Any available 12 months), from a 12-month study is recommended.studies carried out on the drug product outside its imme- Reduced designs (i.e., matrixing or bracketing), in whichdiate container or in other packaging materials can form the testing frequency is reduced or certain factor combi-a useful part of the stress testing of the dosage form or nations are not tested at all, can be applied if justified.can be considered as supporting information, respectively. A powder product may be typically for 7 days. RH, relative humidity.E. product. Itmainly refers to the U.S. and European regions, and again is noteworthy that the regulatory agencies consider con-the formulator is referred to the original guideline for full tainers and packaging systems, all those components thatguidance. Handbook of Pharmaceutical Manufacturing Formulations: Liquid Products Volume 4 Handbook of Pharmaceutical Manufacturing Formulations: Semisolid Products Volume 5 Handbook of Pharmaceutical Manufacturing Formulations: Over-the-Counter Products Volume 6 Handbook of Pharmaceutical Manufacturing Formulations: Sterile Products Sarfaraz K. Niazi If it is inappro- (e.g., strength, package size) are tested at all time pointspriate to combine data from several batches, the overall as in a full design. This is not acceptable. There should be well-established spec-an effect on the amount of drug in solution. These requirements A container closure system is the sum of packaging are defined in the “General Notices and Requirements”components that together contain and protect the dosage (Preservation, Packaging, Storage, and Labeling) sectionform. ability issue, which is an inherent problem of compressedThe cost of taking a new chemical entity to final regulatory dosage forms. The dosage form may be used as is or admixedfirst with a compatible diluent or dispersant. In situations where manufacturers For oral solutions and suspensions, the amount anduse flexible hoses to transfer product, it is not unusual to control of temperature is important from a microbiologicalsee these hoses lying on the floor, thus significantly as well as a potency aspect. As a rule ofthumb, the closure system for a product should be the first Section II contains formulations of liquid products andcriterion selected before development of the dosage form. Pharmaceutical Manufacturing Formulations Volume Series VOLUME 1 Volume 1 ... Handbook of pharmaceutical manufacturing formulations / Sarfaraz K. Niazi. of the drug product vehicle may reasonably be expected to differ from that of water (e.g., because of high or low Injectable drug products may be liquids in the form pH or a solubilizing excipient), then drug product shouldof solutions, emulsions, suspensions, or dry solids that are be used as the extracting medium. The Handbook of Pharmaceutical Manufacturing Formulations, Third Edition: Volume Five, Over-the-Counter Products is an authoritative and practical guide to the art and science of formulating drugs for commercial manufacturing. E-BOOK DESCRIPTION. Raw Materials........................................................................................................................................................... 4V. The general case (Table 2.4) shouldof time sufficient to cover the proposed shelf life. The testing tions and the lengths of studies chosen should be sufficientshould cover, as appropriate, the physical, chemical, bio- to cover storage, shipment, and subsequent use.logical, and microbiological attributes; preservative content(e.g., antioxidant, antimicrobial preservative); and function- Stability testing of the drug product after constitutionality tests (e.g., for a dose delivery system). Reprinted material is quoted with permission, and sources areindicated. Particle size tems are possible, liquids and suspensions undergoingis also important, and at this point it would seem that any stability studies should be stored on their side or inverted. dosing regimen is completed.New materials may result in new substances beingextracted into the dosage form or in a change in the amount The complete and assembled component and its partsof known extractables. Polyethylene Containers (USP <661>)................................................................................................. 26 2. C. STABILITY DATA (PACKAGING CONCERNS) The tests and methods used by the applicant for accep- Stability testing of the drug product should be conductedtance of each batch of a packaging component that they using the container closure systems proposed in the appli-receive should be described. Ocular systems are inserted under the lower eyelid,tube, or a flexible pouch). Having formulated hundreds of products from consumer products to complex bio- technology-derived products, he has accumulated a wealth of knowledge in the science of formulations and regulatory filings of Investigational New Drugs (INDs) and New Drug Applications (NDAs). Both ucts also include some nasal and otic preparations as wellbottles and pouches may use an overwrap, which is usually as some ophthalmic drug products. Organizational Chart ............................................................................................................................. 47 5. For unit dose solution products the label compressed gas from oil-free compressors. In addition, such prod-size may dissolve faster than those of a larger particle size ucts might also require storage in sealed tanks, rather thanwhen the product is compounded. PACKAGING shrink-wrapped in plastic to minimize contamination from fiberboard cartons, and many manufacturers use com-Problems in the packaging of oral liquids have included pressed air to clean the containers. This discussion can be supported, retest period should be based on the real-time data obtainedif appropriate, by further testing on a single batch of the at long-term storage conditions (Table 2.3). Climatic Zones — The four zones in the world that are distinguished by their characteristic, prevalent annual cli- Limited extrapolation of the real-time data from the matic conditions. ICH Q5C Quality of Biotechnological Products: Stability TestingExcursions that exceed the defined tolerances for morethan 24 hours should be described in the study report and of Biotechnological/Biological Products (July 1996)their effect assessed. A topical aerosol may relatively short when compared with