Alternative storage conditions can bethe registration application should be submitted to the used if justified.TABLE 2.4General Case Study Storage Condition Minimum Time Period Covered byLong-term 25˚C ± 2˚C, 60% RH ± 5% RH Data at Submission (months)Intermediate 30˚C ± 2˚C, 60% RH ± 5% RH 12Accelerated 40˚C ± 2˚C, 75% RH ± 5% RH 6 6Note. ForMean Kinetic Temperature — A single derived temper- most biotechnological/biological substances known to beature that, if maintained over a defined period of time, labile, it is more appropriate to establish a shelf life thanaffords the same thermal challenge to a drug substance or a retest period. The higher viscosity of semi- be expected to be no greater than the exposure throughsolid dosage forms and transdermal systems may cause foods or if the length of exposure is supported by toxico-the rate of migration of leachable substances into these logical information. environments (Table 2.5). The standard life acceptance criteria for preservative content.conditions for photostability testing are described inanother chapter. An overwrap syringe to deliver the labeled amount of the drug product.may be used with flexible bags to retard solvent loss andto protect the flexible packaging system from rough han- These drug products are usually solutions marketeddling. This consideration is First, consider container closure system functionality:especially important for those packaging components that the container closure system may be designed to improvemay be in direct contact with the dosage form, but it is patient compliance (e.g., a cap that contains a counter),also applicable to any component from which substances minimize waste (e.g., a two-chamber vial or IV bag),may migrate into the dosage form (e.g., an ink or adhe- improve ease of use (e.g. The key Chapter 4 introduces the area of preapproval inspec- application of the data provided herein is to allow thetions, a process initiated by the FDA in the wake of the formulator to select the ingredients that are reportedlygrand scandals in the generic pharmaceutical industry a compatible, avoiding need for long-term studies to estab-few years ago. There are three levelsstage can be a very expensive exercise. A single-dose cup may be metal or products may be considered to be topical if they areplastic with a heat-sealed lid made of a laminated material. An ocularmade of glass or polypropylene with a screw cap. (PDF) Handbook of pharmaceutical manufacturing ... ... tá dươc An alternative approach to studying at the reference A linear water loss rate at the alternative RH over theRH as recommended in Table 2.5 (for either long-term storage period should be demonstrated. specifically apply to materials for packaging drug prod- ucts, they include purity criteria and limitations pertaining Some interactions between a packaging component to the use of specific materials for packaging foods thatand dosage form will be detected during qualification may be acceptable for the evaluation of drug productstudies on the container closure system and its compo- packaging components. methods, acceptance criteria, reference standards, and val- idation information for the studies should be provided. When testing at the intermediate storagetions is useful in establishing degradation pathways and condition is called for as a result of significant change atin developing and validating suitable analytical proce- the accelerated storage condition, a minimum of four timedures. Acceptance of a packaging component lot acteristics of their product. This chapter does often goes on to revise the specifications of the activenot address the specific cGMP parameters but deals with pharmaceutical ingredient to the detriment of the genericthe practical aspects as may arise during a U.S. Food and manufacturer. Not all tablets are subject to loss of quality inhalation, injectable, powders, suspensions caused by absorption of moisture. If significant. 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. This discussion can be supported, ifextent of water loss. Over The Counter Products ( 2004) ... HANDBOOK OF Pharmaceutical Manufacturing Formulations Vol 5. The FDA is always very helpful in this phase ofpresented in another volume. 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). New Molecular Entity — An active pharmaceutical sub-Drug Substance — The unformulated drug substance that stance not previously contained in any drug product reg-may subsequently be formulated with excipients to pro- istered with the national or regional authority concerned.duce the dosage form. There should be a direct link between the labelfuture production batch will remain within specification storage statement and the demonstrated stability of thethroughout its shelf life. Significant change for a drug substance is defined as failure to meet its specification.When significant change occurs at any time during 6months of testing at the accelerated storage condition, B. Unintended variations in dimensional parameters, if attached to the container on opening or used only when aundetected, may affect package permeability, drug deliv- dose is to be administered. Information intended to establishA packaging system found acceptable for one drug prod- suitability may be generated by the applicant, by the sup-uct is not automatically assumed to be appropriate for plier of the material of construction or the component, oranother. p. cm. 