Sahil Jasuja1*, Mahesh Kumar Kataria2
1Department of Quality Assurance,
Seth G.L. Bihani S.D. College of Technical education (Institute of Pharmaceutical Sciences & Drug Research),
Sri Ganganagar, (Raj.), India.
Packaging of materials is an integral part of any pharmaceutical industry. Packaging affects the quality stability and identification of drug product. Packaging provide an adequate degree of protection, minimize the loss of constituents and should not interact physically or chemically with the contents in a way that will alter their quality to an extent beyond the limits given in the individual monograph, or present a risk of toxicity. Pharmaceutical packaging is the means of providing protection, presentation, identification, information and convenience to encourage compliance with a course of therapy. The commonly used packaging materials are Container, Closure, Carton or Outer and Box. The containers may be made of glass, plastic, matel or paper. The material for closure may include Cork, Glass, Plastic, Metal or rubber. There are various tests for determination of quality, integrity and compatibility of packaging materials. The specification and requirement of quality testing depends on type of pharmaceutical materials used. Containers are tested by many methods of which commonly used test for glass are Crushed glass test, Whole-Container test, Chemical resistance of test, Water Attack Test etc. Similarly test. Closure materials are tested by Transparency test Penetrability Fragmentation test Self seal ability test, Extractive test etc. The requirement of packaging material testing is set according to specification of regulatory agencies like WHO GMP, USFDA and ICH guidelines.
Reference Id: PHARMATUTOR-ART-1609
Packaging 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 may be defined as the art and science which involves preparing the articles for transport, storage display and use. Pharmaceutical packaging is the means of providing protection, presentation, identification, information and convenience to encourage compliance with a course of therapy.
Composition of package:
(c) Carton or Outer
PACKAGE TESTING PROCEDURES:-
The testing procedures may be divided into two groups according to whether the test is applied to the packaging material in isolation or to the entire package.
1. Testing material: Tests applied to packaging materials may be:
a. Chemical - The pH value of materials chloride and sulphate in paper or board, alkalinity of glass, compatibility test with chemicals or medicaments are typical of the chemical tests.
b. Mechanical-Standard tests are available for the effect of creasing, folding and so on.
c. Environmental-Materials may be tested by standard methods for absorption of water, permeability to water vapour, gases, oils, odours etc. and for characteristics such as light transmission.
2. Testing Packages
a. Mechanical – Mechanical tests are applied mainly to outer packaging for protection from transportation hazards. They consist of the use of a standardized test procedure to compare the effect of different protective materials to prevent damage to the contents.
b. Environmental- Packages are subjected to conditions that reproduce the environment and some evaluation is made at suitable intervals. Such procedures may be applied to testing closures for water vapour transmission.
HAZARDS ENCOUNTERED BY A PACKAGE:-
a) Mechanical hazards – shock, compression, puncture, vibration etc.
b) Environmental Hazards-temperature, pressure, moisture, gases, light, contamination etc.
There are various tests to ensure that the resultant product will comply with its specification. Tests applied to the environment or to equipment, as well as to products in process, may also be regarded as a part of in-process control.
PRINCIPAL INSTRUMENTAL TECHNIQUES EMPLOYED FOR PACKAGING CONTROLS
ii. Chromatographic Methods
iii. Thermal analysis techniques
iv. Gas transmission analysis
v. Leak detection
vi. Physical test methods
vii. X-ray Fluorescence Analysis
IDEAL REQUIREMENTS OF GOOD PACKAGE:-
1. They should be able to hold the product without loss on account of leakage, spoilage or permeation.
2. They should afford protect against environmental conditions like light, air and moisture during storage.
3. They should not have any permeability for gases.
4. They should possess sufficient strength to withstand shocks of handling, transportation etc.
5. They should facilitate efficient safe and convenient use of contents.
6. The material must not interact with the contents.
7. The containers should afford protection from moulds, bacteria etc.
8. The cost of material should be as low as possible without compromising the quality.
9. They should facilitate easy identification.
10. They should afford protection from moulds, bacteria etc.
11. The container should not absorb or adsorb any material containing.
12. The closure should provide air tight closing to the container.
13. The closure should be compatible with the preparation.
2. QUALITY CONTROL OF CONTAINERS
A container for a pharmacopoeial article is intended to contain a drug substance or drug product with which it is, or may be in direct contact. The closure is a part of the container.
