Ph. Eur. Commission adopts revised general monographs 2034 and 2619 after inclusion of a new paragraph on control of N-nitrosamines At its 174th session in November 2022, the European Pharmacopoeia (Ph. Eur.) Commission adopted the revised general monographs Substances for pharmaceutical use (2034) and Pharmaceutical preparations (2619), which now include a paragraph explaining the Ph. Eur. approach to N-nitrosamine impurities. This approach was defined based on the comments received during the last round of public consultation in Pharmeuropa together with recent feedback from Heads of Medicines Agency (Homeopathic Medicinal Products Working Group) and European Medicines Agency (Joint Committee for Medicinal Products for Human Use/Committee for Medicinal Products for Veterinary Use Quality Working Party, Biologics Working Party, Committee for Veterinary Medicinal Products, Herbal Medicinal Products Committee) groups and from the national competent authorities of non-EU Ph. Eur. member states. The following paragraph has been added to 2034 under “Production”: “N-Nitrosamines. As many N-nitrosamines are classified as probable human carcinogens, manufacturers of active substances for human use are expected to evaluate the potential risk of N-nitrosamine formation and contamination occurring throughout their manufacturing process and during storage. If the risk is confirmed, manufacturers should mitigate as much as possible the presence of N-nitrosamines – for example by modifying the manufacturing process – and a control strategy should be implemented to detect and control these impurities. General chapter 2.5.42 N-Nitrosamines in active substances is available to assist manufacturers.” A similar paragraph has been added to the same section in 2619: “N-Nitrosamines. As many N-nitrosamines are classified as probable human carcinogens, manufacturers of medicinal products, except products for veterinary use only and unlicensed pharmaceutical preparations, are expected to evaluate the potential risk of N-nitrosamine formation and contamination occurring throughout their manufacturing process and throughout their shelf-life, according to the requirements of the relevant competent authorities. If the risk is confirmed, manufacturers should mitigate as much as possible the presence of N-nitrosamines – for example by modifying the manufacturing process – and a control strategy must be implemented to detect and control these impurities. General chapter 2.5.42. N-Nitrosamines in active substances is available to assist manufacturers.” The revised monographs will be published in Ph. Eur. Supplement 11.3 and implemented as from 1 January 2024. The Ph. Eur. Commission will now start reflecting on how to address the issue of nitrosamine control in individual monographs.

Pastes are semisolid preparations of stiff consistency and contain a high percentage (20%–50%) of finely dispersed solids. Pastes are intended for application to the skin, oral cavity, or mucous membranes. Pastes ordinarily do not flow at body temperature and thus can serve as occlusive, protective coatings. As a consequence, pastes are more often used for protective action than ointments. Fatty pastes that have a high proportion of hydrophilic solids appear less greasy and are more absorptive than ointments. They are used to absorb serous secretions and are often preferred for acute lesions that have a tendency toward crusting, vesiculation, or oozing. Dental pastes are applied to the teeth. Other orally administered pastes may be indicated for adhesion to the mucous membrane for a local effect. Although rare, pastes can be administered orally, for example to evaluate pharyngeal function. In veterinary medicine, pastes are typically administered orally and are intended for systemic delivery of drug substances. The paste is squeezed into the mouth of the animal, generally at the back of the tongue, or is spread inside the mouth.