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. It is also a good idea to benchmark the productthe filling problems of powder dosage forms, and the against the innovator product. If the tube material is self-sealing through the application should be consulted.application of heat alone, this should be stated. At present, therepackaging component and to prevent adverse effects on is no general policy concerning the monitoring of a pack-the quality of a dosage form. primary batch may be a production batch.Long-Term Testing — Stability studies under the recom- Production Batch — A batch of a drug substance or drugmended storage condition for the retest period or shelf life product manufactured at production scale by using pro-proposed (or approved) for labeling. Insight is also provided This volume is dedicated to one of the great educators and a leader in the pharmaceutical profession, August P. Lemberger, who is truly a Wisconsin man. Introduction............................................................................................................................................................... 3II. The General Chapters do not specificallyeither follow this system or provide an adequate justifica- address safety for polyethylene (HDPE or LDPE),tion for any deviations from the system. 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). Manufacturing Directions....................................................................................................................................... 53XIII. The subsections on associated components andcontainer closure system used by a contract packager that secondary components describe the tests and studies forshould be submitted in the Chemistry, Manufacturing, and establishing suitability and quality control for these typesControl (CMC) section of an application (New Drug of components. Title RS200.N53 2004 615'19—dc21 2003051451This book contains information obtained from authentic and highly regarded sources. Some examples of a packaging system is a change in the supplier of a pure chemical compound,for which drug delivery aspects are relevant are a prefilled because polymeric and natural materials are often com-syringe, a transdermal patch, a metered tube, a dropper or plex mixtures. For liquid-based oral drug products that PRODUCTS AND TOPICAL DELIVERY SYSTEMS the patient will continue to take for an extended period (i.e., months or years [chronic drug regimen]), a materialA wide variety of drug products falls into this category. The equipment should be capable of con-trolling the storage condition within the ranges defined in Products (November 1996)this guidance. Changes in theoperate as designed. Handbook of Pharmaceutical Manufacturing Formulations: Uncompressed Solid Products Volume 3 Handbook of Pharmaceutical Manufacturing ... Volume 6 Handbook of Pharmaceutical Manufacturing Formulations: Sterile Products. I would likethus require a new stability testing exercise. RAW MATERIALS validation. appearance, physical attributes, and functional- ity test (e.g., color, phase separation, resuspend- When significant change other than water loss occurs ibility, caking, hardness, and dose delivery per during the 6 months of testing at the accelerated storage actuation). handbook_of_pharmaceutical_manufacturing_formulations_Semisolid_products.pdf - Google Drive. The long-term testing should cover a minimum of 12 Long-term, accelerated, and where appropriate, inter-months’ duration on at least three primary batches at the mediate storage conditions for drug products are detailedtime of submission and should be continued for a period in the sections below. information for the labeling on the preparation, storageWhether and to what extent replication should be performed condition, and in-use period of the constituted or dilutedwill depend on the results of validation studies. Therefore, any change noted during a stability forms intended for chronic use.study that may be attributable to interaction between thedosage form and a packaging component should be inves- For drug products that undergo clinical trials, thetigated, and appropriate action should be taken, regardless absence of adverse reactions traceable to the packagingof whether the stability study is being conducted for an components is considered supporting evidence of materialoriginal application, a supplemental application, or as ful- safety. 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. Supporting data of the manufacturing procedure. Where applicable, specific instructions should be provided, in particular for, 10 Handbook of Pharmaceutical Formulations: Liquid Productsdrug substances that cannot tolerate freezing. Hemolytic effects may ucts use a glass container because of stability concernsresult from a decrease in tonicity, and pyrogenic effects. A significant change in water loss alone at the acceler- ated storage condition does not necessitate testing at the • Failure to meet the acceptance criterion for pH. 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. The compounding stage should be obtained in writing from CRC Press LLC, 2000 N.W the... The bottle pos-voluminous presentation on storage addi- apply if the product inhalation drug products topical delivery systems:,... Current good Manufacturing practice, as it might Chapter 5 includes highlights of Topics importanceresult... 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