Containers must be chosen with care and after taking into consideration the nature of the articles and the likely effects of transportation and storage, even for short periods of time.
A container should be designed so that the contents may be removed in a manner suitable for the intended use of the article in it. It should also provide an adequate degree of protection, minimize the loss of constituents and should not interact physically or chemically with the contents in a way that will alter their quality to an extent beyond the limits given in the individual monograph, or present a risk of toxicity.
· Airtight containerA container that is impermeable to solids, liquids and gases under ordinary conditions of handling, storage and transport. If the container is intended to be opened on more than once, it must be so designed that it remains airtight after re-closure.
· Hermetically Sealed container. A container that is impervious to air or any other gas under normal conditions of handling, shipment, storage and distribution, e.g. sealed glass ampoule, gas cylinder etc.
· Light-resistant container. A container that protects the contents from the effects of actinic light by virtue of the specific properties of the material of which it is made.
· Multidose containerA container that holds a quantity of the preparation suitable for two or more doses.
· Sealed container. A container closed by fusion of the material of the container.
· Single-dose container. A container that holds a quantity of the preparation intended for total or partial use as a single administration.
· Tamper-evident container. A container fitted with a device or mechanism that reveals irreversibly whether the container has been opened.
· Tightly-closed containerA tightly-closed container protects the contents from contamination by extraneous liquids, solids or vapours, from loss or deterioration of the article from effervescence, deliquescence or evaporation under normal conditions of handling, shipment, storage and distribution. A tightly-closed container must be capable of being tightly re- closed after use.
· Well-closed containerA well-closed container protects the contents from extraneous solids and liquids and from loss of the article under normal conditions of handling, shipment, storage and distribution.
2.1 GLASS CONTAINERS
Glass containers may be colourless or coloured. Neutral glass is a borosilicate glass containing significant amounts of boric oxide, aluminum oxide, alkali and/or alkaline earth oxides. It has a high hydrolytic resistance and a high thermal shock resistance.
Soda-lime-silica glass is a silica glass containing alkali metal oxides, mainly sodium oxide and alkaline earth oxides, mainly calcium oxide. It has only a moderate hydrolytic resistance.
According to their hydrolytic resistance, glass containers are classified as:
– Type I glass containers which are of neutral glass, with a high hydrolytic resistance, suitable for most preparations whether or not for parenteral use,
– Type II glass containers which are usually of soda-lime- silica glass with high hydrolytic resistance resulting from suitable treatment of the surface. They are suitable for most acidic and neutral, aqueous preparations whether or not for parenteral use,
– Type III glass containers which are usually of soda- lime-silica glass with only moderate hydrolytic resistance. They are generally suitable for non-aqueous preparations for parenteral use, for powders for parenteral use (except for freeze-dried preparations) and for preparations not for parenteral use.
Glass containers intended for parenteral preparations may be ampoules, vials or bottles. The glass used in the manufacture of such containers complies with one of the requirements for hydrolytic resistance given below:-
Containers of Type II or Type III glass should be used once only. Containers for human blood and blood components must not be re-used. Glass containers with a hydrolytic resistance higher than that recommended for a particular type of preparation may generally also be used.
Containers for parenteral preparations are made from uncoloured glass except that coloured glass may be used for substances known to be light - sensitive; in such cases, the containers should be sufficiently transparent to permit visual inspection of the contents.
Glass is a common material to be used in either no sterile or sterile liquid dosage forms. It leaches alkali from its surface. Leaching of alkali can be reduced but cannot be zero. Hence, a limit test for alkalinity is to be performed before using it for a particular product.
(A) Crushed – glass test:
This test is official in USP. The container is crushed and sieved to produce uniform particles of which a definite weight of taken. The control of the particle size and weight of powder ensures that a constant surface area is exposed to the solution. Because all of the glass (not just the surface layer) is examined and extraction is enhanced by the rough surfaces of the particles, this is a severe test, and, if a glass passes, it is unlikely that containers made from it will give trouble while is use. Nevertheless, the technique is tedious and is not applicable to surface treated containers (sulphured or siliconed) because crushing would expose the alkaline glass below the surface. This test can be used for determining the nature of a glass or for distinguish between two types of glasses, such as neutral or surface – treated.
