Mn 2 Flashcards by SATRA JULYHA HALIPA

• Poor quality medicines do not meet official standards for
STRENGTH
QUALITY
PURITY
PACKAGING
LABELING

The Grim Reality

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• First WHO draft text on good manufacturing practices requested by the Twentieth World Health Assembly (resolution WHA20.34)
• Twenty-first World Health Assembly
• “Draft requirements for good manufacturing practice in the manufacture and
quality control of drugs and pharmaceutical specialties”

1967

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WHO Certification Scheme on the Quality of Pharmaceutical (GMP text as an integral part of the Scheme

1969

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• revised versions of both the Certification Scheme and the GMP text

1975

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includes the following:

veterinary products administered to food-producing animals;

starting materials for use in dosage forms, when they are subject to control

by legislation in both the exporting and importing member country
information on safety and efficacy

CERTIFICATION SCHEME

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• Presented in 1992
• Quality management in the drug industry: philosophy and essential elements”, outlines the general concepts of quality assurance as well as the principal components or subsystems of GMP, which are joint responsibilities of top management and of production and quality control management.
• These include:
• hygiene
• validation
• self-inspection
• Personnel
• premises,
• equipment,
• materials and documentation.

REVISED REQUIREMENTS FOR GMP

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• Part of QA aimed at ensuring that PRODUCTS are consistently MANUFACTURED and CONTROLLED to the quality standards appropriate to their intended use (WHO, 2007)

GMP/cGMP

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• system of QA aimed at ensuring that products are consistently manufactured to a quality appropriate for their intended use and is concerned with both manufacturing and QC processes and procedures (AO 43 s. 1999)

GMP/cGMP

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• recognized worldwide for the control and management of manufacturing and quality control testing of foods and pharmaceutical products.

GMP/cGMP

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Philippine GMP Regulations
(Adoption of the 1st edition of the Current Good Manufacturing Practice Guidelines by the Bureau of Food and Drugs)

• AO 43 S. 1999

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(Adoption and Implementation of the GMP as the standard on the manufacture of pharmaceutical products)

• AO 2012-2008

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(Philippine FDA mandated all drug manufacturers to ensure strict and full compliance to the newly adopted GMP)

• FDA MC 2012-004

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a. All manufacturing processes are clearly defined, systematically reviewed in the light of experience and shown to be capable of consistently manufacturing medicinal products of the required quality and complying with their specifications;
b. Critical steps of manufacturing processes and significant changes to the process are validated;

Basic Requirements of GMP

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• The regulatory process through which industry measures actual performance, compares it with standards, and acts on the difference
• A tool which gives the assurance that a product conforms to standards and specifications through a system of inspection, analysis and action.
• The day to day control of quality within the company
• A department staffed with scientists and technicians responsible for the acceptance and rejection of incoming raw materials and packaging components
• To assure that systems are being controlled and monitored
• For the approval or rejection of completed dosage forms

QUALITY CONTROL

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• is a process by which the pharmaceuticals are suitably packed so that they should retain their therapeutic effectiveness from the time of packaging till they are consumed.

Packaging

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• may be defined as the art and science which involves preparing articles for transport, storage display and use.

Packaging

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is the means of providing protection, presentation, Identification, Information and convenience to encourage compliance with a course of therapy.
• Economic way of protecting, preparing, identifying and containing the drug products
• Labels, containers

Pharmaceutical packaging

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Role of packaging

Protection
Presentation
Identification
Information

against light
against reactive gases
against moisture
against microbes
against physical damage
against adulteration

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•is the material that first envelops the product and holds it.
• This usually is the smallest unit of distribution or use and is the package which is in direct contact with the contents.
• Immediate container
• Indirect contact with the product
• May be used for administration
e.g. bottles, caps, liner, cottons (coil or filler) silica gel (desiccant), glass, plastic, rubber

Primary packaging

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• is out side the primary packaging - used to group primary packages together.
• Outer packaging
• Not always present
e.g. carton boxes, corrugated boxes (also considered as Tertiary
packaging) Labels, inserts
• designates the packaging used to group various pre-packaged products together.

Secondary packaging

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•is not in direct contact with the actual product, its use and application usually differ distinctly from those of primary packaging, although the purpose of both type may at times converge.

secondary packaging

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Secondary packaging said to have two central functions:

Branding & Display
Logistics

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: Secondary packaging plays a vital role in the marketing strategy surrounding the product. This is especially relavent in case of display packaging.

