TOPICAL AND TRANSDERMAL DRUG …

1 Interim Revision Announcement Official November 1, 2013 3 TOPICAL and TRANSDERMAL drug Products 1. should establish the identity of the drug or drugs present in 3 TOPICAL AND TRANSDERMAL the article and should discriminate between compounds of closely related structures that are likely to be present. Iden- drug PRODUCTS PRODUCT tity tests should be specific for the drug substance(s) ( , infrared spectroscopy). Near infrared (NIR) or Raman spec- QUALITY TESTS trophotometric methods also could be acceptable for the identification of the drug product (see Near-Infrared Spec- troscopy 1119 and Raman Spectroscopy 1120 ). Identifica- tion solely by a single chromatographic retention time is not specific. INTRODUCTION Assay: A specific and stability-indicating test should be used to determine the strength (content) of the drug prod- Topically applied drug products fall into two general cat- uct.

2 In cases when the use of a nonspecific assay ( , egories: those applied to achieve local action and those ap- Titrimetry 541 ) is justified, other supporting analytical pro- plied to achieve systemic effects after absorption through cedures should be used to achieve overall specificity. the skin into the blood circulation. Local action can occur Impurities: Process impurities, synthetic by-products, at or on the surface of the application site ( , stratum impurities associated with the adhesive ( , residual mo- corneum, ocular epithelium), in the underlying tissues ( , nomers), residual solvents (see Residual Solvents 467 ), epidermis and/or dermis), and on subcutaneous tissues heavy metals (see Heavy Metals 231 ), and other inorganic ( , muscle or joint).

3 And organic impurities may be present in the drug sub- Topically applied drug products include but are not re- stance and excipients used in the manufacture of the drug stricted to creams, gels, ointments, pastes, suspensions, lo- product, and should be assessed and controlled. Impurities tions, foams, sprays, aerosols, solutions, and TRANSDERMAL arising from the degradation of the drug substance and delivery systems (TDS, also known as patches). The defini- those arising during the manufacturing process of the drug tions and descriptions of these dosage forms, and brief in- product should also be assessed and controlled. formation on their composition and/or manufacturing pro- cess, can be found in Pharmaceutical Dosage Forms 1151 . Procedures and acceptable criteria for testing topically Specific Tests applied drug products can be divided into those that assess general product quality attributes and those that assess In addition to the universal tests previously listed, the fol- product performance.

4 The product quality attributes in- lowing specific tests should be considered on a case-by- clude the following: description, identification, assay case basis. (strength), impurities, physicochemical properties, uniform- Uniformity of dosage units: This test is applicable for ity of dosage units, water content, pH, apparent viscosity, TDS and for dosage forms packaged in single-unit contain- microbial limits, antimicrobial preservative content, antioxi- ers (see Uniformity of Dosage Units 905 ). dant content, sterility (if applicable), and other tests that Water content: A test for water content should be in- may be product-specific. Product performance testing as- cluded when appropriate (see Water Determination 921 ). sesses drug release and other attributes that affect drug This test is generally formulation dependent.

5 Therefore, it is release from the finished dosage form. not included in the compendial drug product monograph Although most topically applied drug products are semis- but is part of the manufacturer's specification for the drug olids, liquids, or suspensions, TDS are physical devices that product. are applied to the skin and vary in their composition and Microbial limits: Microbial examination of nonsterile method of fabrication. TDS release their active ingredients drug products is performed according to the methods by different mechanisms. They can be passive or active. given in general chapters Microbiological Examination of This chapter covers only the tests related to passive TDS. Nonsterile Products: Microbial Enumeration Tests 61 and Mi- crobiological Examination of Nonsterile Products: Tests for PRODUCT QUALITY TESTS FOR TOPICALLY Specified Microorganisms 62 , unless the formulation itself is demonstrated to have antimicrobial properties.

6 Acceptance APPLIED drug PRODUCTS criteria for nonsterile pharmaceutical products based on to- tal aerobic microbial count (TAMC) and total combined yeasts and molds count (TYMC) are given in Microbiological Universal Tests Examination of Nonsterile Products: Acceptance Criteria for Pharmaceutical Preparations and Substances for Pharmaceuti- Universal tests (see ICH Guidance Q6A Specifications: Test cal Use 1111 . Procedures and Acceptance Criteria for New drug Substances Antimicrobial preservative content: Acceptance crite- and New drug Products: Chemical Substances, available at ria for antimicrobial preservative content in multidose prod- ) are listed as follows and are applicable to all ucts should be established. They should be based on levels topically applied drug products.

7 Of antimicrobial preservative necessary to maintain the Description: A qualitative description of the drug product's microbiological quality at all stages throughout product should be provided. The acceptance criteria should its proposed usage and shelf life (see Antimicrobial Effective- include the final acceptable appearance of the finished dos- ness Testing 51 ). age form and packaging. A visual examination should iden- Antioxidant content: If antioxidants are present in the tify changes in color, adhesive migration ( , cold flow) for drug product, tests of their content should be established TDS, separations, crystallization, etc., that are specific to unless oxidative degradation can be detected by another the drug product. The description should specify the con- test method such as impurity testing.

8 Acceptance criteria tent or the label claim of the article. This is not a com- for antioxidant content should be established. They should pendial test but is part of the manufacturer's specification be based on the levels of antioxidant necessary to maintain for the drug product. the product's stability at all stages throughout its proposed Identification: Identification tests are discussed in Gen- usage and shelf life. eral Notices and Requirements, Identification tests 2013 The United States Pharmacopeial Convention All Rights Reserved. Interim Revision Announcement 2 3 TOPICAL and TRANSDERMAL drug Products Official November 1, 2013. Sterility: Depending on the use of the dosage form the dosage form ( , semisolid dosage form). Because ( , ophthalmic preparations, products that will be ap- only Newtonian fluids possess a measurable viscosity that is plied to open wounds or burned areas), sterility of the independent of shear rate, semisolid pharmaceutical dosage product should be demonstrated as appropriate (see Steril- forms that are non-Newtonian products exhibit an appar- ity Tests 71 ).

9 Ent viscosity. pH: When applicable, topically applied drug products The apparent viscosity of semisolid drug products should should be tested for pH at the time of batch release and at be tested at the time of batch release and initially at desig- designated stability time points for batch-to-batch monitor- nated stability test time points to set specifications for ing. Because some topically applied drug products contain batch-to-batch and shelf life monitoring. Measurement pro- very limited quantities of water or aqueous phase, pH cedures should be developed as outlined in Viscosity Capil- measurements may not always be warranted. This test is lary Viscometer Methods 911 . For semisolids that show generally formulation dependent. Therefore, it is not in- thixotropy and/or irreversible changes in viscosity after cluded in the compendial drug product monograph but is shearing, specific attention should be given to sample prep- part of the manufacturer's specification for the drug prod- aration procedures to minimize variability in the measure- uct.

10 Ment of apparent viscosity caused by variable shear histo- Particle size: The particle size of the active drug sub- ries ( , mixing speed and temperature, filling operation, stance(s) in topically applied drug products is usually deter- sample handling). Furthermore, for some products it may mined and controlled at the formulation development be warranted to have apparent viscosity specifications at stage. However, topically applied drug products should be more than one set of conditions ( , bulk in-process examined for evidence of particle size alteration ( , ap- stage, final packaged product, high and low shear rates, pearance of particles; changes in particle form, size, shape, different temperatures). habit, or aggregation) of the active drug substance that Apparent viscosity specifications based on data obtained may occur during the course of product processing and during product development and shelf life testing should storage.