LISTA DE TABLAS
A: Área perpendicular al flujo, cm 2
3.3.2.1. Clasificación de la permeabilidad:
3.2.3.2.2 Factores que Afectan la Permeabilidad:
Poly(ethylene/vinyl acetate), complying with the following requirements, is suitable for the manufacture of contain- ers and tubing for total parenteral nutrition preparations. Poly(ethylene/vinyl acetate) is obtained by copolymeriza- tion of mixtures of ethylene and vinyl acetate. This copoly- mer contains a defined quantity of not more than 25% of vinyl acetate for material to be used for containers and not more than 30% for material to be used for tubing. A certain num- ber of additives are added to the polymer to optimize their chemical, physical, and mechanical properties to adapt them for the intended use. All these additives are chosen from the appended list, which specifies for each product the maximum allowable content. Poly(ethylene/vinyl acetate) may contain not more than three of the following antioxidants:
1. Butyl hydroxytoluene (plastic additive 07) (not more than 0.125%)
2. Pentaerythrityl tetrakis[3-(3,5-di-tert-butyl-4-hydroxy- phenyl)propionate] (plastic additive 09) (not more than 0.2%)
3. Octadecyl 3-(3,5-di-tert-butyl-4-hydroxyphenyl)propio- nate (plastic additive 11) (not more than 0.2%),
4. Tris(2,4-di-tert-butylphenyl) phosphite (plastic additive 12) (not more than 0.2%)
5. 2,2,2,6,6,6-hexa-tert-butyl-4,4,4-[(2,4,6-trimethyl-1, 3,5-benzenetriyl)trismethylene]triphenol (plastic addi- tive 10) (not more than 0.2%). It may also contain a. oleamide (plastic additive 20) (not more than 0.5%), b. erucamide (plastic additive 21) (not more than 0.5%), c. calcium stearate or zinc stearate or a mixture of both
(not more than 0.5%),
d. calcium carbonate or potassium hydroxide (not more than 0.5% of each),
e. colloidal silica (not more than 0.2%). The supplier of the material must be able to demonstrate that the qual- itative and quantitative composition of the type sam- ple is satisfactory for each production batch.
XI. PLASTIC CONTAINERS FOR AQUEOUS SOLUTIONS
FOR INFUSION
Plastic containers for aqueous solutions for infusion are man- ufactured from one or more polymers, if necessary with additives. The containers described in this section are not necessarily suitable for emulsions. The polymers most com- monly used are polyethylene, polypropylene, and poly(vinyl chloride). The containers may be bags or bottles. They have a site suitable for the attachment of an infusion set designed to ensure a secure connection. They may have a site that al- lows an injection to be made at the time of use. They usually have a part that allows them to be suspended and which will withstand the tension occurring during use. The containers must withstand the sterilization conditions to which they will be submitted. The design of the container and the method of sterilization chosen are such that all parts of the containers that may be in contact with the infusion are sterilized. The containers are impermeable to microorganisms after closure. The containers are such that after filling they are resistant to damage from accidental freezing which may occur dur- ing transport of the final preparation. The containers are and remain sufficiently transparent to allow the appearance of the contents to be examined at any time, unless otherwise justified and authorized. The empty containers display no defects that may lead to leakage and the filled and closed containers show no leakage. For satisfactory storage of some preparations, the container has to be enclosed in a protec- tive envelope. The initial evaluation of storage has then to be carried out using the container enclosed in the envelope.
A plastic container for pharmaceutical use is a plastic article, which contains or is intended to contain a pharmaceu- tical product and is, or may be, in direct contact with it. The closure is a part of the container. Plastic containers and clo- sures for pharmaceutical use are made of materials in which may be included certain additives; these materials do not in- clude in their composition any substance that can be extracted by the contents in such quantities as to alter the efficacy or the stability of the product or to present a risk of toxicity. The most commonly used polymers are polyethylene (with and without additives), polypropylene, poly(vinyl chloride), poly(ethylene terephthalate), and poly(ethylene/vinyl ac- etate). The nature and amount of the additives are determined by the type of the polymer, the process used to convert the polymer into the container, and the intended purpose of the container. Additives may consist of antioxidants, stabilizers, plasticizes, lubricants, coloring matter, and impact modifiers. Antistatic agents and mould-release agents may be used only for containers for preparations for oral use or for external use for which they are authorized Acceptable additives are in- dicated in the type specification for each material described in the Pharmacopoeia. Other additives may be used provided they are approved in each case by the competent authority responsible for the licensing for sale of the preparation. For se- lection of a suitable plastic container, it is necessary to know the full manufacturing formula of the plastic, including all materials added during formation of the container so that the potential hazards can be assessed. The plastic container chosen for any particular preparation should be such that
1. the ingredients of the preparation in contact with the plastic material are not significantly adsorbed on its sur- face and do not significantly migrate into or through the plastic,
2. the plastic material does not release substances in quan- tities sufficient to affect the stability of the preparation or
Material for Containers 51
to present a risk of toxicity. Using material (or materials) selected to satisfy these criteria, a number of identical type samples of the container are made by a well-defined procedure and submitted to practical testing in condi- tions that reproduce those of the intended use, including, where appropriate, sterilization. To confirm the compat- ibility of the container and the contents and to ensure that there are no changes detrimental to the quality of the preparation, various tests are carried out, such as verifica- tion of the absence of changes in physical characteristics, assessment of any loss or gain through permeation, de- tection of pH changes, assessment of changes caused by light, chemical tests, and, where appropriate, biological tests. The method of manufacture is such as to ensure reproducibility for subsequent bulk manufacture and the conditions of manufacture are chosen so as to preclude the possibility of contamination with other plastic materi- als or their ingredients. The manufacturer of the product must ensure that containers made in production are sim- ilar in every respect to the type samples.