(B) Whole-Container test:
This test is official in European, British and International Pharmacopoeias. it is used in the USP for treated soda-lime containers only. The containers are simply filled with the test solution and exposed to the test conditions. Glassware may pass the whole container test more easily because the surface layer of a container is smooth and less reactive.
In this test, surface area does not increase as much as volume with the increase in container size, consequently, the small sized containers are more attacked by the leaching of the alkali from the surface.
Surface area which supplies alkali to each milliliter of the solution.
Ampoule (1 ml.)
Ampoule (10 ml.)
Bottle (1000 ml)
(C) Chemical resistance of test
USP and IP provide two tests to determine the chemical resistance of glass containers.
Table shows limits of alkalinity for glass containers:-
Limits ml of 0.02 N H2so4
1. Powdered Glass Test
2. Water Attack Test
type II (100ml of less)
type II (over 100ml)
(D)Powdered Glass Test
From the glass containers, alkaline constituents (oxides of sodium, potassium, calcium, aluminum, etc.) are leached into purified water under conditions of elevated temperatures. When the glass is powdered the leaching of alkali can be enhanced in the powdered is critical.
The principle involved in the powdered glass test in estimate the amount of alkali leached form the glass powder. The amount of acid that is necessary to neutralize the released alkali (a specified limit) is specified in the pharmacopoeia. The basic analysis is acid-base titration using methyl red indicator.
(E)Water Attack Test
This test is used only with containers that have been exposed to sulphur dioxide fumes under controlled humidity conditions. Such a treatment neutralizes the surface alkali. Now the glass becomes chemically more resistant. The principle involved in the water attack test is to determine whether the alkali leached form the surface of a container is within the specified limits or not. Since the inner surface is under test entire container (ampoule) has to be used. The amount of acid that is necessary to neutralize the released alkali from the surface is estimated, the leaching of alkali is accelerated using elevated temperature for a specified time. Methyl red indicator is used to determine the end point. The basic is acid-base titration.
2.2 PLASTIC CONTAINERS
Plastic containers for pharmaceutical products are made from plastics based on the following polymers: polyethylene (low or high density), polypropylene, polyvinyl chloride, polystyrene and to a lesser extent polyethylene terephthalate. The containers consist of one or more polymers together with certain additives if necessary. They should be manufactured from materials that do not include in their composition any substances that can be extracted by any contents in such quantities so as to alter the efficacy or stability of the product or to present a toxic hazard. Additives may consist of antioxidants, lubricants, plasticizers and impact modifiers but not antistatic agents and mould- release agents.
Drug Plastic Consideration
1. Permeation: The transmission of gases, vapours or liquid through plastic packaging materials can have an adverse effect on self life of drug. Permeation of water vapour and oxygen through the plastic wall into the drug can present a problem if the dosage form is sensitive to hydrolysis and oxidation. Temperature and humidity are important factors influencing the permeability of oxygen and water through plastic. An increase in the temperature increases the permeability of gas.
2. Leaching: Since most plastic containers have one or more ingredients added in small quantities to stabilize a specific to the plastic the prospect of leaching or migration from the container to the product is present. Problems may arise with plastics when coloring agents in relatively small quantities are added to the formula. Release of a constituent from the plastic container to the drug product may lead to drug contamination and necessitate removal of the product from the market.
3. Sorption: It may be defined as bonding of a solute to a plastic .This process involves the removal of constituents from the drug product by the packaging material. Sorption may lead to serious problem for drug preparation in which important ingredients are in solution. Since drug substances of high potency are administered in small doses, losses due to sorption may significantly affects therapeutic efficacy of the preparation.
4. Chemical Reactivity: Certain ingredients that are used in plastic formulations may react chemically with one or more components of a drug product. At times ingredients in the formulation may react with the plastic. Even micro quantities of chemically incompatible substance can alter the appearance of the plastic or the drug product.
A. TESTS ON PLASTIC CONTAINER
PARENTERAL AND NON-PARENTERAL PREPARATIONS:-
1. Leakage test: Fill ten container with water. Fit with intended closures and keep tem inverted at room temperature for 24 hour. There are no signs of leakage from any container.
2. Collapsibility Test: This test applicable to containers. Which are to be squeezed in order toe remove the contents. A container by collapsing inwards during use yields at least 90% of its nominal contents at the required rate of flow at ambient temperature.
