PARENTERALSMANUFACTURINGLAYOUTEQUIPMENTS

Swapnil Sanghavi

Introduction Sterile - Absolute term as the state of freedom from all viable

organism.

Type of sterile preparations OPTHALMIC PARENTERAL IRRIGATING PREPARATION

DIAGNOSTIC AGENTS ALLERGIC EXTRACTS SURGICALS RADIO PHARMACEUTICALS

Parenteral : The dosage form for conveying a drug by means of injection through the skin or mucous membranes.

Parenteral drugs are administered directly into the veins, muscles or under the skin, or more specialized tissues such as the spinal cord.

Circumvented the highly efficient first line body defense that is skin and mucus membrane.

Thus they should be free from microbial contamination and should have high purity.

Aseptic- “without sepsis” Used to designate a practical level of sterility.

Parenteral

Sterile

Alert level- An established microbial or airborne particle level giving early warning of potential drift from normal operating conditions.

Action Level- An established microbial or airborne particle level that, when exceeded, should trigger appropriate investigation and corrective action based on the investigation.

HVAC- Heating, ventilation, and air conditioning.

Laminar flow of air- Airflow moves in a single direction and in parallel layers at constant velocity.

ULPA filter : Ultra-low penetration air filter with minimum 0.3 µm particle retaining efficiency of 99.999 percent.

LVP : A liquid intended for infusion and hermetically sealed in a container of greater than 100 ml volume.

SVP : A parenteral preparation hermetically sealed in a container of 100 ml or less volume.

Pyrogen : The fever producing lipid associated with polysaccharide or polypeptide of microbial origin.

Sterilization : A process designed to completely eliminate or destroy all living microorganism.

Process validation:

SAL :

A. IV Admixtures consist of one or more sterile drug products added to an IV fluid.

Used for • Drugs intended for continuous infusion • For drugs that may cause irritation or toxicity when

given by direct IV injection.

B. IV fluidsThese fluids have multiple uses, • Vehicles in IV admixtures• Provide means for reconstituting sterile powders• Serve as the basis for correcting body fluids and

electrolyte disturbances• For administering parenteral nutrition

Dextrose : Generally, a solution of 5% dextrose in water• pH of 5% dextrose ranges from 3.5-6.5. Instability may result if it

is combined with an acid sensitive drug.• In higher conc. (e.g. 10% solution in water), dextrose provides a

source of carbohydrate in parenteral nutrition solutions.• Should used cautiously in patients with diabetes mellitus.

Sodium chloride : usually given as 0.9% solution called as normal saline solution.

Sterile sodium chloride for injection: • Used as vehicle in IV admixtures and fluid for electrolyte replacement.

Bacteriostatic sodium chloride for injection: • It contains an agent that inhibits bacterial growth (e.g. Benzyl alcohol,

Propyl paraben. Methyl papaben), allowing its use in multiple dose preparation.

Water • Used for reconstitution and for dilution of IV solutions such as

dextrose and sodium chloride. • Water suitable for parenteral preparations include sterile water

for injection and bacteriostatic water for injection.

Ringer solutions • Used for fluid and electrolyte replacement. • Commonly administered to post surgical patients.• It contains sodium lactate, sodium chloride, potassium chloride,

and calcium chloride.

C. Electrolyte preparation• Ions present in both intracellular and extracellular fluid.• Surgical and medical patients who can not take food by

mouth or who need nutritional supplementation require the addition of electrolytes in hydrating solutions or parenteral nutrition solutions.

D. Dialysate• Used in paients with disorder as renal failure, poisoining, and

electrolyte disturbances.• In peritoneal dialysis, a hypertonic dialysis is infused directly

into peritoneal cavity via a surgically implanted catheter. It contains Dextrose and electrolyte, which removes the harmful substances by osmosis and diffusion.

E. Irrigating solutions• Not intended for infusion into the venous system. Topical administration• Used in irrigating wounds, moistening dressings, and

cleaning surgical instruments.

