PHARMACEUTICAL DOSAGE FORMS
〈1151〉 PHARMACEUTICAL DOSAGE FORMS This article is based on the requirement of the United State Pharmacopoeia. ( #usp , #pharmacopoeia , #MOA , #testprocedure , #qc , #qualitycontrol , #usp43 , #nf38 ) GENERAL CONSIDERATIONS This chapter provides general descriptions of and definitions for drug products, or dosage forms, commonly used to administer the drug substance (active pharmaceutical ingredient; API). It discusses general principles involved in the manufacture or compounding of these dosage forms. A glossary is provided as a nomenclature resource and should be used in conjunction with the NomenclatureGuidelines A dosage form is a pharmaceutical preparation consisting of drug substance(s) and/or excipient(s) to facilitate dosing, administration, and delivery of the content of the drug product or placebo to the patient. The design, materials, manufacturing, and testing of all dosage forms target drug product quality. A testing protocol must consider not only the physical, chemical, microbiological, and biological properties of the dosage form as appropriate but also the administration route and desired dosing regimen. These considerations, organized by route of administration, are detailed in general chapters Injections and Implanted DrugProducts (Parenterals) — Product Quality Tests 〈1〉, Oral Drug Products — Product Quality Tests 〈2〉, Topical and Transdermal DrugProducts — Product Quality Tests 〈3〉, Mucosal Drug Products — Product Quality Tests 〈4〉, Inhalation and Nasal Drug Products — general information and Product Quality Tests 〈5〉, and Ophthalmic Products — Quality Tests 〈771〉. The organization of this general information chapter is by the quality attributes of each particular dosage form, generally without specific reference to the route of administration. The list below provides the preferred dosage forms used in official article titles. In addition to the preferred dosage forms, the Glossary contains other terms that have been used in current official article titles but are not preferred and should not be used for new drug product titles. Official Dosage Forms Used in Official Article Titles Aerosols Capsules Creams Emulsions Films Foams Gases Gels Granules Gums Implants Injections Inserts Irrigations Liquids Lotions Lozenges Ointments Pastes Pellets Pills Powders Rinses Shampoos Soaps Solutions Sprays Strips Suppositories Suspensions Systems Tablets Tests to ensure compliance with USP standards for dosage form performance fall into one of the following areas. Dose Uniformity (See also Uniformity of Dosage Units 〈905〉 .) Consistency in dosing for a patient or consumer requires that the variation in the drug substance content of each dosage unit be accurately controlled throughout the manufactured batch or compounded lot of drug product. Uniformity of dosage units typically is demonstrated by one of two procedures: content uniformity or weight variation. The procedure for content uniformity requires the appropriate assay of the drug substance content of individual units. The procedure for weight variation uses the weight of the individual units to estimate their content. Weight variation may be used where the underlying distribution of the drug substance in the blend is presumed to be uniform and well-controlled, as in solutions. In such cases, the content of the drug substance may be adequately estimated by the net weight. Content uniformity does not rely on the assumption of blend uniformity and can be applied in all cases. Successful development and manufacture of dosage forms requires careful evaluation of the drug substance particle or droplet size, incorporation techniques, and excipient properties. Stability Drug product stability involves the evaluation of chemical stability, physical stability, and performance over time. The chemical stability of the drug substance in the dosage form matrix must support the expiration dating for the commercially prepared dosage forms and a beyond-use date for a compounded dosage form. Test procedures for potency must be stability-indicating (see Validation of Compendial Procedures 〈1225〉). Degradation products should be quantified. In the case of dispersed or emulsified systems, consideration must be given to the potential for settling or separation of the formulation components. Any physical changes to the dosage form must be easily reversed (e.g., by shaking) prior to dosing or administration. For tablets, capsules, oral suspensions, and implants, in vitro release test procedures such as dissolution and disintegration provide a measure of continuing consistency in performance over time (see Dissolution 〈711〉 , Disintegration 〈701〉 , and Drug Release 〈724〉 ). Bioavailability (See also In Vitro and In Vivo Evaluation of Dosage Forms 〈1088〉 and Assessment of Solid Oral Drug Product Performance and Interchangeability, Bioavailability, Bioequivalence, and Dissolution 〈1090〉 .) Bioavailability is influenced by factors such as the method of manufacture or compounding, particle size, crystal form (polymorph) of the drug substance, the properties of the excipients used to formulate the dosage form, and physical changes as the drug product ages. Assurance of consistency in bioavailability over time(bioequivalence) requires close attention to all aspects of the production (or compounding) and testing of the dosage form. With proper justification, in vitro release testing (e.g., disintegration and dissolution) may be used as a surrogate to demonstrate consistent availability of the drug substance from the formulated dosage. Release Profile Two principal categories of drug release are recognized: immediate-release and modified-release. “Immediate-release” is observed when no deliberate effort has