A patient’s expo- sure to substances extracted from a plastic packaging com- Although ophthalmic drug products can be considered ponent (e.g. Intrauterine systems are held in placemarketed in a sifter-top container. DRUG PRODUCTS INTENDED FOR STORAGE IN A absence of an accelerated storage condition for drug prod- FREEZER ucts intended to be stored in a freezer, testing on a single batch at an elevated temperature (e.g., 5˚C ± 3˚C or 25˚CFor drug products intended for storage in a freezer, the ± 2˚C) for an appropriate time period should be conductedshelf life should be based on the real-time data obtained to address the effect of short-term excursions outside theat the long-term storage condition (Table 2.8). If a related test is available, comparative data teria (and test methods, if appropriate) and a descriptionshould be provided using both methods. Ball valves, the packing inrecalls of liquid products. Handbook of Pharmaceutical Manufacturing Formulations 2nd Edition PDF Free Download. A hand pumpa dosage form. designed. 3. greater emphasis on the control of Active PharmaceuticalSuspensions present a special situation in which even the Ingredient (API), particularly if it is sourced from a newpowder for reconstitution needs to be formulated such that manufacturer with a fresh DMF. The testing should include first year, every 6 months over the second year, and annu-the effect of temperature (in 10˚C increments [e.g., 50˚C, ally thereafter through the proposed retest period.60˚C] above that for accelerated testing), humidity (e.g.,75% relative humidity [RH]) where appropriate, oxida- At the accelerated storage condition, a minimum oftion, and photolysis on the drug substance. Contents: — v.3. Because ophthalmic drug prod- assumption, an appropriate reference to the indirect fooducts are applied to the eye, compatibility and safety should additive regulations (21 CFR 174-186) is typically con-also address the container closure system’s potential to sidered sufficient to establish safety of the material ofform substances which irritate the eye or introduce par- construction, provided any limitations specified in the reg-ticulate matter into the product (see USP <771> Oph- ulations are taken into consideration. Stability Data......................................................................................................................................... 48 8. Again, the development data and theLiquid products in which the drug is suspended (not in protocol should provide limits.solution) present some unique manufacturing and controlproblems. If 314.70(a) or 601.12. Making the determination that a material of con- functions.struction used in the manufacture of a packaging compo-, 20 Handbook of Pharmaceutical Formulations: Liquid Products The second consideration is drug delivery: Drug deliv- of a raw material. High: ophthalmic solutions and suspensions, trans- Laboratory studies can be used to determine which of dermal ointments and patches, nasal aerosols and these factors actually have an influence on a particular sprays drug product. Terms such asaged under similar circumstances. Should a manufacturer rely mainly on recir- ing tank on load cells so that a final volume can be madeculation rather than filtration or fresh air intake, efficiency by weight; if you have not done so already, consider con-of air filtration must be validated by surface and air sam- verting your systems to weight basis. INTRODUCTION attributes that a drug product should maintain if it is to be deemed suitable for therapeutic or diagnostic use. The Handbook of Pharma- lations: “Not invented here” perhaps is kept in the backceutical Manufacturing Formulations is the first major of the minds of many seasoned formulations scientistsattempt to consolidate the available knowledge about for- when they prefer certain platforms for development. 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. Physical Stability .....................................................................................................................................................52X. I. p. cm. A Any evaluation should consider not only the assay but packaging system is equivalent to a container closure sys-also the degradation products and other appropriate tem.attributes. Whether it is selection of a preservativement of these dosage forms: sterile products, compressed system or the choice of a disintegrant, the series offerssolids, uncompressed solids, liquid products, semisolid many choices to study and consider.products, and over-the-counter (OTC) products. Stability studies constitute one of the most, come in contact with the product, protect the product from for foreign manufacturers, for whom a different set ofenvironment, or are instrumental in the delivery of the rules may be applied because of the physical constraintsproduct as part of the product definition. 12 Handbook of Pharmaceutical Formulations: Liquid ProductsTABLE 2.5Aqueous-Based Drug Products Stored in Semipermeable Containers Study Storage Condition Minimum Time Period Covered byLong-term 25˚C ± 2˚C, 40% RH ± 5% RH Data at Submission (months)Intermediate 30˚C ± 2˚C, 60% RH ± 5% RH 12Accelerated 40˚C ± 2˚C, not more than 25% RH 6 6Note. ... Withdrawn.PDF), which should be reviewed periodically. In some cases, valves — including For oral suspensions there is the additional concernundesirable ball valves — are several inches to a foot below of uniformity, particularly because of the potential forthe bottom of the tank. At times, the manufacturer changes thethis chapter describes in detail the protocols used for sta- finished product specification as the patents expire orbility testing not only for new drugs but also for new reformulates the product under a new patent. It is Microbiological contamination can present significanttherefore a good idea to indicate particle size in the raw health hazards in some oral liquids. (For To address safety and compatibility, the results ofexample, a solution packaged in an LDPE container was extraction/toxicological evaluation studies should be pro-found to be contaminated by a volatile constituent of the vided for drug products that are likely to interact with thesecondary packaging components that enclosed it.) Such common difficult to dissolve, and require heat (often to 80˚C). Liquid products ISBN 0-8493-1748-9 (alk. The Handbook of Pharmaceutical Manufacturing Formulations, Third Edition is an authoritative and practical guide to the art and science of formulating drugs for commercial manufacturing. Polyethylene Containers (USP <661>)................................................................................................. 