Infusion of irrigating solutions• Surgeons performing urological procedure often use

irrigating solution to perfuse tissues in order to maintain the integrity of surgical field, remove blood, and provide a clear field of view.

Parenteral preparation Intravenous, Intraspinal, Intramuscular, Subcutaneous, and Intradermal.

Intravascular route complete drug availability occurs immediately

For all other routes, at least a blood vessel wall, and usually one or more tissue cell walls, must be permeated before the drug can enter the circulation.

Most often this occurs by passive diffusion and is most favourable when the drug has both lipophilic and hydrophilic properties, with the former being predominant.

So with nonvascular injection, absorption is also affected by such factorso Size and number of blood vessels supplying the tissue, o Physical & chemical properties of drugo Characteristic of the dosage form as whether it is a solution, suspension or emulsion

o Nature of vehicle & its pH

No absorption is necessary

and package components

• TYPES OF PROCESSING

Terminal sterilization • The product in its final container is subjected to a sterilization

process such as heat or irradiation. • In most cases, the product, container, and closure have low bio-

burden, but they are not sterile.

Aseptic process • The drug product, container, and closure are first subjected to

sterilization methods separately, as appropriate, and then brought together.

• Because there is no process to sterilize the product in its final container, it is critical that containers be filled and sealed in an extremely high-quality environment.

• Types of Operations for Terminally Sterilized Products

Grade Types of Operations for Terminally Sterilized Products

A Filling of products, when unusually at risk

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

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

Note

Grade A and B correspond to with class 100, M 3.5, ISO 5Grade C correspond to with class 10000, M 5.5, ISO 7Grade D correspond to with class 100000, M 6.5, ISO 8

Grade Types of Opeartions for Aseptic PreparationsA Aseptic preparation and filling

B Background room conditions for activities requiring Grade A

C Preparation of Solution to be filtered

D Handling of components after washing

Types of Operations for Aseptic preparations

NoteGrade A and B correspond to with class 100, M 3.5, ISO 5 Grade C correspond to with class 10000, M 5.5, ISO 7Grade D correspond to with class 100000, M 6.5, ISO 8

Parameters to be taken into consideration in the Design of a

Parenteral Production Facility: • Environmental factors such as site selection, area

planning, space planning, design and construction features, traffic flow of personnel and supplies, and service features.

1. Site selection Criteria for site selection

Basic factors Pharmaceutically important factors

land availability, land cost, construction cost, taxes,

utility costs, labor availability, labor cost and so on.

Requires special consideration because of unique

pharmaceutical needs.

• Basic plant requirement includes an adequate supply of raw materials, transportation availability, market proximity, adequate utilities, and labor supply.

• Minimizing shipping may aid in minimizing potential contamination, material degradation due to ageing or lack of environmental control (e.g. temp. & humidity).

2. Area planning it depends on a) Type of production

Batch operations -Suited to small production volume & minimum financial investment is necessary.

Advantages• Product quality, consistency, and homogeneity are relatively

easily controlled.• Production documentation is easy.

Disadvantages• Economically undesirable because it is labor intensive and

does not exploit the economies of volume.

Continuous operations: It is suited to very high volume production requirements.

• It requires more space and more complex equipments.

Advantages• Minimizes shortcoming of batch operations; labor, production

time, and environmental exposure of the product.• Since the intermediate material handling steps are eliminated,

the potential for product contamination during those steps is no longer exists.

Disadvantages• Product quality assurance is difficult.• It is very difficult to document the ingredients or process

cyclefor a product produced in a continuous process.

b)Container sizeSVPs and LVPs obviously requires different space considerations.All the production equipment has container size limitations- large container requires large equipments and more space.

c)Environment control needs

For aseptic filling processProvision must

be made for

Sterilization and Depyrogenation of

containers before filling, normally hot air oven

or autoclave.

Filling requires

An aseptic environment with the attendant support rooms Inspection and Packaging

• Non aseptic filling, followed by terminal sterilization, normally requires less rigid environmental control.

