injectable

PARENTERAL PREPARATION

Prepared By:Roshni S. VoraPhD Research Scholar

Guided By:Dr. Yamini D. ShahAssociate Professor

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L. M. College Of Pharmacy-Ahmedabad

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Para-other than ; enteron-intestine

According to I.P "parenterals are injectable preparations, sterile products intended

for administration by injection, infusion or implantation in to the body."

Parenteral products are unique from any other type of pharmaceutical dosage

form for the following reasons:

Parenterals should be free of physical, chemical and biological contamination.

Parenteral preparations are sterile, pyrogen free liquids (solutions, emulsions,

or suspensions) or solid dosage forms packaged in either single-dose or multi

dose containers.

These preparations are administered through the skin or mucus membranes into

internal body compartments.

These includes any method of administration that does not involve passage

through the digestive tract.

Injectable solutions must be free from visible particulate matter. This includes

reconstituted sterile powders.

Products should be isotonic, although strictness of isotonicity depends on the

route of administration.

Ophthalmic products, although not parenteral, must also be isotonic. Products to

be administered by bolus injection by routes other than intravenous (IV) should

be isotonic, or at least very close to isotonicity. IV infusions must be isotonic.

All products must be stable, not only chemically and physically like all other

dosage forms, but also ‘stable’ microbiologically (i.e., sterility, freedom from

pyrogenic and visible particulate contamination must be maintained throughout

the shelf life of the product).

Products must be compatible, if applicable, with IV diluents, delivery systems,

and other drug products co administered.

a small-volume therapeutic injection (SVI), such as an antibiotic, to large-

volume injections (LVIs), such as 1000 mL of 0.9% sodium chloride solution, to

avoid the discomfort, for the patient, of a separate injection. 5

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During hospital pharmacy practice a pharmacist have been undertaken and more

information has been gained, it has been shown that knowledge of variable

factors, such as pH and the ionic character of the active constituents, aids

substantially in understanding and predicting potential incompatibilities.

Kinetic studies of reaction rates may be used to describe or predict the extent of

degradation.

a thorough study should be undertaken of each therapeutic agent in combination

with other drugs and IV fluids, not only of generic, but also of commercial

preparations, from the physical, chemical, and therapeutic aspects.

Types of Processes

Small scale dispensing - usually one unit at a time : Hospital Pharmacy

Large scale - manufacturing in which hundreds of thousands of units may

constitute one lot of product : In pharmaceutical Industry

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Parenteral products from non-sterile components in the highly technologically

advanced plants of the pharmaceutical industry, using cGMP principles includes

following

1. Ensuring that the personnel responsible for assigned duties are capable and

qualified to perform them.

2. Ensuring that ingredients used in compounding the product have the required

identity, quality, and purity.

3. Validating critical processes to be sure that the equipment used and the

processes followed ensure that the finished product has the qualities expected.

4. Maintaining a production environment suitable for performing the critical

processes required, addressing such matters as orderliness, cleanliness, asepsis,

and avoidance of cross contamination.

5. Confirming, through adequate quality-control procedures, that the finished

products have the required potency, purity, and quality.

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6. Establishing, through appropriate stability evaluation, that the drug products retain their

intended potency, purity, and quality, until the established expiration date.

7. Ensuring that processes are always carried out in accord with established, written

procedures.

8. Providing adequate conditions and procedures for the prevention of mix-ups.

9. Establishing adequate procedures, with supporting documentation, for investigating and

correcting failures or problems in production or quality control.

10. Providing adequate separation of quality-control responsibilities from those of production to

ensure independent decision making.

General Manufacturing Process The preparation of a parenteral product may encompass four general areas:

1. Procurement and accumulation of all components in a warehouse area, until released to

manufacturing;

2. Processing the dosage form in appropriately designed and operated facilities;

3. Packaging and labeling in a quarantine area, to ensure integrity and completion of the

product; and

4. Controlling the quality of the product throughout the process.

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Procurement:- selecting and testing according to specifications of the raw-material

ingredients and the containers and closures for the primary and secondary

packages

Processing :- cleaning containers and equipment to validated specifications,

compounding the solution (or other dosage form), filtering the solution, sanitizing

or sterilizing the containers and equipment, filling measured quantities of product

into the sterile containers, stoppering (either completely or partially for products to

be freeze-dried), freeze-drying, terminal sterilization (if possible), and final sealing

of the final primary container. Packaging normally consists of the labeling and

cartoning of filled and sealed primary containers.

Control of quality :- the incoming supplies, being sure that specifications are met.

Each step of the process involves checks and tests to ensure the required

specifications at the respective step are being met. The quality control unit is

responsible for reviewing the batch history and performing the release testing

required to clear the product for shipment to users.

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Typical water storage and distribution schematic

Water must be kept

circulating

Spray ballCartridge

filter 1 µm

Air breakto drain

Outlets

Hygienic pump

Optionalin-line filter

0,2 µm

UV light

Feed Water from

DI or RO

Heat ExchangerOzone Generator

Hydrophobic air filter& burst disc

Water for Pharmaceutical Use

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On site inspection:• Walk through the system, verifying the parts of the system as indicated in the drawing• Review procedures and "on site" records, logs, results• Verify components, sensors, instruments• Start with source water supply – follow whole system "loop“

Water treatment system inspection – Dead Legs– Filters – Pipes And Fittings– Ionic Beds– Storage Tanks– By-pass Lines– Pumps– UV Lights– Sample Points– Reverse Osmosis– Valves– Heat Exchangers

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Additional documentation to review• Qualification protocols and reports• Change control request (where applicable)• Requalification (where applicable)• QC and microbiology laboratory• SOP for sampling

Sampling• There must be a sampling procedure• Sample integrity must be assured• Sample point and Sample size

Testing• Chemical testing• Microbiological testing

– Test method– Types of media used– Incubation time and temperature– Objectionable and indicator organisms

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Suggested bacterial limits (CFU /mL)

Sampling location Target

Alert Action

Raw water 200 300 500

Post multimedia filter 100 300 500

Post softener 100 300 500

Post activated carbon filter 50 300 500

Feed to RO 20 200 500

RO permeate 10 50 100

Points of Use 1 10 100

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Water systems

Water systems (water used for product compounding or final rinsing of surfaces which will contact the product), are typically operated in the temperate ranges hot, ambient and cold:

• Hot systems are operated above 70 °C and Cold systems are

operated in the range between 2°C and 10°C

• Ambient systems are operated in the range of the environment in

which the system is located.

• Purified water systems can be operated at any temperature.

• WFI systems are preferably operated hot and with continuous

recirculation to control microbial growth. When WFI is stored and

distributed at cold or ambient temperatures, special precautions are

taken to prevent the ingress and proliferation of microbial

contaminants, as e.g. appropriate sanitization cycles which are

defined as part of the system qualification

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• Pharmaceutical water - used for product compounding or final

rinsing of surfaces - exists in different (compendia) qualities such as:

• Preparation of the different types of water must be performed according to

current USP and/or European Pharmacopoeia

• requirements and - if applicable - according to other pharmacopoeias (e.g.

Japanese) and local requirements.

http://www.nayagara.net/

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Monitoring – General Requirements

– Water systems undergo periodic monitoring of the specified required

characteristics.

– The monitoring program is based on the results of the qualification work

and/or according to the results of a risk assessment.

– Monitoring is performed according to written procedures, describing in

sufficient detail the responsibilities for sampling, the sampling sites,

and the sampling frequencies.

– Typical minimum sampling frequencies for process systems are described in

slide 11-12.

– Higher or lower sampling frequencies for specific processes or products are

justified according to the results of a risk assessment.

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Sampling

– Sampling sites must be selected based on a risk evaluation and / or as result of

the initial qualification.

– Samples have to be taken from representative locations within the distribution

and processing system.

– Selection of sampling sites must not compromise the quality (e.g.:

microbiological status) of the system being monitored.

– The sampling plan has to be dynamic allowing for adjustments to sampling

frequency and locations based on system performance trends.

– When routine monitoring points are reduced or increased, the reason for the

change has to be documented.

– Sampling practice must simulate the use of a process system during

manufacturing,

for example where water for manufacturing is delivered through a hose,

sampling has to be performed through this hose.

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Monitoring – Typical Minimum Sampling & Testing Frequencies 1

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Water For Injection (WFI) The source water contaminated with natural

suspended mineral and organic substances,

dissolved mineral salts, colloidal material, viable

bacteria, bacterial endotoxins, industrial or

agricultural chemicals, and other particulate

matter.

The degree of contamination varies with the

source and will be markedly different, whether

obtained from a well or from surface sources,

such as a stream or lake.

The source water must be pretreated by one or a

combination of the following treatments:

chemical softening, filtration, deionization,

reverse osmosis, purification.

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A conventional still consists of a boiler (evaporator), containing feed water

(distilland); a source of heat to vaporize the water in the evaporator; a

headspace above the level of distilland, with condensing surfaces for refluxing

the vapor, thereby returning nonvolatile impurities to the distilland; a means for

eliminating volatile impurities (demister/separation device) before the hot water

vapor is condensed; and a condenser for removing the heat of vaporization,

thereby converting the water vapor to a liquid distillate.

The specific construction features of a still and the process specifications have a

marked effect on the quality of distillate obtained from a still. Several factors

must be considered in selecting a still to produce WFI:

1. The quality of the feed water will affect the quality of the distillate. For

example, chlorine in water, especially, can cause or exacerbate corrosion in

distillation units, and silica causes scaling within. Controlling the quality of the

feed water is essential for meeting the required specifications for the distillate.

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2. The size of the evaporator will affect the efficiency. It should be large enough to provide a

low vapor velocity, thus, reducing the entrainment of the distilland either as a film on

vapor bubbles or as separate droplets.

3. The baffles (condensing surfaces) determine the effectiveness of refluxing. They should

be designed for efficient removal of the entrainment at optimal vapor velocity, collecting

and returning the heavier droplets contaminated with the distill and.

4. Redissolving volatile impurities in the distillate reduces its purity. Therefore, they should

be separated efficiently from the hot water vapor and eliminated by aspirating them to the

drain or venting them to the atmosphere.

5. Contamination of the vapor and distillate from the metal parts of the still can occur.

Present standards for high-purity stills are that all parts contacted by the vapor or distillate

should be constructed of metal coated with pure tin, 304 or 316 stainless-steel, or

chemically resistant glass.

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There are two basic types of WFI distillation units—the vapor compression still and

the multiple effect still.

Compression Distillation

The vapor-compression still, primarily designed for the production of large

volumes of high-purity distillate with low consumption of energy and water.

To start, the feed water is heated from an external source in the evaporator to

boiling. The vapor produced in the tubes is separated from the entrained

distilland in the separator and conveyed to a compressor that compresses the

vapor and raises its temperature to approximately 107°C.

It then flows to the steam chest, where it condenses on the outer surfaces of the

tubes containing the distilland; the vapor is, thus, condensed and drawn off as a

distillate, while giving up its heat to bring the distilland in the tubes to the boiling

point.

Vapor-compression stills are available in capacities from 50 to 2800 gal/hr.

24vapor-compression still

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Multiple-Effect Stills The multiple-effect still is also designed to conserve energy and water usage. In

principle, it is simply a series of single-effect stills or columns running at

differing pressures where phase changes of water take place.

