You are hereReview on: THE PHARMACEUTICAL PACKAGING

Review on: THE PHARMACEUTICAL PACKAGING


8.3-Stage in the development of a package product combination:
    The stages broadly associated with packaging developments are as follows:

8.3.1- Pre formulation:
Pre formulation studies are essential for all packaging components. This provide information relating to the limitations of the packaging material.

8.3.2- Product formulation:
All formulations are required to be documented and stored. It is therefore necessary to make certain that all packaging materials are defined and that all packaging parameters (torque, heat, seal etc) are identified, controlled and documented (all part of Good Laboratory Practice (GLP) and Good Manufacturing Practice (GMP) during formulation studies).

8.3.3- Consideration of container materials:
It is important to have a basic knowledge of all packaging materials, their properties, characteristics etc. and the process by which they are fabricated/ decorated as a packaging container or component, as well as how these and any subsequent process may affect their properties, e g: sterilization by ethylene oxide can lead to ethylene oxide and ethylene glycol residues. Gamma radiation of low density poly-ethylene marginally reduces the flexibility owing to molecular cross linkage and can give rise to formic acid and formaldehyde residues.

8.3.4- Pack feasibility tests:
This is the stage where a product (preferably the formulation selected for / ultimate scale) is tested in a range of possible package, usually over a range of conditions from say 200C to 450C, together with alteration in temperature –humidity range. In addition to the storage tests indicated above the immersion of pieces of package or package components if plastic, in the product or a stimulant i.e. an extractive-type-test may also be employed. Extractive tests are usually mandatory for plastics used for injectables and ophthalmic products. Feasibility tests usually extend over a period of 1-12 months. Only after a period of normally 3-6months any decision about the package is taken.

8.3.5- Formal stability test:
Formal stability test is conducted only after a suitable package –product combination is selected. By conducting the formal stability test, the shelf life of a product can be determined. Test conditions has been specified by the International Conference on Harmonization and adopted by the major regulatory bodies in Europe, The USA and Japan. Normally three large-scale batches of product in each package is selected.For long term stability test purpose the temperature is maintained at 250C with a relative humidity of 60% and in case of accelerated stability test , the temperature is maintained at 400c with a relative humidity of 75%. The samples are kept over a period of 5 years and examinations are conducted at the intervals of 0 (optimal), 3,6,9,12,18,24,30,36,48 and 60 months. The data generated are send to the regulatory authorities as part of the marketing authorization application.

8.3.6- Ongoing stability:
This consist of repeated stability on random batches from production in order confirm that the shelf life does not change during the manufacture of each batch.

8.3.7- Complaints:
This is the final means of monitoring the success of the product and pack. It is somewhat similar to the monitoring and recording of adverse reactions in that it is a safeguard to both the company producing the drug and the person receiving it. In all the above tests analytical and packaging technological support is essential to check both the product and the package.

9)Qualification and quality control of packaging components:    
A packaging system found acceptable for one drug product is not automatically assumed to be appropriate for another. Each application should contain enough information to show that each proposed container closure system and its components are suitable for its intended use. The type and extent of information that should be provided in an application will depend on the dosage form and the route of administration. For example, the kind of information that should be provided about a packaging system for an injectable dosage form or a drug product for inhalation is often more detailed than that which should be provided about a packaging system for a solid oral dosage form. More detailed information usually should be provided for a liquid-based dosage form than for a powder or a solid, since a liquid-based dosage form is more likely to interact with the packaging components.19

TABLE9.1:Examples of Packaging Concerns for Common Classes of Drug Products: 20

Degree of Concern Associated with the Route of Administration

Likelihood of Packaging Component-Dosage Form Interaction

 

High

Medium

Low

Highest

Inhalation Aerosols and Solutions; Injections and Indictable Suspensions

Sterile powders and Powders for Injection; Inhalation Powders 

 

High

Ophthalmic Solutions and Suspensions; Transdermal Ointments and Patches; Nasal Aerosols and Sprays

 

 

Low

Topical Solutions and Suspensions; Topical and Lingual Aerosols; Oral Solutions and Suspensions