Terminal sterilization Eliminates the sterilization prior

to filling

Following to filling and sealing

An accumulation and segregation area is required to accumulate the product for transfer to the

next process step

d) Product characteristicsLiquids are probably the easiest product to handle.

Emulsion may require compounding areas close to filling lines to ease transfer problems. Pumping systems will be very critical.

Suspension will require a means of maintaining a homogenous mixture prior to filling. To minimize the time the suspension resides in piping, reservoir, and pump system, filling rate should be kept high and the distance from compounding to filling should be minimized.

e) Environmental control zone groupings

1

7

Zone 7:- Filling line Zone 6:- Filling areaZone 5:- Weighing, mixing & transfer area. Zone 4:- Clean area Zone 3:-General production Zone 2:- Warehouse Zone 1:- Exterior

Zones as per cGMP

Zones as per Gazette of India

WHITE

GRAY

BLACK

White zone:-Final step ( filling of parenteral)Grey zone:-weighing, Dissolution & filtration.Black zone:-Storage, Worst area from contamination view point

Zone 7

f) Space requirementsFUNCTION Area

Square meter Percentage

Production 11,094 45.1

Warehouse 7,606 30.9

Administration 1,018 4.1

Utility 1,716 4.1

Quality control 1,716 7.0

Maintenance 1,014 4.5

Employee services 1,014 4.1

Security 39 0.9

Total 24,607 100.0

g) Personnel flow • Discontinuous and crowded flow patterns can

decrease production efficiency, increase security problems, and increase the problems of maintaining a clean environment.

• Personnel flow path from zone to zone must be such that access to higher level of cleanliness is only through change rooms, gowning rooms, locker rooms, or other areas as may be required to prepare the personnel for the cleaner area.

• Access should be restricted.

1

4

3

2

× Design

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43

2

√ Design

• CHANGE ROOM

FILLING AREA The product & sterilized components are exposed to room environment.Therefore these areas are specially constructed, filtered, and maintained to prevent environmental contamination.

Clean room must meet several requirements:

The room should undergo 15-20 air changes per hour.

HEPA filters are to clean the air entering the room.

HEPA filters remove all airborne particles of size 0.3 or larger with an efficiency of 99.97%.

Maintaining higher air pressure (+ve pressure) within the critical area to minimize infiltration of airborne contaminants from outside.

Adjacent rooms of different grades should have a pressure differential of 10 - 15 Pascals.

Care should be taken to ensure that air flows do not distribute particles from a particle-generating person, operation or equipment to a zone of higher product risk. A warning system should be provided to indicate failure in the air supply.

Counters in the clean room should be made of stainless steel or other non-porous, easily cleaned material.

Walls and floors should be free from cracks or crevices and have rounded corners. If the walls or floors are to be painted, epoxy paint is used.

The air flow should move with uniform velocity along parallel lines. The velocity of the air flow is 90 ± 20 ft/m3.

Providing temp. & humidity controls appropriate to the product being manufactured.

Sources ControlPeople Total body covering in critical area and partial covering in

non critical area.Adequate personal flow and restricted access to aseptic and critical environment.Minimum movement of personal.Adequate operation procedure for personal.

Barrier Adequate sterilization procedureProtective laminar flow equipmentBarrier and separation between high risk and low risk operation.Adequate operation procedure to assure proper handling, cleaning, and sterilization of machinery and equipment

Material Adequate material control and selection Adequate sterilization and filtration procedure

Air Adequate air filtration system Adequate monitoring of air cleanliness level.Adequate air system validation procedure.

Environmental control

PERSONNEL & GOWNINGNo. of workers should kept to a minimum. Training of personalPersonal hygiene:-All employees should be in good health, Subjected to Physical examination, Understood their responsibilities to report own illness like cold, a sore throat, or other infection.

ClothingUniform is made up of Dacron and Span polyethylene.Hats & masks are sometimes made of special parchment paper. Foot wears plastic and rubber material.