Branding & Display

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: secondary packaging serves to group sevaral products together for ease of handling, transport and storage. This means that secondary packaging must be able to :
• Contain relatively large volume of primary packaged product
• Transport the product safely to the retailer or consumer destination
• Keep the primary packaging in its original condtion during storage

Logistics

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Different type of Secondary Packaging materials

• Paper and boards • Cartons • Corrugated fiberboard

is used for bulk handling, warehouse storage and transport. Most common form is palletized unit load that packs tightly in to containers. Examples: Brown cardboard boxes, wood pallets

Tertiary packaging

2 COMPONENTS OF PACKAGING:

• Composed of a container and its closure

may be defined as a device in which the drug is enclosed and is in direct contact with the drug.

Container

is a device which seals the container to exclude oxygen, carbon dioxide, moisture, micro-organisms and prevent the loss of volatile substances.It also prevents the loss of medicament during transport and handling.

Closures

• is defined as a object that can be used to hold or transport something.

Container

is a device that hold the pharmaceutical product and it may or may not be in direct contact with it.

• Pharmaceutical container

Types of containers

• Multi dose container • Air tight container • Light resistant container • Aerosol container • Well closed container • Single dose container

: is used to protect the preparation from contamination by extraneous solids to prevent the loss of potency of active constituents and to prevent the loss of contents during transport, storage and handling.

Well closed containers

: are used to protect the containers from atmospheric contamination of liquids, solids or vapors. They prevent the drugs due to efflorescence, deliquescence or evaporation.

Air-tight containers

is that which does not allow the air or other gases to pass through it. They are generally used for injectables.

Hermetically sealed container

are used to protect the drugs which undergo decomposition in the presence of light. For e.g .Amber colored glass or opaque glass.

Light resistant containers

They are used to supply only one dose of the medicament. They are sealed in such a way that the contents cannot be removed without removing the seal, the contents so removed are consumed immediately.e,g. ampoules.

• Single dose containers:

should hold a number of doses. It is sealed in such a way that success doses can be withdrawn easily without changing the strength, quality or purity of the remaining contents e.g multi dose vials.

A multi dose container

•Containers for aerosols must be strong enough to withstand the pressure evolved inside the container at the time of use of preparation. • Only true tamper-resistant packaging • Cannot change the inside of canister because it is pressurize

Aerosol containers

• are devices and techniques used to close or seal container such as a bottle, jug, jar, tube, can etc. • can be a cap, cover, lid, plug, etc.

Closures

Types of closure

Screw top Snap on Spray bottle Crown cap Child resistant Friction fit

is a mechanical device which is screwed on and off of a threaded "finish" on a container. • Either continuous threads or lugs are used. • Metal caps can be either preformed or in some instances, rolled on after application. • Plastic caps may use several types of molded polymer.

Screw top

•Beverage bottles are frequently closed with crown beverage caps. These are shallow metal caps that are crimped into locking position around the

Crown cap

Some closures snap on. For opening, the top is designed to pry off or, break off, or have a built in dispenser.

Snap on

is a bottle that can dispense, squirt, spray or mist fluids. A common use for spray bottles is dispensing cool cleaners, cosmetics, and chemical specialties.

Spray bottle A spray bottle

– Difficult for children under 5 years of age to open Instruction: • Press down first, and turn open • Squeeze and turn • Align the arrows • Latch top – thumb and flip open

Child resistant

has special closures designed to reduce the risk of children ingesting dangerous items. • This is often accomplished by the use of a special safety cap. • It is required by regulation for prescription drugs, over-the-counter medications, pesticides, and household chemicals.

• Child-resistant packaging

• Some containers have a loose lid for a closure. • Laboratory glassware often has ground glass joints that allow the pieces to be fitted together easily. • An Interference fit or friction fit requires some force to close and open, providing additional security. • Paint cans often have a friction fit plug.

Friction fit

• Resistance to tampering is required for some types of products. Container closures can be one of several layers of packaging to deter tampering and to provide evidence of attempts at tampering. Sometimes tamper resistance is obtained by or integral with the closure. • Uses an indicator which if breached or missing can provide evidence that tampering is occurred ❑ Shrink seal/wrap ❑ Breakable caps ❑ Tape seal ❑ Bottle seal

Tamper-Resistant

TYPES OF INJECTION CONTAINERS

SINGLE DOSE MULTI DOSE

Each dose is in a separate container from which it is given to the patient with a syringe. Usual volumes are from 0.5-10mL. They may be packed in ampoules, cartridges or injection units.

