installation qualification: The performance of tests to ensure that the installations (such as machines, measuring devices, utilities and manufacturing areas) used in a manufacturing process are appropriately selected and correctly installed. Utilities and equipment should be correctly installed, in an appropriate location. There should be documented evidence of the installation. This should be in accordance with the IQ protocol, which contains all the relevant details. IQ should include identification and installation verification of relevant components identified (e.g. services, controls and gauges). Identified measuring, control and indicating devices, should be calibrated on site, unless otherwise appropriately justified. The calibration should be traceable to national or international standards. Traceable certificates should be available. Deviations and non-conformances, including those from URS, DQ and acceptance criteria specified and observed during installation, should be recorded, investigated and corrected or justified. The outcome of the IQ should be recorded in the conclusion of the report, before OQ is started.

Chromatographic systems: Chromatographic systems should meet regulatory and GXP requirements. This should include, for example, ensuring that data are acquired, processed and stored in accordance with ALCOA+ principles Supplier selection and vendor qualification should ensure that hardware and software are suitable for their intended application. Valid agreements should specify the respective responsibilities between the purchaser and supplier and include arrangements for after-sales services. Chromatographic systems selected, installed and qualified should be appropriate for their intended use. The environment in which such systems are placed should be appropriate to support their performance. This may include, for example, control of temperature and relative humidity in the area. Qualification, validation, maintenance and calibration The scope and the extent of validation and qualification of chromatographic systems should be determined based on risk management principles. This includes hardware and software. The approach to, and execution of, validation and qualification should be described in an authorized document such as a validation master plan. All stages of qualification should be considered and may include, for example, user requirement specifications (URS), design qualification (DQ), factory acceptance test (FAT), site acceptance test (SAT), installation qualification (IQ), operational qualification (OQ), and performance qualification (PQ). Validation and qualification should be described in protocols and recorded in reports. Reports should contain documented evidence and include, for example, screenshots, printouts or other source data and metadata of tests executed as part of validation and qualification. The data should provide evidence of the consistency of performance of the system and reliable and accurate results. Parameters such as, but not limited to, password control, audit trail, access and privileges should be described and verified during validation and qualification. Maintenance, preventive maintenance and calibration of chromatographic systems should be done in accordance with written procedures. Records should be maintained. Root cause analysis, impact assessment and risk assessment should be done when any calibration parameter is found to be out of calibration or not meeting the predefined limits. Appropriate corrective and preventive action should be taken and documented. Access and privileges There should be a standard operating procedure (SOP) for the creation and deletion of user groups and users of the chromatographic system, indicating the relevant privileges allocated to each user. Records should be maintained. An up-to-date record of user groups and users should be maintained. Users in each group should be appropriately qualified for the responsibility and privileges allocated. Where required, justification should be provided for privileges granted to user groups or users, including all exceptions. User privileges reflected in written procedures should be a true reflection of the privileges allocated electronically. Administrator access rights should not be given to other users on the system. Audit trail Chromatographic systems should have an audit trail(s) which reflect(s), for example, users, dates, times, original data and results, changes and reasons for change. Full audit trails should be enabled from the time of installation of software. Audit trails should remain enabled throughout the life-cycle of a chromatographic system. Audit trails should be reviewed in accordance with an SOP and include systems and project audit trails. There should be evidence of regular review of an audit trail (for example, each sample sequence or sample set in chromatographic analysis) and of periodic review of audit trails. (Periodic review should be done at specified intervals, based on risk management principles.) Audit trails are part of metadata and should be stored as part of the data set for all chromatographic analyses. Date and time functions Chromatographic systems should have date and time functions enabled from the time of installation of the software. The date and time function should be locked, and access to change the date and time should be controlled. (This includes changes to time zone setting.) All GMP actions on chromatographic systems should be date- and time-tracked. Electronic systems Note: This includes computerized systems. Written procedures should be followed when a new electronic system is taken into use. Procedures should also be followed for the removal of a system from use. Records should be maintained. Software selected, installed and applied for acquisition, processing and calculation of results should be suitable for its intended use, validated, and render results meeting regulatory, GXP and ALCOA+ principles. It is preferable that all chromatographic systems be linked to a network system where data are stored and managed on a centralized server. Stand-alone systems should be appropriately managed. Risk assessment should be done to ensure that sufficient controls are in place to eliminate the risks associated with stand-alone systems. These include, but are not limited to, access, privileges, date and time function, audit trail, data backup and data management. Electronic data management systems (EDMS) should be considered for the appropriate management of data, including acquisition, processing and storage of data. EDMS should be appropriate for their intended use and ensure the accuracy and reliability of data acquired and processed. Solvents, buffer solutions and mobile phases Solvents, buffer solutions and mobile phases should be prepared, stored and used in accordance with authorized specifications and procedures and a relevant pharmacopeia recognized by the national medicines regulatory authority. These should be used within appropriate, scientifically justifiable timelines. Records for their preparation and use should be maintained. Chemicals, reagents and other materials used should be of appropriate grade and quality. Liquid mobile phases should be filtered, degassed and pressurized when required. Carrier gases used for gas chromatography should have the appropriate purity and be suitable for their intended use. Column management Columns used in chromatography should be appropriate for their intended use. Columns should be purchased from approved suppliers. Columns should be verified on initial receipt and checked for their suitability as part of the chromatographic system, prior to use in analysis. Tubing and fittings should be appropriate to ensure that the system performs as expected. The number of theoretical plates (column efficiency) should be monitored to ensure efficiency is obtained for acceptable chromatography. Columns should be equilibrated before the analysis. The column oven (and column) temperature should be controlled when specified in the analytical procedure. The required flow rate should be specified in relevant test procedures. It should be appropriate for the column to be used, to ensure optimal chromatographic separation without exceeding recommended maximum backpressure. The use of columns should be recorded in a traceable manner. This includes, for example, the unique column identification number, number of injections and washing of the column. Columns should be washed (cleaned or flushed) according to defined procedures describing the steps and parameters, such as sequence, temperature, flow rate and time. Columns should be stored in a manner that ensures that they are not damaged. Sample management and sample set Note: Inappropriate management of samples may result in errors during analysis. Written procedures should be followed to avoid such risks. Sample management in the laboratory (including the receipt and preparation of samples) should be considered an important aspect in good chromatography practices. Samples received for analysis should be entered in an appropriate record that ensures the traceability of the sample detail and analysis. Samples should be stored under appropriate conditions. Samples (as well as blank and standard solutions) should be prepared in accordance with the authorized specifications and standard test procedures. Records for the preparation should be maintained. Official, secondary or working standards used should be traceable to the records maintained for their purchase, preparation and storage. Standard and sample solutions prepared for use in chromatography should be used within defined timelines derived from analytical procedure validation and stability data, as appropriate. The sample-set should be defined. The vials with standard solution(s), sample solution(s) and blank solution(s) should be verified to ensure the correct sequence of injections in the chromatographic system before starting the sequence of injections. Where carry-over or interference in analysis is relevant, suitable precautions should be taken, such as the inclusion of a blank in the sequence of injections. The use of “trial injections”, “system check