Topical powders Oral powders

Oral Tablets and Oral (Hard and Soft Gelatin) Capsules

9.1-Protection:
A container intended to provide protection from light or offered as a light-resistant container must meet the requirements of the USP<661> Light Transmission test. The procedure requires the use of a spectrophotometer, with the required sensitivity and accuracy, adapted for measuring the amount of light transmitted by the plastic materials used for the container. The ability of a container closure system to protect against moisture can be ascertained by performing the USP <661> Water Vapor Permeation test°. The USP sets limits to the amount of moisture that can penetrate based upon size and composition of the plastic components (HDPE, LDPE, or PET). The integrity of the container can be evaluated in several ways. A couple of the most common tests are dye penetration and microbial ingress. Container closure systems stored in a dye solution and exposed to pressure and vacuum cycles are examined for dye leakage into the container. The microbial ingress is similar in fashion, but determines the microbial contamination of the contents when soaked in a media contaminated with bacteria. Other quantitative tests that can be run are vacuum/ pressure decay, helium mass spectrometry, and gas detection.

9.2-Compatibility:
Components compatible with a dosage form will not interact sufficiently to change the quality of the product or its components. A leachability study designed to evaluate the amount and/or nature of any chemical migrating from the plastic material to the pharmaceutical product should be implemented. The study should evaluate substances that migrate into the pharmaceutical product vehicle for the length of shelf-life claim. The drug product should be evaluated at regular intervals, such as at one, three, or six months or at one or two years, until the length of the shelf life claim has been met.
Analytical techniques such as Liquid Chromatography/ Mass Spectrometry to evaluate nonvolatile organics, Gas Chromatography/Mass Spectrometry (GC/MS) to evaluate semi volatile organics, and Inductively Coupled Plasma (ICP) spectroscopy to detect and quantitate inorganic elements should be a part of this study. Coupling MS to LC and GC methods provides a definitive and effective tool for identifying unknown impurities and degradation products.
Other changes such as pH shifts, precipitates, and discoloration, which may cause degradation of pharmaceutical product must be evaluated. Changes in the physical characteristics of the container, such as brittleness must be evaluated using thermal analysis and hardness testing.An infrared (IR) scan of each plastic component should also be included. An IR scan can fingerprint the materials and also provide proof of identity, which will later become part of quality control.

9.3-Safety:
All packaging components should be constructed of materials that will not leach harmful or undesirable amounts of substances to which a patient will be exposed during drug treatment. Determining the safety of a packaging component is not a simple process, and a standardized approach has not been established. However, an extraction study should be one of the first considerations. Isolation is accomplished through sample preparation, followed by incubation in solvents at well-defined and well-controlled times and temperatures. Sample preparation is an area in which an experienced chemist's knowledge of chemical procedures is indispensable.
Prior to performing any of the chemical tests, it is important to have precise information on the synthesis of the polymer itself. This includes descriptions of the monomers used in the polymerization, the solvents used in the synthesis, and the special additives that have been added during material production. For containers used to package drugs ranked with a high degree of concern, such as inhalation aerosols and injectables, this type of information is imperative. Knowledge of degradation products that may be released into the drug product is also important.
Some potential extractable chemicals from packaging materials are water soluble, while others are soluble only in non polar environments. For the packaging which are in contact with the drug products, extraction in both polar and non polar environments is relevant. The USP includes physicochemical tests for plastics based on water extracts; while water, alcohol, and hexane extracts are required for polyethylene containers under controlled temperature and time parameters (700C for 24 hours for water and alcohol and 50°C for 24 hours for hexane). These tests are particularly useful in defining materials as rich or poor in extractable chemicals. The tests categorize material extracts in general terms, such as nonvolatile residue (total extractables), residue on ignition, buffering capacity, heavy-metals content, and turbidity.
Biological reactivity is the second part of safety testing and is designed to test extractable chemicals for toxicological properties. FDA's guidance document suggests that the USP biological reactivity tests can determine the safe level of exposure via the label-specified route of administration.

9.4-Performance:
The fourth attribute of suitability of the container closure system, performance and drug delivery, refers to its ability to function in the manner for which it was designed. There are two major considerations when evaluating performance. The first consideration is functionality that may be to improve patient compliance, minimize waste, or improve ease of use. The second consideration is drug delivery, which is the ability of the packaging system to deliver the right amount or rate. Packaging systems that address this consideration are pre filled syringes, trans dermal patches, dropper or spray bottles, and metered-dose inhalers.

