Primary and Secondary Packaging

The primary and secondary packaging of pharmaceutical products is closely linked to their production and constitutes an integral part of the value-added process. The quality control unit is responsible for the control of pharmaceutical packaging materials including their receipt, identification, sampling, testing, and approval or rejection of drug product containers and closures. The responsibility for the tests lies now more and more with the manufacturers of packaging materials. However, as a precondition for this, additional QA measures, like vendor qualification, supplier audit and technical agreements, have to be taken. The Federal Food, Drug, and Cosmetic Act mandate the need for adequate information related to packaging materials. Section 501(a)(3) of the Act states that a drug is deemed to be adulterated, if its container is composed, in whole or in part, of any poisonous or deleterious substance which may render the contents injurious to health. In addition, section 502 of the Act states that a drug is considered misbranded if there are packaging omissions. Also, section 505 of the Act requires a full description of the methods used in, and the facilities and controls used for, the packaging of drugs. Section 505(b)(1)(D) of the Act states that an application shall include a full description of the methods used in, the manufacturing, processing and packing of such drug. This includes facilities and controls used in the packaging a drug product. Primary packaging means any single part of a container closure system. Typically containers (e.g. ampoules, vials, bottles), container liners (e.g…. tube liners), closure. Screw caps, stoppers), closure liners, stopper overseas, container inner seals, administration on large-volume parenteral (LVPs)), overwraps, administration accessories, and container labels. A primary packaging component means a packaging component that is or may be in direct contact with the dosage form. A secondary packaging component means a packaging component that is not and will not be in direct contact with the dosage form. Standard on containers and closures Current good manufacturing practice (cGMP) requirements for the control of drug product containers and closures are included in 21 CFR Parts 210 and 211. A listing of the relevant sections is provided in Attachment A. In addition, a listing of compliance policy guides that deal with packaging issues is provided in Attachment B. References in this guidance to CGMP regulations are provided for completeness. The FDA requirement for tamper-resistant closures is included in 21 CFR 211.132 and the Consumer Product Safety Commission (CPSC) requirements for child-resistant closures are included in 16 CFR 1700. An outline of these and other applicable regulatory requirements is provided in Attachment A. Sterilization packaging systems are classified as Class II medical devices and require a 510(k) for their intended use to be legally marketed. Manufacturers of sterilization packaging systems must submit a Premarket Notification 510(k) Submission to the FDA prior to marketing their product. The submission includes a completed application, extensive data, documentation of testing and validation studies, special labeling, intended use, and instructions for use. The United States Pharmacopoeia Convention has established requirements for containers, which are described in many of the drug product monographs in The United States Pharmacopoeia/ National Formulary (USP/NF). For capsules and tablets, these requirements generally relate to the design characteristics of the container (e.g. tight, well-closed or light-resistant). For injectable products, materials of construction are also addressed (e.g. Preserve in single-dose or in multiple-dose containers, preferably of Type I glass, protected from light). These requirements are defined in the General Notices and Requirements (Preservation, Packaging, Storage, and Labeling) section of the USP. The requirements for materials of construction are defined in the general chapters of the USP. Types of material Only the most commonly used packaging materials and containers are described here. 2.1.1 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 syringes 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. Suppliers133 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. 2.1.2 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 describe 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. 2.1.3 Metal Metal containers are used solely for medicinal products for nonparenteral administration. They include tubes, packs made from foil or blisters, cans, and aerosol and gas cylinders. Aluminium and stainless 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 conducting stability studies in which the material is in contact with the drug in question.134 2.2 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 aluminium 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. 2.2.1 Rubber closures Rubber consists of several ingredients, one of which is elastomer. Modern rubber compounds used in packaging pharmaceuticals contain only a limited number of ingredients, which are very difficult to extract. Closures made from such materials generally do not pose any problems, and can be used in contact with a large number of drug preparations. Rubber closures for pharmaceutical use must meet the relevant requirements of the most important pharmacopoeias (the European,135 Japanese and United States pharmacopoeias). International standards have also been established (ISO 8871). It should be emphasized that the requirements of pharmacopoeias and standards must be seen as minimal requirements. The suitability of a rubber closure for a given application can only be established by means of stability . What is packaging? Packaging is defined as the collection of different components, which surround the pharmaceutical product from the time of production until its use. Importance of packaging • Protect against all adverse external influences that can alter the properties of the product. • Protect against biological contamination. • Protect against physical damage. • Carry the correct information and identification of the product. • Tamper evident / Child resistance / Anti counterfeiting Functions of packaging Containment Not to leak, nor allow diffusion and permeation Strong enough to hold the contents during handling Protection Light Moisture Oxygen Biological contamination Mechanical damage Counterfeiting