SINGLE DOSE INJECTIONS OF SMALL VOLUMES

AMPOULES CARTRIDGES INJECTION UNITS

• Most common • Made entirely of glass in a size range of 0.5-50mL. • Glass may be neutral or lime soda but former is preferred. • Can be used only once and consequently need not be very strong. • Their walls can be thin with the advantages of lightness, greater thermal resistance and more rapid heat conduction to the contents during sterilisation. • After filling, ampoules are sealed by fusion of glass, so there is no danger of entry of microorganisms. • Plastic ampoules have not been extensively used.

Ampoules

• Cylindrical glass tubes with a capacity of slightly more than 1mL. • They are closed at one end with a rubber stopper and the other end by a rubber plunger. • Compared with ampoules, they are quicker and easier to use. They are safer as accidental contact with potent drug preparations in the injection is minimised as well as there is no possibility of injecting glass spicules. • More suitable for suspensions. • Syringe is unbreakable and only the needle mount need to be sterilised (only part touched by the injection). • Major disadvantages are use of rubber and the need for special syringe.

Cartridges

• Disposable injection units combining container and syringe which eliminates the need to transport sterile syringes or facilities for sterilisation. • Early development was a soft metal tube with a needle attached. It has two major disadvantages viz-a-viz contents are invisible and it is necessary to guard against the solution corroding the container as well as container affecting the solution. • Automatic injector was developed which is packed in a neutral glass ampoule containing an inert gas under pressure. Advantage is that the user has nothing to sterilise or assemble, therefore time saved and safety are even greater. • Plastic syringes consists of the injection in small plastic syringe. The absence of gas is an advantage but the contents are not clearly visible. Care must be taken not to squeeze it after the cap has been removed because the barrel is not rigid. Its use is limited because of various

Imjection Units

Infusion fluids usually given IV, are slowly dripped into the patient’s body and 3-4L may be given in 24 hours. Containers must be large and strong enough to withstand frequent cleaning, sterilisation, transport and handling. Bactericides are not permitted in large volume intravenous injections, therefore infusion fluids must always be regarded as single dose injections.

SINGLE DOSE INJECTIONS OF LARGE VOLUME

: • It is often called a blood bottle because it is used for giving and taking blood. • It is most popular for IV fluids. • The graduated capacity is 540mL, volume being the sum of anticoagulants(120mL) and blood when the bottle is used for taking blood(added 500mL, normally). • There are two scales moulded on the outside, one reading from the base when the bottle is upright and the other from neck when the bottle is inverted.

British standard transfusion bottle

Other containers: SINGLE DOSE INJECTIONS OF LARGE VOLUME

GIVING SETS Plastic containers DISPOSABLE PLASTIC/GLASS SYRINGES

It is used for transferring IV injections from the bottle to the patients. Disposable giving sets consists of a piece of tubing about 1.5m long with a needle at one end for insertion into vein and a means of piercing the bottle closure at the other. Near to the bottle is a drip chamber from which speed of administration can be estimated. The unit must have a filter to prevent the transfusion of clots from blood. These have replaced the non-disposable types.

GIVING SETS:

: These are being increasingly used for infusion and dialysing fluid and for blood as they are unbreakable, light, disposable and occupy less storage space. However, they have some disadvantages like labels printed on the plastic are more difficult to read, less transparent than glass and can be punctured by the needles of giving sets. Commonly used plastics are PVC, polythene and polypropylene.

PLASTIC CONTAINERS

They are not a type of single dose large volume injections but are commonly used for injecting, withdrawing or instilling fluids. It consists of a glass or plastic barrel with a tight fitting plunger at one end and a small opening at the other end which accommodates the head of a needle. Needle gauge is the outside diameter of needle shaft.

DISPOSABLE PLASTIC/GLASS SYRINGES:

With this it is more difficult to comply with the official requirement that an injection must be dispensed in a container sealed to exclude microorganisms. Hence there have been various improvements in its design

MULTIPLE DOSE INJECTIONS

MULTIPLE DOSE INJECTIONS examples

RUBBER CAPPED VIAL CLINBRITIC BOTTLE ANTIBIOTIC VIAL

TYPES OF PACKAGING MATERIAL

Glass Plastic Rubber Metal

Bottles ,Vials, Ampoules, Syringes, etc

Glass

Bottles, Syringes, Bags, Tubes.

Plastic

Closure, Vials Wrappers, Cap, Plungers

Rubbers

Label, Pouches, Cartons, Paper Drum.