TABLE9.2:Typical Suitability Considerations for Common Classes of Drug Products:

ROUTE OF ADMINISTRATION/ DOSAGE FORM

SUITABILITY

Protection

Compatibility

Safety

Performance/ Drug Delivery

Inhalation Aerosols and Solutions, Nasal Sprays

L, S, M, W, G

Case 1 c

Case 1 s

Case 1 d

Inhalation Powders

L, W, M

Case 3c

Case 5s

Case 1d

injections, Indictable Suspensions

L, S, M, G

Case 1 c

Case 2s 

Case 2d

Sterile Powders and Powders for Injection

L, M, W

Case 2c

Case 2s 

Case 2d

Ophthalmic Solutions and

Suspensions

L, S, M, G

Case 1 c

Case 2s 

Case 2d

Topical Delivery Systems

L, S

Case 1 c 

Case 3s

Case I d 

Topical Solutions and

Suspensions, and Topical and Lingual Aerosols

Case 3s

L, S, M

Case 1c

Case 2d

Topical Powders

L, M, W

Case 3c

Case 4s

Case 3d 

Oral Solutions and Suspensions

L, S, M

Case 1c

Case 3s 

Case 2d 

Oral Powders

L, W

Case 2c

Case 3s 

Case 3d

Oral Tablets and Oral (Hard and soft Gelatin ) Capsule

L, W

Case 3c 

Case 4s

Case 3d

 Explanation of the codes in the table:

Protection: L (protects from light, if appropriate)

S (protects from solvent loss/leakage)

M(protects sterile products or those with microbial limits from microbial contamination)

W(protects from water vapor, if appropriate)

G (protects from reactive gases, if appropriate)(19,20)


9.5-Compatibility:

Case 1c: Liquid-based dosage form that conceivably could interact with its container closure system components

Case 2c: Solid dosage form until reconstituted; greatest chance for interacting with its container closure system components occurs after it is reconstituted. 

Case 3c: Solid dosage form with low likelihood of interacting with its container closure system components.21

Safety:

Case 1s: Indicates the USP Biological Reactivity Test data, extraction /toxicological evaluation, limits on extractable, and batch-to-batch monitoring of extractables.

Case 2s:Indicates the USP Biological Reactivity Test data and possibly extraction/toxicological evaluation.

Case 3s:Indicates an appropriate reference to the indirect food additive regulations is sufficient for drug products with aqueous-based solvents. Drug products with non-aqueous based solvent systems or aqueous based systems containing co-solvents generally require additional suitability information

Case 4s: Indicates an appropriate reference to the indirect food additive regulations is sufficient.

Case 5s:Indicates an appropriate reference to the indirect food additive regulations for all components except the mouthpiece for which USP Biological Reactivity Test data is provided.

10)Package inspection:
More critical part of packaging operation is package inspection. In the past this was largely carried out by people under the heading of quality control. With the increase in output of typical packaging lines the inspection task has become difficult for the human person to accomplish. Several important electronics techniques have been developed which allow the for graphic inspection of a number of packaging variables and the rapid rejection of those which to not meet an established standard , and with the passing of those which do. One notable variable is the accuracy of weight or fill volume. Automatic check weight systems handle all of these. In the case a product sold by volume, a machine-vision system can determine whether the liquid level. in a bottle for example is at the proper level.. Labeling is another variable which is regulated. Again machine –vision systems are able to scan each label to be sure that it is correctly applied and that the text is correct for the product being and that the text is correct for the product being packaged. Metal detection in a product and /or package can be accomplished with several techniques with an X-ray able to detect particulars as small as 0.01 mm at high line outputs. Leaking packages can be detected at high speed with helium leak detection.

10.1-FDA regulation:
Food and Drug Administration evaluates a drug and the agency must be firmly convinced that the package for a specific drug will preserve the drug's efficacy as well its purity, identity, strength and quality for its entire shelf life. Under the provisions of the Food and Drug Administration Act , however, no specifications or standards for containers or container closures are provided. Under the Act, it is the responsibility of the manufacturer to prove the safety of a packaging material and to get approval before using it for any pharmaceutical product. The Food and Drug Administration does not approve containers as such, but only the materials used in the container are approved. A list of substances considered "Generally Recognised As Safe" (GRAS) has been published by the FDA. In the opinion of the qualified experts they are safe under specified conditions, assuming they are of good commercial quality. A material that is not included under GRAS or prior sanction, and is intended to be used with food, must be tested by the manufacturer, and the data must be submitted to the FDA.
The specific FDA regulation states that "containers, closures and other component parts of drug packages, to be suitable for their intended use, must not be reactive, additive or absorptive to an extent that the identity, strength, quality or purity of the drug will be affected." The packaging material must be approved for such use, along with the drug, before going to the market. The drug manufacturer must include data on the container and package components in contact with the pharmaceutical product in its New Drug Application (NDA). If the FDA can determine that the drug is safe and effective, and that the package is suitable, it approves the drug and package. Once approved, however, the package may not be altered in any manner without prior FDA approval. In the case of plastics, most resin manufacturers maintain Master Files on their resins with the FDA. Upon request from the resin manufacturer, the FDA uses this file as a reference to support a New Drug Application that which a drug manufacturer files22.