been made to modify the drug substance release prole. For example, capsules and tablets are considered immediate-release even if a disintegrating agent or a lubricant has been used. “Modied-release” is a term used when the rate and/or time of release of the drug substance is altered as compared to what would be observed or anticipated for an immediate-release product. Two modified-release profiles, delayed-release, and extended-release are recognized. The term “modified-release” is not used for official article titles. “Delayed-release” is used when deliberate formulation achieves a delay in the release of the drug substance for some period of time after initial administration. For oral products, expressions such as “enteric-coated” or “gastro-resistant” have also been used where release of the drug substance is prevented in the gastric environment but promoted in the intestinal environment. However, the term “delayed-release” is used for official article titles. “Extended-release” is used when the deliberate formulation achieves prolongation of drug substance release compared to that observed or anticipated for an immediate-release dosage form. Expressions such as “prolonged-release”, “repeat-action”, “controlled-release”, “long-acting”, and “sustained-release” have also been used to describe such dosage forms. However, the term “extended-release” is used for official article titles. The Nomenclature Guidelines should be consulted for naming conventions for products with a single drug substance or for products with a combination of more than one drug substance displaying the combination of release profiles of immediate-release and extended-release, immediate-release and delayed-release, or extended-release and delayed-release. Manufacture Although detailed instructions about the manufacture of any of these dosage forms are beyond the scope of this general information chapter, general manufacturing principles have been included. Information relative to extemporaneous compounding of dosage forms can be found in Pharmaceutical Compounding — Nonsterile Preparations 〈795〉 and Pharmaceutical Compounding — Sterile Preparations 〈797〉. Route of Administration The primary routes of administration for pharmaceutical dosage forms can be dened as parenteral (see 〈1〉 ), gastrointestinal (see 〈2〉 ), topical (see 〈3〉 ), mucosal, and (see 〈4〉 ), inhalation (see 〈5〉 ). Each has subcategories as needed. Many tests used to ensure quality generally are applied across all of the administration routes, but some tests are specific for individual routes. For example, products intended for injection must be evaluated using Sterility Tests 〈71〉 , Bacterial Endotoxins Test 〈85〉 , or Pyrogen Test 〈151〉 , and the manufacturing process (and sterilization technique) employed for parenterals (by injection) should ensure compliance with these tests. Tests for particulate matter may be required for certain dosage forms depending on the route of administration (e.g., by injection — Particulate Matter in Injections 〈788〉 , or mucosal — Particulate Matter in Ophthalmic Solutions 〈789〉 ). Additionally, dosage forms intended for the inhalation route of administration must be monitored for particle size and spray pattern (for a metered-dose inhaler or dry powder inhaler) and droplet size (for nasal sprays). Further information regarding administration routes and suggested testing can be found in the Guide to General Chapters , Chapter Charts , Charts 4–8, 10, and 13. An appropriate manufacturing process and testing regimen helps ensure that a dosage form can meet the appropriate quality attributes for the intended route of administration. Packaging and Storage Suitable packaging is determined for each product. For additional information about meeting packaging requirements listed in the individual labeling, refer to Packaging and Storage Requirements 〈659〉 , Containers — Performance Testing 〈671〉 , and Good Repackaging Practices 〈1178〉 . Product labeling must specify storage requirements that describe environmental conditions, limitations, and restrictions. For instance, exposure to excessive temperature, humidity, and light can influence the ability of the packaging to protect the product. Labeling Statements Some dosage forms or articles have mandatory labeling statements that are given in the Code of Federal Regulations (e.g., 21 CFR§201.320 and 21 CFR §369.21). The text of 21 CFR should be consulted to determine the current recommendations. PRODUCT QUALITY TESTS, GENERAL International Council for Harmonisation (ICH) Guidance Q6A recommends specifications (list of tests, references to analytical procedures, and acceptance criteria) to ensure that drug products are safe and effective at the time of release and over their shelf life. Tests that are universally applied to ensure safety, eefficacy, strength, quality, and purity include description, identification, assay, and impurities. Description The Definition section (see General Notices, 4.10 Monographs ) in a USP monograph describes the drug product and specifies the range of acceptable assayed content of the drug substance(s) present in the dosage form. For certain products, the definition includes any relevant additional information, such as the presence or absence of other components, excipients, or adjuvants, cautionary statements on toxicity and stability, etc. While appearance information to aid in identification is used in a regulatory submission (e.g., a qualitative description of size, shape, color, etc.) it is typically not required as part of a USP monograph. This information is drug product specific. Identification Identication tests are discussed in General Notices, 5.40 Identification tests should establish the identity of the drug