)

Subcutaneous (SC; SQ ;Sub Q): The injection is given under the skinNeed to be isotonicUpto 2 ml is givenUsing ½ to 1 inch 23 gauge needle or smaller

needleGiven:

Vaccines Insulin Scopolamine Epinephrine

Intramuscular (IM):

Striated muscle fibre0.5 to 2 ml sometimes upto 4 ml1 to 1.5 inch & 19 to 22 gauge needle is used Preferably isotonic

Principle sites:Gluteal (buttocks)Deltoid (upper arms)Vastus lateralis (lateral thigh)

Given: SolutionsEmulsionsOilsSuspension

Intravenous (IV): Into the vein 1 to 1000 ml 1 inch ,19 to 20 gauge needle with injection

rate 1ml/ 10 sec. for volume upto 5 ml & 1 ml/ 20 sec. for volume more than 5 ml.

Given: Aqueous solutionsHydro alcoholic solutionsEmulsionsLiposome

Intra-arterial (IA):

Direct into the artery2 to 20 ml 20 to 22 gaugeSolutions & emulsions can be administered

Given:Radio opaque mediaAntineoplasticAntibiotics

Intrathecal:

Also called intra-spinalDirectly given into the spinal cord1 to 4 ml24 to 28 gaugeMust be isotonic

Given:LAAnalgesicsNeuroleptics

Intraarticular:

Given directly into the joints2 to 20 ml 5 inch 22 gaugeMust be isotonic

Given:MorphineLASteroidsNSAID’sAntibiotics

Intrapleural:

Given directly into the pleural cavity or lungUsed for fluid withdrawal2 to 30 ml 2 to 5 inch, 16 to 22 gauge needle

Given: LANarcoticsChemotherapeutic agents

Intracardial:

Directly given into the heart

0.2 to 1 ml

5 inch , 22 gauge needle

Given: Cadiotonics

Calcium salts as a calcium channel blockers

Intradermal:

Also called as diagnostic testing0.05 ml ½ inch, 25 to 26 gauge needleShould be isotonic

Given: Diagnostic agents

Official Types of Injections:

1. Solutions of Medicinal Example: Codeine Phosphate Injection Insulin Injection2. Dry solids or liquid concentrate does not

contain diluents etc. Example: Sterile Ampicillin Sodium3. If diluents present, referred to as.....for

injection Example: Methicillin Sodium for injection

4. Suspensions "Sterile....Suspension" Example: Sterile Dexamethasone Acetate

Suspension5.Dry solids, which upon the addition of

suitable vehicles yield preparations containing in all respects to the requirements for sterile suspensions.

Title: Sterile....for Suspension Example: Sterile Ampicillin for Suspension6. Injectable Emulsions: Example: Propofol injection

Formulation of Parenteral:

1. Therapeutic agents2. Vehicles

i. Waterii. Water miscible vehiclesiii. Non- aqueous vehicles

3. Added substances (Additives)i. Antimicrobialsii. Antioxidantsiii. Buffersiv. Bulking agentsv. Chelating agentsvi. Protectantsvii. Solubilizing agentsviii. Surfactantsix. Tonicity- adjusting agents

General steps involved

1. Cleaning

2. Preparation of bulk products

3. Filtration

4. Filling of solution in or product in ampoule or vial

7. Tests for Quality control

5.Sealing

6. Sterilization

Formulation of Parenteral Solvents:

o Water

o Should meet compendial requirements

o Water miscible vehicles

o Ethyl alcohol

o PEG

o PG

o Non aqueous vehicles

o Fixed oils

Solvents

Solvents used must be:Non-irritatingNon-toxicNon-sensitizingNo pharmacological activity of its ownNot affect activity of medicinal

Added substances (Additives)

Antimicrobials: Added for fungistatic or bacteriostat action or

concentration Used to prevent the multiplication of micro-

organisms Ex..

Benzyl alcohol ------ 0.5 – 10 % Benzethonium chloride - 0.01 % Methyl paraben ---- 0.01 – 0.18 % Propyl paraben --- 0.005 – 0.035 % Phenol --- 0.065 – 0.5 %

Preservatives: Multidose containers must have preservatives unless prohibited by monograph.

Large volume parenteral must not contain preservative becoz it may be dangerous to human body if it contain in high doses.

