DISSERTATION REPORT

PACKAGING OF PHARMACEUTICALS
As on

23th October, 2012

Submitted by: - ROHIT D GHULE

Intensive Training Course Batch- 46th Year 2012-13

ACKNOWLEDGEMENT

I would like to express my gratitude towards my teachers who have helped me throughout the completion of the dissertation. The ultimate objective of this dissertation is to learn new concepts and apply them in an innovative manner. I have put in my best while working on this project and it is my pleasure to present the dissertation report on PACKAGING OF PHARMACEUTICALS. I express true sense of

gratitude towards the Head of Department, Mrs. Jyoti Baliga and my dissertation guide, Mr. T.M. Mallik for their invaluable guidance and help. I would also like to express my appreciation and thanks to all my friends who knowingly and unknowingly have assisted me throughout my hard work.

ROHIT D GHULE

CONTENTS

1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12.

INTRODUCTION ASPECTS OF PACKAGING PACKAGING MATERIALS AND CLOSURES QUALITY ASSURANCE ASPECTS OF PACKAGING PROTECTION OF THE ENVIRONMENT QUALITY SPECIFICATIONS REFERENCES BIBLIOGRAPHY APPENDIX I APPENDIX II APPENDIX III APPENDIX IV

1. INTRODUCTION
This review of the various elements of the packaging of a pharmaceutical product is aimed at ensuring that medicines arrive safely in the hands of the patients for whom they are prescribed. In the manufacture of pharmaceutical products, quality assurance is defined as the totality of the arrangements made with the object of ensuring that pharmaceutical products are of the quality required for their intended use In addition, the system of quality assurance for the manufacture of pharmaceutical products should ensure that arrangements are made for the manufacture, supply and use of the correct starting and pack- aging materials Public opi ni on sometimes considers packaging to be superfluous. However, it must be emphasized that packaging preserves the stability and quality of medicinal products and protects them against all forms of spoilage and tampering. All medicinal products need to be protected and consequently need to be packaged in containers that conform to prescribed standards, particularly with respect to the exclusion of moisture and light and the prevention of leaching of extractable substances into the contents and of chemical interaction with the contents. . . . However, the limits of acceptability in these v a r i o u s r e s p e c t s depend, at least in part, on climatic variables. Recommendations in The international pharmacopoeia can only be advisory; precise quantitative standards will have to be locally determined The complexity of packaging materials and the highly technological nature of medicinal products is such that manufacturers are con- fronted with significant problems. Interaction between packaging and such products is possible due to the combination of a multiplicity of container components and active pharmaceutical ingredients, excipients and solvents used in a variety of dosage forms. The quality of the packaging of pharmaceutical products plays a very important role in the quality of such products. It must: protect against all adverse external influences that can alter the properties of the product, e.g. moisture, light, oxygen and temperature variations; protect against biological contamination; protect against physical damage; carry the correct information and identification of the product. The kind of packaging and the materials used must be chosen in such a way that: the packaging itself does not have an adverse effect on the product (e.g. through chemical reactions, leaching of packaging materials or absorption); the product does not have an adverse effect on the packaging, changing its properties or affecting its protective function. The resulting requirements must be met throughout the whole of the intended shelflife of the product. Given the link between the quality of a pharmaceutical product and the quality of its packaging, pharmaceutical packaging materials and systems must be subject, in principle, to the same quality assurance requirements as pharmaceutical products. The appropriate system of quality assurance for the manufacture of pharmaceutical products should therefore follow the WHO guide- lines for good manufacturing practices (GMP) (1).

The requirements to be met by pharmaceutical packaging and pack- aging materials as described in compendia (pharmacopoeias) and standards (e.g. those of the International Organization for Standardization (ISO)) must be considered only as general in character. The suitability of packaging or packaging material for any particular requirements and conditions can only be ascertained through detailed packaging and stability studies on the product concerned

2. ASPECTS OF PACKAGING
2.1 General considerations

Packaging may be defined as the collection of different components (e.g. bottle, vial, closure, cap, ampoule, blister) which surround the pharmaceutical product from the time of production until its use. The aspects of packaging to be considered (4) include: the functions of packaging; the selection of a packaging material; the testing of the material selected; filling and assembling; sterilization; storage and stability.