injections”, or other injections that are not specified as part of a sample set, is not recommended. In exceptional cases where this is done, authorized procedures should clearly describe this approach. (Normally, only standard solutions may be used for this purpose, unless otherwise needed and justified e.g. biologics). The electronic record of results in such cases should be saved and stored, together with the results of the sample set for analysis. A system suitability test (SST) should be part of the sample set. The SST should be performed as described in the respective pharmacopeia monograph or validated in-house specification and standard test procedure. The SST should meet the predefined acceptance criteria, before samples are injected and throughout the analysis. Acceptance criteria should be set for the SST, bracketing standards, deviation from relative retention and any other aspect that may be deemed necessary for the chromatographic analysis. This includes acceptability of peak shapes. Bracketing standards (standard solution injections) should be included in the sample set, at defined intervals, where appropriate. The number of bracketing standards included in a sample set should be defined. Compliance with the defined acceptance criteria should be verified. Where blank interferences are detected, these should be within predefined limits. Chromatographic methods (acquisition and processing) Chromatographic methods should be suitable for their intended use. Appropriate acceptance criteria should be specified for parameters such as selectivity (resolution and/or peak-to-valley ratio), sensitivity (signal to- noise ratio), peak symmetry, repeatability and integration conditions (if applicable). Where non-pharmacopeia methods are to be used, these should be developed, validated and described in detail in standard procedures. These procedures should be followed by qualified, trained, experienced personnel. It is preferable that methods are created and saved in the chromatographic system by authorized personnel. The method selected for analysis from the saved methods should not be modified unless approved for the intended purpose by authorized personnel. Data acquisition and processing software should be appropriately validated or verified as being suitable for use. Methods selected for acquisition and processing should be traceable and reflected in the audit trail. Methods should be proven to remain in a validated state throughout their life-cycle. Chromatographic conditions (such as the composition of the mobile phase, pH, column dimensions) may be adjusted, within specified limits and in accordance with written procedures, to obtain the separation required. The adjustments made should be within the limits specified (such as defined in the design space of the analytical procedure). The SST requirements (e.g. resolution, symmetry, repeatability) should be met, and retention times and relative retention should be similar. Peak integration Peak areas in chromatograms should be accurately and consistently integrated in a scientifically sound manner. Where possible, HPLC and GC instruments should be interfaced with computerized chromatographic data-capturing and processing systems that are capable of applying the integration parameters set, automatically and consistently. To facilitate the accurate integration of chromatographic peaks, it is preferable that all of the peaks are fully separated. However, when quantitative data are to be obtained from unresolved peaks, the laboratory should have clear policies as to how such peaks should be integrated. This should include a description of the type of integration to be used, with a justification for its use, including, for example: tangential skim; exponential skim; exponential curve fitting; straight line skim; front peak skim; rear peak skim; peak-to-valley ratio; and valley height ratio. Validated methods, specified chromatographic conditions and good chromatography practices should facilitate obtaining symmetrical peaks. Where atypical peak shapes are observed, these should be investigated and appropriate action taken. Where manual integration has to be done, authorized procedures should be followed. Records should be maintained and include the authorization and justification for manual integration. Using a procedure to integrate peak height or area by manually setting the baseline using chromatographic software should only be allowed in exceptional cases. Only trained, experienced users should be granted privileges to do so. Records and justification should be given when this procedure is followed. Where smoothing is applied, the type of “filter” used and the extent of smoothing should be justified. Data management Chromatographic data should be managed in accordance with this guideline and other related guidelines. Procedures should be followed for timely processing and review of data and reporting of results. Data should be backed up according to procedures, and records maintained as proof thereof. Special care should be taken to ensure frequent back-up of data from stand-alone systems, to prevent loss of data. Data should be safely stored in a way that includes control over access to data. Backed-up data should be stored at a separate location. Some data should be randomly selected for restoration and verification, at defined intervals, in accordance with a written procedure. Where appropriate, paper printed records (including data and metadata) may be retained as part of the analytical report reflecting analyses performed. Procedures should be in place to allow for recovery of chromatographic data in case of disasters such as instrument failure, viruses, hardware or software failure and power failure. Complete data should be retained for appropriate periods of time, to allow for data verification, inspection, registration or other reasons.

Personal hygiene All personnel, prior to and during employment, as appropriate, should undergo health examinations. Personnel conducting visual inspections should also undergo periodic eye examinations. All personnel should be trained in the practices of personal hygiene. A high level of personal hygiene should be observed by all those concerned with manufacturing processes. In particular, personnel should be instructed to wash their hands before entering production areas. Signs to this effect should be posted and instructions observed. Any person shown at any time to have an apparent illness or open lesions that may adversely affect the quality of products should not be allowed to handle starting materials, packaging materials, in-process materials or drug products until the condition is no longer judged to be a risk. All employees should be instructed and encouraged to report to their immediate supervisor any conditions (relating to plant, equipment or personnel) that they consider may adversely affect the products. Direct contact should be avoided between the operator’s hands and starting materials, primary packaging materials and intermediate or bulk product. To ensure the protection of the product from contamination, personnel should wear clean body coverings appropriate to the duties they perform, including appropriate hair covering. Used clothes, if reusable, should be stored in separate closed containers until properly laundered and, if necessary, disinfected or sterilized. Smoking, eating, drinking, chewing, and keeping plants, food, drink, smoking material and personal medicines should not be permitted in production, laboratory and storage areas, or in any other areas where they might adversely influence product quality. Personal hygiene procedures including the use of protective clothing should apply to all persons entering production areas, whether they are temporary or full-time employees or non-employees, e.g. contractors’ employees, visitors, senior managers, and inspectors. Dear readers; I am Inviting you to become a part of the DPT Family (Dynamic Pharma Team) To update yourself; regularly visit our website: www.pharmaceuticalguideline.com and become a member (it's FREE) by clicking the Login button at the top right corner of the webpage, also subscribe to our newsletter, Like our website, follow us on Facebook(https://www.facebook.com/pharmaceuticalguideline)Instagram(https://www.instagram.com/pharmaceuticalguideline/)LinkedIn (https://www.linkedin.com/company/pharmaceuticalguideline) Twitter (https://twitter.com/pharma_guidance) Telegram, Download Telegram App on your Mobile and use @pharmaceuticalguideline for search. Your like is inspiring us to prepare the articles...

〈1151〉 PHARMACEUTICAL DOSAGE FORMS This article is based on the requirement of the United State Pharmacopoeia. (#usp, #pharmacopoeia, #MOA, #testprocedure, #qc, #qualitycontrol, #usp43, #nf38) Films Films are thin sheets that are placed in the oral cavity. They contain one or more layers. A layer may or may not contain the drug substance. Typically, these thin sheets are formed by casting or extrusion that results in a dispersion of the components through the film. Films are classified by the site of application. “Oral 􀂦films” can be formulated to deliver medication to the mouth such as oral hygiene products or to deliver medication to the gastrointestinal tract for absorption. “Buccal 􀂦films” and “sublingual films” are formulated to facilitate absorption through the proximal mucosal membranes avoiding 􀂦first-pass metabolism or degradation in the gastrointestinal tract and providing a quick onset of action. Films can be formulated with edible polymers such as pullulan or with water-soluble polymers such as modified cellulose, edible gums, and copolymers. The dissolution rate of the 􀂦film is controlled to facilitate incorporation of the medication into saliva or for absorption by the proximal mucosa. These films must be substantial enough to maintain their integrity during manufacture and packaging and permit handling by the patient. Because of the rapid dissolution, taste and mouthfeel are important considerations. Note: The detailed information regarding individual Official Dosage Forms in subsequent articles, Visit our website https://www.pharmaceuticalguideline.com/ regularly.