A series of up to seven effects may be used, with the first effect operated at the

highest pressure and the last effect at atmospheric pressure. Steam from an

external source is used in the first effect to generate steam under pressure from

feed water; it is used as the power source to drive the second effect.

The steam used to drive the second effect condenses as it gives up its heat of

vaporization and forms a distillate.

This process continues until the last effect, when the steam is at atmospheric

pressure and must be condensed in a heat exchanger.

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The capacity of a multiple-effect still can be increased by adding effects. The quantity of

the distillate will also be affected by the inlet steam pressure; thus, a 600-gal/hr unit

designed to operate at 115 psig steam pressure could be run at approximately 55 psig and

would deliver about 400 gal/hr. These stills have no moving parts and operate quietly. They

are available in capacities from about 50 to 7000 gal/hr.

Multiple-Effect Stills

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Reverse Osmosis (RO) It is a natural process of selective permeation of molecules through a semi

permeable membrane separating two aqueous solutions of different

concentrations is Reverse osmosis.

Pressure, usually between 200 and 400 psig, is applied to overcome osmotic

pressure and force pure water to permeate through the membrane.

Membranes, usually composed of cellulose esters or polyamides, are selected to

provide an efficient rejection of contaminant molecules in raw water. The

molecules most difficult to remove are small inorganic molecules, such as sodium

chloride.

Passage through two membranes in series is sometimes used to increase the

efficiency of removal of these small molecules and decrease the risk of structural

failure of a membrane to remove other contaminants, such as bacteria and

pyrogens.

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Several WFI installations utilize both RO and distillation systems for generation of

the highest quality water. Since feedwater to distillation units can be heavily

contaminated and, thus, affect the operation of the still, water is first run through

RO units to eliminate contaminants.

Whichever system is used for the preparation of WFI, validation is required to be

sure that the system, consistently and reliably, produces the chemical, physical,

and microbiological quality of water required.

Such validation should start with the determined characteristics of the source

water and include the pretreatment, production, storage, and distribution systems.

Storage and Distribution

The rate of production of WFI is not sufficient to meet processing demands;

therefore, it is collected in a holding tank for subsequent use. In large operations,

the holding tanks may have a capacity of several thousand gallons and be a part

of a continuously operating system. In such instances, the USP requires that the

WFI be held at a temperature too high for microbial growth, normally a constant

80°C.

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Such a system requires frequent sanitization to minimize the risk of viable

microorganisms being present. The stainless-steel storage tanks in such systems

are usually connected to a welded stainless steel distribution loop, supplying the

various use sites with a continuously circulating water supply. The tank is

provided with a hydrophobic membrane vent filter capable of excluding bacteria

and nonviable particulate matter. Such a vent filter is necessary to permit changes

in pressure during filling and emptying.

The construction material for the tank and connecting lines is usually electro

polished 316L stainless steel with welded pipe. The tanks also may be lined with

glass or a coating of pure tin. Such systems are very carefully designed and

constructed and often constitute the most costly installation within the plant.

When the water cannot be used at 80°C, heat exchangers must be installed to

reduce the temperature at the point of use. Bacterial retentive filters should not be

installed in such systems, due to the risk of bacterial buildup on the filters and the

consequent release of pyrogenic substances.

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Purity Although certain purity requirements have been alluded to, the USP and EP

monographs provide the official standards of purity for WFI and Sterile Water

for Injection (SWFI).

The chemical and physical standards for WFI have changed in the past few

years. The only physical/chemical tests remaining are the new total organic

carbon (TOC), with a limit of 500 ppb (0.5 mg/L), and conductivity, with a limit

of 1.3 μS/cm at 25°C or 1.1 μS/cm at 20°C. The pH requirement of 5 to 7 in

previous revisions has been eliminated.

The SWFI requirements differ in that, since it is a final product, it must pass the

USP Sterility Test. WFI and SWFI may not contain added substances.

Bacteriostatic Water for Injection (BWFI) may contain one or more suitable

antimicrobial agents in containers of 30 mL or less.

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Sampling Point & Point of Use

PreparationVessel

point of use point of use= sampling point

sampling pointsampling point

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UVDisinfection

unit

Points of Use

Return

Storage Tank

Mixed ionexchange bed

Particle Filter

Pump

Ventilation Filter

Particle Filter

UVdisinfection

unit

Feed Water

Inflow

Monitoring – Typical Minimum Sampling & Testing Frequencies

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System-specific sampling points Depend on the construction and the technical conditions of the installation or system(e.g. Begin and end [=return] of the distribution system).

Relevant sampling points(API/potable water)

Evenly distributed throughout the plant (e.g. One sampling point per floor).

Critical points of use Depend on the individual manufacturingprocess: - For cleaning product contacting surfaces - During final crystallization of APIs - for final rinsing of product contacting- For aqueous granulation processes)

Selected sampling points Not directly relevant for the production(e.g. In cleaning/washing areas)

Selected sampling points for endotoxin testing

Where purified water is ultra-filtered to meet the endotoxin specification)


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ReturnInflow


35









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process-relevantbut not critical:organic coating

critical:aqueous coating


37









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selected:washing/cleaning


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Physical, Chemical and Microbiological Testing ParametersTEST MODULE SPECIFICATIONS REFERENCE

Appearance Clear, Colorless Liquid Ph. Eur. and USP

Conductivity < 1.1 µS / cm (20oC) or values as per Ph. Eur. Ph. Eur. and USP

Ammonium Not more intense in color than reference, corresponding to < 0.05 ppm

JP

Chlorides Complies to the test JP

Nitrates and Nitrites Not more intense in color than reference, corresponding to < 0.2 ppm

Ph. Eur. and JP

Total Organic Carbon (TOC) < 0.5 mg / L Ph. Eur. and USP

Oxidizable Substances Complies to the test JP

Acidity or Alkalinity Complies to the test JP

Heavy Metals Not more intense in color than reference, corresponding to < 0.1 ppm

Ph. Eur. and JP

Sulfates Complies to the test JP

Residue on Evaporation < 10 ppm JP

Microbial Contamination max. 10 cfu / 100 ml Ph. Eur. and USP

Bacterial Endotoxins < 0.25 EU / ml Ph. Eur. and JP

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Test Methods and Method Requirements

– All methods must be performed according to current USP and/or European Pharmacopoeia

and, if applicable other pharmacopoeia and/or local requirements (e.g. in case of potable

water).

– All methods or culture media have to be suitable to detect microorganisms that may be

present.

– The cultivation conditions, are selected to be appropriate for the specific growth

requirements of microorganisms to be detected, for example:

• Total aerobic count can be obtained by incubating at 30 to 35 °C for not less than three days

• Suitable culture media (low nutrient medium) is used for monitoring of water systems (30 to

35°C, at least 5 days).

– Testing of viable monitoring samples is performed under aerobic conditions unless there are

indications that the process is at risk for contamination with anaerobic microorganisms.

– It must be assured that cleaning or disinfection agents remaining on surfaces sampled does

not interfere with microbial recovery when methods using culture media are applied.

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Alert and Action Level in Microbiological Monitoring

– An Alert level in microbiological monitoring is that level of microorganisms that shows

significant differences from normal operating conditions.

– Alert levels are usually based upon historical information gained from the routine operation of the

process in a specific controlled environment.

– In a new facility, these levels are based on prior experience from similar facilities/ processes.

– Alert levels are re-examined and – if necessary – re-set at an established frequency. Trends that

show a deterioration of the environmental quality require respective CAPAs.

– An Action level is that specification level of microorganisms or particles that when exceeded

requires immediate follow-up and, if necessary, corrective action.

Common procedure of setting alter level based on a set of at least 12 months

data: 95% of all results < alert level AND 5 % of all results ≥ alert level

Typically, the initial alert level is set to… 50 % of the action level

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Procedures when an Alert level is exceeded

– Exceeding the Alert level does not necessarily require

a definitive corrective action, but it prompts at least

documented follow-up measures, as established in

a local procedure.

– These measures include but are not limited to the following:

o Comparison with results obtained concurrently with other related sampling

points.

o Comparison with historical data from the same sampling point.

o If possible re-sampling of the affected sampling point; routine sample(s) taken

from the affected point(s) within this period can be considered as resample.

no further Alert level => no additional action

again Alert level exceeding => repetition of re-sampling according to the procedure described above

consecutive Alert level exceeding => escalation of measures (e.g. following the procedures of exceeding an Action level)

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Procedures when an Action level is exceeded

– As soon as an Action level excursion is reported,

“immediate corrective actions” and an investigation have to be performed as

described in a local procedure.

– An evaluation of the potential impact this exceeding has on manufactured

products has to be made.

– When a definitive cause for the excursion can be determined immediately,

specific corrective actions are performed before re-sampling starts.

– Re-sampling of the affected points has to be performed immediately after the

implementation of “immediate / specific corrective actions”.

– Monitoring critical sampling points includes routine identification of

microorganisms to the species (or, where appropriate, genus) level at least

when Alert and Action Levels are exceeded.

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Documentation and Trending of Monitoring Data

All monitoring activities are documented properly (typically on form sheets

which are laid down in SOPs).

The results from critical sampling locations must be assignable to the respective

activity at the time of sampling (important in case of batch-related monitoring,

i.e. the environmental monitoring data must have a formal linkage to product

release as defined by procedures).

Monitoring data must be summarized on a periodic basis and issued to the

responsible senior management on a periodic basis (e.g. via Product Quality

Review).

Based on this summary, trends have to be evaluated and corrective action to be

defined, if appropriate.

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Q & A

Purified water systems have to be sampled (monitored) daily for microbiological

testing.

For chemical/physical testing of water systems, it is highly recommended to define

the last point of use (return) in the system as a routine sampling point.

Any Alert Level excursion initiates an immediate procedure.

Purified water with endotoxin limit is required for the final purification of a non-

sterile API to be used in a sterile parenteral Drug Product.

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Process Systems – General Qualification Provisions

Qualification is required for any process system (e.g. Water,

Nitrogen, Clean Steam, Compressed Air) …

• that is involved in the manufacture of APIs (beginning with

the regulatory starting materials), Drug Products or

intermediates

• that may affect testing results of an API, Drug Product or

intermediate, that is involved in final cleaning processes,

• where the utility supplied directly contacts an API, Drug

Product or intermediate,

• where the utility supplied comes in contact with surfaces

that have direct contact with APIs, Drug Products or

intermediates,

… and, therefore, could have an impact on the quality of the API,

Drug Product or intermediate.

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Before beginning the qualification of a process system, the following documentation has to be available:

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Test Items for Qualification of Process Systems

• Following table outlines parameters and aspects to be checked, evaluated and

tested within the qualification study of a process system, provided that these

are relevant for the particular qualification (see following slide).

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• Based on this table, the qualification team determines by means of a risk-based• approach … – the sampling points, e.g. by answering the following questions…

Which points of use are critical ? Which points of use are system-specific ? Is it necessary to realize a particular sampling point (due to the unattainability of

the point of use) ?

Usually, selected sampling

points include…

significant points of use

return loop

points prior to and after each

significant treatment step

storage tank

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Requalification of Process Systems• For-Cause Requalification• Generally, in case of changes or modifications, the same test items apply for requalification as for

initial qualification. However, based on a risk evaluation, the extent of a requalification may be reduced in comparison to the initial qualification.