substance(s) present in the drug product and should discriminate between compounds of closely related structure that are likely to be present. Identication tests should be specific for the drug substance(s). For example, the infrared absorption spectrum is often used (see Mid-Infrared Spectroscopy 〈854〉 and Spectroscopic Identification Tests 〈197〉) . If no suitable infrared spectrum can be obtained, other analytical methods can be used. Near-infrared (NIR) or Raman spectrophotometric methods could also be acceptable as the sole identification method of the drug product formulation (see Near-Infrared Spectroscopy — Theory and Practice 〈1856〉 and Raman Spectroscopy — Theory and Practice 〈1858〉) . Identification by a chromatographic retention time from a single procedure is not regarded as specific. The use of retention times from two chromatographic procedures for which the separation is based on different principles or a combination of tests in a single procedure can be acceptable (see Chromatography 〈621〉 and Thin-Layer Chromatographic Identification Test 〈201〉 ). Assay A specific and stability-indicating test should be used to determine the strength (drug substance content) of the drug product. Some examples of these procedures are Antibiotics — Microbial Assays 〈81〉, 〈621〉 , or Assay for Steroids 〈351〉. In cases when the use of a nonspecific assay is justified (e.g., Titrimetry 〈541〉 ), other supporting analytical procedures should be used to achieve specificity. When evidence of excipient interference with a nonspecific assay exists, a procedure with demonstrated specificity should be used. Impurities Process impurities, synthetic byproducts, and other inorganic and organic impurities may be present in the drug substance and excipients used in the manufacture of the drug product. These impurities are evaluated by tests in the drug substance and excipient monographs. Impurities arising from degradation of the drug substance or from the drug-product manufacturing process should be monitored. Residual Solvents 〈467〉 is applied to all products where relevant. In some cases, testing for heavy metal impurities is appropriate. In addition to the universal tests listed, the following tests may be considered on a case-by-case basis. Physicochemical Properties Examples include pH 〈791〉 , Viscosity — Capillary Methods 〈911〉 or Viscosity — Rotational Methods 〈912〉 , and Specific Gravity 〈841〉 . Particle Size For some dosage forms, particle size can have a significant effect on dissolution rates, bioavailability, therapeutic outcome, and stability. Procedures such as those found in Inhalation and Nasal Drug Products: Aerosols, Sprays, and Powders — Performance QualityTests 〈601〉 and Particle Size Distribution Estimation by Analytical Sieving 〈786〉 could be used. Uniformity of Dosage Units See the discussion of Dose Uniformity in the General Considerations section. Water Content A test for water content is included when appropriate (see Water Determination 〈921〉 ). Microbial Limits The type of microbial test(s) and acceptance criteria are based on the nature of the nonsterile drug product, method of manufacture, and the route of administration (see Microbiological Examination of Nonsterile Products: Microbial Enumeration Tests 〈61〉 , Microbiological Examination of Nonsterile Products: Tests for Specified Microorganisms 〈62〉 , and Microbiological Examination of nonsterile Products: Acceptance Criteria for Pharmaceutical Preparations and Substances for Pharmaceutical Use 〈1111〉) . Antimicrobial Preservative Content Acceptance criteria for preservative content in multidose products should be established. They are based on the levels of antimicrobial preservative necessary to maintain the product’s microbiological quality at all stages throughout its proposed usage and shelf life (see Antimicrobial Effectiveness Testing 〈51〉 ). Antioxidant Content If antioxidants are present in the drug product, tests of their content should be performed to maintain the product’s quality at all stages throughout its proposed usage and shelf life. Sterility Depending on the route of administration (e.g., ophthalmic preparations, implants, aqueous-based preparations for oral inhalation, and injections) sterility of the product is demonstrated as appropriate (see 〈71〉 ). Dissolution A test to measure the release of the drug substance(s) from the drug product normally is included for dosage forms such as tablets, capsules, suspensions, granules for suspensions, implants, transdermal delivery systems, and medicated chewing gums. Single-point measurements typically are used for immediate-release dosage forms. For modified-release dosage forms, appropriate test conditions and sampling procedures are established as needed (see 〈711 〉 and 〈 724〉 ). In some cases, dissolution testing may be replaced by disintegration testing (see 〈 701 〉). Breaking Force and Friability These parameters are evaluated as in-process controls. Acceptance criteria depend on packaging, supply chain, and intended use (see Tablet Friability 〈1216〉 and Tablet Breaking Force 〈1217〉 ). Leachables When evidence exists that leachables from the container–closure systems (e.g., rubber stopper, cap liner, or plastic bottle) have an impact on the safety or efficacy of the drug product, a test is included to evaluate the presence of leachables. Other Tests Depending on the type and composition of the dosage form, other tests such as alcohol content, redispersibility, particle size distribution, rheological properties, reconstitution time, endotoxins/pyrogens, particulate matter, functionality testing of delivery systems, delivered dose uniformity, viscosity, and osmolarity may be necessary. 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