Packaging materials (see section 2) include printed material employed in the packaging of a pharmaceutical product, but not any outer packaging used for transportation or shipment. Examples of the types of materials used are shown in Table 1. A distinction must be made between primary and secondary packaging components. The primary p a c k a g i n g components (e.g. bottles, vials, closures, blisters) are in direct physical contact with the product, whereas the secondary components are not (e.g. aluminum caps, cardboard boxes). The choice of primary and/or secondary packaging materials will depend on the degree of protection required, compatibility with the contents, the filling method and cost, but also the presentation for over-the-counter (OTC) drugs and the convenience of the packaging for the user (e.g. size, weight, method of opening/ reclosing (if appropriate), legibility of printing). Containers may be referred to as primary or secondary, depending on whether they are for immediate use after production of the finished product or not. Both single-dose and multi-dose containers exist. Containers may be well-closed, tightly closed, hermetically closed or light-resistant, as defined in the glossary (3). The packaging process, as defined in the glossary, is the process that a bulk material must undergo to become a finished product. The properties and attributes of the product should be as specified by the manufacturer and required by the user. The packaging process consists of the following stages: filling and assembling; sterilization in the final container, if applicable; placing labels on the container; storage at the manufacturing and shipping sites. Packaging documentation (1) includes aspects related to: specifications and quality control, including batch records; labels, inks and adhesive materials (e.g. glue); package inserts for patients. Apart from primary and secondary packaging, two types of special packaging are currently in use, as follows: Unit-dose packaging. This packaging guarantees safer medication by reducing medication

errors; it is also more practical for the patient. It may be very useful in improving compliance with treatment and may also be useful for less stable products. Device packaging. Packaging with the aid of an administration device is user-friendly and also improves compliance. This type of packaging permits easier administration by means of devices such as prefilled syringes, droppers, transdermal delivery systems, pumps and aerosol sprays. Such devices ensure that the medicinal product is administered correctly and in the right amount.

2.2

Functions of packaging

2.2.1 Containment The containment of the product is the most fundamental function of packaging for medicinal products. The design of high-quality packag- ing must take into account both the needs of the product and of the manufacturing and distribution system. This requires the packaging: not to leak, nor allow diffusion and permeation of the product; to be strong enough to hold the contents when subjected to nor- mal handling; not to be altered by the ingredients of the formulation in its final dosage form. 2.2.2 Protection The packaging must protect the product against all adverse external influences that may affect its quality or potency, such as:

light moisture oxygen biological contamination mechanical damage. The compatibility of the packaging with the active pharmaceutical ingredients is very important in maintaining the integrity of the product. Stability. Information on stability is given in the guidelines for stability testing of pharmaceutical products containing well-established drug substances in conventional dosage forms. For primary packaging, it is necessary to know the possible interactions between the container and the contents. Normally, product/ component stability and compatibility are confirmed during the pri- mary research and development stage. While excluding the effect of external factors on the product, the packaging itself should not interact with it so as to introduce unacceptable changes. There are numerous possibilities of interactions between (primary) packaging materials and pharmaceutical products, such as: the release of chemicals from components of the packaging materials; the release of visible and/or sub visible particles; the absorption or adsorption of pharmaceutical components by the packaging materials; chemical reactions between the pharmaceutical product and the packaging materials; the d e g r a d a t i o n of packaging components in contact with the pharmaceutical products; the influence of the manufacturing process (e.g. sterilization) on the container.

The active pharmaceutical ingredients should remain within their specification limits over the shelf-life of the pharmaceutical product. The question of whether a packaging will provide the required protection for the pharmaceutical product and the required stability over a certain time period can only be answered by means of real-time stability studies. Such studies must evaluate the changes in the quality of the product, in contact with its packaging, during a period equivalent to its intended shelf-life. In addition, packaging must meet the following requirements: it must preserve the physical properties of all dosage forms and protect them against damage or breakage; it must not alter the identity of the product; it must preserve the characteristic properties of the product, so that the latter complies with its specifications; it must protect the product against undesirable or adulterating chemical, biological or physical entities. Storage. Packaging m a t e r i a l s should b e stored i n accordance with GMP for storage areas. The characteristics of the active pharmaceutical ingredients will determine whether different packaging will be needed. For example, the packaging requirements of medicinal products kept at temperatures between 2 and 8 C may differ from those of products intended for tropical countries or light- sensitive products. If the contents are sterile, sterility must be maintained, including that of any unused remaining product. The shelf-life and utilization period are always determined in relation to storage conditions and the stability of the active pharmaceutical ingredient. Normal storage conditions are defined as storage in dry, well- ventilated premises at temperatures of 1525 C or, depending on climatic conditions, up to 30 C. Extraneous odors, other indications of contamination, and intense light have to be excluded