• Air handling system

Clean Area Classification

<0.5 µm Particles/ft3

<0.5 µm Particles/mt3

Microbiological Limit

cfu/ft3 cfu/m3

100 100 3,500 <1 <3

1000 1000 35,000 <2 <7

10000 10000 350,000 <3 <18

100000 100000 3,500,000 <25 <88

GradeMaximum permitted number of particles/m3 equal or above

at rest in operation0.5µm 5.0µm 0.5µm 5.0µm

A 3,520 29 3,500 29B 35,200 293 3,52,000 2,930C 3,52,000 2,930 35,20,000 29,300D 35,20,000 29,300 not defined not defined

1. Air Classification as per Schedule M

2. Air Classifications by USFDA guideline on Sterile Drug Products

Grade ISO Class Particle/cum Class(SI)A 5 100 3.5 M 3.5(filling)

B 6 1000 35 M 4.5

C 7 10000 350 M5.5 (preparation)

D 8 100000 3500 M 6.5

GradeMaximum Number Permitted / M3

ParticlesMicroorganisms

0.5µm 5.0µmA (LAF) 3,500 0 <1

B 3,500 0 5C 3,50,000 2,000 100D 3,500,000 20,000 500

3. Air Classifications as per WHO 2002

4. As per ISO

Class Maximum microorganism

1(A)HEPA filter every where

<1

1(B)only at station 5

2 100

3 500

5. As per British Pharmacopoeial Codex

• QUALITATIVE LAYOUT OF PARENTERAL MANUFACTURING (circular flow)

• QUALITATIVE LAYOUT OF PARENTERAL MANUFACTURING (parallel flow)

MaterialEntrySoln

Prepn

Area

Oven

Autoclave

Equipment &Component

Prepn

Area

Hatch Comp.Entry

CleanChanging

Room

AsepticReceiving

Area

Entry

Unidirectional

Clean Zone

AsepticFilling zone

Pdt.Exit

Layout for Aseptic Production

MaterialEntry

SolutionPrepn

Area

Clean

Changing

area

Equipment & Component prepn

Area

Clean Filling Area

TerminalSterilization

lamimar flow

MaterialEntry

SolutionPrepn

Area

Clean

Changing

area

Equipment & Component prepn

Area

Comp.Entry

Clean Filling Area

TerminalSterilization

Unidirectional

Clean Zone

Layout for Terminal Sterilization

•EQUIPMENTS

• The following equipments as pre Schedule-M are recommended:

a) Manufacturing area1. Storage equipment for ampoules, vials bottles and

closures. 2. Washing and drying equipment. 3. Dust proof storage cabinet 4. Water still. 5. Mixing and preparation tanks or other containers.

• The tanks or containers shall be made of either glass or such materials as will not react with the liquid.

6. Mixing equipment where necessary. 7. Filtering equipment. 8. Hot air sterilizer.

b) Aseptic filling and sealing rooms 9. Benches for filling and sealing. 10. Bacteriological filters. 11. Filling and sealing unit under laminar flow work

station.

c) General Room12. Inspection table. 13. Leak testing table. 14. Labeling and packing benches. 15. Storage of equipment including cold storage and

refrigerators if necessary.

•Sterile Garment CabinetStainless steel Ensure a clean storage space by making use of UV disinfectant and heating through IR lamps.These cabinets may be designed in horizontal air flow system and clean air through HEPA filters

Cooler or Cold Storage

HEPA FilterHEPA filters can remove at least 99.97% of airborne particles 0.3 µm in diameter. HEPA filters are composed of a mat of randomly arranged fibres (poly-vinylidene fluoride -PVDF) Key metrics affecting function are fibre density and diameter, and filter thickness. The air space between HEPA filter fibres is much greater than 0.3 μm. The common assumption that a HEPA filter acts like a sieve where particles smaller than the largest opening can pass through is incorrect. Smaller pollutants and particles are mainly trapped (they stick to a fibre) by one of the following three mechanisms

1. Interception2. Impaction3. Diffusion

• Clean air work benches are specially designed to ensure the aseptic preparation of sterile products.