• Periodic Requalification• The following periodic requalification

intervals apply:

• However, the regular evaluation of the• existing documentation such as…

– monitoring data,– quarterly reports,– change documentation,– logbooks,– maintenance/servicing documentation,– technical reports

• … equates to periodic requalification, provided that relevant• requalification item are appropriately covered.

“streamlined”requalificationapproach

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• In case of water systems, the qualification process entails a three-phase approach in order to satisfy the objective of demonstrating the reliability and robustness of the system in service over an extended period.

52

• Phase 1:

– Initial phase, usually taking 2 to 4 weeks, serves to establish operating parameters and procedures,

– Does not end until the system operates stable and within the required ranges,

– Might be shortened in case of modifications to a water system already in use.

• Phase 2:

– Short-term control phase usually taking 2 to 4 weeks.

– Before water is permitted to be used for pharmaceutical purposes, an interim qualification report is

required, documenting the successful completion of Phase 2.

– However, water can also be used for pharmaceutical purposes during this phase, provided that the

respective batches are not released until the interim qualification report has been finalized.

• Phase 3:

– Long-term control phase usually taking 1 year, serves to demonstrate continuous and consistent

operation irrespectively of external and seasonal variations.

– Physico-chemical properties, microbial counts (as well as endotoxin where required) are

monitored and evaluated at close intervals, Where the season affects the quality of the feed water

(e.g. potable water), sampling should be increased.

– Phase 3 ends with the preparation of the final Qualification Report.

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Water-Miscible Vehicles These solvents are used to solubilize certain drugs in an aqueous vehicle and to

reduce hydrolysis. The most important solvents in this group are ethyl alcohol,

liquid polyethylene glycol, and propylene glycol.

Ethyl alcohol is used in the preparation of solutions of cardiac glycosides and

the glycols in solutions of barbiturates, certain alkaloids, and certain

antibiotics. Such preparations are given intramuscularly. There are limitations

with the amount of these co-solvents that can be administered, due to toxicity

concerns, greater potential for hemolysis, and potential for drug precipitation at

the site of injection.

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Non-Aqueous Vehicles The most important group of non-aqueous vehicles is the fixed oils. The

USP provides specifications for such vehicles, indicating that the fixed oils

must be of vegetable origin so they will metabolize, will be liquid at room

temperature, and will not become rancid readily. The USP also specifies

limits for the free fatty acid content, iodine value, and saponification value

(oil heated with alkali to produce soap, i.e., alcohol plus acid salt).

The oils most commonly used are corn oil, cottonseed oil, peanut oil, and

sesame oil. Fixed oils are used as vehicles for certain hormone (e.g.,

progesterone, testosterone, deoxycorticicosterone) and vitamin (e.g.,

Vitamin K, Vitamin E) preparations.

The label must state the name of the vehicle, so the user may beware in

case of known sensitivity or other reactions to it.

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Solutes

Care must be taken in selecting active pharmaceutical ingredients and

excipients to ensure their quality is suitable for parenteral administration.

A low microbial level will enhance the effectiveness of either the aseptic or

the terminal sterilization process used for the drug product.

It is now a common GMP procedure to establish microbial and endotoxin

limits on active pharmaceutical ingredients and most excipients.

Chemical impurities should be virtually nonexistent in active pharmaceutical

ingredients for parenterals, because impurities are not likely to be removed by

the processing of the product.

Depending on the chemical involved, even trace residues may be harmful to

the patient or cause stability problems in the product. Therefore,

manufacturers should use the best grade of chemicals obtainable and use its

analytical profile to determine that each lot of chemical used in the

formulation meets the required specifications.

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Reputable chemical manufacturers accept the stringent quality requirements for parenteral

products and, accordingly, apply good manufacturing practices to their chemical

manufacturing. Examples of critical bulk manufacturing precautions include:

1. Using dedicated equipment or properly validated cleaning to prevent cross-

contamination and transfer of impurities;

2. Using WFI for rinsing equipment;

3. Using closed systems, wherever possible, for bulk manufacturing steps not followed

by further purification; and

4. Adhering to specified endotoxin and bioburden testing limits for the substance.

Added Substances

The USP includes in this category all substances added to a preparation to improve or

safeguard its quality. An added substance may:

Increase and maintain drug solubility. Examples include complexing agents and surface

active agents. The most commonly used complexing agents are the cyclodextrins,

including Captisol. The most commonly used surface active agents are polyoxyethylene

sorbitan monolaurate (Tween 20) and polyoxyethylene sorbitan monooleate (Tween 80).

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Provide patient comfort by reducing pain and tissue irritation, as do

substances added to make a solution isotonic or near physiological pH.

Common tonicity adjusters are sodium chloride, dextrose, and glycerin.

Enhance the chemical stability of a solution, as do antioxidants, inert gases,

chelating agents, and buffers.

Enhance the chemical and physical stability of a freezedried product, as do

cryoprotectants and lyoprotectants. Common protectants include sugars, such

as sucrose and trehalose, and amino acids, such as glycine.

Enhance the physical stability of proteins by minimizing self-aggregation or

interfacial induced aggregation. Surface active agents serve nicely in this

capacity.

Minimize protein interaction with inert surfaces, such as glass and rubber and

plastic. Competitive binders, such as albumin, and surface active agents are

the best examples.

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Protect a preparation against the growth of microorganisms. The term ‘preservative’ is

sometimes applied only to those substances that prevent the growth of microorganisms

in a preparation. However, such limited use is inappropriate, being better used for all

substances that act to retard or prevent the chemical, physical, or biological

degradation of a preparation.

Although not covered in this chapter, other reasons for adding solutes to parenteral

formulations include sustaining and/or controlling drug release (polymers), maintaining

the drug in a suspension dosage form (suspending agents, usually polymers and surface

active agents), establishing emulsified dosage forms (emulsifying agents, usually

amphiphilic polymers and surface active agents), and preparation of liposomes

(hydrated phospholipids). Although added substances may prevent a certain reaction

from taking place, they may induce others. Not only may visible incompatibilities

occur, but hydrolysis, complexation, oxidation, and other invisible reactions may

decompose or otherwise inactivate the therapeutic agent or other added substances.

Therefore, added substances must be selected with due consideration and investigation

of their effect on the total formulation and the container-closure system.

59

Antimicrobial Agents The USP states that antimicrobial agents in bacteriostatic or fungistatic

concentrations must be added to preparations contained in multiple-dose

containers.

The European Pharmacopeia requires multiple-dose products to be bacteriocidal

and fungicidal. They must be present in adequate concentration at the time of use

to prevent the multiplication of microorganisms inadvertently introduced into the

preparation, while withdrawing a portion of the contents with a hypodermic needle

and syringe.

The USP provides a test for Antimicrobial Preservative Effectiveness to determine

that an antimicrobial substance or combination adequately inhibits the growth of

microorganisms in a parenteral product.

60

Large-volume, single-dose containers may not contain an added antimicrobial

preservative. Therefore, special care must be exercised in storing such products after the

containers have been opened to prepare an admixture, particularly those that support the

growth of microorganisms, such as total parenteral nutrition (TPN) solutions and

emulsions.

It should be noted that, although refrigeration slows the growth of most microorganisms,

it does not prevent their growth. Buffers are used to stabilize a solution against chemical

degradation or, especially for proteins, physical degradation (i.e., aggregation and

precipitation) which might occur if the pH changes appreciably.

Buffer systems should have as low a buffering capacity as feasible, so as not to

significantly disturb the body’s buffering systems when injected. In addition, the buffer

type and concentration on the activity of the active ingredient must be evaluated

carefully. Buffer components are known to catalyze degradation of drugs. The acid salts

most frequently employed as buffers are citrates, acetates, and phosphates. Amino acid

buffers, especially histidine, have become buffer systems of choice for controlling

solution pH of monoclonal antibody solutions.

61

Because antimicrobials may have inherent toxicity for the patient, the USP prescribes

maximum volume and concentration limits for those commonly used in parenteral

products (e.g., phenylmercuric nitrate and thimerosal 0.01%, benzethonium chloride

and benzalkonium chloride 0.01%, phenol or cresol 0.5%, and chlorobutanol 0.5%).

Benzyl alcohol, phenol, and the parabens are the most widely used antimicrobial

preservative agents used in injectable products. In oleaginous preparations, no

antibacterial agent commonly employed appears to be effective. However, it has been

reported that hexylresorcinol 0.5% and phenylmercuric benzoate 0.1% are moderately

bactericidal.

A physical reaction encountered is that bacteriostatic agents are sometimes removed

from solution by rubber closures. Protein pharmaceuticals, because of their cost and/or

frequency of use, are preferred to be available as multiple dose formulations (e.g.,

Human Insulin, Human Growth Hormone, Interferons, Vaccines, etc.).

Phenoxyethanol is the most frequently used preservative in vaccine products. Single-

dose containers and pharmacy bulk packs that do not contain antimicrobial agents are

expected to be used promptly after opening or discarded.

62

Anitoxidants are frequently required to preserve products, due to the ease with

which many drugs, including proteins with methionine or cysteine amino acids

conformationally exposed, are oxidized.

Sodium bisulfite and other sulfurous acid salts are used most frequently. Ascorbic acid

and its salts are also good antioxidants. The sodium salt of ethylenediaminetetraacetic

acid (EDTA) has been found to enhance the activity of antioxidants, in some cases, by

chelating metallic ions that would otherwise catalyze the oxidation reaction. Displacing

the air (oxygen) in and above the solution, by purging with an inert gas, such as nitrogen,

can also be used as a means to control oxidation of a sensitive drug.

Process control is required for assurance that every container is deaerated adequately and

uniformly. However, conventional processes for removing oxygen from liquids and

containers do not absolutely remove all oxygen. The only approach for completely

removing oxygen is to employ isolator technology, where the entire atmosphere can be

recirculating nitrogen or another non-oxygen gas. Tonicity Agents are used in many

parenteral and ophthalmic products to adjust the tonicity of the solution.

63

The water is contaminated as it passes through the valve

Bacteria can grow when the valve is closed

Stagnant water inside valve

Bio contamination control techniques There should be no dead legs

Water scours dead leg

If D=25mm & distance X isgreater than 50mm, we havea dead leg that is too long

Dead leg section

>1.5D

Flow direction arrows on pipes are important

Sanitary Valve

D

X

Ball valves are unacceptable

64

Bio contamination control techniques

• Pressure gauges separated from system membranes• Pipe work laid to fall (slope) – allows drainage• Maintain system at high temperature (above 70 degrees Celsius)• Use UV radiation

– Flow rate, life-cycle of the lamp• Suitable construction material• Periodic sanitization with hot water• Periodic sanitization with super-heated hot water or clean steam

– Reliable– Monitoring temperature during cycle

• Routine chemical sanitization using, e.g. ozone– Removal of agent before use of water important

65

Although it is the goal for every injectable product to be isotonic with physiologic

fluids, this is not an essential requirement for small volume injectables administered

intravenously. However, products administered by all other routes, especially into the

eye or spinal fluid, must be isotonic.

Injections into the subcutaneous tissue and muscles should also be isotonic to minimize

pain and tissue irritation. The agents most commonly used are electrolytes and mono-

or disaccharides.