〈1151〉 PHARMACEUTICAL DOSAGE FORMS This article is based on the requirement of the United State Pharmacopoeia. (#usp, #pharmacopoeia, #MOA, #testprocedure, #qc, #qualitycontrol, #usp43, #nf38) Capsules Capsules are solid dosage forms in which the drug substance and/or excipients are enclosed within a soluble container or shell or coated on the capsule shell. The shells may be composed of two pieces (a body and a cap), or they may be composed of a single piece. Two-piece capsules are commonly referred to as hard-shell capsules, and one-piece capsules are often referred to as soft-shell capsules. This two-piece and one-piece capsule distinction, although imprecise, reflects differing levels of plasticizers in the two compositions and the fact that one-piece capsules typically are more pliable than two-piece capsules. The shells of capsules are usually made from gelatin. However, they may also be made from cellulose polymers or other suitable material. Most capsules are designed for oral administration. When no deliberate effort has been made to modify the drug substance release rate, capsules are referred to as immediate release. TWO-PIECE OR HARD-SHELL CAPSULES Two-piece capsules consist of two telescoping cap and body pieces in a range of standard sizes. ONE-PIECE OR SOFT-SHELL CAPSULES One-piece capsules typically are used to deliver a drug substance as a solution or suspension. Liquid formulations placed into one-piece capsules may offer advantages by comparison with dry-filled capsules and tablets in achieving content uniformity of potent drug substance(s) or acceptable dissolution of drug substance(s) with poor aqueous solubility. Because the contact between the shell wall and its liquid contents is more intimate than in dry-filled capsules, undesired interactions may be more likely to occur(including gelatin crosslinking and pellicle formation). MODIFIED-RELEASE CAPSULES The release of drug substance(s) from capsules can be modified in several ways. There are two categories of modified-release capsule formulations recognized by USP. Delayed-release capsules: Capsules are sometimes formulated to include enteric-coated granules to protect acid-labile drug substances from the gastric environment or to prevent adverse events such as irritation. Enteric-coated multiparticulate capsule dosage forms may reduce variability in bioavailability associated with gastric emptying times for larger particles (i.e., tablets) and to minimize the likelihood of a therapeutic failure when coating defects occur during manufacturing. Alternatively, a coating may be applied to the capsule shell to achieve delayed release of the contents. Extended-release capsules: Extended-release capsules are formulated in such a manner as to make the contained drug substance available over an extended period of time following ingestion. Requirements for dissolution (see 〈711〉) are typically specified in the individual monograph. PREPARATION Two-piece capsules: Two-piece gelatin capsules are usually formed from blends of gelatins that have relatively high gel strength in order to optimize shell clarity and toughness or from hypromellose. They may also contain colorants such as Drug & Cosmetic (D&C) and Food, Drug, & Cosmetic (FD&C) dyes or various pigments, opaquing agents such as titanium dioxide, dispersing agents, plasticizers, and preservatives. Gelatin capsule shells normally contain between 12% and 16% water. The shells are manufactured in one set of operations and later filled in a separate manufacturing process. Two-piece shell capsules are made by a process that involves dipping shaped pins into gelatin or hypromellose solutions, followed by drying, cutting, and joining steps. Powder formulations for two-piece gelatin capsules generally consist of the drug substance and at least one excipient. Both the formulation and the method of 􀂦filling can affect release of the drug substance. In the filling operation, the body and cap of the shell are separated before 􀂦filling. Following the 􀂦filling operation, the machinery rejoins the body and cap and ensures satisfactory closure of the capsule by exerting appropriate force on the two pieces. The joined capsules can be sealed after filling by a band at the joint of the body and cap or by a designed locking joint between the cap and body. In compounding prescription practice, two-piece capsules may be hand-filled. This permits the prescriber the choice of selecting either a single drug substance or a combination of drug substances at the exact dose level considered best for an individual patient. One-piece capsules: One-piece capsules are formed, filled, and sealed in a single process on the same machine and are available in a wide variety of sizes, shapes, and colors. The most common type of one-piece capsule is that produced by a rotary die process that results in a capsule with a seam. The soft gelatin shell is somewhat thicker than that of two-piece capsules and is plasticized by the addition of polyols such as glycerin, sorbitol, or other suitable materials. The ratio of the plasticizer to the gelatin can be varied to change the flexibility of the shell depending on the nature of the fill material, its intended usage, or environmental conditions. In most cases, one-piece capsules are filled with liquids. Typically, drug substances are dissolved or suspended in a liquid vehicle. Classically, an oleaginous vehicle such as a vegetable oil was used. However, nonaqueous, water-miscible liquid vehicles such as the lower molecular weight polyethylene glycols are now more common. The physicochemical properties of the vehicle can be chosen to ensure stability of the drug substance as well as to influence the release pro􀂦le from the capsule shell. Note: The detailed information regarding individual Official Dosage Forms in subsequent articles, Visit our website https://www.pharmaceuticalguideline.com/ regularly.

〈1151〉 PHARMACEUTICAL DOSAGE FORMS This article is based on the requirement of the United State Pharmacopoeia. (#usp, #pharmacopoeia, #MOA, #testprocedure, #qc, #qualitycontrol, #usp43, #nf38) Aerosols Aerosols are dosage forms packaged under pressure and contain therapeutic agent(s) and a propellant that are released upon actuation of an appropriate valve system. Upon actuation of the valve system, the drug substance is released as a plume of 􀂦fine particles or droplets. Only 1 dose is released from the preparation upon actuation of a metered valve. In the case of topical products and depending on the nature of the drug substance and the conditions being treated, actuation of the valve may result in a metered release of a controlled amount of the formulation or the continuous release of the formulation as long as the valve is depressed. The aerosol dosage form refers only to those products packaged under pressure that release a 􀂦fine mist of particles or droplets when actuated (see Glossary). Other products that produce dispersions of 􀂦fine droplets or particles will be covered in subsequent sections (e.g., Powders and Sprays). TYPICAL COMPONENTS Typical components of aerosols are the formulation containing one or more drug substance(s) and propellant, the container, the valve, and the actuator. Each component plays a role in determining various characteristics of the emitted plume, such as droplet or particle size distribution, uniformity of delivery of the therapeutic agent, delivery rate, and plume velocity and geometry. The metering valve and actuator act in tandem to generate the plume of droplets or particles. The metering valve delivers an accurate volume of the pressurized liquid formulation from the container. The actuator directs the metered volume to a small orifice that is open to the atmosphere. Upon actuation, the formulation is forced through the opening, forming the 􀂦fine mist of particles that are directed to the site of administration. Aerosol preparations may consist of either a two-phase (gas and liquid) or a three-phase (gas, liquid, and solid or liquid) formulation. The two-phase formulation consists of drug substance(s) dissolved in liquefied propellant. Co-solvents such as alcohol may be added to enhance the solubility of the drug substance(s). Three-phase inhalation and nasal aerosol systems consist of suspended drug substance(s) in propellant(s), co-solvents, and potentially other suitable excipients. The suspension or emulsion of the 􀂦finely divided drug substance is typically dispersed in the liquid propellant with the aid of suitable biocompatible surfactants or other excipients. Propellants for aerosol formulations are typically low molecular weight hydrofluorocarbons or hydrocarbons that are liquid when constrained in the container, exhibit a suitable vapor pressure at room temperature, and are biocompatible and nonirritating. Compressed gases do not supply a constant pressure over use and typically are not used as propellants. Metal containers can withstand the vapor pressure produced by the propellant. Excess formulation may be added to the container to ensure that the full number of labeled doses can be accurately administered. The container and closure must be able to withstand the pressures anticipated under normal use conditions as well as when the system is exposed to elevated temperatures. TYPES OF AEROSOL DOSAGE FORMS Aerosol dosage forms can be delivered via various routes. The container, actuator, and metering valve, as well as the formulation, are designed to target the site of administration. Inhalation aerosols, commonly known as metered-dose inhalers (MDIs), are intended to produce fine particles or droplets for inhalation through the mouth and deposition in the pulmonary tree. The design of the delivery system is intended to release measured mass and appropriate quality of the active substance with each actuation. Nasal aerosols, commonly known as nasal MDIs, produce 􀂦fine particles or droplets for delivery through the nasal vestibule and deposition in the nasal cavity. Each actuation of the valve releases a measured mass of the drug substance with appropriate quality characteristics. Lingual aerosols are intended to produce fine particles or droplets for deposition on the surface of the tongue. The design of the delivery system releases 1 dose with each actuation. Topical aerosols produce 􀂦fine particles or droplets for application to the skin. LABELING FOR PROPER USE Refer to 21 CFR §201.320 and 21 CFR §369.21. Note: The detailed information regarding individual Official Dosage Forms in subsequent articles, Visit our website https://www.pharmaceuticalguideline.com/ regularly.