• Air flow rates • 0.3 m/s (vertical)• 0.45 m/s (horizontal)

• Introduction of personnel, equipment, and material into the work area provides sources of particulate matter which may contaminate the product.

• Very small particles are not heavy enough to settle due only to the force of gravity, but instead are carried and directed by air currents. and if there is turbulent air, particles may be driven into product.

• Laminar air flow velocity satisfactorily sweeps the area yet does not create unacceptable turbulence.

Laminar flow hoods

• Types of containers

Ampoules• They are intended for single

use only. • Because glass particles may

become dislodged during ampoule opening, the product must be filtered before it administered.

Limitation• Unsuitability for multiple-

dose use• The need to filter solutions

before use • Other safety considerations

• Vials Glass or plastic containers are closed with a rubber stopper and sealed with an aluminum crimp.

Advantages over ampoules.

They can be designed to hold multiple doses (if prepared with a bacteriostatic agent). It is easier to remove the product. They eliminate the risk of glass particle contamination during opening.

Drawbacks• Multiple withdrawals (as with

multiple-dose vials) may result in microbial contamination.

•Double Chambered Vials• Some drugs that are unstable in solution

are packaged in vials in powder form and must be reconstituted with sterile sodium chloride for injection before use.

• Some of this drugs come in vials that contain a double chamber.

• Top chamber - sterile water for injection

• Bottom chamber- unreconstituted drug

• Both chambers are separated by a rubber closure.

• To dislodge the inner closure and mix the contents of the compartments, external pressure is applied to the outer rubber closure.

• Prefilled syringes

Designed for quickest administration and maximum convenience.

Drugs administered in an emergency (e.g.atropine, epinephrine) may be available for immediate injection when packaged in prefilled syringes.

•Rubber Stopper Washing Machine

• Syringe Filling MachineCharacteristics• Barrier isolators• In-process check weighing • Filling : rotary piston pumps. • 0.2 to 29 ml.

Filling : -- All types of syringe including glass, plastic can be filled. -- 300 to 600 syringes in a minute.

•Ampoule Washing Machine

PROCESSWater is sprayed onto the

ampoules.Turned to an angle of 180 degree

with their mouth downward to remove water.

Finally the ampoules are filled with compressed air to remove residual water.

Certain machines have a high temperature zone meant for killing any bacteria.

•Vial Washing And Sterilizing Machine

• Automatic Intelligent Light Inspection Machine

•Vial Filling Machine• Fill vials and bottles • liquids, viscous material and

suspensions and powders.

PROCESS The machine comprises of an intake

section which loads the vials. Transferred through an intermittent

transport section. liquid filling section which fill the vials

with predetermined quantity. Finally the filled and rubber stoppered

vials are released and discharged.

• Fully automated inspection systems

58/94

•Vial Inspection Machine

•Vial Labeling Machine

• Ampoule Filling MachineNote = vertical laminar air flow, plastic

curtain. Filling range of these machines is

normally between 1ml to 20 ml.Features of Ampoule Filling Machines

Accommodate a variety of ampoules in terms of shapes and size.

'no ampoule no fill' capability Check weight mechanism of the machine

helps to maintain consistency in each batch.

Sealing is done either by laser sealing system or conventional gas flame. Application of Ampoule Filling Machine

• Pharmaceutical • Neutraceutical

•SIP System • For in-line sterilization of various

processing equipments.

• Handling various biological solutions and mixtures requires cleaning and sterilizing these equipments from time to time as they are susceptible to contamination.

• Proper SIP integration with

pharmaceutical equipment is very important for the overall success of the operation.

• ANTIMICROBIAL EFFICACY OF A SILVER-ZEOLITE MATRIX COATING ON STAINLESS

STEEL • A silver and zinc-containing zeolite matrix (AgION) used as a coating for stainless steel.