For the results of the testing on type samples to remain valid, it is important that
1. there is no change in the composition of the material as defined for the type samples,
2. there is no change in the manufacturing process as defined for the type samples, especially as regards the temperatures to which the plastic material is exposed during conversion or subsequent procedures such as sterilization,
3. scrap material is not used. Recycling of excess material of well-defined nature and proportions may be permit- ted after appropriate validation. Subject to satisfactory testing for compatibility of each different combination of container and contents, the materials described in the
Pharmacopoeia are recognized as being suitable for the
specific purposes indicated, as defined above.
XII. STERILE SINGLE-USE PLASTIC SYRINGES
Sterile single-use plastic syringes are medical devices in- tended for immediate use for the administration of injectable preparations. They are supplied sterile and pyrogen-free and are not to be resterilized or reused. They consist of a syringe barrel and a piston which may have an elastomer sealing ring; they may be fitted with a needle which may be nondetach- able. Each syringe is presented with individual protection for maintaining sterility. The barrel of the syringe is sufficiently transparent to permit dosages to be read without difficulty and allow air bubbles and foreign particles to be discerned. The plastics and elastomer materials of which the barrel and piston are made comply with the appropriate specification or with the requirements of the competent authority. The most commonly used materials are polypropylene and polyethy- lene. The syringes comply with current standards regarding dimensions and performance. Silicone oil may be applied to the internal wall of the barrel to assist in the smooth oper- ation of the syringe but there remains no excess capable of contaminating the contents at the time of use. The inks, glues, and adhesives for the marking on the syringe or on the pack- age and, where necessary, the assembly of the syringe and its package do not migrate across the walls.
XIII. RUBBER CLOSURES FOR CONTAINERS
FOR AQUEOUS PARENTERAL PREPARATIONS,
FOR POWDERS, AND FOR FREEZE-DRIED POWDERS
Rubber closures for containers for aqueous parenteral prepa- rations for powders and for freeze-dried powders are made of materials obtained by vulcanization (cross-linking) of macro- molecular organic substances (elastomers) with appropriate additives. The specification also applies to closures for con- tainers for powders and freeze-dried products to be dissolved in water immediately before use. The elastomers are pro- duced from natural or synthetic substances by polymeriza- tion, polyaddition, or polycondensation. The nature of the principal components and of the various additives (e.g., vul- canizers, accelerators, stabilizers, pigments) depends on the properties required for the finished article. Rubber closures may be classified in two types: type I closures are those which meet the strictest requirements and which are to be preferred; type II closures are those which, having mechanical proper- ties suitable for special uses (e.g., multiple piercing), cannot meet requirements as severe as those for the first category because of their chemical composition. The closures chosen for use with a particular preparation are such that1. the components of the preparation in contact with the closure are not adsorbed onto the surface of the closure and do not migrate into or through the closure to an extent sufficient to affect the preparation adversely, 2. the closure does not yield to the preparation substances
in quantities sufficient to affect its stability or to present a risk of toxicity. The closures are compatible with the preparation for which they are used throughout its period of validity. The manufacturer of the preparation must ob- tain from the supplier an assurance that the composition of the closure does not vary and that it is identical to that of the closure used during compatibility testing. When the supplier informs the manufacturer of the prepara- tion of changes in the composition, compatibility testing must be repeated, totally or partly, depending on the na- ture of the changes. The closures are washed and may be sterilized before use.
XIV. SILICONE OIL USED AS A LUBRICANT
Silicone oil used as a lubricant is a poly(dimethylsiloxane) obtained by hydrolysis and polycondensation of dichlorodimethylsilane and chlorotrimethylsilane. Dif- ferent grades exist which are characterized by a number indicating the nominal viscosity placed after the name. Silicone oil used as lubricants have a degree of polymeriza- tion (n= 400–1200) such that their kinematic viscosities are nominally between 1000 mm2·s−1and 30,000 mm2·s−1.