〈1151〉 PHARMACEUTICAL DOSAGE FORMS This article is based on the requirement of the United State Pharmacopoeia. (#usp, #pharmacopoeia, #MOA, #testprocedure, #qc, #qualitycontrol, #usp43, #nf38) GENERAL CONSIDERATIONS This chapter provides general descriptions of and definitions for drug products, or dosage forms, commonly used to administer the drug substance (active pharmaceutical ingredient; API). It discusses general principles involved in the manufacture or compounding of these dosage forms. A glossary is provided as a nomenclature resource and should be used in conjunction with the NomenclatureGuidelines A dosage form is a pharmaceutical preparation consisting of drug substance(s) and/or excipient(s) to facilitate dosing, administration, and delivery of the content of the drug product or placebo to the patient. The design, materials, manufacturing, and testing of all dosage forms target drug product quality. A testing protocol must consider not only the physical, chemical, microbiological, and biological properties of the dosage form as appropriate but also the administration route and desired dosing regimen. These considerations, organized by route of administration, are detailed in general chapters Injections and Implanted DrugProducts (Parenterals) — Product Quality Tests 〈1〉, Oral Drug Products — Product Quality Tests 〈2〉, Topical and Transdermal DrugProducts — Product Quality Tests 〈3〉, Mucosal Drug Products — Product Quality Tests 〈4〉, Inhalation and Nasal Drug Products — general information and Product Quality Tests 〈5〉, and Ophthalmic Products — Quality Tests 〈771〉. The organization of this general information chapter is by the quality attributes of each particular dosage form, generally without specific reference to the route of administration. The list below provides the preferred dosage forms used in official article titles. In addition to the preferred dosage forms, the Glossary contains other terms that have been used in current official article titles but are not preferred and should not be used for new drug product titles. Official Dosage Forms Used in Official Article Titles Aerosols Capsules Creams Emulsions Films Foams Gases Gels Granules Gums Implants Injections Inserts Irrigations Liquids Lotions Lozenges Ointments Pastes Pellets Pills Powders Rinses Shampoos Soaps Solutions Sprays Strips Suppositories Suspensions Systems Tablets Tests to ensure compliance with USP standards for dosage form performance fall into one of the following areas. Dose Uniformity (See also Uniformity of Dosage Units 〈905〉.) Consistency in dosing for a patient or consumer requires that the variation in the drug substance content of each dosage unit be accurately controlled throughout the manufactured batch or compounded lot of drug product. Uniformity of dosage units typically is demonstrated by one of two procedures: content uniformity or weight variation. The procedure for content uniformity requires the appropriate assay of the drug substance content of individual units. The procedure for weight variation uses the weight of the individual units to estimate their content. Weight variation may be used where the underlying distribution of the drug substance in the blend is presumed to be uniform and well-controlled, as in solutions. In such cases, the content of the drug substance may be adequately estimated by the net weight. Content uniformity does not rely on the assumption of blend uniformity and can be applied in all cases. Successful development and manufacture of dosage forms requires careful evaluation of the drug substance particle or droplet size, incorporation techniques, and excipient properties. Stability Drug product stability involves the evaluation of chemical stability, physical stability, and performance over time. The chemical stability of the drug substance in the dosage form matrix must support the expiration dating for the commercially prepared dosage forms and a beyond-use date for a compounded dosage form. Test procedures for potency must be stability-indicating (see Validation of Compendial Procedures 〈1225〉). Degradation products should be quantified. In the case of dispersed or emulsified systems, consideration must be given to the potential for settling or separation of the formulation components. Any physical changes to the dosage form must be easily reversed (e.g., by shaking) prior to dosing or administration. For tablets, capsules, oral suspensions, and implants, in vitro release test procedures such as dissolution and disintegration provide a measure of continuing consistency in performance over time (see Dissolution 〈711〉, Disintegration 〈701〉, and Drug Release 〈724〉). Bioavailability (See also In Vitro and In Vivo Evaluation of Dosage Forms 〈1088〉 and Assessment of Solid Oral Drug Product Performance and Interchangeability, Bioavailability, Bioequivalence, and Dissolution 〈1090〉.) Bioavailability is influenced by factors such as the method of manufacture or compounding, particle size, crystal form (polymorph) of the drug substance, the properties of the excipients used to formulate the dosage form, and physical changes as the drug product ages. Assurance of consistency in bioavailability over time(bioequivalence) requires close attention to all aspects of the production (or compounding) and testing of the dosage form. With proper justification, in vitro release testing (e.g., disintegration and dissolution) may be used as a surrogate to demonstrate consistent availability of the drug substance from the formulated dosage. Release Profile Two principal categories of drug release are recognized: immediate-release and modified-release. “Immediate-release” is observed when no deliberate effort has been made to modify the drug substance release pro􀂦le. For example, capsules and tablets are considered immediate-release even if a disintegrating agent or a lubricant has been used. “Modi􀂦ed-release” is a term used when the rate and/or time of release of the drug substance is altered as compared to what would be observed or anticipated for an immediate-release product. Two modified-release profiles, delayed-release, and extended-release are recognized. The term “modified-release” is not used for official article titles. “Delayed-release” is used when deliberate formulation achieves a delay in the release of the drug substance for some period of time after initial administration. For oral products, expressions such as “enteric-coated” or “gastro-resistant” have also been used where release of the drug substance is prevented in the gastric environment but promoted in the intestinal environment. However, the term “delayed-release” is used for official article titles. “Extended-release” is used when the deliberate formulation achieves prolongation of drug substance release compared to that observed or anticipated for an immediate-release dosage form. Expressions such as “prolonged-release”, “repeat-action”, “controlled-release”, “long-acting”, and “sustained-release” have also been used to describe such dosage forms. However, the term “extended-release” is used for official article titles. The Nomenclature Guidelines should be consulted for naming conventions for products with a single drug substance or for products with a combination of more than one drug substance displaying the combination of release profiles of immediate-release and extended-release, immediate-release and delayed-release, or extended-release and delayed-release. Manufacture Although detailed instructions about the manufacture of any of these dosage forms are beyond the scope of this general information chapter, general manufacturing principles have been included. Information relative to extemporaneous compounding of dosage forms can be found in Pharmaceutical Compounding — Nonsterile Preparations 〈795〉 and Pharmaceutical Compounding — Sterile Preparations 〈797〉. Route of Administration The primary routes of administration for pharmaceutical dosage forms can be de􀂦ned as parenteral (see 〈1〉), gastrointestinal (see 〈2〉), topical (see 〈3〉), mucosal, and (see 〈4〉), inhalation (see 〈5〉). Each has subcategories as needed. Many tests used to ensure quality generally are applied across all of the administration routes, but some tests are specific for individual routes. For example, products intended for injection must be evaluated using Sterility Tests 〈71〉, Bacterial Endotoxins Test 〈85〉, or Pyrogen Test 〈151〉, and the manufacturing process (and sterilization technique) employed for parenterals (by injection) should ensure compliance with these tests. Tests for particulate matter may be required for certain dosage forms depending on the route of administration (e.g., by injection — Particulate Matter in Injections 〈788〉, or mucosal — Particulate Matter in Ophthalmic Solutions 〈789〉). Additionally, dosage forms intended for the inhalation route of administration must be monitored for particle size and spray pattern (for a metered-dose inhaler or dry powder inhaler) and droplet size (for nasal sprays). Further information regarding administration routes and suggested testing can be found in the Guide to General Chapters, Chapter Charts, Charts 4–8, 10, and 13. An appropriate manufacturing process and testing regimen helps ensure that a dosage form can meet the appropriate quality attributes for the intended route of administration. Packaging and Storage Suitable packaging is determined for each product. For additional information about meeting packaging requirements listed in the individual labeling, refer to Packaging and Storage Requirements 〈659〉, Containers — Performance Testing 〈671〉, and Good Repackaging Practices 〈1178〉. Product labeling must specify storage requirements that describe environmental conditions, limitations, and restrictions. For instance, exposure to excessive temperature, humidity, and light can influence the ability of the packaging to protect the product. Labeling Statements Some dosage forms or articles have mandatory labeling statements that are given in the Code of Federal Regulations (e.g., 21 CFR§201.320 and 21 CFR §369.21). The text of 21 CFR should be consulted to determine the current recommendations. PRODUCT QUALITY