• Test against- e coli, s aereus, p aeroginosa etc.

• Result:- The silver-zeolite mixture reduced microbial colony-forming units upto 84.536 – 99.999% after 4 h exposure, and upto 99.992-100% after24 h in all cases.

• FILTERS IN FILTRATION STERILIZATION

Millipore’s Airvent filters • Constructed with a PTFE membrane. • These filters have been qualified to

withstand at least 40 SIP cycles at 135 °C for 30 minutes.

Millipore’s Durapore filters • Constructed with a PVDF membrane • These filters have been qualified to

withstand 5 to 30 SIP cycles at 135 °C for 30 minutes

Verification of integrity of filter • Bubble point method• Diffusive flow• Pressure hold test

•Bubble Point Test

Test Method

1. Record the filter part number(s), lot number, and product information. Also include physical observations.

2. Wet the filter to be tested with the appropriate solvent (water for hydrophilic filters, alcohol for hydrophobic filters).

3. Place the wetted filter in the appropriate housing.4. Connect the outlet fitting from the compressed air pressure regulator to the

upstream side of the test filter.6. Connect a piece of flexible tubing from the downstream port of the test filter

into a beaker filled with water.7. Starting from zero pressure, gradually increase the pressure to the test filter

using the pressure regulator.8. Observe the submerged end of the tubing for the production of bubbles as

the upstream pressure is slowly increased in 0.5 psig increments. Note the rate that the bubbles appear for the end of the submerged tube.

9. The bubble point of the test filter is reached when bubbles are produced from the tube at a steady rate. Record the pressure to the nearest 0.5 psig as indicated on the pressure gauge.

• STANDARAD OPERATION PROCEDURE

For aseptic filling:-Check all sterilized material has indicator and expiration date.

Open sterilized container, filling assembly and tubing on LAF bench.

Connect the tubing of filling lines.Connect solution tank to the inlet of the filling assembly.

Connect the nitrogen over lay in tank for pre and post flushing.

Pump the solution in filling tubing up to the filling nozzle (remove any air bubble)

After that wipe the filling nozzle with 70%alcohol.Switch on the machine.

S.O.P FOR OTHER MENUFACTURING PROCESSES IS SAME AS THAT OF NON STERILE DOSAGE FORMS

• VALIDATIONPurpose : To minimize this reliance on end product sterility

testing.

Three principle involved in validation process.• To built sterility in the product.• To demonstrate the maximum level of probability that the

processing and sterilization method have establish sterility to all units of product batch.

• To provide greater assurance and support to the result of the end product sterility.

• Validationa) Pre-processing quality control testb) In process quality control testc) Finished product quality control test

Pre-processing quality control test:-d) Raw material testing and assayse) Packaging material test (glass, plastic, rubber etc)f) sterility test and media fill (process simulation test )

• Tests for containers

(a). For Glass containers.(i). Test for hydrolytic resistance.(ii). Arsenic test.

(b). For Plastic container.(i). Non volatile matter.(ii). Sulphated ash.(iii). Heavy metals.(iv). Buffering capacity.(v). Biological test. (Adverse reaction or toxicity)

• Media fill (process simulation test):-

Evaluation of the environment along with the process, the operator and the equipment is the media fill.

Procedure Sterile Trypticase soy broth is filled into sterile container under

condition simulating as for a product. Entire lot at least 3000 units is incubated at suitable temp for 14

days . To pass the test not more than 0.1% of the unit may show growth. This is very stringent evaluation of an aseptic fill process and is

considered to be the most evaluative test available.

• In Process Quality Control Test Conductivity measurementVolume filledTemp for heat sterilized productEnvironmental control testsVisual inspection

•Finished product quality control test

Leaker testPyrogen test Particulate test Sterility test.Uniformity of weight.Uniformity of content

• Leak test• To detect incompletely sealed

ampoules.Principle

10% methylene blue or 0.1% FDC red one or red two.Generally combined with autoclave.