Cryoprotectants and Lyoprotectants are additives that servem to protect

biopharmaceuticals from adverse effects, due tofreezing and/or drying of the product

during freeze-dry processing. Sugars (non-reducing), such as sucrose or trehalose,

amino acids, such as glycine or lysine, polymers, such as liquid polyethylene glycol or

dextran, and polyols, such as mannitol or sorbitol, all are possible cryo- or

lyoprotectants.

66

What do you need to know about Injection Sites?

Safety Considerations:

When preparing multiple injections, always label the

syringe immediately .

Keep the medication container with the syringe

Do not rely on memory to determine which solution is in

which syringe.

Carefully monitor the patient for any adverse effects for at

least 5 minutes after administration of any medication.

Handle multi-dose vials carefully and with aseptic

technique so that medicines are not wasted or contaminated.

67

Primary Parenteral Routes

Routes 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


LVP 101 and larger(infusion unit)

Venoclysis 1.5 in. ,18-19 gauge

Solutions and some emulsions


68

No. ADVANTAGES DISVANTAGES1. Quick onset Wrong dose or over dose can be fatal

2. Vomiting and unconscious patients can take Pain at site3. Prolonged action by modified formulation Trained person required

4. Nutritive fluids can be given Expensive5. Drugs with poor absorption or instability from

GITNecessity Of Aseptic Conditions In Production, Compounding And Administration

When to Aspirate (IM & SC injection)

The reason for aspiration before injection a medication is to ensure that the needle is

not in a blood vessel. If blood appears in the syringe, withdraw the needle, discard the

syringe, and prepare a new injection.

When Not To Aspirate

When administering SC heparin/ insulin, it is recommended that you do NOT aspirate.

Because of the anticoagulant properties of heparin, aspiration could damage

surrounding tissue and cause bleeding and bursting.

69

Parenteral products: routes of administration

Intravenous (IV)Vein

Intramuscular (IM)

Muscle

Intradermal (ID)Into the kin

IntraarticularJoints

IntrasynovialJoint-fluid area

IntraosseousBones

Intraspinal Spinal column

IntracerebralBrain

Sublingual below tounge

Endotracheal Down the trachea

IntracardiacHeart

Intra-arterialArteries

IntrathecalSpinal fluid

Subcutaneous (SC)

Under the skin

Intramuscular Administration

Administered into a muscle or muscle group

Onset: variable

Volume: up to 4ml

Equipment:1-5 ml syringe, needle (18-23 g, ⅝ to 3 inch needle),

alcohol swab

Identify site and Cleanse site with alcohol

Pull skin taut and Hold needle like “dart”

Insert quickly at a 90° angle and Stabilize needle

Aspirate for blood, If no blood, instill medication slow and

steady and Quickly remove needle.

DO NOT RECAP. Activate safety feature. Place needle in

sharps container uncapped. Massage site with alcohol swab70

71

Injection Sites – Deltoid

Location: upper arm

Landmarks: Acromion Process, axillary fold

Muscle mass: triangle apex at axillary line and base of

triangle 2-3 finger breadths below acromion process.

Injection area: in the middle of the triangle / into belly of

the muscle mass. Avoid Brachial artery & Radial nerve

(BARN)

Should not be used in infants or children because of the

muscle’s small size.

Injection volume should not exceed 1ml in the adult

Use a 23-28 gauge, 5/8 to 1 inch needle

Rarely used for hospitalized patients. Primarily used for

immunizations.

72

Injection Sites – Ventrogluteal

Location: lateral (ventral) side of the hip

Landmarks: Iliac crest, anterosuperior illiac spine, greater trochanter of femur

Muscle mass: Gluteus medius and minimus

Injection area: opposing palm of hand over greater trochanter, middle finger

pointed toward the iliac crest, index finger toward anterosuperior iliac spine.

Inject into the triangle created by these fingers. No major vessels / nerves.

73

Injection Sites – Vastus Lateralis

Location: anterolateral aspect of the thigh

Landmarks: greater trochanter, lateral femoral

condyle

Muscle mass: vastus lateralis muscle

Injection area: between one handbreadth below the

greater trochanter and one handbreadth above the knee.

Width of area is from the midline on the anterior

surface of the thigh to midline on the lateral thigh.

Best to inject into outer middle third of the thigh.

No major vessels or nerves to avoid.

Identify the greater trochanter and the lateral femoral

condyle.

Select the site using the middle third and the anterior

lateral aspect of the thigh.

74

Injection Sites – Dorsal Gluteal

Location: Upper lateral aspect of the buttock

Landmarks: Posterior superior iliac spine,greater

trochanter

Muscle mass: Gluteus maximus muscle

Injection area: Draw an imaginary line between

the anatomic landmarks listed above. Administer

the injection lateral and slightly superior (2 inches)

to the midpoint of this line.

Avoid the sciatic nerve & superior gluteal artery

Most dangerous site because of sciatic nerve

location

75

Z – track

Seals the medication into the muscle tissue.

Minimizes subcutaneous tissue irritation from tracking of the medication as the

needle is withdrawn.

Used more frequently now to decrease discomfort and pain.

Used for irritating medications (Vistaril) and tissue staining meds (iron dextran –

Imferon).

Use in ventrogluteal or dorsogluteal sites

76

Intradermal Administration

Used for allergy and tuberculin

skin testing

Site: inner forearm (may use back

and upper chest)

Volume: 0.01-0.05 ml

Equipment: TB syringe (1ml, 25-

27g, ⅝ or ½ inch needle), alcohol

swab.

Administration angle: 10-15°

DO NOT massage. DO NOT

RECAP.

Subcutaneous Administration

Site: deep into tissue

Administration angle: 45-90 °

DO NOT ASPIRATE.

DO NOT RECAP.

Common drugs given SC:

1. Anticoagulants Lovenox

(enoxaparin sodium)

2. Insulin

3. Erythropoitic agents

4. Some Analgesics (-caine

type drugs)

77

Why there is requirement for Regulation for Pharmaceutical packaging

materials?? “A container closure system refers to the sum of packaging components

that together contain and protect the dosage form. This includes primary

packaging components and secondary packaging components, if the

latter are intended to provide additional protection to the drug product. A

packaging system is equivalent to a container closure system.” FDA 1999

“The primary packaging components (e.g. bottles, vials, closures, blisters)

are in direct physical contact with the product, whereas the secondary

components are not (e.g. aluminium caps, cardboard boxes).” WHO

guideline “Guidelines on packaging for pharmaceutical products, Annex 9”

Selecting types of packaging is a critical point because packaging

components are the major source of particulate matter; pyrogen and stability

problems.

78

Packaging Materials – Ideal Requirements

Protect the preparation from environmental conditions

Non-reactive with the product and so does not alter the identity of the product

Does not impart tastes or odors to the product

Nontoxic and Protect the dosage form from damage or breakage

Presentation & information

Packaging is essential source of information on medicinal product.

Information provided to patient may include:

Identification no. for dispensing records. Direction for use and Name and

address of dispensers.

Name, strength, quantity and Storage instructions.

Compliance

Design should be such that product can be easily administered in safer manner

to patient.

79

Packaging Components:

1. Primary components:

Syringes ,

Ampoules ,

Flexible Bags,

Bottles And

Closures

2. Secondary components:

Cartons and

Overlaps

3. Associated components:

Dosing Droppers And

Calibrated Spoon

80

ContainersGlass Plastic Rubber

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.

Plastic

containers are

used but they

face following

problems Permeation Sorption Leaching Softening

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

81

Advantages

Economical

Superior protective

qualities

Readily available in a

wide variety of sizes &

shapes

Excellent barrier against every element

except light. Colored glass, especially

amber, can give protection against light

Disadvantages: Fragility

Heavy Weight

Glass Containers

82

Types Of Glass

Type I: Borosilicate Glass

Highly resistant glass.

Composed principally of silicone dioxide and boron oxide.

It is used to contain strong acids & alkalies as well as all types of solvents.

It is more chemically inert than the soda-lime glass.

Type II: Treated Soda-Lime Glass

When glassware is stored for several months, especially in a damp atmosphere or

with extreme temperature variations, the wetting of the surface by condensed

moisture (condensation) results in salts being dissolved out of the glass. This is called

“blooming” or “weathering” & it gives the appearance of fine crystals on the glass.

Type II containers are made of commercial soda-lime glass that has been treated with

sulfur dioxide or other dealkalizers to remove surface alkali. The de-alkalizing

process is known as “sulfur treatment” which increases the chemical resistant of the

glass.

83

Type III – Regular Soda-Lime Glass

Containers are untreated & made up of commercial soda-lime glass of

average or better-than-average chemical resistance.

Type NP – General Purpose Soda-Lime Glass

Containers made up of soda-lime glass are supplied for non-parenteral

products, those intended for oral or topical use.

84

QUALITY CONTROL TESTS FOR GLASSES

1) Chemical Resistant Of Glass Containers

A) Powdered Glass Test:

It is done to estimate the amount of alkali leached from the powdered glass

which usually happens at the elevated temperatures. When the glass is

powdered, leaching of alkali is enhanced, which can be titrated with 0.02N

sulphuric acid using methyl red as an indicator

Step-1: Preparation of glass specimen: Few containers are rinsed thoroughly

with purified water and dried with stream of clean air. Grind the containers in a

mortar to a fine powder and pass through sieve no.20 and 50.

Step-2: Washing the specimen: 10gm of the above specimen is taken into 250

ml conical flask and wash it with 30 ml acetone. Repeat the washing, decant the

acetone and dried after which it is used within 48hr.

85

Procedure: 10gm sample is added with 50ml of high purity water in a 250ml flask. Place

it in an autoclave at 121 C±2 C for 30min.Cool it under running water. ⁰ ⁰Decant the solution into another flask, wash again with 15ml high purity

water and again decant. Titrate immediately with 0.02N sulphuric acid using

methyl red as an indicator and record the volume.

B) Water Attack Test: Principle involved is whether the alkali leached or not from the surface of the

container.

Procedure: Fill each container to 90%of its overflow capacity with water and is

autoclaved at 121 C for 30min then it is cooled and the liquid is decanted ⁰which is titrated with 0.02N sulphuric acid using methyl red as an indicator.

The volume of sulfuric acid consumed is the measure of the amount of

alkaline oxides present in the glass containers.

86

3) Arsenic Test: This test is for glass containers intended for aqueous parenterals. Wash the inner and

outer surface of container with fresh distilled water for 5 min.

50ml.pipette out 10ml solution from combined contents of all ampoules to the flask.

Add 10ml of HNO3 to dryness on the water bath, dry the residue in an oven at

130 C for 30min cool and add 10ml hydrogen molybdate reagent.⁰ Swirl to dissolve and heat under water bath and reflux for 25min. Cool to room temp

and determine the absorbance at 840nm.Do the blank with 10ml hydrogen

molybdate.

The absorbance of the test solution should not exceed the absorbance obtained by

repeating the determination using 0.1ml of arsenic standard solution (10ppm) in

place of test soln.

87

4 ) Thermal Shock Test: Place the samples in upright position in a tray. Immerse the tray into a hot water

for a given time and transfers to cold water bath, temp of both are closely

controlled. Examine cracks or breaks before and after the test.

The amount of thermal shock a bottle can withstand depends on its size, design

and glass distribution. Small bottles withstand a temp differential of 60 to 80 C ⁰and 1 pint bottle 30 to 40 C.A typical test uses 45C temp difference between hot ⁰and cold water.