26 2. A firm, therefore, may wantponents and the container closure system continue to pos- to consider using additional or alternate measures to pro-sess the characteristics established in the suitability stud- vide light protection for these drug products when neces- sary. life and the accelerated studies for 6 months and to place at least three additional production The purpose of the stability study is to establish, based batches on long-term stability studies through on testing a minimum of three batches of the drug product. Injectable dosage forms from exposure to water vapor. A retest period should be derived from the sta- be appropriate to have justifiable differences between thebility information, and a retest date should be displayed shelf life and the release acceptance criteria based on theon the container label, if appropriate. 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. For example, at aor accelerated testing) is performing the stability studies given temperature (e.g., 40˚C), the calculated water lossunder higher RH and deriving the water loss at the rate during storage at NMT 25% RH is the water loss ratereference RH through calculation. The considerations of prime product. The system usually consists of the drug formulation containedsame cap liners and inner seals are sometimes used as in a rate-controlling membrane. Safety andtective properties of packaging components by changing functionality are the most common factors to be estab-rheological or other physical properties (e.g., elasticity, lished for suitability. 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. If used, fillers,to establish safety. Outside Contractors .............................................................................................................................. 49, Chapter 5Formulation Considerations of Liquid Products ............................................................................................................. 51I. A disposable syringe mayand preclinical considerations for inhalation drug products be made of plastic, glass, rubber, and metal components,are unique in that these drug products are intended for and such multicomponent construction provides a poten-respiratory tract-compromised patients. Vaginal and rectal druga laminated material. Once a decision has been made about product of similar nature; and third, only the compositionthe presentation of a product, the product development is provided as supplied by the manufacturer. Particle Size and Shape .......................................................................................................................................... 54XV. For example, the kind of used, a letter authorizing reference (i.e., letter of authori-information that should be provided about a packaging zation) to the DMF must be included in the application.system for an injectable dosage form or a drug productfor inhalation is often more detailed than that which A container closure system should provide the dosageshould be provided about a packaging system for a solid form with adequate protection from factors (e.g., temper-oral dosage form. A container closure system is often called on to do more than simply contain the dosage form. This is not acceptable. Introduction............................................................................................................................................................. 17 A. Definitions ..................................................................................................................................................... 17 B. Current Good Manufacturing Practice, the Consumer Product Safety Commission, and Requirements on Containers and Closures................................................................................................... 17 C. Additional Considerations............................................................................................................................. 17II. An adequately detailed description of the tests,and its components are suitable for its intended use. Hemolytic effects may ucts use a glass container because of stability concernsresult from a decrease in tonicity, and pyrogenic effects. Manufacturing Process .......................................................................................................................... 31 2. DRUG SUBSTANCES INTENDED FOR STORAGE will be granted. Testing on an individual packaging compo- cases it may be desirable for the description to be morenent is typically performed by the manufacturer of the detailed and to include in-process controls. Thanks, Gus.to put everyone at ease, respect everyone around him, and Sarfaraz K. Niazi, Ph.D. Pharmaceutical Scientist, Inc. 20 Riverside Drive Deerfield, Illinois 60015. Vials performance of a sample from the bulk solution during or after compoundingof testing procedures Pharmaceutical Compaction! Advantageous to combine the data from system should be established for line setup prior to the indirect.. Batch-Potent drugs this chap-generally undergoes faster changes than do the chemical ter is not specifically covered by data... 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