Disadvantage Leakage of 15 micron in diameter or smaller is not detected.Vial and bottles are not subjected to this test.

• Pyrogen test

• LAL test Limulus amoebocyte test or bacterial Endotoxin test for the validation of depyrogenation process.

Reagent - LAL reagent (limulus Polyphemus)Reaction - In presence of Endotoxin a firm gel is formed within 60 min when incubated at 370 C.

CHARACTERISTIC• Test tube scale.• Only pyrogen of gram negative bacteria detected.• Semi quantitative test.• Sensitivity in terms of Endotoxin unit.• In-vitro test.• Doesn’t measure fever producing potential of Endotoxin.• Sensitivity varies with different microbial source of LAL.

• LAL TESTER

•Pyrogen test- Fever response of rabbit

• Sham test is performed to select the proper animals for the main tests.• Rabbit test - Qualitative fever response test. Procedure• Test solution is injected into the vein of rabbit. Temperature elevation is

seen for 3 hrs.

DisadvantageBiological variationExpensive LaboriousDose dependent.Not for anti pyretic drug.

• Particulate test

USPVisually inspected- all (WHITE AND BLACK )Any with visible particle is discarded.Large volume parental

50 particles of 10μm 5 particulates of 25 μm per ml

1. Light obscuration particle count test2. Microscopic particle count test

• HVAC Validation Features of HVAC affect product quality (sterility).1. HEPA integritya) Certification: by filter manufacturer indicates that filter is capable of removing all

particulate matter equal to or greater than 0.3 in size with an efficiency of 99.97%.b) Installation: a certified filter if improperly installed will not perform its function &

provides a false sense of security.c) Integrity testing: A popular method for certifying integrity of filter installation uses

polydisperse aerosol, created by blowing air through liquid Dioctyl phthalate, introduced into upstream of HEPA filter followed by scanning the entire downstream of filter face with a probe nozzle of an aerosol photometer.

• This testing will indentify “leaks” caused by damage due to mishandling or faulty construction.

• Small leaks can be repaired with a suitable silicone based compound without removing filter.

• HVAC Validation (Cont.)d) Airflow resistance : Caused by dirty filter may reduce airflow volume, thereby

reducing the air change rate in critical areas.Airflow resistance is expressed as pressure differential between the air pressure upstream of the filter and the downstream air filter.If the filters are not changed when they reach the maximum resistance as specified by manufacturer, they may begin to lose their physical integrity or rupture, thereby releasing some of the dust they have accumulated.

2. Airborne particle control Particle count surveys should be performed at regular intervals.

3. Airflow directionDetermination of unidirectional flow involves measuring the parallelism of air flow generating from HEPA filter throughout the work zone.This can be accomplished using an isokinetic smoke generator & measuring devices to determine offset from straight line flow.

4. Room pressure difference• Special monitoring devices which measure the pressure differential are

connected directly to an alarm system that will cause a visual signal (flashing light) or an audible signal (Alarm buzzer) to report a deviation outside a prescribed range of pressure differential.

5. Temp. & Humidity control

Sr.No Test Frequency1 Particle Monitoring in air 6 monthly

2 HEPA Filter Integrity Testing Yearly

3 Air Changes Rate Calculation 6 Monthly

4 Air Pressure Differentials Daily

5 Temperature and Humidity Daily

6 Microbiological monitoring by settle plates and / or swabs in aseptic areas

Daily, and at decreased frequency in other areas

HVAC Validation (Cont.)

Cleanroom Environmental Monitoring

• Packaging of finished product Packaging material. (1) Glass(2) Plastic

• Plastic is more preferred over glass as packaging material for no of reasons.- Ease to form - High quality- Freedom of design

E.g.--Polypropylene, PVC, Polystyrene, Nitrile polymers.

•USP requirements for packaging.

• Single dose container should not be more than 1 liter.

• Intra-spinal and intra-cisternal administered product must be in single dose container.