Paper

. Collapsible tubes ,Foils ,Canes, Aerosol.

Metals

• They are transparent. • They can withstand the variation in temperature and pressure during sterilization. • They can protect the photosensitive medicaments from light during storage. • They are neutral after proper treatment. • They are impermeable to moisture and other gases.

Advantages of glass containers:

• Glass is fragile, so its containers are easily broken when dropped or knocked. • Glass container are heavy. • Glass container may release alkali to aqueous preparation. • They may crack when subjected to sudden changes of temperature. •Some containers can impart alkalinity and insoluble flakes to the formulations.

Disadvantages of glass containers

• During ________the alkali is extracted from the surface of the glass containers and a silica rich layer is formed which sometimes gets detached from the surface and can be seen in the contents in the form of shining flakes.

Flaking

is a common problem with glass containers in which sometimes moisture condensed on the surface of glass container, can extract some weakly bonded alkali, leaving behind a white deposit of alkali carbonate.

Weathering

Disadvantages of glass containers

Flaking Weathering

Type of glass l and test

Highly resistant borosilicate Powdered glass

Type of glass ll and test

Treated soda-lime glass Water attack

Type of glass llland test

Soda lime glass Powdered glass

Type of glass lVand test

General purpose soda lime glass Powdered glass

Quality control test for glass containers

1. Chemical Resistance Test 2. Hydrolytic Resistance Test 3. Arsenic Test 4. Thermal Shock Test 5. Internal Bursting Pressure Test

1. Chemical Resistance Test

a)Powdered attack test b)Water attack test

It is done to estimate the amount of alkali leached from the powdered glass, which happens at elevated temperatures.

Powdered Glass Test

This test is for type II glass. The principle involved in this is whether the alkali leaches from surface of container.

Water Attack Test

The test is directly related to the stability of pharmaceuticals packed in it.

Hydrolytic Resistance Test

This test is for glass containers intended for aqueous parenterals.

Arsenic Test

Sample container is placed in upright position in tray and the tray is immersed in hot water for a given time The container is then transferred in cold water bath and temp should be controlled. Cracks are examined before and after test (45°C temp. difference should be there)

Thermal Shock Test

Instrument used American glass research increment pressure tester.

Internal Bursting Pressure Test

for pharmaceutical product are made from plastic based polymer such as polyethylene ,polypropylene, polyvinyl chloride. The containers consist of one or more polymer together with certain additives if necessary

Plastic container

Advantages: 1.Very good mechanical strength. 2.Poor conductor of heat. 3.Low freight cost due to less weight. 4.Non breakable. Disadvantages: 1.Drug –plastic interaction may occur due to presence of many additives. 2.Permeated by vapors.

Plastic

DRUG PLASTIC CONSIDERATION

Permeation sorption leaching

• The transmission of gases,vapour,liquid through plastic material have adverse reaction on shelf life.

Permeation

• Most of the plastic material have one or ingredients added in small qty leaching occurs.

leaching

• The process involve removal of constituent from the product by packaging material.

sorption

TYPES OF PLASTICS

POLY ETHYLENE: POLY PROPYLENE:- POLYSTYRENE POLYVINYLCHLORIDE

⚫ This is used as high and low density polyethylene ⚫ Low density polyethylene (LDPE) is preferred plastic for squeeze bottles. ⚫ High density poly ethylene (HDPE) is less permeable to gases and more resistant to oils, chemicals and solvents. ⚫ It is widely used in bottles for solid dosage forms.

POLY ETHYLENE

Used as rigid packaging material and main component of intravenous bags.

POLYVINYLCHLORIDE (PVC):-

It has good resistance to cracking when flexed. Suitable for use in closures , tablet containers and intravenous bottles.

POLY PROPYLENE:-

. It is also used for jars for ointments and creams with low water content.

POLYSTYRENE:-

Quality control test for Plastic containers

1. Leakage test 2. Collapsibility test 3. Clarity of aqueous extract 4. Water vapour permeability test 5. Transparency test

Test for plastic preparations For non-injectable preparations

1) Leakage test 2) Collapsibility test

10 containers are filled with water and fitted with intended closures They are kept inverted at room temperature for 24 hours The test is said to be passed if there is no sign of Leakage from any container

Leakage Test

• This test is applicable to containers which are to be squeezed in order to remove the contents. • A container by collapsing inward during use, yield at least 90% of its normal contents at the required rate of flow at ambient temperature.