2.3 Presentation and information

Packaging is also an essential source of information on medicinal products. Such information is provided by labels and package inserts for patients. The information provided to the patient may include the following: the name of the patient; the identification number for dispensing records; the name, strength, quantity and physical description or identifica- tion of the medicinal product; directions for use and cautionary statements, if applicable; the storage instructions; the date of dispensing and period of use (related to the expiry date); the name and address of the dispenser. 2.2.1 Labels Throughout manufacturing, a succession of specific outer labels are applied to the container of the medicinal product. The level of pro- cessing is indicated by the following words: quarantine Storage Distribution.

Specifications for labels for finished drug products are defined in the WHO guidelines on GMP for pharmaceutical products Written labels on the packaging: Permit the identification of each active ingredient by means of its INN, and also give the dosage form and the trade name/trademark. All information concerning the medicinal product, as required by national legislation, must be stated on the packaging. Preserve the stability of the medicinal product by giving advice on its storage : After t h e stability of the product has been evaluated, one of the following recommendations as to storage conditions can be prominently indicated on the label: store store store store store under normal storage conditions; between 2 and 8 C (under refrigeration, no freezing); below 8 C (under refrigeration); between -5 and -20 C (in a freezer); below -18 C (in a deep freezer).

Permit the follow-up of a specific medicinal product by means of the batch number on the labels. It must be possible to follow the route of distribution of a product from the manufacturing process to its administration to the patient with the aim of locating and identifying products that are of potential risk (e.g. blood products, blood-derived products). Mask the real identity of the medicinal product in clinical studies. This is extremely important in clinical trials in determining the real efficacy of a medicinal product in blinded studies. If the identity is masked by a code, it must be possible to disclose it at any time in a medical emergency. National legislation must be followed with regard to the information provided to the patient, as well as the record-keeping and packaging instructions. 2.3.2 Repacking, relabeling and dispensing In some countries, it is common practice not to dispense drugs in the original packaging, but rather in a personalized manner to each patient. This applies especially to solid oral dosage forms, and involves the repacking and relabeling of drugs in small quantities. Different drugs may even be included in customized medication pack- ages, also referred to as patient med packs. The quantities of drugs supplied in this way are usually enough only for a short period of time, i.e. to provide drugs for immediate use. It should be remembered, however, that data obtained in stability studies undertaken by the manufacturer are no longer valid for drugs removed from the original package. Where repacking and relabeling are necessary, the WHO guidelines on GMP for pharmaceutical products should be followed to avoid any mix-up or contamination of the product, which could place the patients safety at risk. 2.3.3 Package inserts for patients (patient information leaflets) Product information must help patients and other users to understand the medication. The patient package insert, together with the label, provides the patient with key information concerning the proper use of the product, potential adverse drug reactions and interactions, storage conditions and the expiry date. In OTC medicinal products, the package insert, together with constitute the only pharmaceutical advice that the patient receives. the label, may

2.4

Compliance Packaging and labeling may help to reinforce the instructions given by the physician or the pharmacist, and improve compliance with drug therapy. In this respect, packaging becomes a compliance aid. The des i gn o f pharmaceutical packaging should be such that the product can easily be administered in a safe manner to the patient. If the patient feels at ease with the packaging and route of administration, the design of the packaging may become a key factor in increasing compliance. This is also an important factor in clinical trials.

2.5

Protection of Patients Packaging must not only increase compliance through its design, but must also protect the patient and indicate the integrity of the product. Packaging equipped with a tamperevident device protects against incidental and accidental poisoning. To protect children, several child-resistant closures have been developed Detecting of Counterfeiting The Forty-first World Health Assembly, after reviewing the report of the Executive Board on the implementation of WHOs revised drug strategy, requested: . . . governments and pharmaceutical manufacturers to cooperate in the detection and prevention of the increasing incidence of the export or smuggling of falsely labeled, spurious, counterfeited or substandard pharmaceutical preparations Several documents show that counterfeit pharmaceutical products are in wide circulation. In November 1985, during the WHO Conference of Experts on the Rational Use of Drugs in Nairobi, Kenya, concern was expressed regarding the extent to which counterfeit pharmaceutical products were in circulation in developing countries. In view of the importance of this issue, a text has been drafted to provide model provisions to deal with counterfeit drugs The design of the packaging must therefore contribute to preventing tampering with, or the counterfeiting of, certain medicinal products. Such tamper-evident containers can allow the visual inspection of the medicinal product before use, and this may serve as a first stage in detecting counterfeit drugs.