Antioxidants:

Used to protect product from oxidation Acts as reducing agent or prevents oxidation Ex:

A) Reducing agent: Ascorbic acid - 0.02 – 0.1 % Sodium bisulphite - 0.1 – 0.15 % Sodium metabisulphite - 0.1 – 0.15 % Thiourea - 0.005 %

B) Blocking agents: Ascorbic acid esters - 0.01 – 0.015% BHT - 0.005 – 0.02 %

C) Synergistic: Ascorbic acid , Citric acid , Tartaric acid

D) Chelating agent: EDTA - 0.01- 0.075 %

Buffers:

Added to maintain pH, Change in pH may causes degradation of the products Acetates, citrates, phosphates are generally used.

Factors affecting selection of buffers: Effective range, Concentration Chemical effect on the total product

EXAMPLES: Acetic acid ,adipic acid, benzoic acid, citric acid,

lactic acid Used in the conc. of 0.1 to 5.0 %

Chelating agents:

Used to form the complex with the metallic ions present in the formulation so that the ions will not interfere during mfg. of formulation.

They form a complex which gets dissolved in the solvents.

Examples: Disodium edetate – 0.00368 - .05 % Disodium calcium edetate - 0.04 % Tetrasodium edetate – 0.01 %

Stabilizers:

As parenterals are available in solution form they are most prone to unstabilize

Used to stabilize the formulation Maintain stable

Examples: Creatinine – 0.5- 0.8 % Glycerin – 1.5 – 2.25 % Niacinamide – 1.25 -2.5 % Sodium saccharin – 0.03 %Sodium caprylate – 0.4 %

Solubilizing agents:

Used to increase solubility of slightly soluble drugs

they acts by any one of the following: solubilizers, emulsifiers or wetting agents.

Examples: Dimethylacetamide, Ethyl alcohol Glycerin Lecithin PEG – 40 castor oil PEG – 300 Polysorbate 20, 40, 80

Tonicity- adjusting agents:

Used to reduce the pain of injection. Buffers may acts as tonicity contributor as

well as stabilizers for the pH. Isotonicity depends on permeability of a

living semipermaeable membrane Hypotonic : swelling of cells (enlargement) Hypertonic: shrinking of cells (reduction)

Example: Glycerin Lactose Mannitol Dextrose Sodium chloride Sorbitol

LABELING:

Name of productQuantity of the product% of drug or amount of drug in specified

volume of amount of drug and volume of liquid to be added

Name and quantity of all added substancesMfg. license no.Batch no.Manufacturer/DistributorMfg. & Expiration dateRetail price (incl. of all taxes)Mfger. addressVeterinary product should be so labeled

Must check each individual monogram for: Type of container:

Glass Plastic Rubber closure

Type of glass Type I Type II Type III NP

Tests for glass containers Powdered Glass test Water Attack test

Package size Special storage instructions

Production facilities Types :

Emulsion SuspensionSolutions

Preparation of IV fluidsIV admixturesTPNDialysis fluids

QC tests for parenteral

Production facilities:

Clean- up area

Preparation area

Aseptic area

Quarantine area

Finishing and packaging area

LAY OUT OF PARENTERAL MANUFACTURING AREA

STOCK ROOM

COMPOUNDING AREA

CLEAN UP AREA

ASEPTIC AREA

STERILIZATION

QUARANTINE AREA

QUARANTINE AREA

STORAGE

AND

TRANSPORT

Working areaIncoming goods are stored in special areas for

Quarantine, Released and Rejected status. A cold room is available for storage of

temperature-sensitive products. Entrance into the warehouse and production areas is restricted to authorized personnel.

Sampling and weighing of the raw material is performed in a dedicated sampling area and a central weighing suite, respectively.

The route for final products is separated from the incoming goods; storage of final products is done in designated areas in the warehouse while they are awaiting shipment.

Several clothing and cleaning procedures in the controlled transport zone and production area ensure full quality compliance.

In addition, a technical area is located in between the production zone and the area for formulation development.

Here, the water for injection equipment is located, as well as the technical installation of the lyophilizer.

Clean- up area:Non aseptic area

Free from dust ,fibres & micro-organisms

Constructed in such a way that should withstand

moisture, steam & detergent

Ceiling & walls are coated with material to prevent

accumulation of dust & micro-organisms

Exhaust fans are fitted to remove heat & humidity

The area should be kept clean sodium that to avoid

contamination to aseptic area

The containers & closures are washed & dried in

this area.