11)Robotics:
The introduction of robotics has given a new dimension to packaging in that it is now possible to do repetitive tasks with speed and accuracy at notably lower cost than if done by people. The manufacturer of robots is well established providing a quality product with continuity of service, supply and software support. Economic analysis needs to be done before making the decision as to whether to automate doing robots, fixed automation, or the labor of people aided by work aids.
There are two principle classes of robots. One type involves a fixed position for a central control and manipulator unit. This type of device is particularly useful where a repetitive motion is required, such as taking a package component from one position and then rapidly and accurately placing it in another position. The robot functions in an X-Y-Z axis basis. This permits the device is perform relatively crude tasks such as picking up a component, orienting it, and then moving it to the desired place and precisely positioning it in the X., Y or Z planes. The term package components can mean any part of the package itself or the product which is to be packaged.
A second type, generally regarded as being more versatile than the fixed point robot is the gantry robot . This device also offers capability of the X, Y and Z directions. Programming is usually more simple for the gantry than for the fixed-position robot. The gantry robot can also use a manipulator at its pickup and discharge points. This often is as simple as a clamp or a device that has its own X-Y-Z degrees of freedom.
A robot often can be economically justified when the task of doing a certain packaging operation is analyzed in detail. When the work rids are considered and their cost determined the additional cost for providing robot capability is often of a small magnitude, which justifies, it is to replace human labor. There are many examples where a single operator controls an entire production and packaging operation where robotics do all of the manual tasks. The robots are under the direction of their software. The operator is often a person who has at least an associate in science degree from a country college. Programming languages used for robots is becoming more standardized. This allows robotic equipment to be reused many times after the original operation has been abandoned.23

12)The child resistant packaging:
The definition of Child Safe Packaging is "packaging that is difficult for a child to open within a reasonable period but that presents no difficulty for an adult to use properly and flexible packages with hidden tear starts or peel back and push blister packs did and still do present problems for elderly or handicapped people to use properly.The Child-Safe Packaging Group (CSPG) was formed eleven years ago and its objective is to promote the specification and success of child resistant packaging systems for all products whose ingestion or other contact could prove seriously distressing to a child.

The Child-safe Packaging Group has been a catalyst for the introduction two new standards: one British and the Pan-European which will help to create better flexible packs. A new standard for rigid packs has been published, this again will make them more acceptable to adults and help to banish forever the old quip about adults not being able to access their medicines when packed in child resistant packs because child resistant packaging remains the only packaging for any product which has to be tested for openability by adults. It has already and will continue to make for a more consumer acceptable pack and the system of testing for adult openability could well be applied to packaging generally.

The report of the inquest into the circumstances surrounding the death of three year old Yaqoob Lookman, published in most national newspapers on Thursday August 3rd, has been described by members of the Child-Safe Packaging Group as predictable, avoidable and the result of pure negligence.Briefly, the child swallowed 44 ferrous sulfate tablets, which he extracted from two blister packages. The Child-Safe Packaging Group had declared this type of packaging to be dangerous since its own research was published in 1995. Blister packages are tested for child resistance in the United States, Canada and Germany. Pharmaceuticals and other hazardous products are packaged in either rigid or flexible containers. Rigid packaging systems, bottle and child resistant closure, are subject to testing for child resistance and have been so since 1975.

The Child-Safe Packaging Group consists of the greater part of the supply industry for re closable packaging systems for pharmaceutical or other hazardous products. The Child-Safe Packaging Group commissioned research in 1995 that conclusively proved that blister packages in common use in the United Kingdom and other European countries were not child resistant. The results of this research were announced in the press then and have subsequently been referred to in papers published by the group and debates in the packaging and pharmaceutical industries.24

13)Economic growth and marketing strategy:
Pharmaceutical and medical device industries are under the same pressures as other manufacturing industries to do more with less and to deliver higher quality and value to customers. One way for companies to meet both demands is to automate their operations. Companies would be wise to employ machine vision systems in addition to relying on robotics and automation to mechanize their manufacturing, packaging, and labeling operations. The Automated Imaging Association conducts a study each year to identify industries of potential growth for machine vision systems. While final results of the most recent study are not in, preliminary results suggest that the market for machine vision in the pharmaceutical industry increased 15-20% in 1997 to approximately $35 million following a 25% increase from 1995 to 1996.