2.5

3. PACKAGING MATERIALS AND CLOSURES

In accordance with the methods of use and administration of medicinal products, packaging materials, closures and containers vary a great deal and have to meet a wide variety of different requirements. All the routes used for systemic access have demanding requirements, which often can only be met by complex structured and formulated medicinal products. This is particularly true of the new medicinal products that are now appearing, such as those administered via transdermal delivery systems. To ensure the efficacy of a product during its total shelf-life, pharmaceuticals must be regarded as a combination of the medicinal product itself and the packaging 3.1 Types of material

3.1.1 Glass For a large number of pharmaceuticals, including medicinal products for oral and local administration, glass containers are usually the first choice (e.g. bottles for tablets, injection s y r i n g e s for unit- or multi- dose administration). Different types of glass may be necessary, depending on the characteristics and the intended use of the medicinal products concerned. Manufacturers should arrange with their suppliers to obtain the appropriate type of glass container for the intended use. Suppliers should provide the raw and packaging materials in conformity with industrial norms. Classifications of types of glass are given in the European and United States pharmacopoeias, whereas no such classification exists in the Japanese pharmacopoeia. Glass can be tested for light transmission and hydrolytic resistance. In the Japanese pharmacopoeia, such tests are described only for glass containers for injection, whereas in the European and United States pharmacopoeias they are given for all types of glass containers. 3.1.2 Plastics Some containers are now being made of plastics; the main use is for bags for parenteral solutions. Plastic containers have several advantages compared with glass containers: they are unbreakable they are collapsible they are light. The European, Japanese and United States pharmacopoeias all de- scribe materials of the same type, but there are considerable differences in the classification and presentation. As far as tests are concerned, the three pharmacopoeias are extremely difficult to compare. The European pharmacopoeia is the most detailed and requires tests in relation to the use and routes of administration of the medicinal product. Moreover, the same concept is extended to bulk containers for active ingredients. 3.1.3 Metals Metal c o n t a i n e r s are used solely for medicinal products for nonparenteral administration. They include tubes, packs made from foil or blisters, cans, and aerosol and gas cylinders. Aluminum and stain- less steel are the metals of choice for both primary and secondary packaging for medicinal products. They have certain advantages

and provide excellent tamper-evident containers. Since metal is strong, impermeable to gases and shatterproof, it is the ideal packaging material for pressurized containers. Descriptions and tests can be found in the norms and standards of the ISO; these have been established in collaboration with manufacturers. Requirements are not given in pharmacopoeias; the suitability of a particular material for a container is normally established by con- ducting stability studies in which the material is in contact with the drug in question. 3.2 Closures Closures used for the purpose of covering drug containers after the filling process should be as inert as possible. They should not give rise to undesired interactions between the contents and the outside environment, and should provide a complete seal. Besides their protective function, closures must also allow the easy and safe administration of the drug. Depending on the application, closures may have to be pierced with a needle for intravenous sets. Such closures are made from elastomeric materials (rubbers), while those that cannot be pierced are generally made from plastics such as polyethylene or polypropylene. Depending on the type of container, closures may have different shapes and sizes, e.g. stoppers for infusion or injection bottles or plungers for prefilled syringes. A special design of stopper may also be required for some pharmaceutical production processes such as lyophilization. Closures, as primary packaging components, are of critical importance and must be carefully selected. They are an essential component of the container and, as such, an integral part of the drug preparation. A container type which does not require a removable closure at the time of administration is usually preferred since such a container/ closure system avoids, or at least minimizes, the risk of biological and other contamination as well as tampering. For parenteral preparations, the combination of glass containers and elastomeric closures, usually secured by an aluminum cap, is widely used. Typical examples are infusion bottles, injection vials and prefilled syringes. The rubber closures used within such a system must be carefully selected in accordance with the intended purpose. Most often, improper rubber closures are the cause of incompatibility between the packaging and the drug.
4.