5) Internal Bursting Pressure Test: The test bottle is filled with water and placed inside the test chamber. A scaling

head is applied and the internal pressure automatically raised by a series of

increments each of which is held for a set of time. The bottle can be checked to a

preselected pressure level and the test continues until the container finally bursts.

88

TESTS CONTAINER

Powdered glass test Type I Type II Type III

Water attack test Type II(100ml or below) Type II(above 100ml)

6) Leakage Test: Drug filled container is placed in a container filled with coloured solution (due to the

addition of dye)which is at high pressure compared to the pressure inside the glass

container so that the coloured solution enters the container if any cracks or any

breakage is present.

89

GLASS PROPERTIES:

1. Chemical properties

Sodium/alkali leaching Alkali/Acid resistance

4. Optical properties Refractive index Dispersion Absorption Transmission Reflectivity

2. Electrical properties Volume resistivity Surface resistivity Dielectric constant

5. Thermal properties Coefficient of thermal expansion (CTE) Thermal conductivity Specific heat

3. Mechanical properties Stress Density Specific gravity

90

PLASTIC CONTAINERS

Advantage:

Ease of manufacturing

High quality

Extremely resistant to breakage

Limitations:

Permeation

Leaching and Sorption

Chemical reactivity

COMMONLY USED POLYMERS

LESS COMMONLY USED POLYMERS

PolyethylenePolypropylene

Polyvinyl chloride (PVC)

Polystyrene

Polymethyl methacrylatePolyethylene terephthalate

PolytrifluoroethyleneAminoformaldehydes

Polyamides

91

QUALITY CONTROL TESTS FOR PLASTICS

Leakage test for Injectable & Non-Injectable(IP 1996)

Fill the 10 containers with water and fit the closure.

Keep them inverted at RT for 24 hours.

No sign of leakage from any container.

92

Water vapor permeability test for injectable preparation(IP 1996)

Fill the 5 containers with nominal volume of water and seal.

Weigh the each container.

Allow to stand for 14 days at RH of 60 + 5% at 20 c to 25 c.

Reweigh the container.

Loss of the weight in each container should not be more than 0.2%.

93

Collapsibility test for Injectable and Non-Injectable preparation(IP 1996)

This test is applicable for those containers, which have to be squeezed for the

withdrawal of product.

A container by squeezing yields at least 90% of its nominal contents at require

flow rate at ambient temperature.

Measurement of diffusion coefficient through plastic

Stopcock A is first opened allowing evacuation of the system and this gives rise to a

barometric leg in the manometer .

As soon as A is closed, gas will diffuse through the membrane and mercury level

will increase.

The height of mercury level indicates diffusion of gas through the plastic.

94

Physicochemical tests

USP specifies the extracting medium; otherwise purified water is maintained

at 70 c. After the extraction following tests are performed:

Non-volatile residue which measures organic and inorganic residue soluble in

extracting medium.

Heavy metals: This detects the presence of metals such as lead, tin, zinc etc.

Buffering capacity: It measures the alkalinity/acidity of the extract.

Compatibility test

Compatibility components will not interact with the dosage form and may not

show leaching. Regular screening is done by liquid chromatography, mass

spectrometry, GC-MS etc.

Other changes like PH shift, precipitation, discoloration, which may cause the

degradation of the product should be evaluated.

95

Specific Types Of Closures:-

•Tamper-evident closures

• Child resistant closures

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

96

Closures

Most vulnerable & critical component of a container..

Resistant & compatible with the product & the product/air space.

Should not lead to undesired interactions between contents and environment.

If closure is re-closable, it should be readily openable & effectively resealed.

Capable of high-speed application for automatic production by high speed

machines without loss of seal efficiency.

Offers additional functions: aid-pouring, metering, administration, child

resistance, tamper evidence, etc.

97

Available in various designs like…

Threaded screw cap

Crown cap

Roll on closures Pilferproof closures

Closures

98

CLOSURE

Closures are devices and techniques used to close or seal a bottle, jug, jar,

tube, can, etc

Closures can be a cap, cover, lid, plug, etc

The closure is normally the most vulnerable and critical component of a

container

An effective closure must prevent the contents from escaping and allow

no substance to enter the container

99

Function Of A Closure Provide a totally hermetic seal

Provide an effective seal which is acceptable to the products

Provide an effective microbiological seal

Characteristics Of Closure

It should be resistant and compatible with the product

If closure is of re closable type, it should be readily operable and should

be re-sealed effectively

It should be capable of high speed application

It should be decorative and of a shape that blends with the main

containers

100

Types Of Closures

Closures are available in five basic designs

1. Screw-on, threaded, or lug

2. Crimp-on (crowns)

3. Press-on (snap)

4. Roll-on

5. Friction.

Many variations of these basic types exist, including

1. Tamperproof

2. Child resistant

3. Dispenser applicators

101

THREADED SCREW CAP

The screw cap provides physical and chemical protection to content being

sealed.

The screw cap is commonly made of metal or plastics.

The metal is usually tinplate or aluminum, and in plastics, both

thermoplastic and thermosetting materials are used.

102

LUG CAP

The lug cap is similar to the threaded screw cap and operates on the same

principle

It is simply an interrupted thread on the glass finish, instead of a

continuous thread

Unlike the threaded closure, it requires only a quarter turn

The cap is widely used in the food industry

103

CROWN CAPS

This style of cap is commonly used as a crimped closure for beverage

bottles and has remained essentially unchanged for more than 50 years

http://en.wikipedia.org/wiki/File:Bottle_caps.jpg

104

ROLL-ON CLOSURES

The aluminum roll-on cap can be sealed securely, opened easily,

and resealed effectively

It finds wide application in the packaging of food, beverages,

chemicals, and pharmaceuticals

The roll-on closure requires a material that is easy to form, such as

aluminum or other light-gauge metal

105

PILFER PROOF CLOSURES

The pilfer proof closure is similar to the standard roll-on closure except

that it has a greater skirt length

When the pilfer proof closure is removed, the bridges break, and the bank

remains in place on the neck of the container

The torque is necessary to remove the cap.

106

TAMPER RESISTANT

Resistance to tampering is required for some types of products.

107

DISPENSING

• A wide variety of convenience dispensing features can be built in to

closures. Spray bottles and cans with aerosol spray have special closure

requirements.

108

CHILD-RESISTANT

• Child-resistant packaging or C-R packaging has special closures designed

to reduce the risk of children ingesting dangerous items Tamper-evident

109

CLOSURE LINES

A liner may be defined as any material that is inserted in a cap to effect a

seal between the closure and the container.

Liners are usually made of a resilient backing and a facing material. The

backing material must be soft enough to take up any irregularities in the

sealing surface and elastic enough to recover some of its original shape

when removed and replaced.

110

FACTORS IN SELECTING A LINER

The most important consideration is that the liner should be chemically inert with its

product.

Gas and vapor transmission rates are usually relative and depend chiefly on the

shelf life required for the product.

Homogenous Liner: These one piece liners are available as a disk or as a ring of

rubber and plastic.

– Expensive & Complicated to apply

– Widely used in pharmaceuticals

– Uniform properties

– Can withstand high-temperature sterilization

Heterogenous liner or composite liner: They are composed of layers of different

materials. It consists of two parts: a) facing and b) backing

111

PLASTIC CLOSURES

• The two basic types of plastic generally used for closures are

Thermosetting

Thermoplastic resins

Urea

phenols

112

RUBBER CLOSURES

Rubber is used in the pharmaceutical industry to make closures, cap liners

and bulbs for dropper assemblies.

The rubber stopper is used primarily for multiple dose vials and

disposable syringes.

Rubber closures for containers for aqueous parenteral

Preparations for powders and for freeze-dried powders

113

GLASS CLOSURE

114

METAL CLOSURE

115

Packaging Evaluation

An important step -- characterizing the materials and the chemicals that can

migrate or extract from packaging components to the drug product.

Figure shows the various types of chemicals that can migrate from polymeric

materials.

antioxidant

stabilizer plasticizermonomer

lubricantcontaminant

A number of tests can be used to establish initial qualification of the container

closure system, and a quality control plan can help ensure compatibility and safety.

116

Test on Rubber closures

1. Closure efficiency

Placing a desiccant in a packed stored under high RH.

Putting liquid in side pack, storing at high temperature and low RH,

detecting any moisture loss as reduction in weight.

Checking of cap removal torque.

Checking on compression ring seal in cap liner when a system contains

a liners.

Putting liquid in pack, inverting and applying a vaccum. A poor seal is

detected by liquid seeping.

117

2. Fragmentation test

Place a volume of water corresponding to nominal volume minus 4 ml in each of 12 clean vials.

Close the vial with closure and secure caps for 16 hours.

Pierce the closures with 21 SWG hypodermic needle (bevel angle of 10 to 14) and inject 1 ml

water and remove 1 ml air.

Repeat the above operation 4 times for each closure (use new needle for each closure).

Count the number of the fragments visible to the naked eye.

Total numbers of the fragments should not be more than 10 except butyl rubber where the

fragments should not exceed 15.

118

3. Self – sealability

• This test is applicable to closures intended to be used with water

close the vials

with the

‘Prepared’

closures

For each closure, use a

new hypodermic needle

with an external

diameter of 0.8 mm &

pierce the closure 10

times, each time at a

different site.

Immerse the vials

upright in a 0.1% w/v

solution of methylene

blue & reduce the

external pressure by

27KPa for 10 min.

Restore the atmospheric

pressure and leave the

vials immersed for 30

minutes. Rinse the outside

of the vials.

None of the vials

contains any trace

of coloured

solution.

119

4) PH OF AQUEOUS EXTRACT:

20ml of solution A is added with 0.1ml bromothymol blue when it is added with a

small amount of 0.01M NaOH which changes the colour from blue to yellow. The

volume of NaOH required is NMT 0.3ml .

5) LIGHT ABSORPTION TEST:

Solution is filtered through 0.5μ filter and its absorbance is measured at 220 to

360nm. Blank is done without closures and absorbance is NMT 2.0.

6) REDUCING SUBSTANCES:

20ml of solution A is added with 1ml of 1M H2SO4 and 20ml of 0.002M KMnO4

and boil for 3min then cool and add 1gm of potassium iodide which is titrated

with sodium thio-sulphate using starch as an indicator. The difference between

titration volumes is NMT 0.7ml.

7) RESIDUE ON EVAPORATION:

50ml of solution A is evaporated to dryness at 105 C.Then weigh the residue ⁰NMT 4mg.

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Evaluations

To establish suitability , evaluation of four attributes is required : protection,

compatibility, safety, and performance/ drug delivery .

Suitability refers to the tests used for the initial qualification of the container

closure system with regard to its intended use.

Which tests…….???

Suitability testing should be able to establish the following criteria:

Materials of construction of container and closure components are safe for

their intended use.

Container components are compatible with the dosage form

The container and closure system adequately protects the dosage form

The entire system functions in the manner in which it is intended.