3.Clarity of aqueous extract : Select unlabelled, unmarked and non-laminated portions from suitable containers, taken at random sufficient to yield a total area of sample required taking into account the surface area of both sides Cut these portions into strips none of which has a total area of more than 20 cm2. Wash the strips free from extraneous matter by shaking them with at least two separate portions of distilled water for about 30 seconds in each case, then draining off the water thoroughly.
4.Transparency test: Fill five empty containers to their nominal capacity with diluted. suspension as described in IP 1966. The cloudiness of the diluted suspension in each container is detectable when viewed through the containers as compared with a container of the same type filled with water.
5.Water vapour permeability test: Fill five containers with nominal volume of water and heat seal the bottles with an aluminum foil-poly ethylene laminate or other suitable seal. Weigh accurately each container and allow to stand (without any overwrap) for 14 days at a relative humidity of 60+5% and a temperature between 20 and 25 0C Reweigh the containers. The loss in weight in each container is not more than 0.2%.
PLASTIC CONTAINERS FOR OPHTHALMIC PREPARATIONS:-
Plastic containers for ophthalmic preparations comply with the following tests:
1 Leakage test; Collapsibility test Clarity of aqueous extract; Non-volatile residue
Comply with the tests described under Plastic containers for Non-parenteral Preparations.
2 Systemic injection test; Intracutaneous test Comply with the tests described under Plastic containers for Parenteral Preparations.
3 Eye irritation test. This test is designed to evaluate responses to the instillation of extracts of material under examination in the eye of a rabbit.
B. TESTS ON PLASTIC MATERIAL
The following tests are based on the extraction of the plastic material, and it is essential that the designated amount of the plastic be used. Also, the specified surface area must be available for extraction at the required temperature.
2. Light absorption
4. Non-volatile matter
5. Residue on ignition
6. Heavy metals
7. Buffering capacity
8. Oxidisable substances
BIOLOGICAL TESTS: -
The USP has provided its procedures for evaluating the toxicity of plastic materials Essentially the tests consist of three phases:
· Implantation test: Implanting small pieces of plastic material intramuscularly in rabbits.
· Systemic injection test: Injecting eluates using sodium chloride injection, with and without alcohol intravenously in mice and injecting eluates using poly ethylene glycol 400 and sesame oil intraperitoneally in mice.
· Intracutaneous test: Injecting all four eluates subcutaneously in rabbits. The reaction from test samples must not be significantly greater than nonreactive control samples.
2.3 METAL CONTAINERS
The materials used for various pharmaceutical drug delivery systems include tin plated steel, mild steel, stainless steel, tin free steel, aluminum and its various alloys..Tin is frequently used in the production of aerosolcans by electroplating it onto sheet steel to improvecorrosion resistance and facilitate soldering. Incontrast; aluminum is used in its pure form as foil.Often, aluminum foil is used as an impermeable layerin a multilayer laminate that may include paper and plasticsas well. Aluminum foil can be formed intorigid containers, semi rigid containers, blister construction,or laminates.
Metals have a number of advantages over otherpackaging materials. Like glass, metal is nearly totallyimpermeable to gas and water. In addition, metalcontainers are extremely strong and are shatterproof. For applications requiring malleability such as collapsibletubes, metal offers relatively easy manufacturingand very easy use .Metals can also be fashioned into more complex delivery systems such as metered-dose inhalers, dry powder inhalers, aerosol administration devices, and even ready-to-use needles. The primary disadvantages of metals relate to their cost and quality control. Metals are inherently more expensive to purchase and to fabricate into a useful container. Metals also are prone to the development of ‘‘pinhole’’ defects during manufacturing that can drastically compromise their barrier properties—especially in particularly thin sections. Not only can these defects be deleterious to the container, but they can also compromise the quality of the pharmaceutical.
2.4 PAPER, PAPERBOARD, AND CARDBOARD
The most common applications of paper, paperboard, and cardboard are in blister lidding stock and in over-the-counter (OTC) outer packaging. Because paper, paperboard, and cardboard offer virtually no moisture or gas barrier, they are typically part of the secondary pharmaceutical container. To provide additional protection, paper can be laminated or coated with a variety of materials. More commonly, when paper is involved in critical packaging functions, it is the only one component of a multicomponent system that offers optimal environmental protection to the drug environment. .Although paper does not offer high shear strength, its relatively high tensile strength makes it an easy barrier to overcome if one intends to do so, but is an exceedingly confounding one for a child. Paper also simplifies printing on the blister itself. Other uses of paper, paperboard, and cardboard are as secondary packaging or for shipping packaging (e.g., corrugated cardboard).