TESTS, GENERAL International Council for Harmonisation (ICH) Guidance Q6A recommends specifications (list of tests, references to analytical procedures, and acceptance criteria) to ensure that drug products are safe and effective at the time of release and over their shelf life. Tests that are universally applied to ensure safety, e􀂨efficacy, strength, quality, and purity include description, identification, assay, and impurities. Description The Definition section (see General Notices, 4.10 Monographs) in a USP monograph describes the drug product and specifies the range of acceptable assayed content of the drug substance(s) present in the dosage form. For certain products, the definition includes any relevant additional information, such as the presence or absence of other components, excipients, or adjuvants, cautionary statements on toxicity and stability, etc. While appearance information to aid in identification is used in a regulatory submission (e.g., a qualitative description of size, shape, color, etc.) it is typically not required as part of a USP monograph. This information is drug product specific. Identification Identi􀂦cation tests are discussed in General Notices, 5.40 Identification tests should establish the identity of the drug substance(s) present in the drug product and should discriminate between compounds of closely related structure that are likely to be present. Identi􀂦cation tests should be specific for the drug substance(s). For example, the infrared absorption spectrum is often used (see Mid-Infrared Spectroscopy 〈854〉 and Spectroscopic Identification Tests 〈197〉). If no suitable infrared spectrum can be obtained, other analytical methods can be used. Near-infrared (NIR) or Raman spectrophotometric methods could also be acceptable as the sole identification method of the drug product formulation (see Near-Infrared Spectroscopy — Theory and Practice 〈1856〉 and Raman Spectroscopy — Theory and Practice 〈1858〉). Identification by a chromatographic retention time from a single procedure is not regarded as specific. The use of retention times from two chromatographic procedures for which the separation is based on different principles or a combination of tests in a single procedure can be acceptable (see Chromatography 〈621〉 and Thin-Layer Chromatographic Identification Test 〈201〉). Assay A specific and stability-indicating test should be used to determine the strength (drug substance content) of the drug product. Some examples of these procedures are Antibiotics — Microbial Assays 〈81〉, 〈621〉, or Assay for Steroids 〈351〉. In cases when the use of a nonspecific assay is justified (e.g., Titrimetry 〈541〉), other supporting analytical procedures should be used to achieve specificity. When evidence of excipient interference with a nonspecific assay exists, a procedure with demonstrated specificity should be used. Impurities Process impurities, synthetic byproducts, and other inorganic and organic impurities may be present in the drug substance and excipients used in the manufacture of the drug product. These impurities are evaluated by tests in the drug substance and excipient monographs. Impurities arising from degradation of the drug substance or from the drug-product manufacturing process should be monitored. Residual Solvents 〈467〉 is applied to all products where relevant. In some cases, testing for heavy metal impurities is appropriate. In addition to the universal tests listed, the following tests may be considered on a case-by-case basis. Physicochemical Properties Examples include pH 〈791〉, Viscosity — Capillary Methods 〈911〉 or Viscosity — Rotational Methods 〈912〉, and Specific Gravity 〈841〉. Particle Size For some dosage forms, particle size can have a significant effect on dissolution rates, bioavailability, therapeutic outcome, and stability. Procedures such as those found in Inhalation and Nasal Drug Products: Aerosols, Sprays, and Powders — Performance QualityTests 〈601〉 and Particle Size Distribution Estimation by Analytical Sieving 〈786〉 could be used. Uniformity of Dosage Units See the discussion of Dose Uniformity in the General Considerations section. Water Content A test for water content is included when appropriate (see Water Determination 〈921〉). Microbial Limits The type of microbial test(s) and acceptance criteria are based on the nature of the nonsterile drug product, method of manufacture, and the route of administration (see Microbiological Examination of Nonsterile Products: Microbial Enumeration Tests 〈61〉, Microbiological Examination of Nonsterile Products: Tests for Specified Microorganisms 〈62〉, and Microbiological Examination of nonsterile Products: Acceptance Criteria for Pharmaceutical Preparations and Substances for Pharmaceutical Use 〈1111〉). Antimicrobial Preservative Content Acceptance criteria for preservative content in multidose products should be established. They are based on the levels of antimicrobial preservative necessary to maintain the product’s microbiological quality at all stages throughout its proposed usage and shelf life (see Antimicrobial Effectiveness Testing 〈51〉). Antioxidant Content If antioxidants are present in the drug product, tests of their content should be performed to maintain the product’s quality at all stages throughout its proposed usage and shelf life. Sterility Depending on the route of administration (e.g., ophthalmic preparations, implants, aqueous-based preparations for oral inhalation, and injections) sterility of the product is demonstrated as appropriate (see 〈71〉). Dissolution A test to measure the release of the drug substance(s) from the drug product normally is included for dosage forms such as tablets, capsules, suspensions, granules for suspensions, implants, transdermal delivery systems, and medicated chewing gums. Single-point measurements typically are used for immediate-release dosage forms. For modified-release dosage forms, appropriate test conditions and sampling procedures are established as needed (see 〈711〉 and 〈724〉). In some cases, dissolution testing may be replaced by disintegration testing (see 〈701〉). Breaking Force and Friability These parameters are evaluated as in-process controls. Acceptance criteria depend on packaging, supply chain, and intended use (see Tablet Friability 〈1216〉 and Tablet Breaking Force 〈1217〉). Leachables When evidence exists that leachables from the container–closure systems (e.g., rubber stopper, cap liner, or plastic bottle) have an impact on the safety or efficacy of the drug product, a test is included to evaluate the presence of leachables. Other Tests Depending on the type and composition of the dosage form, other tests such as alcohol content, redispersibility, particle size distribution, rheological properties, reconstitution time, endotoxins/pyrogens, particulate matter, functionality testing of delivery systems, delivered dose uniformity, viscosity, and osmolarity may be necessary. Note: The detailed information regarding individual Official Dosage Forms in subsequent articles, Visit our website https://www.pharmaceuticalguideline.com/ regularly.

Working document QAS/21.875, February 2021. World Health Organization (WHO) has published the DRAFT WORKING DOCUMENT FOR COMMENTS. (Working documents in public consultation) You can give your comment to WHO for improvement in this guideline. This Draft Working document is providing guidance on Good manufacturing practices (GMP) for medical gases; Personnel Documentation Complaints Recalls Returns Self-inspection Premises Equipment and utilities Qualification and validation Production Quality control Product life cycle and continuous improvement Storage and distribution

<1> INJECTIONS AND IMPLANTED DRUG PRODUCTS (PARENTERALS)—PRODUCT QUALITY TESTS This article is based on the requirement of the United State Pharmacopoeia General Chapter. (#usp, #pharmacopoeia, #MOA, #testprocedure, #qc, #qualitycontrol, #usp43, #nf38) INTRODUCTION PRODUCT QUALITY TESTS COMMON TO PARENTERAL DOSAGE FORMS Universal Tests Specific Tests PRODUCT QUALITY TESTS FOR SPECIFIC PARENTERAL DOSAGE FORMS Solutions Sterile Powders for Solutions Suspensions Liposomes Sterile Powders for Suspensions Emulsions Implants Drug-Eluting Stents INTRODUCTION Parenteral drug products include both injections and implanted drug products that are injected through the skin or other external boundary tissue, or implanted within the body to allow the direct administration of the active drug substance(s) into blood vessels, organs, tissues, or lesions. Injections may exist as either immediate- or extended-release dosage forms. Implanted parenteral drug products are long-acting dosage forms that provide continuous release of the active drug substance(s), often for periods of months to years. For systemic delivery, they may be placed subcutaneously; for local delivery, they may be placed in a specific region of the body. Routes of administration for parenteral drug products include intravenous, intraventricular, intra-arterial, intra-articular, subcutaneous, intramuscular, intrathecal, intracisternal, and intraocular. Parenteral dosage forms include solutions, suspensions, emulsions, sterile powders for solutions and suspensions (including liposomes), implants (including microparticles), and products that consist of both a drug and a device such as drug-eluting stents. The definitions and descriptions of these dosage forms, and brief information about their composition and manufacturing processes, are found in Pharmaceutical Dosage Forms 〈1151〉. [NOTE—All references to chapters above 1000 are for informational purposes only, for use as a helpful resource. These chapters are not mandatory unless explicitly called out for application] This chapter is divided into three main sections: (1) universal product quality tests that are applicable to parenteral dosage forms; (2) specific product quality tests, which are tests that should be considered in addition to Universal Tests; and (3) product quality tests for specific dosage forms, which list applicable tests (universal and specific) for the specific dosage form. This chapter applies, in whole or in part, when referenced in a drug product monograph (see General Notices, 3.10 Applicability of Standards). The pharmacopeial definitions for sterile preparations for parenteral use may not apply to some biologics because of their special nature and licensing requirements (see Biologics 〈1041〉). However, some biological finished drug products containing “Injection” in the monograph title must meet the requirements of 〈1〉 or indicated chapter subparts, where it is specified in the monograph. PRODUCT QUALITY TESTS COMMON TO PARENTERAL DOSAGE FORMS Universal Tests Universal tests are listed below and are applicable to parenteral dosage forms. IDENTIFICATION Identification tests are discussed in General Notices, 5.40 Identification cation should establish the identity of the drug or drugs present in the article and should discriminate between compounds of closely related structure that are likely to be present... ASSAY A specific and stability-indicating test should be used to determine the strength (content) of the drug product. In cases where the use of a nonspecific assay is justified, other supporting analytical procedures should be used to achieve overall specificity. A specific procedure should be used when there is evidence of excipient interference with the nonspecific assay. IMPURITIES Tests for Impurities are discussed in General Notices, 5.60 Impurities and Foreign Substances All articles should be tested to ensure that they meet the requirements. FOREIGN AND PARTICULATE MATTER Articles intended for parenteral administration should be prepared in a manner designed to exclude particulate matter as defined in Subvisible Particulate Matter in Therapeutic Protein Injections 〈787〉, Particulate Matter in Injections 〈788〉, or Particulate Matter in Ophthalmic Solutions 〈789〉, as well as excluding other foreign matter as appropriate for the dosage form. Each final container of all parenteral preparations should be inspected to the extent possible for the presence of observable foreign and particulate matter(hereafter termed visible particulates) in its contents. The inspection process should be designed and qualified to ensure that every lot of all parenteral preparations is essentially free from visible particulates, as de􀂦ned in Visible Particulates in Injections 〈790〉. Qualification of the inspection process should be performed with reference to particulates in the visible range and those particulates that might emanate from the manufacturing or filling process. Every container in which the contents show evidence of visible particulates must be rejected. The inspection for visible particulates may take place during examination for other defects such as cracked or defective containers or seals, or when characterizing the appearance of a lyophilized product. When the nature of the contents or the container–closure system permits only limited inspection of the total contents, the 100%inspection of a lot should be supplemented with the inspection of constituted (e.g., dried) or withdrawn (e.g., from a dark amber container) contents of a sample of containers from the lot. Large-volume injections for single-dose infusion, small-volume injections, and pharmacy bulk packages (PBPs) are subject to the light obscuration or microscopic procedures and limits for subvisible particulate matter set forth in 〈788〉 unless otherwise specified in the chapter or in the individual monograph. An article packaged as both a large-volume and a small-volume injection meets the requirements set forth for small-volume injections where the container is labeled as containing 100 mL or less. It meets the requirements set forth for large-volume injections for single-dose infusion where the container is labeled as containing more than 100 mL. STERILITY The sterility of all drug products intended for parenteral administration should be confirmed by the use of methods described in Sterility Tests 〈71〉 or by an approved alternative method. BACTERIAL ENDOTOXINS All articles intended for parenteral administration should be prepared in a manner designed to limit bacterial endotoxins as defined in Bacterial Endotoxins Test 〈85〉 or Pyrogen Test 〈151〉. CONTAINER CONTENT Container contents should be determined when appropriate (see Container Content for Injections 〈697〉). PACKAGING SYSTEMS The packaging system should not interact physically or chemically with the preparation to alter its strength, quality, or purity beyond the official or established requirements. The packaging system should meet the requirements in Elastomeric Components Used in Injectable Pharmaceutical Packaging/Delivery Systems 〈381〉 (CN 1-Dec-2020), Packaging and Storage Requirements 〈659〉, Containers Glass 〈660〉, Plastic Packaging Systems and their Materials of Construction 〈661〉, Plastic Materials of Construction 〈661.1〉, and Plastic Packaging Systems for Pharmaceutical Use 〈661.2〉. Further information regarding packaging systems testing may be found in Assessment of Extractables Associated with Pharmaceutical Packaging/Delivery Systems 〈1663〉 and Assessment of Drug Product Leachables Associated with Pharmaceutical Packaging/Delivery Systems 〈1664〉. CONTAINER–CLOSURE INTEGRITY The packaging system should be closed or sealed in such a manner as to prevent contamination or loss of contents. Validation of container integrity must demonstrate no penetration of microbial contamination or gain or loss of any chemical or physical parameter deemed necessary to protect the product (see Package Integrity Evaluation — Sterile Products 〈1207〉, Package IntegrityTesting in the Product Life Cycle — Test Method Selection and Validation 〈1207.1〉, Package Integrity Leak Test Technologies 〈1207.2〉, and Package Seal Quality Test Technologies 〈1207.3〉). LABELING All articles intended for parenteral administration should meet the labeling requirements de􀂦ned in Labeling 〈7〉. Specific Test In addition to the Universal Tests listed above, the following specific tests may be necessary depending on the dosage form. UNIFORMITY OF DOSAGE UNITS This test is applicable for parenteral drug products and dosage forms packaged in single-unit containers. It includes both the mass of the dosage form and the content of the active substance in the dosage form (see Uniformity of Dosage Units 〈905〉). VEHICLES AND ADDED SUBSTANCES There are other vehicles, both aqueous and nonaqueous, beyond those that are discussed below. All vehicles should be suitable for their intended use and not impact drug product quality. Aqueous vehicles: Aqueous vehicles must meet the requirements of 〈151〉 or 〈85〉, whichever is specified in the monograph. Water for injection is generally used as the vehicle. Sodium chloride or dextrose may be added to render the resulting solution isotonic, and sodium chloride injection or Ringer's injection may be used in whole or in part instead of water for injection. Nonaqueous vehicles: Fixed oils are classified under Nonaqueous vehicles. Fixed oils used as vehicles are of vegetable origin and are odorless. They meet the requirements in the test for Solid Paraffin in Mineral Oil monograph with the cooling bath maintained at 10°. Nonaqueous vehicles should also meet the requirements of the following tests: Fats and Fixed Oils 〈401〉, Saponification Value: Between 185 and 200 Fats and Fixed Oils 〈401〉,Iodine Value : Between 79 and 141 Fats and Fixed Oils 〈401〉, Unsaponifiable Matter : NMT 1.5% Fats and Fixed Oils 〈401〉, Acid Value : NMT 0.2 Fats and Fixed Oils 〈401〉, Peroxide Value : NMT 5.0 Water Determination 〈921〉, Method Ic : NMT 0.1% Limit of Copper, Iron, Lead, and Nickel : [NOTE —The test for nickel is not required if the oil has not been subjected to hydrogenation, or a nickel catalyst has not been used in processing.] Proceed as directed in Fats and Fixed Oils 〈401〉, Trace Metals or Elemental Impurities — Procedures 〈233〉. Meet the requirements in Elemental Impurities — Limits 〈232〉. Synthetic mono- or diglycerides of fatty acids may be used provided they are liquid and remain clear when cooled to 10° and have a Iodine Value of NMT 140. Added substances: Suitable substances may be added to preparations in order to increase stability or usefulness unless they are prescribed in the monograph. No coloring agent may be added to a preparation solely for the purpose of coloring the finished preparation (see General Notices, 5.20 Added Substances and Antimicrobial Effectiveness Testing 〈51〉). Observe special care in the choice and use of added substances in preparations with volumes that exceed 5 mL. The following limits prevail unless otherwise directed: Mercury and cationic surface-active agents: NMT 0.01% Chlorobutanol, cresol, phenol, and similar substances: NMT 0.5% Sulfur dioxide or an equivalent amount of sulfite, bisulfite, or metabisulfite of potassium or sodium: NMT 0.2% ANTIMICROBIAL PRESERVATIVES Antimicrobial agents must be added to preparations intended for injection that are packaged in multiple-dose containers unless one of the following conditions prevails: (1) there are different directions in the individual monograph; (2) the substance contains a radionuclide with a physical half-life of less than 24 h; or (3) the active ingredients are themselves antimicrobial. Substances must meet the requirements of 〈51〉 and Antimicrobial Agents — Content 〈341〉. WATER CONTENT The water content of freeze-dried (lyophilized) products should be determined when appropriate (see 〈921〉). ALUMINUM CONTENT See Labeling 〈7〉, Aluminum in Large-Volume Injections (LVIs), Small-Volume Injections (SVIs), and Pharmacy Bulk Packages (PBPs)Used in Parenteral Nutrition (PN) Therapy for information related to specific labeling requirements associated with aluminum content. COMPLETENESS AND CLARITY OF SOLUTIONS The following tests are performed to demonstrate suitability of constituted solutions prepared before administration. Constitute the solution as directed in the labeling supplied by the manufacturer: The solid dissolves completely, leaving no undissolved matter. The constituted solution is not significantly less clear than an equal volume of the diluent or of purified water contained in a similar vessel and examined similarly. Protein solutions may exhibit an inherent opalescence. The constituted