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Dosage Form Condition Route Of Delivery Possible Package Form

Solids Aseptic Inhalation -Dry-Powder Inhaler

Liquids Sterile Parenteral,Ophthalmic

-Glass Ampoules-Glass Or Plastic Vial With Stopper-Glass Or Plastic Vials With Applicators-Pre-Filled Syringe-Bag-Pre-Filled Form-Fill-Seal Plastic Container

Ointments Sterile Ophthalmic

-Collapsible Tube-Glass Or Plastic Bottle And Cap-Form-Fill-Seal Plastic Bottle-Glass Of Plastic Jar-Soft Gelatin Capsules

Dosage forms and package forms

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OVERVIEW OF MANUFACTURING PROCESS OF PARENTERALS

documentationPlanning & scheduling

Material management-Raw material & API-Packaging material

Warehousing

Equipment & facility Manufacturing

requirement

personal

Finishing

Manufacturing

Bulk analysis

Sterilization

Q.C. Testing

Aseptic filling

Visual inspection

Labeling & packing

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FLOW OF MATERIALS:-

Ingredients vehicle solute

Processing equipment

Container component

Compounding of product

Cleaning

Cleaning

Filtration of solutes

Sterilization

Sterilization

Filling PackagingSealing Product storage

Diagram of flow of materials through the production department

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[QUALITATIVE LAYOUT OF PARENTERAL MANUFACTURING]

Function Area

Square meter Percentage

Production 11,094 45.1

Warehouse 7,606 30.9

Utility 1,716 4.1

Quality control 1,716 7.0

Administration 1,018 4.1

Maintenance 1,014 4.5

Employee services 1,014 4.1

Security 39 0.9

Total 24,607 100.0

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1.AREA PLANING AND ENVIRONMENTAL CONTROL:- Area planning may be addressed by functionalgroups ground this critical area with particular attention given to maintaining

cleanliness.Functional groupings:-Warehousing:- The storage of spare parts, air filters, change parts, water treatment chemicals,

office supplier, janitorial supplies, uniforms, an so on may be handled as central storage or individually by department.

Finished product and certain raw materials need special environmental storage conditions, such as, temperature and humidity control.

Administrative areas :- Administrative area planning requires careful analysis of the direct and indirect

administrative requirements of a particular plant. Successively higher levels of supervision are usually provided successively larger

office areas. Some offices are individual, while some are grouped in an “open area concept”,

126

ZONES AS PER GAZZETE OF INDIA:

1st.zones as per gazette of India

• White zone:- final step (filling of parenteral)• Grey zone:- weighing, dissolution & filtration.• Black zone:- storage, worst area from contamination view point.

BLACK

GRAY

WHITE

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ENVIRONMENTAL CONTROL ZONE GROUPING :-

1st.zones as per the c GMP:-

• Zone 1:- Exterior

• Zone 7:- Filling line• Zone 6:- Filling area

• Zone 5:- Weighing, mixing & transfer area• Zone 4:- Clean area

• Zone 3:- General production • Zone 2:- Warehouse

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Zone 7:- filling line:- The walls of the filling area are the last physical barrier to the ingress of

contamination, but within the filling area a technique of contamination control known as laminar flow may be considered as the barrier to contamination.

For aseptic filling process

Sterilization and Depyrogenation of containers

before filling, normally hot air oven or autoclave.

Provision must be made for

Filling requires

An aseptic environment with the attendant support roomsInspection and packaging

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Zone 6:- filling area:- Zone 6 is a distinct zone of the controlled environment area for an aseptic filling

process but may not be distinct zone for non-aseptic filling process.Zone 5:- weighing, mixing, and transfer area:- Zone 5 encompasses activities of “weighing, mixing, filling or transfer

operations” addressed by c GMP section 212.81 which are not handled as zone 6 but which require a controlled environment.

Zone 4:- clean area:- Activities in this may include washing and preparations of equipment or

accumulation and sampling of filled product. Zone 3:- general production and administration area:- The third zone of environmental controls is formed by the periphery of the general

production area.Only essential materials-handling equipment and personnel.Zone 2:- plant exterior:- It is a base point from which to work in determining the requirements for the

various control barriers.Control zone 1 might include the maintenance of sterile areas around the facility.

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2. WALL & FLOOR TREATMENT:

The design of filling areas or more generally, controlled environment areas

involves attention to many seemingly minor details. The basic cleanlability

requirement includes smooth, celanable walls, floors, ceilings, fixtures, and

partition exposed columns, wall studs, bracing, pipes, and so on are unacceptable.

The need for cleanability also eliminates the open floor system commonly used in

the microelectronics industry for laminar airflow rooms.

The goal of the designer, when creating the details for the architectural finishes

and joining methods, is to eliminate all edges or surfaces within the room where

dirt may accumulate.

All inside walls must be finished;

Example: common methods of finish are block, plaster, or gypsum board.

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3. LIGHTNING FIXTURES : Lighting fixtures should be reduced flush with the ceiling. Areas having a full HEPA

ceiling obviously cannot accommodate recessed lighting fixtures. In these areas, fixtures are of a special “tear drop” shape which minimizes disruption to the laminar airflow pattern.

4. CHANGE ROOMS : Personnel access to all controlled areas should be through change rooms. Change

rooms concepts and layouts vary from single closet size rooms to expensive multi-room complexes.

Entrance to a change area is normally through vestibules whose doors are electrically interlocked so that both cannot be opened simultaneously, thus maintaining the necessary air pressure differential to prevent the entry of airborne contamination.

Upon entry into the change room wash skins are provided for scrubbing hands and forearms.

Further control may be achieved by using filtered and heated compressed air for drying to reduce further particular potential.

After hands are dry, garments are taken from dispensers and donned while moving across a dressing bench.

As a final growing step, aseptic gloves are put on and sanitized. Exit from the change room to the controlled area is, like entrance, through an interlocked vestibule.

132

Clothing dispenser hand dryer hand wash

Exit Glove dispenser Change bench entrance

Change room

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5. Personnel flow :- The movement of personnel should be planned during the design of individual

plant areas. Each individual production area may have a smooth and efficient personnel flow pattern, a discontinuous or crowded pattern may develop when several individual production area plants are combined.

The flow of material and personnel through corridors are inefficient and unsafe paths for moving materials, particularly if heavy forklifts are required.

Discontinuous and crowed flow patterns can decrease production efficiency, increase security problems, and increase the problem of maintaining a clean environment.

x Design \/ Design

31

4 2

1 2

4 3

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6. UTILITES AND UTILITY EQUIPMENT LOCATION :- Utilities :- Piping system in particular, must be initially and often periodically cleaned and

serviced. Exposed overhead piping is not acceptable from a cleanliness or contamination stand point since it collects dirt, is difficult to clean and may leak. Buried or concealed pipe may require unacceptable demolition for cleaning or repair.

Utilities equipment location :- Public utilities require space for metering. In addition to meeting, electrical power

system require for switchgear and transformer. Water systems usually require treatment to ensure consistent quality. Plant generated

utilities typically require steam boilers, air compressors, and distillation, the typical “boiler room” approach. Proper equipment maintenance is difficult in foul weather, especially winter.

Heavy equipment may damage the roof-structure, particularly if the equipment location requires numerous penetrations through the roof which, coupled with equipment vibration, will invariable lead to leakage.

135

7.Engineering and maintenance :- From an engineering stand point, even a location outside the plant can serve well if

access to the production area by engineers for field work is not too difficult often particularly in small or less complex plants, maintenance or other plant service functions such as utilities or combined with engineering, making an in-plant location desirable.

Maintenance responsibilities cover all areas of the plant and can generally be grouped into two categories: plant maintenance and production maintenance.

production maintenance is a direct production support function and all the routine and recurring operating maintenance work. Production maintenance facilities are usually minimal, often only a place to store a tool box, and seldom have more than a small workbench.

plant maintenance operations, in contrast, are more diverse. They vary from heavy maintenance on production equipment to cosmetic work on the building exterior and often include plant service functions such as sanitation, ground sweeping, or waste disposal.

136

LIST OF EQUIPMENTS (as per schedule-M):The following equipments is recommended: a)Manufacturing area :-1. 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.6. Mixing equipment where necessary.7. Filtering equipment.8. Hot air sterilizer.b) Aseptic filling and sealing room:-9. Benches for filling and sealing.10. Bacteriological filters.11. Filling and sealing unit under laminar flow work station.C) General room:-12. Inspection table 13. Leak testing table.14. Labeling and packing benches.15. Storage of equipment including cold storage and refrigerators if necessary.

137

Production facilities of parenterals• The production area where the parenteral preparation are manufactured can be divided into

five sections: Clean-up 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.

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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.

139

Quarantine area:

After filling, sealing & sterilization the parenteral product are held up in

quarantine area.

Randomly samples were kept for 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

140

Aseptic Processing

• Certain pharmaceutical products must be sterile

– injections, ophthalmic preparations, irrigations solutions, haemodialysis

solutions

• Two categories of sterile products

– those that can be sterilized in final container (terminally sterilized)

– those that cannot be terminally sterilized and must be aseptically prepared

• Objective is to maintain the sterility of a product, assembled from sterile

components

• Operating conditions so as to prevent microbial contamination

• To review specific issues relating to the manufacture of aseptically prepared

products

141

WHO GMP US 209E US Customary ISO/TC (209) ISO 14644

EEC GMP

Grade A M 3.5 Class 100 ISO 5 Grade A Grade B M 3.5 Class 100 ISO 5 Grade B Grade C M 5.5 Class 10 000 ISO 7 Grade C Grade D M 6.5 Class 100 000 ISO 8 Grade D

Manufacturing Environment

Classification of Clean Areas

Grade At rest In operation

maximum permitted number of particles/m3 0.5 - 5.0 µm > 5 µm 0.5 - 5.0 µm > 5 µ

A 3 500 0 3 500 0

B 3 500 0 350 000 2 000

C 350 000 2 000 3 500 000 20 000

D 3 500 000 20 000 not defined not defined

“At rest” - production equipment installed and operating

“In operation” - Installed equipment functioning in defined operating mode and specified number of personnel present

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• Grade D (equivalent to Class 100,000, ISO 8):

Clean area for carrying out less critical stages in manufacture of aseptically

prepared products eg. handling of components after washing.

• Grade C (equivalent to Class 10,000, ISO 7):

Clean area for carrying out less critical stages in manufacture of aseptically

prepared products eg. preparation of solutions to be filtered.

• Grade B (equivalent to Class 100, ISO 5):

Background environment for Grade A zone, eg. cleanroom in which laminar flow

workstation is housed.

• Grade A (equivalent to Class 100 (US Federal Standard 209E), ISO 5

Local zone for high risk operations eg. product filling, stopper bowls, open vials,

handling sterile materials, aseptic connections, transfer of partially stoppered

containers to be lyophilized. Conditions usually provided by laminar air flow

workstation.

• Each grade of cleanroom has specifications for viable and non-viable particles

– Non-viable particles are defined by the air classification

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Limits for viable particles (microbiological contamination)

Grade Air sample (CFU/m3)

Settle plates (90mm diameter)

(CFU/4hours)

Contact plates (55mm

diameter) (CFU/plate)

Glove print (5 fingers)

(CFU/glove)

A < 3 < 3 < 3 < 3 B 10 5 5 5 C 100 50 25 - D 200 100 50 -

These are average values Individual settle plates may be exposed for less than 4 hours• Values are for guidance only - not intended to represent specifications• Levels (limits) of detection of microbiological contamination should be established for alert and action purposes and for monitoring trends of air quality in the facility

144

Environmental Monitoring - Physical

• Particulate matter

– Particles significant because they can contaminate and also carry organisms

– Critical environment should be measured not more than 30cm from worksite, within

airflow and during filling/closing operations

– Preferably a remote probe that monitors continuously

– Difficulties when process itself generates particles (e.g. powder filling)

– Appropriate alert and action limits should be set and corrective actions defined if limits

exceeded

• Differential pressures

– Positive pressure differential of 10-15 Pascals should be maintained between adjacent

rooms of different classification (with door closed)

– Most critical area should have the highest pressure

– Pressures should be continuously monitored and frequently recorded.

