Drinking Water can be referred to as Potable Water (meaning drinkable or fit to drink), National Primary Drinking Water, Primary Drinking Water, or EPA Drinking Water. Except where a singular drinking water specification is stated (such as the U.S. EPA’s NPDWR, as cited in 40 CFR Part 141), this water must comply with the quality attributes of either the NPDWR or the drinking water regulations of the EU or Japan, or the WHO Guidelines for Drinking-Water Quality. Drinking Water may originate from a variety of sources including a public water supply, a private water supply (e.g., a well), or a combination of these sources (see Source Water Considerations). Drinking Water may be used in the early stages of cleaning pharmaceutical manufacturing equipment and product-contact components. Drinking Water is also the minimum quality of water that should be used for the preparation of official substances and other bulk pharmaceutical ingredients. Where compatible with the processes, the contaminant levels allowed in Drinking Water are generally considered safe for use in preparing official substances and other drug substances. However, where required by the processing of the materials to achieve their required final purity, higher qualities of water may be needed for these manufacturing steps, perhaps even water as pure as Water for Injection or Purified Water. Such higher-purity waters, however, might require only selected attributes to be of higher purity than Drinking Water (see Figure 1 and Figure 2). Drinking Water is the prescribed source or feed water for the production of bulk monographed pharmaceutical waters. The use of Drinking Water specifications establishes a reasonable set of maximum allowable levels of chemical and microbiological contaminants with which a water purification system will be challenged. Because seasonal variations in the quality attributes of the Drinking Water supply can occur, it is important to give due consideration to its uses. The processing steps in the production of pharmaceutical waters must be designed to accommodate this variability.

SOURCE WATER CONSIDERATIONS Source water is the water that enters the facility. The origin of this source water can be from natural surface waters like rivers and reservoirs, deep-bed well waters, sea waters, or some combination of these, potentially including multiple locations of each type of source water. Thus, source water can be supplied from these various origins (public or private), from municipalities’ on-site water sourcing, or by external delivery such as a truck. It is possible that source water may not be potable and safe to drink. Such water may require pretreatment to ensure that it meets drinking water standards. It is the responsibility of the users of any source water to ensure that the water used in the production of drug substances (API), as well as water for indirect drug product contact or for purification system feed water purposes meets, at a minimum, drinking (potable) water standards as defined by the requirements of the National Primary Drinking Water Regulations (NPDWR) (40 CFR 141) issued by the U.S. EPA or the drinking water regulations of the European Union (EU) or Japan, or the WHO drinking water guidelines (see 3.3.1 Drinking Water). These regulations establish limits on the types and quantities of certain chemical and microbiological contaminants and ensure that the water will contain safe quantities of chemical and microbial species. Where water supplies are from regulated water utility companies, less stringent monitoring may be possible because the attributes may be tested regularly and ensured by the supplier (see 9.4.5 Source Water Control). Water being withdrawn from a nonregulated supply should be sampled and tested appropriately at a suitable frequency that takes into account local environmental and seasonal changes and other quality fluctuations. Testing should ensure conformance with one of the drinking water standards discussed above. The use of water complying with one of these designated drinking waters as a source water allows water pretreatment systems to only be challenged to remove small quantities of potentially difficult-to-remove chemicals. Control of objectionable chemical contaminants at the source water stage eliminates the need to specifically test for some of them [e.g., trihalomethanes and elemental impurities (see Elemental Impurities—Limits <232>)] after the water has been further purified, assuming there is no opportunity for recontamination. Source waters can be used for nonproduct contact purposes such as for non-contact cooling systems. Such water may not normally be required to meet drinking water standards. Under such circumstances, the quality standards for this water when used in a pharmaceutical facility should be subject to quality standards established by the user and defensible to regulatory agencies.

GUIDANCE DOCUMENT Multiple Endpoints in Clinical Trials Guidance for Industry OCTOBER 2022 Docket Number: FDA-2016-D-4460 Issued by: Center for Biologics Evaluation and Research Center for Drug Evaluation and Research This guidance provides sponsors and review staff with the Agency’s thinking about the problems posed by multiple endpoints in the analysis and interpretation of study results and how these problems can be managed in clinical trials for human drugs, including drugs subject to licensing as biological products. Most clinical trials performed in drug development contain multiple endpoints to assess the effects of the drug and to document the ability of the drug to favorably affect one or more disease characteristics. As the number of endpoints analyzed in a single trial increases, the likelihood of making false conclusions about a drug’s effects with respect to one or more of those endpoints becomes a concern if there is not appropriate adjustment for multiplicity. The purpose of this guidance is to describe various strategies for grouping and ordering endpoints for analysis and applying some well-recognized statistical methods for managing multiplicity within a study in order to control the chance of making erroneous conclusions about a drug’s effects. Basing a conclusion on an analysis where the risk of false conclusions has not been appropriately controlled can lead to false or misleading representations regarding a drug’s effects. You can submit online or written comments on any guidance at any time (see 21 CFR 10.115(g)(5)) If unable to submit comments online, please mail written comments to: Dockets Management Food and Drug Administration 5630 Fishers Lane, Rm 1061 Rockville, MD 20852 All written comments should be identified with this document's docket number: FDA-2016-D-4460.