solution is free from particulate matter that can be observed on visual inspection (see 〈790〉). PRODUCT QUALITY TESTS FOR SPECIFIC PARENTERAL DOSAGE FORMS Product quality tests for the specific dosage forms are listed below. Specific chapter(s) referenced for the test can be found in the Universal Tests and Specific Tests sections. Solutions A solution is a clear, homogeneous liquid dosage form that contains one or more chemical substances (e.g., drug substances or excipients) dissolved in a solvent (aqueous or nonaqueous) or a mixture of mutually miscible solvents. Solutions intended for parenteral administration (e.g., by injection or for irrigation) must be sterile and biocompatible with the intended administration site. This includes consideration of factors such as tonicity, pH, pyrogenicity, extraneous particulate matter, and physicochemical compatibility, among others. Unless otherwise justified, the following tests are required for solutions for injection: Universal Tests Specific Tests Antimicrobial Preservatives Sterile Powders for Solutions Sterile powders for solutions (also referred to as sterile powders for injection) consist of drug substances and other components as dry-formulation ingredients to ensure the chemical and physical stability of the presentation within a final-use container. Companion sterile diluent or diluent compartments may be provided to facilitate constitution to the desired final volume. The sterile article for injection may be presented in several forms: lyophilized powder intended for final solution, powdered solids intended for final solution, or dry solids that form viscous liquids upon constitution. The description should include a section that deals with ease of dispersion and reconstitution. The dosage form is a homogeneous solid that is readily constituted to the final form with the specified diluent, and dispersion is completed with gentle agitation. Unless otherwise justified, the following tests apply to sterile powders for injection: Universal Tests The following applies to constituted solutions: Chapter 〈905〉: To ensure the consistency of dosage units, each unit in a batch should have a drug substance content within a narrow range around the label claim. Dosage units are defined as dosage forms that contain a single dose or a part of a dose of drug substance in each unit. For liquid dosage forms analysts should conduct the assay on an amount of well-mixed constituted material that is removed from an individual container under conditions of normal use, should express the results as delivered dose, and should calculate the acceptance value. The following applies to dry cake: Loss on Drying 〈731〉: The procedure set forth in this chapter determines the amount of volatile matter of any kind that is driven off under the conditions specified. Chapter 〈921〉: Water or solvent content may have important effects on reconstitution and stability. For articles that require water or solvent content control, analysts should perform one of the methods described in 〈921〉 or a suitable replacement. Appearance: Analysts should assess the level of and the unit variation for the following parameters: Color of Dry Cake: Varies within target parameters Texture and Homogeneity of Dry Cake: Varies within target parameters Presence of Foreign Material: All units with visible foreign material must be rejected Suspensions Parenteral suspensions are liquid dosage forms that contain solid particles in a state of uniform dispersion. Suspensions for parenteral administration must be sterile and compatible with the administration site. Consideration should be given to pH and pyrogenicity, and appropriate limits should be identified. Physical stability evaluations of parenteral suspension preparations should include evaluations to confirm that the particle size range of suspended matter does not change with time and to confirm that the solids in the preparation can be readily resuspended to yield a uniform preparation. The following tests are required for suspensions for injection unless otherwise justified: Universal Tests Specific Tests Uniformity of Dosage Units Antimicrobial Preservatives Liposomes Liposomes are unique drug products with unique properties that can be either solutions or suspensions. Liposomes are aqueous dispersions of amphiphilic lipids and have low water solubility. They are organized as a bilayer sheet that encloses an internal aqueous compartment and are known as lipid bilayer vesicles. Liposomes can have a single lipid bilayer (unilamellar vesicle) or can have an onion-like multilayered structure (multilamellar vesicle). The amphiphilic lipids comprise a hydrated head group at the water interface of the bilayer attached to a hydrophobic group that forms the interior of the bilayer by association with the hydrophobic group of lipids from the opposite leaflet of the bilayer. The physical properties of the liposome and its bilayer can vary widely and depend on lipid composition, aqueous composition, and temperature relative to the acyl components' phase transition points.Because of the central aqueous compartment, a simple test for the presence of liposomes in a lipid dispersion is to determine the presence of an entrapped aqueous phase. A liposome drug product consists of the drug substance, liposome components, and other inactive but critical ingredients such as an aqueous dispersion unless the contents are a lyophilized product. Unless otherwise justified, the following tests are required for liposomes: Universal Tests Specific Tests Globule Size Distribution in Lipid Injectable Emulsions 〈729〉 Sterile Powders for Suspensions Sterile powders for suspensions consist of drug substances and other components as dry-formulation ingredients to ensure the chemical and physical stability of the presentation within a final-use container. Companion sterile diluent or diluent compartments may be provided to facilitate constitution to the desired final volume. The sterile article for injection may be presented in several forms: lyophilized powder intended for final suspension, powdered solids intended for final suspension, and microparticles that retain their integrity and are delivered as a sterile suspension. The description should include a section that deals with ease of dispersion and reconstitution. The dosage form is a homogeneous solid that is readily constituted to the final form with the specified diluent, and dispersion is completed with gentle agitation. Unless otherwise justified, the following tests apply to sterile powders for injection: Universal Tests Microparticles: Some microparticles are provided as a sterile powder to be reconstituted as a suspension before injection. The majority of microparticle preparations are for reconstitution as a suspension for injection. For quality test requirements, please refer to Implants. Emulsions Emulsions for parenteral dosage forms are liquid preparations of drug substances dissolved or dispersed in a suitable emulsion medium. Oil-in-water or water-in-oil emulsions typically entrap the drug substance. Emulsions typically are white, turbid, homogeneous liquid dosage forms that contain one or more chemical substances (e.g., drug substances and excipients) dissolved in a solvent (aqueous or nonaqueous) or mixture of mutually miscible solvents. Emulsionsintended for intravenous administration must be sterile and must be compatible with the intended administration site. Unless otherwise justified, the following tests are required for emulsions for injection: Universal Tests Specific Tests Chapter 〈729〉 Implants Implants for extended-release consist of a matrix of drug substance and polymeric excipient that may or may not have an outer rate-controlling membrane. The polymeric excipient must be biocompatible but may or may not be bioresorbable. Some implants are made from medical-grade metal with an osmotic pump inside that effects the extended-release of the drug substance. Implants must be sterile and usually are formed in the shape of a cylinder, although other shapes are used. Solvents used to dissolve the formulation can lead to sterilization, and thus the internal sterility test method should demonstrate that the sample preparation does not lead to sterilization of the test sample. Cylindrically shaped implants for systemic delivery usually are provided in an inserter for subcutaneous or local administration such as local ocular delivery. Implants also can be surgically implanted for local delivery, e.g., ocular delivery. Unless otherwise justified, the following tests are required for implants: Universal Tests Specific Tests Uniformity of Dosage Units In situ Gels Sterile in situ gels are liquid preparations that are intended for injection into specific therapeutic targets. Typically they consist of polymers in organic solvents, and upon injection the solvents migrate away from the site, leaving a gelled mass. The preparations may be injected as-is, upon reconstitution, from in situ formation, or from chemically initiated catalysis that results in the final form. Unless otherwise justified, the following tests are required for in situ gels: Universal Tests Specific Tests Antimicrobial Preservatives Microparticles Injectable, resorbable microparticles for extended-release generally range from 20 to 100 μm in diameter. They consist of drug substances embedded within a biocompatible, bioresorbable polymeric excipient, e.g., polyester excipients. Microparticles are provided as sterile powder in a vial or syringe. Just before intramuscular or subcutaneous administration, the microparticle powder should be suspended in an aqueous injection vehicle (diluent). The injection vehicle usually consists of water for injection, surfactant, and a viscosity enhancer, and the vehicle may contain a compound that adjusts osmolality, e.g., a sugar with or without a compound that controls pH, e.g., an acid. The injection vehicle must be sterile and must be tested according to requirements for solutions that are intended for parenteral administration. Unless otherwise justified, the following tests are required for microparticles for injection: Universal Tests Specific Tests Uniformity of Dosage Units Water Content Drug-Eluting Stents Drug-eluting stents are tiny metal or polymer scaffolds used to keep arteries open following a medical intervention; the drug substance is incorporated into or onto the stent platform. Drug-eluting stents typically have two components of testing: (1) functional tests that generally are American Society for Testing and Materials (ASTM) International methods that fall outside the scope of this chapter and (2) analytical tests. Unless otherwise justified, the following tests are required for drug-eluting stents: Universal Tests Specific Tests Uniformity of Dosage Units. The content of the active substance in the dosage form is applicable for drug-eluting scents packagedeight variation (see 〈905〉). With appropriate justification, the number of stents needed for this test may be fewer than the recommended number of stents in 〈905〉. 〈88〉 Biological Reactivity Tests, In Vivo