Preparation area: The ingredients are mixed & preparation is

prepared for filling

Not essential that the area is aseptic

Strict precaution is taken to prevent

contamination from outside

Cabinets & counters: SS

Ceiling & walls : sealed & painted

Aseptic area: Filtration & filling into final containers & sealing

is done The entry of outside person is strictly prohibited To maintain sterility, special trained persons are

only allowed to enter & work Person who worked should wear sterile cloths Should be subjected for physical examination to

ensure the fitness Minimum movement should be there in this area Ceiling & walls & floors : sealed & painted or

treated with aseptic solution and there should not be any toxic effect of this treatment

Cabinets & counters: SSMechanical equipments : SS AIR:

Free from fibres, dust & micro organisms HEPA filters are used which removes particles upto

0.3 micron Fitted in laminar air flow system, in which air is

free from dust & micro organisms flows with uniform velocity

Air supplied is under positive pressure which prevents particulate contamination from sweeping

UV lamps are fitted to maintain sterility

Quarantine area:

After filling, sealing & sterilization the products or batch is kept in this area

The random samples are chosen and given for analysis to QC dept.

The batch is send to packing after issuing satisfactory reports of analysis from QC

If any problem is observed in above analysis the decision is to be taken for reprocessing or others..

Finishing and packaging area:

After proper label, the product is given for packing

Packing is done to protect the product from external environment

The ideal Packing is that which protects the product during transportation, storage, shipping & handling.

The labeled container should be packed in cardboard or plastic containers

Ampoules should be packed in partitioned boxes.

Class

Air Handling System (Central Air-Conditioning) filling operations shall take place under Grade A conditions - HEPA

filters. aseptic filling area – B conditions. sterilized components unloading area, Manufacturing and

component preparation areas – C conditions. change room conforming – D conditions. Differential pressure - at least 15 Pascal. Temperature – not more than 27 degree unless specified. relative humidity not more than 55%.

AIRBORNE PARTICULATE CLASSIFICATION FOR MANUFACTURE OF STERILE PRODUCTSGrade At rest (b) In Operation (a)

Maximum number of permitted particles per cubic metre equal to or above.

0.5µm 5µm 0.5µm 5µm

A 3520 29 3500 29

B (a) 35,200 293 3,52,000 2,930

C (a) 3,52,000 2930 35,20,000 29,300

D (a) 35,20,000 29,300 Not defined (c) Not defined (c)

For Grade A, B and C, the maximum permitted number of particles in the “at rest” condition shall approximately be as under: Grade A corresponds with Class 100 or M 3.5 or ISO Class 5. Grade B with Class 1000 or M 4.5 ISO Class 6. Grade C with Class 10,000 or M 5.5 or ISO Class 7. Grade D with Class 100,000 or M 6.5 or ISO Class 8.

TYPES OF OPERATIONS TO BE CARRIED OUT IN THE VARIOUS GRADES FOR ASEPTIC PREPARATIONS

Grade Types of operations for aseptic preparations

A Aseptic preparation and filling

B Background room conditions for activities requiring Grade A

C Preparation of solution to be filtered (Terminal sterilization required)

D Handling of components after washing

TYPES OF OPERATIONS TO BE CARRIED OUT IN THE VARIOUS GRADES FOR TERMINALLY STERILIZED PRODUCTS.

Grade Types of operations for terminally sterilized products

A Filling of products, which are usually at risk

C Placement of filling and sealing machines, preparation of solutions when usually at risk. Filling of product when unusually at risk.

D Moulding, blowing (pre-forming) operations of plastic containers, preparations of solutions and components for subsequent filling

Environmental Control & Monitoring

Tied to facility design and operation but carefully designed and evaluated.

HVAC – controls the quality of air, airborne variables, temp., humidity, air flow direction, and air pressure.

HEPA – controls the air quality.

cont…

periodic monitoring shall be as follows:- Particulate monitoring in air . 6 Monthly. HEPA filter integrity testing (smoke testing) .

Yearly Air change rates . 6 Monthly. Air pressure differentials . Daily. Temperature and humidity . Daily Microbiological monitoring by settle plates and/or

swabs in aseptic areas daily, and at decreased frequency in other areas

Monitoring methodsMethods Operation

PrincipleAdv Dis Adv

Biologic evaluation settling plates

Slit sampler

Centrifugal sampler

Gravitational fallout in a given time on a given area

Known volume of air drawn through slit & impacted on nutrient agar as plate turns

Known volume of air centifugally blown on nutrient agar strip.

UncomplicatedLow cost

Known amt of air sampled.Sampling related to time as plate turns.

Measured vol. of air sampled. Unit handled by hand or batery operated.

Heaver particle settle and are collected.Irregularities in counts.Velocity, Drying effect – lethal effect on veg. cells.Must be used with ele. & vaccum.Velocity, Drying effect – lethal effect on veg. cells.