STERILE WATER FOR INHALATION is Water for Injection that is packaged and rendered sterile and is intended for use in inhalators and in the preparation of inhalation solutions. This monograph has no requirement to meet a Particulate Matter in Injections; it carries a less stringent specification for bacterial endotoxins than Sterile Water for Injection, and therefore is not suitable for parenteral applications. Monograph DEFINITION Sterile Water for Inhalation is prepared from Water for Injection that is sterilized and suitably packaged. It contains no added antimicrobial agents. [NOTE—Do not use Sterile Water for Inhalation for parenteral administration or for other sterile compendial dosage forms.] SPECIFIC TESTS TOTAL ORGANIC CARBON USP <643>, Procedures, Sterile Water: Meets the requirements WATER CONDUCTIVITY USP <645>, Sterile Water: Meets the requirements STERILITY TESTS USP <71>, Meets the requirements BACTERIAL ENDOTOXINS TEST USP <85>, Less than 0.5 USP Endotoxin Units/mL ADDITIONAL REQUIREMENTS PACKAGING AND STORAGE: Preserve in glass or plastic containers. Glass containers are preferably of Type I or Type II glass. LABELING: Label it to indicate that it is for inhalation therapy only and that it is not for parenteral administration.

STERILE WATER FOR IRRIGATION is Water for Injection packaged and sterilized in single-dose containers that may be larger than 1 L and allow rapid delivery of their contents. Due to its usage, Sterile Water for Irrigation is not required to meet Particulate Matter in Injections. It may also be used in other applications that do not have particulate matter specifications, where bulk Water for Injection or Purified Water is indicated but where access to a validated water system is not practical, or where somewhat larger quantities are needed than are provided as Sterile Water for Injection.

BACTERIOSTATIC WATER FOR INJECTION is Water for Injection, packaged and rendered sterile, to which has been added one or more suitable antimicrobial preservatives. It is intended to be used as a diluent in the preparation of parenteral products, most typically for multi-dose products that require repeated content withdrawals. It may be packaged in single-dose or multiple-dose containers not larger than 30 mL.

Sterile Water for Injection is water for Injection packaged and rendered sterile. It is used for extemporaneous prescription compounding and as a sterile diluent for parenteral products. It may also be used for other applications where bulk Water for Injection or Purified Water is indicated but access to a validated water system is not practical, or where only a relatively small quantity is needed. Sterile Water for Injection is packaged in single-dose containers not larger than 1 Liter.

Sterile Purified Water is Purified Water, packaged and rendered sterile. It can be used in the preparation of nonparenteral compendial dosage forms or in analytical applications requiring Purified Water where... [1] access to a validated Purified Water system is not practical, [2] only a relatively small quantity is needed, [3] Sterile Purified Water is required by specific monograph or pharmacy practice, or [4] bulk packaged Purified Water is not suitably controlled for the microbiological quality for its intended use.

The US FDA has revised the guideline for Size, Shape, and other physical Attributes of Generic Tablets and capsules, Tablets and capsules are widely manufactured and prescribed and may provide a number of advantages over other dosage forms, including ease of storage, portability, ease of administration, and accuracy in dosing. While generic formulations of these drug products are required to be both pharmaceutically and therapeutically equivalent to a reference listed drug (RLD), we are concerned that differences in physical characteristics (e.g., size and shape of the tablet or capsule) may affect patient compliance and acceptability of medication regimens or could lead to medication errors. We believe these patient safety concerns are important, and we are recommending that generic drug manufacturers consider physical attributes when they develop quality target product profiles (QTPPs) for their generic product candidates. The recommendations in this guidance apply to abbreviated new drug applications (ANDAs) and their supplements for additional strengths that are submitted to the Office of Generic Drugs (OGD). This guidance does not apply to approved ANDAs (generic drugs) already on the market. However, if the Agency determines that an approved product should be modified because the size or shape of a product poses a risk to public health, we will notify the holder of the ANDA. This guidance is not intended to apply to other oral dosage forms (e.g., chewable tablets, oral tablets for suspension/solution, orally disintegrating tablets, sublingual tablets, troches, gums). This guidance revises the guidance of the same name issued in June 2015 to clarify that the largest dimension of a tablet should not exceed 22 mm and that capsules should not exceed a standard 00 size. This guidance also includes updated references. In general, FDA’s guidance documents do not establish legally enforceable responsibilities. Instead, guidances describe the Agency’s current thinking on a topic and should be viewed only as recommendations, unless specific regulatory or statutory requirements are cited. The use of the word should in Agency guidances means that something is suggested or recommended, but not required. To Read the full Guidance document download it from here... #usfda #pharmaguidelines #pharmaceuticals #interview #jobs #interviewtips #fda #pharmaupdates