Pharmaceutical Inspection Co-operation Scheme (PIC/S) Leading the international development, implementation, and maintenance of harmonized GMP standards and quality systems of Inspectorates in the field of medicinal products, PIC/S has revised the guidance document for INSPECTION OF UTILITIES on 19 January 2021, (Geneva), PI 009-4 Aide-Memoire on INSPECTION OF UTILITIES The revision process consisted in updating the cross-references to the PIC/S GMP Guide. No other changes were made. The revised Aide Memoires enter into force on 1 January 2021. The purpose of PI 009-4 Aide-Memoire is to provide guidance for GMP inspectors to use for training purposes and in preparation for inspections. The Aide-Memoire is the direct result of the 2001 PIC/S Seminar and was drafted with the aim of facilitating the effective planning and conduct of GMP inspections of utilities. The Aide-Memoire should enable the inspector to make both an optimal use of the inspection time and an optimal evaluation of GMP compliance. The PI 009-4 Aide-Memoire on INSPECTION OF UTILITIES describes different areas that could be evaluated during the GMP inspection of HVAC systems, pharmaceutical water, steam, and medicinal gases. However, the Aide-Memoire should be considered as a non-exhaustive list of areas to be looked at during an inspection. The document is describing the following points; HVAC Key design parameters Qualification of HVAC System Walk round tour Confront differences between design specifications, drawings (in SMF) and reality, unplanned maintenance, and change control and etc. Monitoring of HVAC systems Maintenance and calibration of HVAC systems Documentation for HVAC systems Pharmaceutical water system Key design parameters Qualification Walk round inspection Is water for injection produced and used according to requirements of Note for Guidance on Quality of Water for Pharmaceutical Purposes and Ph Eur? Confront differences between drawings and reality, unplanned maintenance, and change control. Follow the system from pre-treatment to user points: in each part, check leaks, sampling points (access), who does what, start-up and shutdown, cleaning/disinfection/sterilization), quantities produced. Quality control testing Monitoring Maintenance and calibration of water systems Documentation Pharmaceutical steam systems Key design parameters Qualification Walk round tour What kind of steam is used for the manufacture of pharmaceutical products – factory, clean steam generator)? What kind of source water is used for the production of steam? Confront differences between drawings and reality, unplanned maintenance, and change control. Follow the system in a logical order. Pay attention to leaks, sampling points (access), who does what, start-up and shutdown, cleaning/disinfection/sterilization), quantities produced. Monitoring Quality control testing Maintenance and calibration of the system Documentation Pharmaceutical gases Key design criteria (compressed air) Qualification Walk round inspection Identify all used gases with the risk for medicinal products. Confront differences between drawings and reality, unplanned maintenance and change control Follow the system in a logical order Operating the system Monitoring of the system Quality control Maintenance and calibration of the system Documentation To read the entire Aide-Memoire published by PIC/S Click here This Short Note is published as a news update only; however, the detailed article on INSPECTION OF UTILITIES will be available shortly. Dear readers; I am Inviting you to become a part of the DPT Family (Dynamic Pharma Team. To update yourself; regularly visit our website: www.pharmaceuticalguideline.com and become a member (it's FREE) by clicking the Login button at the top right corner of the webpage, also subscribe to our newsletter, Like our website, follow us on Facebook (https://www.facebook.com/pharmaceuticalguideline) Instagram (https://www.instagram.com/pharmaceuticalguideline/) LinkedIn (https://www.linkedin.com/company/pharmaceuticalguideline) Twitter (https://twitter.com/pharma_guidance) Telegram, Download Telegram App on your Mobile and use @pharmaceuticalguideline for search. Your like is inspiring us to prepare the articles...

Pharmaceutical Inspection Co-operation Scheme (PIC/S) Leading the international development, implementation, and maintenance of harmonized GMP standards and quality systems of Inspectorates in the field of medicinal products, PIC/S has revised the guidance document for GMP INSPECTION RELATED TO PACKAGING on 19 January 2021, (Geneva), PI 028-2 Aide-Memoire on Packaging The revision process consisted in updating the cross-references to the PIC/S GMP Guide. No other changes were made. The revised Aide Memoires enter into force on 1 January 2021. The purpose of PI 028-2 Aide-Memoire is to provide guidance for GMP inspectors in preparation for inspections. This document aims to define the minimal requirements acceptable for an inspector as well as the requirements that provide maximum safety for the finished product (“best practices”). The Aide-Memoire should enable the inspector to assess the GMP compliance of the packaging process using the quality risk management tools. The PI 028-2 Aide-Memoire on GMP INSPECTION RELATED TO PACKAGING has described different areas that could be evaluated during the GMP inspection of the packaging and labeling process. However, the Aide-Memoire should be considered as a non-exhaustive list of areas to be looked at during an inspection. The document is describing following points; Quality and Purchasing of Packaging Material Receipt of Packaging Material Storage Area of Packaging Material Quality Control checks for Packaging Material Manufacturing Premises (Packaging Area) Requirement Packaging Equipment and Process Documentation related to Packaging Material and Packing activity Requirement related to the Personnel engaged with the Packing activity and Packaging material handling The Quality Assurance consideration for Packaging Material and Packing activity To read the entire Aide-Memoire published by PIC/S Click here This Short Note is published as a news update only; however, the detailed article on GMP INSPECTION RELATED TO PACKAGING will be available shortly. Dear readers; I am Inviting you to become a part of the DPT Family (Dynamic Pharma Team. To update yourself; regularly visit our website: www.pharmaceuticalguideline.com and become a member (it's FREE) by clicking the Login button at the top right corner of the webpage, also subscribe to our newsletter, Like our website, follow us on Facebook (https://www.facebook.com/pharmaceuticalguideline) Instagram (https://www.instagram.com/pharmaceuticalguideline/) LinkedIn (https://www.linkedin.com/company/pharmaceuticalguideline) Twitter (https://twitter.com/pharma_guidance) Telegram, Download Telegram App on your Mobile and use @pharmaceuticalguideline for search. Your like is inspiring us to prepare the articles...

Pharmaceutical Inspection Co-operation Scheme (PIC/S) Leading the international development, implementation, and maintenance of harmonized GMP standards and quality systems of Inspectorates in the field of medicinal products, PIC/S has revised the guidance document for Quality Risk Management (QRM) on 19 January 2021, (Geneva), PI 038-2 Aide-Memoire on Assessment of QRM Implementation The revision process consisted in updating the cross-references to the PIC/S GMP Guide. No other changes were made. The revised Aide Memoires enter into force on 1 January 2021. The purpose of PI 038-2 Aide-Memoire is to assist GMP inspectors in the assessment of QRM implementation in the industry during regulatory inspections. Parts of this Aide-Memoire may also be useful (with suitable modification) during other GXP inspections where similar principles of QRM also apply This Aide-Memoire should also contribute to a harmonized approach for inspection of QRM in industry between the different PIC/S Members. The PI 038-2 Aide-Memoire on Assessment of QRM Implementation document has well explained the views and expectations of the Regulatory Authority in the following parts, Overall Systems Expectations on how QRM should be implemented Specific areas and activities where implementation of QRM might be expected Review of residual risk Review and improvement of QRM activities To read the entire Aide-Memoire published by PIC/S Click here This Short Note is published as a news update only; however, the detailed article on Quality Risk Management will be available shortly. Dear readers; I am Inviting you to become a part of the DPT Family (Dynamic Pharma Team. To update yourself; regularly visit our website: www.pharmaceuticalguideline.com and become a member (it's FREE) by clicking the Login button at the top right corner of the webpage, also subscribe to our newsletter, Like our website, follow us on Facebook (https://www.facebook.com/pharmaceuticalguideline) Instagram (https://www.instagram.com/pharmaceuticalguideline/) LinkedIn (https://www.linkedin.com/company/pharmaceuticalguideline) Twitter (https://twitter.com/pharma_guidance) Telegram, Download Telegram App on your Mobile and use @pharmaceuticalguideline for search. Your like is inspiring us to prepare the articles...