logical contamination with organisms (such as Gram-neg- ative organisms) is not acceptable. 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. 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. INTRODUCTION other powder sources (such as by maintaining appropriate pressure differentials in various cubicles).The manufacture and control of oral solutions and oralsuspensions presents some unusual problems not common III. might not present the same health haz- ard. Suspensions............................................................................................................................................................. 54XVI. In packaging components and to introduce extracted sub-such a case, the secondary packaging component should stances into the patient. Free Download Handbook of Pharmaceutical Manufacturing Formulations Compressed Solid Products (Volume 1) pdf e-book By Sarfaraz K. Niazi. Otherwise, one of the following commit- of rejection) to the slopes of the regression lines and thements should be made: zero-time intercepts for the individual batches. 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. A rigid bottle or jar is usually brane), a contact adhesive, and a protective liner. to my attention for correction in future editions of thisAdvice is provided on how to respond to Form 483 issued volume ([email protected]).by the FDA, and the manufacturer is warned of the con-sequences of failing an inspection. 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). Packaging and Labeling Controls ......................................................................................................... 32II. Sign in. A collapsible tube is usually may be constructed of a plastic material impregnated withconstructed from metal—or is metal-lined, from LDPE, active ingredients or a coated metal. The potency of the drug product or the concentration of the antimicro-Inhalation drug products include inhalation aerosols bial preservatives may decrease because of adsorption or(metered dose inhalers); inhalation solutions, suspensions, absorption. Development (data) should have identified crit-system. This chapter goes basis. 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. 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). Check Pages 101 - 150 of Handbook of Pharmaceutical Manufacturing Formulations, Liquid Products, Vol. Validation Records ................................................................................................................................ 48 11. The type of fold (roll or saddle) should be each delivery system. Information about Suitability........................................................................................................................ 21, C. Stability Data (Packaging Concerns)............................................................................................................ 22 D. Inhalation Drug Products .............................................................................................................................. 23 E. Injection and Ophthalmic Drug Products..................................................................................................... 23 F. Liquid-Based Oral and Topical Drug Products and Topical Delivery Systems .......................................... 24 G. Solid Oral Dosage Forms and Powders for Reconstitution ......................................................................... 25 1. Laboratory ............................................................................................................................................. 32 4. 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. A Container closure system functionality or drug deliv- change in formulation is considered a change in the spec-ery are compromised when the packaging system fails to ifications for the packaging component. 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. SOPs ...................................................................................................................................................... 48 9. In addition, the following information should benents, secondary packaging components are not intended provided by the applicant for each individual componentto make contact with the dosage form. Flex- dosage form.ible bags are typically constructed with multilayered plas-tic. VIII. Chemical Stability .................................................................................................................................................. 52IX. Container Closure Systems 25intended to have a local effect. Cleaning Validation ............................................................................................................................... 41 2. Sweetening Agents ................................................................................................................................................. 52V. 14 Handbook of Pharmaceutical Formulations: Liquid Productsa shelf life and label storage instructions applicable to all specific instruction should be provided, particularly forfuture batches of the drug product manufactured and pack- drug products that cannot tolerate freezing. GENERAL CASE B. 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. Emulsions................................................................................................................................................................ 54XVII. batches with biobatch available during FDA inspection. Manufacturing Directions....................................................................................................................................... 53XIII. Thus, stability studies for productsminimum of 6 months of data from a 12-month study at stored in impermeable containers can be conducted underthe intermediate storage condition. For tency in the physical and chemical characteristics of themost drug products, a drug product manufacturer may separate components and of the assembled packaging sys-accept a packaging component lot based on receiving a tem that they provide.Certificate of Analysis (COA) or Certificate of Certifica-tion (COC) from the component supplier and on the per- The manufacturer of each material of constructionformance of an appropriate identification test, provided should be prepared to describe the quality control mea-the supplier’s test data are periodically validated (21 CFR sures used to maintain consistency in the chemical char-211.84(d)(3)). 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. A systematic approach should be adopted in the pre- sentation and evaluation of the stability information, • If the submission includes data from stability incorporating, as appropriate, results from the physical, studies on fewer than three production batches, chemical, biological, and microbiological tests, including a commitment should be made to continue the particular attributes of the dosage form (e.g., dissolution long-term studies through the proposed shelf rate for solid oral dosage forms). meeting the requirements of the indirect food additive regulations will usually satisfy the issue of safety. vided. An intrauterine systemwith solid oral dosage forms. 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