3. QUALITY CONTROL OF CLOSURES
The closure is normally the most vulnerable and critical component of a container as far as stability and compatibility with the product is concerned.
Suitable closing of the container is necessary because
1. It prevents loss of material by spilling or volatilization.
2. It prevents the deterioration of product from the effects of environment such as moisture, oxygen, or carbon dioxide.
3. It avoids contamination of the product from dirt, microorganism or insects.
Types of closures:-
1. Thread screw cap
2. Lug cap
3. Crown cap
4. Pilfer proof closures
Materials used for making closures:-
A closure for a container for an aqueous parenteral preparation or for a sterile powder is a packaging component which is in direct contact with the drug. A rubber closure is made of materials obtained by vulcanization (cross-linking) of elastomers with appropriate additives. The elastomers are produced from natural or synthetic substances by polymerization, polyaddition or polycondensation. The nature of the principal components and of the various additives such as vulcanisers, accelerators, stabilizing agents, pigments, etc. depends on the properties required for the finished closure.
Rubber closures are used in a number of formulations and consequently different closures possess different properties. The closures chosen for use with a particular preparation should be such that the components of the preparation in contact with the closure are not adsorbed onto the surface of the closure to an extent sufficient to affect the product adversely.
TEST FOR CLOSURES:-
1. Penetrability: This is measured to check the force required to make a hypodermic needle penetrate easily through the closure. It is measured by using the piercing machine. The piercing force must not exceed a stated value. If it exceeds that stated value, the hypodermic needle can be damaged as a result of undesirable hardness of the closures.
2.Fragmentation test: This test is performed on 20 closures. Each closure is penetrated with hypodermic needle in a piercing machine five times within a limited area and needle is washed to transfer any fragment present. The contents are filtered through coloured paper that contrasts with the rubber and the fragments counted. On an average there should not be more than three fragments per unit.
3.Self sealability test: Applicable to multidose containers fill 10 vials with water close them with prepared closures and secure with a cap. For each closure use a new hypodermic needle and pierce 10 times each time at different site immerse the vials upright in methylene blue (0.1%) solution and reduce external pressure for 10 minutes. 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.
4.Extractive test: In this test, the closure is boiled with water for four hours under reflux and the water evaporated to dryness. The residue must not exceed the specified amount.
5. Compatibility 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 and the closure.
6.Light absorption Filter solution A through membrane filter. Measure the light absorbance of filtrate in the range 220 to 360 nm using a blank solution (prepared in the same manner as solution A). The absorbance is not more than2.
7. Light absorption : Filter solution A through membrane filter.Measure the light absorbance of filtrate in the range 220 to 360 nm using a blank solution (prepared in the same manner as solution A). The absorbance is not more than2.
4. PACKAGING DESIGN AND SPECIFICATIONS
Quality control of a packaging component starts at the design stage. All aspects of a pack development that may give rise to quality problems must be identified and minimized by good design.
(A) Component Shape and Dimension
Standardizing both component shape and size should be the policy. There are many components that can be standardized such as ampules, vials, cartons, labels and leaflets. Rubber plugs and plastic bottles can be standardized with respect to shape and size, varying only in the material of construction. There will be a variety of sizes of components depending on the dosage, but again the same shape could be used but with different dimensions.
(B)Packaging Validation Trials
When the components have been identified for a particular product, the validation of packaging operation is required. This is to ensure that a consistent pack quality is obtained at the required packaging rate.
(C) Material of Construction
The material of construction requires careful consideration, particularly when the product is in contact with the container. It is necessary to ensure that the product does not deteriorate or does not become contaminated as a result of being in contact with the container, or that the product does not affect the integrity of the pack.
(D) Component /Product Validation
Once a formulation has been agreed, the pharmaceutical company has to perform compatibility studies between the product and container to ensure the product degradation does not occur during the product market life. The container has to be capable of protecting the product from environment.