Collapsibility test

For injectable preparations

Water vapour permeability test Transparency test Clarity of aqueous extract

Unit Dose packaging

Blister Packing Strip Packing

• : the unit dosage forms are enclosed in between transparent blisters and suitable backing material usually aluminum foil.

Blister Packing

: the unit dosage of drugs are hermitically sealed in between strips of aluminum foil and/or plastic film.

• Strip Packing

❖ consist of several ingredients, one of which is an elastomer.

Rubber

used in pharmaceutical packaging contain only limited number of ingredients, which are difficult to extract. ❖ These closure do not pose a problem & can be used in contact with a large number of drug preparations.

❖ Rubber compounds

Test for rubber closures

1)Fragmentation test 3)Extractive test 2)Self sealability test 4)Compatibility test

• In this test, the closure is boiled with water for 4 hours under reflux & The water evaporated to dryness. •The residue must not exceed the specified amount.

EXTRACTIVE TEST

• This test is performed to check the compatibility of the rubber closures with various types of the substances. • Since it is necessary to ensure that there is no interaction between the contents of the bottle & the closure.

COMPATIBILITY TEST

•In addition to glass &plastic certain metals are also employed as containers in pharmaceutical product. • Metals offering relatively easy mfg and us • Metal containers are extremely strong collapsible tubes. ex • Metals arealso fationed into more complex systems ex dry powder inhalers, aerosol delivery container,ready to use needles. • Dispersible system having consistency of sof paste ,gel,cream,ointment can be coveniently packed into collapsible metal tube . • primary disadvantage is high cost and qulity control.

METAL

LIMITS • If total score is less than 100 • If total score is more than 150 • If score is 100 – 150 complies with test fails the test repeat the test

are the devices by means of which containers can be opened and closed. Proper closing of the container is necessary because • It prevents loss of material by spilling or volatilization. • It avoids contamination of the product from dirt, microorganisms or insects. • It prevents deterioration of the product from the effect of the environment such as moisture , oxygen or carbon dioxide.

CLOSURES

Material used for closures are; The closures for containers meant for storage of pharmaceutical products are generally made from the following basic materials.

• Cork • Glass • Plastic • Metal • Rubber

is essentially a wood obtained from the bark of oak tree, It is used for the manufacture of stoppers for narrow mouth bottles.

Cork

As compared to cork glass is an ideal material for stoppers but they do not provide leak proof closure as well as can easily slip out of the neck of the closure during transport and handling.

• Glass

: As compared to cork, glass, rubber and metal Plastic closures are becoming popular day by day as they are unbreakable, light in weight and can be easily molded into various shapes and sizes.

• Plastic

are mostly commonly used for the manufacture of closures but aluminum is mostly used for this purpose.

• Metal: Tin plate and aluminum

LABELLING

AO 55s 1988 AO 8s 2016

• Front of label • Most shown part of the label • PDP – 40%

Principal Display Panel

• Front of label • Most shown part of the label • PDP – 40%

Principal Display Panel

1. Name of Product 2. Dosage form and strength 3. Pharmacologic Category 4. RX Symbol 5. Name of Address of Companies

Information:

shall mean any material, including printed material, employed in the packaging of product, excluding any outer packaging used for transportation or shipment, that is in direct contact with the electronic cigarette refill solution

Primary Packaging

shall mean any material, including printed material, employed in the packaging of product, excluding any outer packaging used for transportation or shipment, that is not in direct contact with the electronic cigarette refill solution (e.g. product inserts, tags, etc.)

Secondary Packaging

D. STORAGE CONDITIONS 1. –NMT 8 degrees Celsius

Cold

– 20 to 10 degrees Celsius

a. Freezer

– 2 – 8 degrees Celsius

b. Refrigerator

– 8-15 degrees Celsius

– Temperature prevailing in the area - NMT 30 degrees Celsius

3. Room Temperature

- 20 – 25 degrees Celsius - Mostly in manufacturer

4. Controlled Room temperature

- 30 – 40 degrees Celsius

5. Warm

- > 40 degrees Celsius - Avoid excessive heat

6. Excessive heat

– Dealer/ Retail of drug prep./ prompt preparation

• S1

• – Prescriber

• – Retail of Drug store/ DDPS

• – Wholesale/ Distribution

• – Compounding/ Manufacturer

• – Importation

S5i

– Exportation

• S5e

• – Depot/ Storage for S4 and S5 license holder •

S5d

– Laboratory Analysis / Technical Research •

Importer / Compounder / Manufacturer

S7 –