• In case of multiple dose container dose should not be more than 30 ml.

• It refers to the technology and related equipment and procedures in which the formation of the container, its filling with liquid pharmaceutical material, and subsequent formation and application of a seal for container are achieved aseptically in an uninterrupted sequence of operations without exposure to nonsterile environments between poerations.

BFS Technology

• BFS Technology1. Extrusion• An endless sterile plastic tube is

continuously extruded from the melted granulate in the filling cavity of the mould.

2. Blowing• Final container is produced

by sterile air pressure from Blow and Fill nozzle.

3. Filling• After the container is formed

inside the mould, sterile liquid product is introduced into the container.

BFS Technology

4. Sealing• Final container is sealed

in place by closing of the seal-mould form onto the container top.

5. Mould opening• Upon completion of filling and

sealing steps, the mould is separated, producing the sterile filled and sealed container.

BFS Technology

• ADVANTAGE OVER CONVECTIONAL ASEPTIC FILLING • There is no need to purchase and stock a range of pre-fabricated container and

closures.• Cleaning and sterilizing pre-fabricated container and closures are not required. A

clean sterile container is made with in the BFS machine.• The cost of material transport, storage and inventory control is reduced.• Validation requirement are reduced.• There is a large choice of neck and opening device shapes.• Saving floor space.• Less labour intensive than conventional one.• The code number and variables can be moulded into container it-self • With blow-fill-seal, you produce a one-piece, aseptically filled container with a built-

in safety seal..• The blow-fill-seal process is suitable for heat-sensitive products.

• Asep-Tech ® Model 603 Blow/Fill/Seal Packaging Machine System

.

• QUESTIONS ASKED1) Differentiate Master formula record (MFR), Batch manufacturing record (BMR) and standard operating

procedure (SOP) by giving a suitable example of a compendia injection product (MARCH- 2004 ). 2) Give qualitative and quantitative lay out, manufacturing steps with suitable equipments, important IPQC

parameter, and packaging records and post marketing surveillance reports for sterile products. (JULY- 2004 )

3) Discuss the department layout, schedule ‘M’ requirement, validation parameters, and PMS report for sterile LVPs?(29th September, 2004 )

4) What is the importance of Bio film removal on product quality?( march 2005) 5) What are the facilities, environment control and air handling system with different types of

classification ?( march 2005) 6) Discuss clean room concept and level of protection in brief?(2005)7) How will you evaluate the package for different sterile DF? Give the legal requirement for keeping their

records and reports? (sep 2006)8) Discuss the qualities , national ,international standard for clean room? Discuss the pressure differential in

the pharma. plant ?(sep 2006)9) Validation of the steam sterilizer and importance of the D, Z, F value? (sep 2006)10) QC. Of aseptic area (may 2003)11) Give detail lay-out of SVP and area and equipment requirement as per CGMP ? (may 2003)

•REFERENCES1. Pharmaceutical dosage forms (Parenteral Preparation) by Kenneth E. Avis, Leon

Lachman, Vol-1.2. Pharmaceutical dosage forms (Parenteral Preparation) by Kenneth E. Avis, Leon

Lachman, Vol-2.3. Drugs & Cosmetics Act 1940.4. The theory and Industrial pharmacy by Leon Lachman, Third edition5. Pharmaceutical science by Remington, 20th edition6. Pharmaceutical process Validation by Loftus & Nash: 29-90.7. Sterile Pharmaceutical Manufacturing by Groves Gisan.8. www.fda.gov.9. American Journal of Hospital Pharmacy, Vol. 38, Issue 8, 1144-114710. Dispensing for pharmaceutical students; 10 th edition; by:-S J Carton11.www.GMP.online.coms12.www.ispc.org13.www.whqlibdoc.who.org14.www.dwscientific.co.uk15.www.pharmamachines.com16.www.bascotech.com17.www.getthatmag.com18.www.fabtecheng.com19.www.ahind.com20.www.nkambica.com

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