1. Sterile product validation:-
a) Product and pack compatibility- the components must be washed and sterilized through a validated procedure. The vials must be filled with the sterile product under sterile conditions and terminally sterilized if this is a part of the intended product operation. Components performance should be monitored during the compatibility trials to ensure that deterioration has not occurred.
b) Seal integrity- the seals of each vial should be examined before the experiment to ensure that there are no defectives, and then each vial should be inserted into a tray containing the challenge bacteria. The samples should be cycled through temperature and pressure changes expected on the market for several weeks. Careful cleaning of the vials and examination of contents for sterility will determine the seal quality.
2. Nonsterile product validation:-
a) Water vapour permeability- the water vapour permeability of the pack containing the product is required. This is necessary because although the bottles will comply with the water vapour permeability test described in USP, permeation through the bottle wall will depend on wheather the product has a high or low affinity for the water. The test split into two parts to enable the maximum amount of information to be obtained and hence possibly eliminating the necessity to perform further time consuming experiments.
· Bottle wall permeation
· Bottle and cap permeation
b) Light transmission- this test is to determine the effect of light passing through the bottle wall on the product stability and appearance. The bottle wall thickness can have a significant effect on the results obtained.
c) Product stability- it is unlikely that a compatibility problem, particularly with the film coated tablet, will occur, although it is necessary to check up full life of the product. There is possibility that either the smell or taste of tablets will be affected.
Every detail concerning a component specification must be communicated to and agreed upon with the manufacture, including packaging, transportation, and labeling requirements. If any of the details are missing confusion or mistakes may occur.
The main specifications requirements are the component drawing, artwork (printed components only) and the quality control testing and standards.
Quality control testing and standards- There are two classes of components:-
1. Primary – in contact with the product, e.g., ampules, vials, plastic bottles, polymer coated foils
2. Secondary – not in contact with the product, e.g., cartons, labels, leaflets
The critical parameters are for setting standard are:-
3. Compatibility and costumer usability
4. Chemical testing
Appearance – This can split into three categories:
(1) Critical – unacceptable at any level, e.g., rogue printed items in a delivery, incorrect printing of data such as the product name or concentration, insects in the bottle etc.
(2) Major- acceptable at a low level, the standard is decided by the pharmaceutical company. Examples of major appearance defects are missing print, making read text difficult, flashing on molded components and other defects.
(3) Minor- acceptable at a higher level than the major appearance defects. These will detract from perfection and include marked components, slight colour variations, slight smudging etc.
Dimensions – The dimensions of a component can be separated into two types:
1. Critical – requiring close control to ensure that the component functions correctly and can be used satisfactorily by packaging equipment.
2. Noncritical – necessary to maintain the component shape but not requiring close control for satisfactory function of the component.
The critical dimensions for each of these components are as follows:-
1. Vial – flange depth , flange diameter , bore diameter , vial height , body diameter , wall thickness, base thickness , concentricity and verticality
2. Rubber plug - flange depth, flange diameter and plug diameter
3. Aluminum overseal- internal skirt depth, external diameter, and aluminum thickness.
Compatibility and costumer usability- This involves checking that each component forming a pack fits together and functions correctly. Example – eye dropper pack
1. The nozzle must have a good interference fit into the bottle and allow one drop at a time deliver through the hole in the nozzle when inverted, but must not leak from the fitted position.
2. The cap must screw into position , and leakage must not occur when the bottle is squeezed into the inverted position, i.e., a sterile seal is maintained.
Chemical testing- The majority of chemical testing is required on primary components. The type of testing required depends on the type of component used.
1. Glass vials and Ampules – The USPXXII requirements for glass containers are chemical resistance and light transmission. The requirements vary from country to country, but basically testing determines whether the correct type of glass has been used for the manufacture and its suitability for use with pharmaceutical products.
2. Plastic primary components- the testing is more extensive with plastic components, requiring both biological and physicochemical tests. This is because plastic components contain other substances, such as plasticizers, stabilizers, antioxidants, pigments, lubricants and possibly residues from polymerization. Therefore, for components that are in direct with the product, this testing is required to ensure that the product is not affected during its life.
5. PHARMACEUTICAL PACKAGING
The quality control of components in pharmaceutical premises starts at the receiving stage. Once the component s are considered acceptable by the packaging material laboratory, the control of components quality must be maintained through each stage of handling and use , that is from the component storage and preparation to the filling , packaging, and dispatch of the product.