Cascade sieve sampler

Mebrane filter sampler

Particulate matter Mebrane filter

Known volume of air cascade through upto six plates of decreasing pore size impacted on nutrient plate, last receives sr mall size particles .Measured volume of air pass through membrane filter.Particles retained on surface is incubated on agar plate.

Measured volume of air pass through filter.Particles retained on surface.

Measured volume of air sampled.Permits gradation of particles by size.

Measured volume of air sampled.Used for microscopic particle counting.

Measured volume of air sampled.Particles microscopicaly visible&counting possible.

Velocity– lethal effect on veg. cells.Must be used in vaccum.Dry condition gives best reslt.

Vaccum required.Drying – lethal effect on veg. cells.Air pockets prevents mic. Growth.Required trained person for counting.Time consuming process.

Light scattering instrumental counterRight angle/Near forward

Particles viewing cell scatter light from the incident light to photodetector tube.

Qantitative count is possible from measured volume of air.Instant result.Ranges of sizes is measured.

Sizing affected by light scattering charecteristics of particle surface.No differentiation between viable and non-viable matter.

Personnel - Garmentsuse by personnel working only in aseptic area and

outdoor clothing shall not be brought into the sterile areas.

made of non-shedding and tight weave material (no fibers or particulate matter).

to protect the product from contaminationsingle piece with fastenings at cuffs, neck and at legs to

ensure close fit. Trouser legs shall be tucked inside the cover boots.

clean, sterilized and protective garments shall be usedmask and gloves shall be changed at every work session footwear shall be of suitable plastic or rubber material,

daily cleaned with bactericide.

SanitationSOP for the sanitation of sterile processing facilities.

Employees to be trained specifically for this purpose.Records of rotational use of sanitizing agents shall be

maintained.Purified water or maintained at 70°C distilled water to

be used for dilution of disinfectants.alcohol or isopropyl alcohol is used for dilution of

disinfectants for use as hand sprays.Formaldehyde or any other equally effective fumigant is

recommended for the fumigation of aseptic areas.Air particulate quality shall be evaluated on a regular

basis and record maintained.

EquipmentArrangement of equipments depending upon the utilities.Unit-sterilizers shall be double-ended with suitable inter-

locking arrangements between the doors. Filling machines shall be challenged initially and then at

periodic intervals by simulation trials including sterile media fill.

direct contact with products and the manufacturing vessels may be stainless steel 316 or Boro-silicate Glass for easy washing and autoclaving.

Equipment for critical processes like aseptic filling and sterilizers shall be suitably validated according to a written program before putting them to use.

SOP shall be available for each equipment for its calibration and operation and cleaning.

Facility Design To provide the control of microbial,

pyrogen and particles controls over the production environment are essential.

Warehousing: All samples should be aseptically taken,

which mandates unidirectional airflow and full operator gowning.

These measures reduce the potential for contamination ingress into materials that are yet to receive any processing at any site.

Preparation Area: The materials utilized for the production of the sterile

products move toward the preparation area through a series of progressively cleaner environments.

First the materials are passed through class 100,000 i.e. grade D environment for presterilization.

Transfer of materials are carried out in air-locks to avoid cross contamination

The preparation areas are supplied with HEPA filters. There should be more than 20 air changes per hour

The preparation place is Class 100 area.

Compounding area:

The manufacture of parenterals is carried out in class 10,000 (Grade C) controlled environments in which class 100 unidirectional flow hoods are utilized to provide greater environmental control during material addition.

These areas are designed to minimize the microbial, pyrogen, and particulate contamination to the formulation prior to sterilization.

Aseptic filling rooms:

The filling of the formulations is performed in an Class 100 environment.

• Capping and Crimp sealing areas: The air supply in the capping line should be of

Class 100• Corridors: They serve to interconnect the various rooms. Fill

rooms, air locks and gowning rooms are assessed from the corridor.

• Aseptic storage rooms.• Air-locks and pass-throughs: Air locks serve as a transition points between one

environment and another. They are fitted with the UltraViolet lights, spray

systems, or other devices that may be effectively utilized for decontamination of materials.

InstrumentationMixer

Homogenizer Filtration assembly

Filling machinery

Mixer/Homogenizer

Filtration assembly

Bottling/Filling machinery

Production Area

65

Sterilization and DepyrogenationSteam sterilizationDry-heat sterilization and

depyrogenationGas and vapour sterilizationRadiation sterilizationSterilization by filteration

66

Aseptic processing control and evaluation

In-process Testing:End-product Testing:Process simulations:

Quality AssuranceParticulate matterPyrogen testStability test

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Particulate matter detector