– Alarms should sound if pressures deviate

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• Air Changes/Airflow patterns

– Air flow over critical areas should be uni-directional (laminar flow) at a velocity

sufficient to sweep particles away from filling/closing area

– for B, C and D rooms at least 20 changes per hour are ususally required

• Clean up time/recovery

– Particulate levels for the Grade A “at rest” state should be achieved after a short

“clean-up” period of 20 minutes after completion of operations (guidance value)

– Particle counts for Grade A “in operation” state should be maintained whenever

product or open container is exposed

• Temperature and Relative Humidity

– Ambient temperature and humidity should not be uncomfortably high (could cause

operators to generate particles) (18°C)

• Airflow velocity

– Laminar airflow workstation air speed of approx 0.45m/s ± 20% at working position

(guidance value)

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Personnel

• Minimum number of personnel in clean areas especially during aseptic processing

• Inspections and controls from outside

• Training to all including cleaning and maintenance staff

– initial and regular

– manufacturing, hygiene, microbiology

– should be formally validated and authorized to enter aseptic area

• Special cases

– supervision in case of outside staff

– decontamination procedures (e.g. staff who worked with animal tissue

materials)

• High standards of hygiene and cleanliness

– should not enter clean rooms if ill or with open wounds

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• Periodic health checks

• No shedding of particles, movement slow and controlled

• No introduction of microbiological hazards

• No outdoor clothing brought into clean areas, should be clad in factory clothing

• Changing and washing procedure

• No watches, jewellery and cosmetics

• Eye checks if involved in visual inspection

• Clothing of appropriate quality:

– Grade D

• hair, beard, moustache covered

• protective clothing and shoes

– Grade C

• hair, beard, moustache covered

• single or 2-piece suit (covering wrists, high neck), shoes/overshoes

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– Grade A and B

• headgear, beard and moustache covered, masks, gloves

• not shedding fibres, and retain particles shed by operators

• Outdoor clothing not in change rooms leading to Grade B and C rooms

• Change at every working session, or once a day (if supportive data)

• Change gloves and masks at every working session

• Frequent disinfection of gloves during operations

• Washing of garments – separate laundry facility

– No damage, and according to validated procedures (washing and

sterilization)

• Regular microbiological monitoring of operators

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Aseptic Processing

• In aseptic processing, each component is individually sterilised, or several

components are combined with the resulting mixture sterilized.

– Most common is preparation of a solution which is filtered through a sterilizing

filter then filled into sterile containers (e.g active and excipients dissolved in

Water for Injection)

– May involve aseptic compounding of previously sterilized components which

is filled into sterile containers

– May involve filling of previously sterilized powder

• sterilized by dry heat/irradiation

• produced from a sterile filtered solution which is then aseptically

crystallized and precipitated

– requires more handling and manipulation with higher potential for

contamination during processing

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Preparation and Filtration of Solutions

• Solutions to be sterile filtered prepared in a Grade C environment

• If not to be filtered, preparation should be prepared in a Grade A environment with Grade B

background (e.g. ointments, creams, suspensions and emulsions)

• Prepared solutions filtered through a sterile 0.22μm (or less) membrane filter into a

previously sterilized container

– filters remove bacteria and moulds

– do not remove all viruses or mycoplasmas

• filtration should be carried out under positive pressure

• consideration should be given to complementing filtration process with some form of heat

treatment

• Double filter or second filter at point of fill advisable

• Same filter should not be used for more than one day unless validated

• If bulk product is stored in sealed vessels, pressure release outlets should have hydrophobic

microbial retentive air filters

151

Preparation and Filtration of Solutions

• Time limits should be established for each phase of processing, e.g.

– maximum period between start of bulk product compounding and sterilization

(filtration)

– maximum permitted holding time of bulk if held after filtration prior to filling

– product exposure on processing line

– storage of sterilized containers/components

– total time for product filtration to prevent organisms from penetrating filter

– maximum time for upstream filters used for clarification or particle removal (can

support microbial attachment)

• Filling of solution may be followed by lyophilization (freeze drying)

– stoppers partially seated, product transferred to lyophilizer (Grade A/B conditions)

– Release of air/nitrogen into lyophilizer chamber at completion of process should be

through sterilizing filter

152

Prefiltration Bioburden (natural microbial load)

• Limits should be stated and testing should be carried out on each batch

• Frequency may be reduced after satisfactory history is established

– and biobuden testing performed on components

• Should include action and alert limits (usually differ by a factor of 10) and action

taken if limits are exceeded

• Limits should reasonably reflect bioburden routinely achieved

• No defined “maximum” limit but the limit should not exceed the validated

retention capability of the filter

• Bioburden controls should also be included in “in-process” controls

– particularly when product supports microbial growth and/or manufacturing

process involves use of culture media

• Excessive bioburden can have adverse effect on the quality of the product and

cause excessive levels of endotoxins/pyrogens

153

Filter integrity

• Filters of 0.22μm or less should be used for filtration of liquids and gasses (if applicable)

– filters for gasses that may be used for purging or overlaying of filled containers or to

release vacuum in lyphilization chamber

• filter intergrity shoud be verified before filtration and confirmed after filtration

– bubble point

– pressure hold

– forward flow

• methods are defined by filter manufacturers and limits determined during filter validation

Filter validation

• Filter must be validated to demonstrate ability to remove bacteria

– most common method is to show that filter can retain a microbiological challenge of

107 CFU of Brevundimonas diminuta per cm2 of the filter surface

– a bioburden isolate may be more appropriate for filter retention studies than

Brevundimonas diminuta

154

– Challenge concentration is intended to provide a margin of safety well beyond

what would be expected in production

– preferably the microbial challenge is added to the fully formulated product

which is then passed through the filter

– if the product is bactericidal, product should be passed through the filter first

followed by modified product containing the microbial challenge (after

removing any bactericidal activity remaining on the filter)

– filter validation should be carried out under worst case conditions e.g.

maximum allowed filtration time and maximum pressure

– integrity testing specification for routine filtration should correlate with that

identified during filter validation

155

Equipment/container preparation and sterilization

• All equipment (including lyophilizers) and product containers/closures should be sterilized

using validated cycles

– same requirements apply for equipment sterilization that apply to terminally sterilized

product

– particular attention to stoppers - should not be tightly packed as may clump together and

affect air removal during vacuum stage of sterilization process

– equipment wrapped and loaded to facilitate air removal

– particular attention to filters, housings and tubing

• heat tunnels often used for sterilization/depyrogenation of glass vials/bottles

– usually high temperature for short period of time

– need to consider speed of conveyor

– validation of depyrogenation (3 logs endotoxin units)

• worst case locations: tunnel supplied with HEPA filtered air

156

• equipment should be designed to be easily assembled and disassembled, cleaned,

sanitised and/or sterilized

– equipment should be appropriately cleaned - O-rings and gaskets should be

removed to prevent build up of dirt or residues

• rinse water should be WFI grade

• equipment should be left dry unless sterilized immediately after cleaning (to

prevent build up of pyrogens)

• washing of glass containers and rubber stoppers should be validated for endotoxin

removal

• should be defined storage period between sterilization and use (period should be

justified)

157

Process Validation

• Not possible to define a sterility assurance level for aseptic processing

• Process is validated by simulating the manufacturing process using

microbiological growth medium (media fill)

– Process simulation includes formulation (compounding), filtration and filling

with suitable media using the same processes involved in manufacture of the

product

– modifications must be made for different dosage formats e.g. lyophilized

products, ointments, sterile bulks, eye drops filled into

semi-transparent/opaque containers, biological products

• Media fill program should include worst case activities

– Factors associated with longest permitted run (e.g. operator fatigue)

158

– Representative number, type, and complexity of normal interventions, non-routine

interventions and events (e.g. maintenance, stoppages, etc)

– Lyophilisation

– Aseptic equipment assembly

• Worst case activities (cont)

– No of personnel and their activities, shift changes, breaks, gown changes

– Representative number of aseptic additions (e.g. charging containers, closures, sterile

ingredients) or transfers

– Aseptic equipment connections/disconnections

– Aseptic sample collections

– Line speed and configuration

– Weight checks

– Container closure systems

• Written batch record documenting conditions and activities Should not be used to justify

risky practices

159

Duration

– Depends on type of operation

– BFS, Isolator processes - sufficient time to include manipulations and

interventions

– For conventional operations should include the total filling time

Size

– 5000 - 10000 generally acceptable or batch size if <5000

– For manually intensive processes larger numbers should be filled

– Lower numbers can be filled for isolators

Frequency and Number

– Three initial, consecutive per shift

– Subsequently semi-annual per shift and process

– All personnel should participate at least annually, consistent with routine duties

– Changes should be assessed and revalidation carried out as required

160

Line Speed: Speed depends on type of process

Environmental conditions

– Representative of actual production conditions (no. of personnel, activity levels etc) -

no special precautions (not including adjustment of HVAC), if nitrogen used for

overlaying/purging need to substitute with air

Media

– Anaerobic media should be considered under certain circumstances, should be tested

for growth promoting properties (including factory isolates)

Incubation, Examination

– In the range 20-35ºC.

– All integral units should be incubated. Should be justification for any units not

incubated.

– Units removed (and not incubated) should be consistent with routine practices

(although incubation would give information regarding risk of intervention)

– Batch reconciliation

161

• Interpretation of Results

– When filling fewer than 5000 units:

• no contaminated units should be detected

• One (1) contaminated unit is considered cause for revalidation, following an

investigation

– When filling from 5000-10000 units

• One (1) contaminated unit should result in an investigation, including

consideration of a repeat media fill

• Two (2) contaminated units are considered cause for revalidation, following

investigation

– When filling more than 10000 units

• One (1) contaminated unit should result in an investigation

• Two (2) contaminated units are considered cause for revalidation, following

investigation

162

• Interpretation of Results

– Media fills should be observed by QC and contaminated units reconcilable with time and

activity being simulated (Video may help)

– Ideally - no contamination. Any contamination should be investigated.

– Any organisms isolated should be identified to species level (genotypic identification)

– Invalidation of a media fill run should be rare

• Batch Record Review

· In-process and laboratory control results

· Environmental and personnel monitoring data

· Output from support systems(HEPA/HVAC, WFI, steam generator)

· Equipment function (batch alarm reports, filter integrity)

· Interventions, Deviations, Stoppages - duration and associated time

· Written instructions regarding need for line clearances

· Disruptions to power supply

163

• Isolators

– Decontamination process requires a 4-6 log reduction of appropriate Biological

Indicator (BI)

– Minimum 6 log reduction of BI if surface is to be free of viable organisms

– Significant focus on glove integrity - daily checks, second pair of gloves inside

isolator glove

– Traditional aseptic vigilance should be maintained

• Blow-Fill-Seal (BFS)

– Located in a Grade D environment

– Critial zone should meet Grade A (microbiological) requirements (particle count

requirements may be difficult to meet in operation)

– Operators meet Grade C garment requirements

– Validation of extrusion process should demonstrate destruction of endotoxin and

spore challenges in the polymeric material

– Final inspection should be capable of detecting leakers

164

• Issues relating to Aseptic Bulk Processing

Applies to products which can not be filtered at point of fill and require aseptic

processing throughout entire manufacturing process.