Sterile Monographed Waters The following monographed waters are packaged forms of either Purified Water or Water for Injection that have been sterilized to preserve their microbiological properties. These waters may have specific intended uses as indicated by their names, and may also have restrictions on the packaging configurations related to those uses. In general, these sterile waters may be used in a variety of applications in lieu of the bulk forms of water from which they were derived. However, there is a substantial difference between the acceptance criteria for the chemical purities of these bulk waters versus sterile waters. The specifications for sterile waters differ from those of bulk waters to accommodate a wide variety of packaging types, properties, volumes, and uses. As a result, the inorganic and organic impurity specifications are not equivalent for bulk and packaged waters. The packaging materials and elastomeric closures are the primary sources of these impurities, which tend to increase over the shelf life of these packaged articles. Therefore, due consideration must be given to the chemical purity suitability at the time of use of the sterile forms of water when used in manufacturing, analytical, and cleaning applications in lieu of the bulk waters from which these waters were derived. It is the user’s responsibility to ensure fitness for use of these sterile packaged waters in these applications. Nevertheless, for the applications discussed below for each sterile water, their respective purities and packaging restrictions generally render them suitable by definition. STERILE PURIFIED WATER STERILE WATER FOR INJECTION BACTERIOSTATIC WATER FOR INJECTION STERILE WATER FOR IRRIGATION STERILE WATER FOR INHALATION Continue...

Most of the volumetric apparatus available in the United States are calibrated at 20°, and the National Institute of Standards and Technology (NIST) has adopted 20° as the reference temperature for the calibration of laboratory glassware, although the temperatures generally prevailing in laboratories are usually between 20° and 25°. To minimize volumetric error, the temperature should be the same for the volumetric apparatus, the material being prepared, the solvents being used to prepare the volumetric solutions, the area in which they are prepared, and the final volume adjustment. To attain the degree of precision required in many Pharmacopeial assays involving volumetric measurements and directing that a quantity be “accurately measured”, the apparatus must be chosen and used with care. STANDARDS OF ACCURACY The capacity tolerances for volumetric flasks, transfer pipets, and burets are those accepted by NIST (Class A), as indicated in Table 1, Table 2, and Table 3, respectively. [NOTE—The tables in this chapter list the tolerances for the most commonly used sizes. See the referenced ASTM standards for a complete list of tolerances and other applicable criteria.] Use Class A volumetric apparatus unless otherwise specified in the individual monograph. When a plastic volumetric apparatus is specified, the accepted capacity tolerances are equal to Class B glass. The capacity tolerances for measuring (i.e., “graduated”) pipets of up to and including 10-mL capacity are somewhat larger than those for the corresponding sizes of transfer pipets, namely, 10, 20, and 30 μL for the 2-, 5-, and 10-mL sizes,respectively. Transfer and measuring pipets calibrated “to deliver” should be completely drained in a vertical position and then touched against the wall of the receiving vessel to drain the pipet tip. Volume readings on burets should be estimated at least to the nearest one-half of a subdivision. Pipets calibrated “to contain” are called for in special cases, generally for measuring viscous fluids such as syrups; however, a volumetric flask may be substituted for a “to contain” pipet. In such cases, the pipet or flask should be washed clean after draining, and the washings should be added to the measured portion. Table 1 Volumetric Flasks Table 2 Transfer Pipets Table 3 Burets Foot Note: See ASTM E288-10, ASTM E287-02, ASTM E1189-00, and ASTM E969-02. See ASTM E288-10 and ISO 384:2015. See ASTM E1293-02.

An emulsion is a dispersed colloidal system consisting of two immiscible liquid phases generally stabilized with one or more suitable agents. Typical pharmaceutical emulsions are prepared from immiscible aqueous and organic (oil) liquids. Complex multiple-phase systems may exist in an emulsion. Whether the organic or the aqueous phase is the dispersed phase depends on the volumes of the two phases, the emulsi􀂦er chosen, and the method of preparation. When an oil phase is dispersed in an aqueous phase, the emulsionis termed an oil-in-water (O/W) emulsion and water is referred to as the continuous phase. When water is dispersed in oil, the emulsion is referred to as a water-in-oil (W/O) emulsion. Emulsions have dispersed phases typically ranging from 0.1 to 100 μm. Emulsions are opaque while microemulsions are usually transparent or translucent. Microemulsions have dispersed phases less than0.1 μm. Emulsions may exhibit three types of instability: 􀂧flocculation, creaming, and coalescence. Flocculation describes the process by which the dispersed phase comes out of suspension in the form of flakes. Coalescence is another form of instability -- small droplets within the media continuously combine to form progressively larger droplets. Emulsions can also undergo creaming, where one of the phases migrates to the top (or the bottom, depending on the relative densities of the two phases) of the emulsion. To prevent􀂧 occulation, creaming, and coalescence of the emulsions, manufacturers commonly add surfactants, pH-modifying agents, emulsifying agents to increase the stability of emulsions so that the emulsion does not change signi􀂦cantly with time. Emulsions are widely used as pharmaceutical dosage forms. Oral emulsions have been prepared to improve taste, solubility, stability, or bioavailability. Emulsions for topical administration are referred to as creams, lotions, and sometimes ointments. Parenteral emulsions have been used for anesthetics, parenteral nutrition, and to deliver poorly water-soluble drugs.