Many companies with drugs under development are already moving to attain high throughput screening by automating. Many feel that their survival depends upon the speed with which they automate drug development. US demand for Pharmaceutical Packaging products will increase by 4.3 per cent per year to US $ 5.2 billion in 2006. Blister packaging will remain the leading product group, generating average annual growth of six per cent. Expanding unit dose, compliance, clinical trial, high barrier and high visibility applications will impact favorably on demand. Pouches and strip packages will also see above average growth based on adaptability to low-cost unit dose formats.

Pre-fillable inhalers will account for the strongest value gains among all pharmaceutical packaging products as design innovations boost applications in the delivery of asthma and allergy medication. Pre-fillable syringes will generate better than average demand growth based on emergency response time and infection prevention advantages over vials and ampoules.

Reflecting cost, regulatory compliance and ease-of-use benefits, dual child-resistant and dispensing closures will fare the best among pharmaceutical packaging accessories in the marketplace. Blister packages will account for over 20 per cent of this amount, gaining growth momentum from widening uses in clinical trials and over-the-counter medication. The combination of compliance and high visibility features will boost the popularity of these containers throughout the drug producing industry. Paperboard boxes and cartons will continue to account for the largest sales gains among secondary pharmaceutical containers. Increasing applications in the high value-added packaging of over-the-counter drugs, herbal supplements, nutraceuticals and alternative medicines will spur growth. Pharmaceutical packaging accessories will generate weaker gains in sales value than pharmaceutical containers. Demand for medication closures will lose growth momentum due to the increasing penetration of blister packages and other closureless containers. Among all medication closures, combined senior-friendly, child-resistant types will fare the best in the marketplace based on strengthened government and industry standards involving the ease-of use and protective features of pharmaceutical Packaging. In packaging, companies continue to shift toward using more plastic. Plastic containers are replacing glass containers, plastic and laminated flexible packaging is replacing paper, and plastic closures are replacing metal ones. Machine vision systems can both control the respective manufacturing processes and sort out products that would be objectionable to consumers.

Machine vision options are now being offered by a number of suppliers of automated and intelligent labelers to ensure label quality as well as placement accuracy and consistency, and to verify date/lot code imprints via OCR or 2-D symbology reading. The increased use of pressure-sensitive labels has also driven the adoption of automated and intelligent labelers with product/label verification systems.The dietary supplement industry, which has been less than sensitive to labeling concerns, is coming under increased FDA scrutiny and developing a heightened awareness to consumer concerns regarding label and package issues.25

Because of vision systems, packaging lines are becoming more flexible without sacrificing throughput. When simple sensors are used to verify line functions, changeover times inevitably increase and physical position changes are often required. A machine vision-based sensor system can be set up once for each product or package handled by a line, and changeover can be initiated easily through a single graphical user interface. This changeover could even include physical changes in camera optics with computer-controlled zoom lenses or servomotors.

Perhaps the most important trend affecting machine vision is the recognition that data can yield insights into machine performance and line productivity on a function by function basis. Machine vision is fundamentally one of the most intelligent data collectors. Interpreting and acting on the trends detected by machine vision systems can make filling and packaging lines far more productive while delivering optimized quality. Engineers should consider employing such systems to ensure product quality while expediting their operations.

The production of pharmaceutical packaging products will account for raw material consumption valued at US$875 million in 2006, up 3.3 per cent annually, from 2001. Plastic resins will continue to account for the largest value based on breadth of applications, cost advantages and favourable intrinsic and processing properties. Paper and paperboard will also generate significant demand, serving as the leading materials for drug labels and secondary containers. The third leading pharmaceutical packaging raw material, aluminium foil, is projected to provide the strongest growth opportunities, which will evolve from expanding applications in blister and strip packs and pouches. Glass will sustain significant demand in small-volume parenteral vials, ampoules and prefillable syringes, but will continue to lose end uses to plastics in oral medication bottles and prescription vials. Based on applications in speciality IV and parenteral closures, rubber and elastomers will provide the best growth opportunities among other pharmaceutical packaging raw materials.

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