Entire aseptic process should be subject to process simulation studies under worst case

conditions (maximum duration of "open" operations, maximum no of operators)

Process simulations should incorporate storage and transport of bulk.

Multiple uses of the same bulk with storage in between should also be included in process

simulations

Assurance of bulk vessel integrity for specified holding times.

Process simulation for formulation stage should be performed at least twice per year.

Cellular therapies, cell derived products etc

•products released before results of sterility tests known

•should be manufactured in a closed system

•sterility testing of intermediates, microscopic examination (e.g. gram stain)

•endotoxin testing

165

Formulation:Methods of Sterilization Steam(autoclave): Steam sterilization is conducted in an autoclave and employs

steam under pressure.The usual temperature and the approximate length of time

required is 121°C for 15 to 30 minutes, depending on the penetration time of moist

heat into the load.

Dry heat: The transfer of energy from dry air to the object that is sterilized. The

transfer occurs through conduction, convection and radiation, higher temperature

and longer time are required(250°C for two hours).

Filtration: Sterilization by filtration depends on the physical removal of

microorganisms by adsorption on the filter medium or by a sieving mechanism, for

heat-sensitive solutions, membrane filters(0.22 μm).

Membrane filters are used exclusively for parenteral solutions, due to their

particle-retention effectiveness, non-shedding property, non-reactivity, and

disposable characteristics.

166

Formulation:Methods of Sterilization

Filtration: The most common membranes are composed of Cellulose

esters, Nylon, Polysulfone, Polycarbonate, PVDF,

Polyethersulfone(PES) or Polytetrafluoroethylene(Teflon). The

integrity of the filters has to be proven. If the drug formulation content

benzyl alcohol, it is recommended to use nylon filter instead of PES

filter due to the incompatibility issue.

Ionizing radiation:High-energy photons are emitted from an isotope

source (Cobalt 60) producing ionization throughout a product. It can be

applied under safe, well-defined, and controlled operating parameters,

and is not a heat- or moisture generating process. Most importantly,

there is no residual radioactivity after irradiation (Gamma Radiation).

168

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

METHOD A: Membrane filtration

METHOD B: Direct inoculation

TEST FOR STERILITY

169

Sterility is defines as freedom from the presence of viable microorganism

170

Media to be used in the sterility test

Fluid Thioglycolate Medium

Soyabean-casein digest Medium

171

MINIMUM QUANTITY TO BE USED FOR EACH MEDIUM

Quantity per container Minimum quantity to be used for each medium

Liquids

1. less than 1 ml The whole contents of each container

2. 1-40 ml Half the contents of each container but not less than 1 ml

3.Greater than 40 ml and not greater than 100 ml

20 ml

4. Greater than 100 ml 10 per cent of the contents of the container but not less than 20 ml

Antibiotic liquids 1 ml

172

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

173

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

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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.

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INTERPRETATION OF RESULTS

• If the material being tested renders the medium turbid so that the presence

or absence of microbial growth cannot be easily determined by visual

inspection,14 days after the beginning of incubation , transfer portion (<

1 ml) of the medium to fresh vessels of the same medium and then

incubate original and transfer vessel for not less than 4 days.

• If No evidence of microbial growth is found- complies with test for

sterility.

• If evidence of microbial growth is found- does not complies with test for

sterility.

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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:

177

Methods for monitoring particulate matter contamination:

1) Visual method

2) Coulter counter method

3) Filtration method

4) Light blockage method

178

C) LEAKAGE TEST

Leakage test is employed to test the package integrity.

Package integrity reflects its ability to keep the product in and to keep

potential contamination out.

Which is the flow of matter through the barrier itself.

Leakage tests are 4 types

1. Visual inspection

2. Bubble test

3.Dye tests

4.Vacuum ionization test

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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

180

Leakage test apparatus

High voltage leak detection

181

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

• TEST FOR PYROGEN

The test involves measurement of the rise in body temperature of rabbits following the

IV injection of a sterile solution into ear vein of rabbit.

Dose not exceeding 10 ml per kg injected intravenously within a period of not more

than 10 min

Test animals: Use healthy, adult rabbits of either sex, preferably of the same variety.

Recording of temperature: Clinical thermometer

182

PRELIMINARY TEST(SHAM TEST)

If animals are used for the first time in a pyrogen test or have not been used during

the 2 previous weeks condition them 1 to 3 days before testing the substance by

injecting IV 10ml per kg pyrogen free saline solution warmed to about 38.5°

Record the temperature of the animals beginning at least 90 min before injection

and continuing for 3 hours after injection. Any animal showing a temperature

variation of 0.6° or more must not be used in main test

MAIN TEST

Carry out the test using a group of 3 rabbits.

Dissolve the substance in or dilute with pyrogen free saline solution . Warm the

liquid to approximately 38.5° before injection. Inject the solution under

examination slowly into the marginal veins of the ear of each rabbit over a

period not exceeding 4 min.

Record the temperature of each animal at half-hourly intervals for 3 hours after

injection. The highest temperature recorded for a rabbit is taken to be its

response.

183

INTERPRETATION OF RESULT

184

E) Assay• Assay is performed according to method given In the monograph of that

parental preparation in the pharmacopoeia • Assay is done to check the quantity of medicament present in the

parenteral preparation

UNIFORMITY OF WEIGHT

Remove the labels& wash the container & dry

Weigh the container along with content

Empty the container completely

Rinse with water & ethanol,dry at 100°C to a constant weight

Cool& weigh

Net weight shout be calculated

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UNIFORMITY OF CONTENT

30 sterile units are selected from each batch. The weight of 10 individual sterile

units is noted and the content is removed from them and empty individual sterile

unit is weighed accurately again.

Then net weight is calculated by subtracting empty sterile unit weight from gross

weight.

The dose uniformity is met if the amount of active ingredient is within the range of

85-115.0% of label claim. Relative standard deviation is equal to or less than 6.0%.

If one unit is outside the range of 85-115.0%, and none of the sterile unit is outside

the range of 75-125.0% or if the relative standard deviation of the resultant is

greater than 6.0% ,or if both condition prevail, an additional 20 sterile unit should

be tested.

The sterile units meet the requirements if not more than one unit is out side the

range of 85-115%, no unit is outside the range of 75-125.0% and the calculated

relative standard deviation is 7.8%.

186

PARTICULATE MATTER TEST

Particulate matter refers to the extraneous, mobile, undissolved particles, other

than gas bubbles, unintentionally present in the solutions.

Two methods are used:

1. Light obstruction Particle Count Test

2. Microscopic particle count test

LIGHT OBSTRACTION PARTICLE COUNT TEST

Use a suitable apparatus based on the principle of light blockage which allows an

automatic determination of the size of particles and the number of particles

according to size.

187

Sample Particle size in μm Maximum no. of particles.

LVP ≥ 100 ml 1025

Average in the units tested25 per ml3 per ml

SVP – 100 ml and less than 100 ml

1025

6000 per container600 per container

Limits

188

MICROSCOPIC PARTICLE COUNT TEST

• Wet the inside of the filter holder fitted with the membrane filter with several

milliliter of particle-free water .

• Transfer the total volume of a solution pool or of a single unit to the filtration

funnel, and apply vacuum.

• Place the filter in a Petri dish and allow the filter to air-dry.

• After the filter has been dried, place the Petri dish on the stage of the microscope,

scan the entire membrane filter under the reflected light from the illuminating

device, and count the number of particles

Sample Particle size in μm Maximum no. of particles.

LVP ≥ 100 ml 1025

Average in the units tested12 per ml2 per ml

SVP – 100 ml and less than 100 ml

1025

3000 per container300 per container

Limits :

189

TEST FOR BACTERIAL ENDOTOXIN

Measures the concenration of bacterial endotoxin

Test is using lysate derived from hemolymph cells or amoebocytes

of horse shoe crab

Endotoxin limit calculated by K/M

K maximum no.of endotoxin which receive the patient without

suffering toxic reaction

M maximum dose administered to a patient/kg/hr

Procedure

Equal volume of LAL reagent and test solution (usually 0.1 ml of

each) are mixed in a depyrogenated test-tube

Incubation at 37oC, for1 hour

Remove the tube – invert in one smooth motion (180o)

Observe the result

190

Mechanism of LAL Test

The test is based on the primitive blood-clotting mechanism of the horseshoe

crabLimulus amebocyte lysate [LAL] test

LAL reagent

Bleeding adult crabs blood into an anticlotting solution

Washing and centrifuging to collect the amoebocytes

Lysing in 3% NaCl

Lysate is washed and lyophilized for storage

191

Different Techniques

Three different techniques:

The gel-clot technique – gel formation

The turbidimetric technique – the development of turbidity after cleavage

of an endogenous substrate

The chromogenic technique – the development of color after cleavage of a

synthetic peptide – chromogen complex

Chromogenic Technique

This is based on the measurement of color change which is caused by the

release of the chromogenic chemical

p-nitroanilide

The quantity of the p-nitroanilide produced is directly proportional to the

endotoxin concentration

192

Gel Clot Technique

A solid gel is formed in the presence of endotoxins

This technique requires positive and negative controls

Positive controls – a known concentration of endotoxin added to the lysate

solution

Negative controls – water, free from endotoxins, added to the lysate solution

Turbidimetric Technique

The test is based on the measurement of opacity change due to the formation

of insoluble coagulin

Opacity is directly proportional to the endotoxin concentration

This technique is used for water systems and simple pharmaceutical

products

193

References

1. Donald C. Liebe, Packaging of Pharmaceutical Dosage Form, Modern Pharmaceutics by

G.S.Banker, Marcel Dekker, p 681-725.

2. C.P.Croce, A.Fischer & R.L.Thomas, Packaging material Science, The theory & Practice of

Industrial Pharmacy by Leon Lachman, Third edition, p 711-732

3. Plastic Packaging , Remington: The Science and Practice of Pharmacy, 19th edition, Volume

II, p 1487

4. Indian Pharmacopoeia, 2007, Government of Indian ministry of health and family welfare,

The Indian pharmacopoeia commission, Ghaziabad, volume-1, 599-609.

5. Dean D. A., Evans E. R. and Hall I. H.: Pharmaceutical Packaging Technology, Taylor and

Francis, London and New York, First Indian reprint, 2006, 5 and 73.

6. Carter S.J., “Packaging”; Cooper and Gunn’s Tutorial Pharmacy, sixth edition, CBS

publicashers and distributors, New Delhi, 2005, 133-136 and 139-140.

7. Pharmaceutical Dosage Forms. Vol. 3 : Parenteral Medications, Pub Informa Healthcare,

Edi. Avis, Kenneth E, Vol I, pg173-180

8. Encyclopedia of pharmaceutical technology by James Swarbrick pg.no.1266-1299

injectable

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