The packaging operation can involve many complex operations, all of which require careful control if product quality and security are to be maintained. The packaging operation means either the filling and packaging of non sterile products or the packaging stage of filled sterile products.
A. Area standard
Depending on the type of product and packaging operation, the standard requirement of the packaging area will vary, although there are several basic standards required:-
1. Each packaging line should be in separate room.
2. There should be covered floors and ceilings for easy cleaning.
3. The packaging operators should wear non –fiber shedding overalls that have a tight fit around the neck and sleeves. There should be no external pockets above waist height.
4. The filling part of the packaging operation should be enclosed and supplied with filtered air.
5. Basic precautions prior to filling can be operated, such as blowing the container with filtered air immediately before filling. Washing of containers should not be necessary, provided that the correct production and operation standards are in use in the supplier premises .
B. Packaging instructions
1. Packaging specifications
The following details must be included in the specifications:
· The product name, strength, and reference code to be packaged.
· The pack size and number of product items to be included in each pack, that is, the number of tablets, ampules, vials, etc.
· A description and reference of each packaging item to be included in the pack.
· Special precautions to be taken during the operation. For example the packaging of a moisture sensitive tablet may need to be performed under low humidity conditions.
· Detail the in-process control system to be operated. This will vary depending on the complexity of the packaging operations.
2. Specific batch details
The line supervisor will need to know the batch numbers and expiry dates for each batch to be packaged. This is to ensure that the correct batches are packaged for a specific customer, with the correct expiry date printed on the packs.
3. Customer requirements
The customer order may be to package all the product in each of the batches allocated or in an exact number of packs. The quantities of components required for each batch to be packaged need to be stated. This quantity must include overages based on expected wastage due to line set up, breakdowns , and in-process checks.
C. Product quality and security
Once the packaging line is set up and the correct packaging instructions are available, product quality and security must be maintained throughout the packaging stage. It can be done in following ways:
1. Critical devices – a critical device is any device that unless it is working correctly, could affect product quality. Each device must be identified and calibrated or challenge on a regular basis to ensure that it is working within specified limits.
2. Bar coding – all the printed items (printed containers , labels , and cartons ) should be bar coded , with the code reader said to read each item immediately to including into the pack. With the ampules and vials , a ring coding system or a similar method should be used.
3. Miss printing and missing component detectors – if these detectors have been proven to work correctly, they can give additional assurance of a satisfactory pack on the market.
6.(A) PACKAGING MATERIAL SPECIFICATIONS:-
Specifications of packaging materials may contain below mentioned particulars:-
(i) Printed strip rolls
* Common name
* Code number
* Colour scheme and design
* Quality of printed matter
* Seal quality
* Effect of heat
* Name of approved supplier
* Frequency of re-inspection of stored material
* Date of issue of specification
* Name (name of the drug and strength)
* Code number
* Dimensions (length, width, height)
* Colour scheme
* Quality of printed matter
* Printed matter
* Gram per square meter
* Name of approved supplier
* Frequency of re-inspection of stored material
* Date of issue of specification
* Common name
* Code number
* Total height
* Neck height
* Body diameter
* Type of glass
* Overflow capacity
* Name of approved supplier
* Date of issue of specification
(iv) Pilfer proof caps
* Common name
* Code number
* Description( including design and monograph )
* Uniformity of weight
* If waded caps thickness of cap
* Sealing quality
* Date of issue of specification
(iv) Finished product specification
* Generic name of the product
* Trade name
* Dosage form and strength
* Description (colour, shape, dimension, taste, etc.)
* Physical properties (pH, dissolution time, disintegration time etc.)
* Name of pharmacopeia or other any other recognized book of standards in which the monograph appears.
* date of expiry, precautions and safety aspects, date of issue of specification
6.(B) PACKAGING OPERATION
It is of utmost importance to ensure that correct packaging materials are used for drug product.
The entire operation should be well defined via written procedure and followed in totality.
Particular attention should be given to ensure that different products are not packed in close proximity unless there is physical segregation. The written procedures should include following features, which will prevent mix-ups and cross contamination:
1. Before packaging operations begin, steps should be taken to ensure that the work area, packaging lines, printing machines and other equipments are clean and free from any products, materials or documents previously used.
2. Identification of drug product with lot or control number that permits determination of the history of the manufacture and control of the batch.