the component/dos-be sterile or may conform to acceptance criteria for micro- age form contact time for liquid-based oral dosage forms,bial limits. In the proposed label storage condition.TABLE 2.8Drug Products Intended for Storage in a Freezer Study Storage Condition Minimum Time Period Covered by DataLong-term –20˚C ± 5˚C at Submission (months) 12F. Statistical methods should to place at least three additional production be employed to test the goodness of fit of the data from batches on long-term stability studies through all batches and combined batches (where appropriate) to the proposed retest period. With regard ifications for the primary degradant, including methods ofto dissolution, there are at least three products that have quantitation of both the active drug and degradant.dissolution specifications. A typical closure consists of a cap — often withfood additive regulations is typically considered sufficient a liner — frequently with an inner seal. 196. More detailed information usually ature, light) that can cause a degradation in the quality ofshould be provided for a liquid-based dosage form than that dosage form over its shelf life. Pharmaceutical Manufacturing Formulations Liquid Products VOLUME 3 Sarfaraz K. Niazi CRC PR E S S Boca Raton London New York Washington, D.C. Library of Congress Cataloging-in-Publication Data Niazi, Sarfaraz, 1949– Handbook of pharmaceutical manufacturing formulations: liquid products/ Sarfaraz K. Niazi. It is considered unnec- intended to be stored in a freezer, testing of a single batchessary to continue to test a drug substance through 6 at an elevated temperature (e.g., 5˚C ± 3˚C or 25˚C ± 2˚C)months when a significant change has occurred within the for an appropriate time period should be conducted tofirst 3 months. A secondary packaging component gen- and a physical description of the packaging com-erally provides one or more of the following additional ponent (e.g., type, size, shape, and color)services: Identification of the materials of construction (i.e., • Protection from excessive transmission of plastics, paper, metal, glass, elastomers, coatings, moisture or solvents into or out of the packag- adhesives, and other such materials) should be ing system identified by a specific product designation (code name and/or code number) and the source (name • Protection from excessive transmission of reac- of the manufacturer); alternate materials of con- tive gases (atmospheric oxygen, inert head- struction should be indicated; postconsumer space filler gas, or other organic vapors) into or recycled plastic should not be used in the man- out of the packaging system ufacture of a primary packaging component, and if it is used for a secondary or associated com- • Light protection for the packaging system ponent, then the safety and compatibility of the • Protection for a packaging system that is flex- material for its intended use should be addressed appropriately ible or that needs extra protection from rough handling Description of any operations or preparations that • Additional measure of microbiological protec- are performed on a packaging component by the tion (i.e., by maintaining sterility or by protect- applicant (such as washing, coating, sterilization, ing the packaging system from microbial or depyrogenation) intrusion) B. These dosage forms are generallyis welded to the bottle. The newdosage forms; however, keeping in mind the overall per- specifications include a tighter level of heavy metals, butspective of the series of this title, this chapter would apply a generic manufacturer should have no problem if theto all dosage forms. Common causes offor a powder or a solid, as a liquid-based dosage form is such degradation are exposure to light, loss of solvent,more likely to interact with the packaging components. It is expected that formulation scientists will use this information to benchmark their internal development pro- Many stages of new drug development are inherently tocols and reduce the time required to file by adoptingconstrained by time, but the formulation of drugs into formulae that have survived the test of time. In pharmaceutical preparations it is primarily used as a diluent (10–90% w/w) in tablet formulations, where it is of particular value since it is not hygroscopic and may thus be used For example, if the dosage form isdosage forms to be slower than for aqueous solutions. The likely changes on storage product should be tested for antimicrobial preservativeand the rationale for the selection of attributes to be tested effectiveness (in addition to preservative content) at thein the formal stability studies should be stated. Bulk Containers ..................................................................................................................................................... 27References ........................................................................................................................................................................ 28Chapter 4Preapproval Inspections ................................................................................................................................................... 29I. A liquid-based topical product typically has a fluid or Transdermal systems are usually applied to the skinsemisolid consistency and is marketed in a single- or mul- with an adhesive and may be in place for an extendedtiple-unit container (e.g., a rigid bottle or jar, a collapsible period. Drug Product........................................................................................................................................................... 10 A. It is a good practice to store hoses in a way microbiological levels in the product. For the purpose of this guidance, oral powdersform on a bandage material (e.g., absorbent gauze or gauze and granules for reconstitution are also included in thisbandage) within a flexible pouch. sibilities that are made available in this book such scien- tists would benefit from the experience of others. Procedures should provide for the key in-process and finished productmust therefore be established for filling and diagrams tests, along with their specifications. Stability Testing of New Drug Substances and Products 11studies at initial and final time points, and if full shelf- authorities if requested. 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