3. The name and lot number of the product being handled should be displayed at each packaging station or line.
4. All the products, labels, labeling and packaging material should be checked on delivery to the packaging department for quantity, identity, and conformity with the packaging instructions.
5. Examination of the packaging and labeling materials for suitability and correctness before start up of packaging operations and documentation of such examination in the batch production record.
6. Containers for filling should be clean before filling. Attention should be given for avoiding and removing contaminants if any, such as glass fragments and metal particles.
7. Online control of the product during packaging should include at least checking the following:
· General properties of the packages.
· Whether the packages are complete and the count is as per specification.
· Whether the correct products and packaging materials are used.
· Correct functioning of line controls.
8. Samples taken away from the packaging line should not be returned. They should where appropriate, be destroyed (e.g. leak tested strips)
9. Product lots which have been involved in special events (rework or re inspection) should be reintroduced into the process only after additional inspection and approval is carried out by authorized personnel.
7. W.H.O GUIDELINES FOR QUALITY CONTROL OF PACKAGING MATERIALS
1. All the containers and closures intended for use shall comply with the pharmacopoeial and other specified requirements.
2. Suitable sample sizes, specifications, test methods, cleansing procedures and sterilization procedures shall be to suitability of packaging materials.
3. Plastic granules should also comply with the pharmocopeial requirements including physio-chemical and biological tests.
4. All the containers and closure shall be rinsed prior to sterilization with water for injection according to written procedure.
5. The design of the closures, containers and stoppers shall be as such as to make an airtight seal when fitted to the bottles.
6. It shall be ensured that containers and closures chosen for a particular product do not affect the product adversely.
7. When the glass bottles are used, the written schedule of cleansing shall be laid down and followed.
8. Individual containers of parenteral preparations, ophthalmic preparations shall be examined against black or white background fitted with diffused light after so as to ensure freedom from foreign matters.
9. Glass bottles-
a) Shape and design of the glass bottle shall be rational and standardized.
b) Glass bottles made of USP Type-1 and USP Type-ll glass shall only be used.
c) USP Type-lll glass containers may be used for non-parenteral sterile products.
10. Plastic containers:-
a) Preformed plastic containers intended to be used for the packing of large volume parenteral shall be moulded in-house by one-continuous operation through an automatic machine.
b) Blowing, filling, and sealing operations shall be conducted in room conforming to requirements.
11. Rubber stoppers:-
The rubber stoppers used for large volume parenterals shall comply with specifications prescribed in the Indian pharmacopeia.
The testing of packaging materials is almost requirement for any pharmaceutical industry. The material of a package affects quality, stability and efficacy of drug product. Thecost of material of a package should be as low as possible without compromising the quality of product. It should pass the specifications of tests before it reached the local markets and made available to the consumers of product. The type of test followed should be according to requirements of regulatory agencies.
1. “INDIAN PHARMACOPOEIA 2007”, Volume-1, published by The Indian Pharmacopoeia Commission, Central Indian pharmacopoeia Laboratory Govt. Of India, Ministry of Health & Family Welfare Sector-23, Raj Nagar, Ghaziabad-201 00 Page no. 363-371
2. “UNITED STATES PHARMACOPOEIA 2007”,Volume-1,Page no.661
3. Swarbrick James, “ENCYCLOPEDIA OF PHARMACEUTICAL TECHNOLOGY”, Volume -1,Third Edition, Page no.2526-2541
4. Lachman leon, Lieberman H.A, Kanig J.L,“THE THEORY AND PRACTICE OF INDUSTRIAL PHARMACY”, Third Indian Edition 1990, Varghese Publishing House, Dadar Bombay Page no.711-732
5. Organization Of Pharmaceutical Producers Of India, “ QUALITY ASSURANCE GUIDE” Fourth Edition 2001, Chapter 11.5 Page no. 1-4
6. Banker G.S, Rhodes C.S, “MODERN PHARMACEUTICS”, Fourth Edition , Published by Marcel Dekker, Page no.587-600
7. “EUROPEAN PHARAMOCOPEIA”5.0, Vol-1,page no.303-317
8. Jerkins W.A, Osborn K.J, “PACKAHING DRUGS AND PHARMACEUTICALS”, edition 1993, Technomic Publishing Co.Inc., Page no. 1372-1389
9. Dean D.A, Evans E.R, and Hall I.H, “PHARMACEUTICAL PACKAGING TECHNOLOGY”
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