WHO Expert Committee on Specifications for Pharmaceutical Preparations has published the Technical Report Series TRS 1044 on 22 Dec 2022 (Fifty-sixth report) Contents Abbreviations WHO Expert Committee on Specifications for Pharmaceutical Preparations Declarations of interest OPEN SESSION Introduction and welcome I. ECSPP procedures and processes II. Update on new guidelines, norms and standards III. Technical agenda topics of the fifty-sixth ECSPP IV. Points of discussion PRIVATE AND CLOSED SESSIONS Opening Election of chairpersons and rapporteurs Participation in ECSPP meetings 1. General policy 1.1 Process for development of WHO norms and standards 2. General updates and matters for information 2.1 Expert Committee on Biological Standardization 2.2 Expert Committee on the Selection and Use of Essential Medicines 2.3 Prequalification of medicines 2.4 Member State Mechanism and post-market surveillance 2.5 International Conference of Drug Regulatory Authorities 3. Quality assurance: collaboration initiatives 3.1 International Meeting of World Pharmacopoeias 4. Nomenclature, terminology and databases 4.1 International nonproprietary names for pharmaceutical substances 4.2 Quality assurance terminology 4.3 Guidelines and guidance texts adopted by the ECSPP 5. Quality control: national laboratories 5.1 External Quality Assurance Assessment Scheme 5.1.1 Final report on EQAAS phase 10 5.1.2 Update on EQAAS phase 11 6. Quality control: specifications and tests 6.1 The International Pharmacopoeia 6.1.1 Workplan 2022–2023 6.2 General chapters 6.2.1 Chromatography 6.3 Specifications and draft monographs for medicines, including paediatrics and candidate medicines for COVID-19 6.3.1 COVID-19 therapeutics 6.3.2 Medicines for maternal, newborn, child and adolescent health 6.3.3 Antimalarial medicines 6.3.4 Antituberculosis medicines 6.3.5 Antiviral medicines, including antiretrovirals 6.3.6 Other medicines 6.4 Update on the virtual consultations on screening technologies, laboratory tools and pharmacopoeial specifications 7. Quality control: international reference materials 7.1 Update on International Chemical Reference Substances 8. Quality assurance: good manufacturing practices and inspection 8.1 Good manufacturing practices for sterile pharmaceutical products 8.2 Good manufacturing practices for investigational radiopharmaceutical products 8.3 Guidelines on technology transfer in pharmaceutical manufacturing 8.4 Good manufacturing practices for medicinal gases 8.5 Good practices for research and development facilities 8.6 Good manufacturing practices for investigational products 8.7 Recommendations from the virtual consultation on good practices for health products manufacture and inspection 9. Quality assurance: distribution and supply chain 9.1 Setting remaining shelf-life for supply and procurement of emergency health kits 9.2 WHO/UNFPA guidance on natural rubber latex condom stability studies 9.3 WHO/UNFPA technical specification for TCu380A intrauterine device 10. Regulatory guidance and model schemes 10.1 WHO Biowaiver List: proposal to waive in vivo bioequivalence requirements for medicines included in the EML 10.2 WHO guidance on registration requirements to establish interchangeability for multisource (generic) products 10.3 Update on WHO-listed authorities 10.4 WHO Certification Scheme on the quality of pharmaceutical products moving in international commerce 10.5 Recommendations from the virtual consultation on regulatory guidance for multisource products 10.6 Ongoing activities and proposed new topics for regulatory guidance and model schemes 11. Miscellaneous: update on COVID-19 activities 11.1 Therapeutic specifications 11.2 Existing guidance 11.3 New activities 12. Closing remarks 13. Summary and recommendations 13.1 Guidelines and decisions adopted and recommended for use 13.2 Texts adopted for inclusion in The International Pharmacopoeia 13.2.1 General chapters 13.2.2 Monographs 13.2.3 International Chemical Reference Substances (ICRS) 13.3 Recommendations 13.3.1 The International Pharmacopoeia 13.3.2 Quality control: national laboratories 13.3.3 Good manufacturing practices and related areas 13.3.4 Distribution and supply chain 13.3.5 Regulatory mechanisms 13.3.6 Other 55 Acknowledgments References Annex 1 Guidelines and guidance texts adopted by the Expert Committee on Specifications for Pharmaceutical Preparations Annex 2 WHO good manufacturing practices for sterile pharmaceutical products Annex 3 IAEA/WHO guideline on good manufacturing practices for investigational radiopharmaceutical products Annex 4 WHO guidelines on technology transfer in pharmaceutical manufacturing Annex 5 WHO good manufacturing practices for medicinal gases Annex 6 WHO good practices for research and development facilities of pharmaceutical products Annex 7 WHO good manufacturing practices for investigational products Annex 8 Points to consider for setting the remaining shelf-life of medical products upon delivery Annex 9 WHO/UNFPA guidance on natural rubber latex male condom stability studies Annex 10 WHO/UNFPA technical specification for TCu380A intrauterine device Annex 11 WHO Biowaiver List: proposal to waive in vivo bioequivalence requirements for WHO Model List of Essential Medicines immediate-release, solid oral dosage forms

Signal-to-noise ratio: revision of Ph. Eur. general chapter Chromatographic separation techniques (2.2.46) The revised general chapter Chromatographic separation techniques (2.2.46) was published in the 11th Edition of the European Pharmacopoeia (Ph. Eur.) in the framework of international harmonisation. This new version (due to be implemented on 1 January 2023) includes many important changes. One of these changes is the sensitivity requirement. The revised chapter instructs users to calculate the signal-to-noise (S/N) ratio on a window of 20 times the peak width at half height (“20 x Wh”), whereas from Ph. Eur. Supplement 6.4 through Supplement 10.8, it is calculated on a window of at least 5 times the peak width at half height (“at least 5 x Wh”). Recent data gathered by the European Directorate for the Quality of Medicines & HealthCare (EDQM) showed that this change might be technically challenging for a number of our users, prompting the Ph. Eur. Commission to reconsider it. As a result, Ph. Eur. users are advised to continue calculating the S/N ratio on a window “at least 5 x Wh”, instead of “20 x Wh”. General chapter 2.2.46 has been revised accordingly and will be included in Supplement 11.3 (to be published in July 2023 and implemented on 1 January 2024). Reference: EDQM News

Reference: EDQM News The European Directorate for the Quality of Medicines & HealthCare (EDQM) has published the revised general chapter on Rubber closures for containers for aqueous parenteral preparations, for powders and for freeze-dried powders (3.2.9) in European Pharmacopoeia Supplement 11.1, with an implementation date of 1 April 2023. This general chapter is mandatory for aqueous parenteral preparations since it is referred to in the general monograph on Pharmaceutical preparations (2619) and in the dosage form monograph Parenteral preparations (0520), both of which are legally binding. The revised chapter was first published in Pharmeuropa 33.2 for public consultation. The comments received were reviewed by the group of experts responsible for the text (Group 16) before the finalised text was adopted by the European Pharmacopoeia Commission at its 172nd session in March 2022. The overall aim of the revision process was to update the text and bring it in line with current practices. The key changes to several sections are detailed below. The Definition and scope section has been changed to prohibit the use of natural rubber latex because of its allergenic potential. However, dry natural rubber is permitted since any allergens it contains are removed during processing. IR has been maintained as the basic identification technique for rubber, and the Total ash test has become optional and complementary. A list of other techniques that can be used is now also included. Acidity or alkalinity has been revised to explain how to choose the titrant depending on the colour of the indicator. For the Absorbance test, filtration is now prescribed for turbid or hazy solutions only. The test for Extractable heavy metals has been deleted to align with ICH Q3D and the Ph. Eur. policy on Elemental impurities. Rubber closures are considered to be part of the container closure system and as such, their impact on the level of elemental impurities is evaluated as part of the risk assessment for the pharmaceutical product. The test for Extractable zinc has been kept as zinc is often intentionally added during the manufacturing process and there is therefore a high probability that it will be found in rubber samples. The introduction to the Functional tests section has been expanded to indicate when to perform, potentially adapt or omit these tests which, due to the many different types of containers and corresponding rubber closures used, might not always be applicable. Fragmentation: the specific testing procedure for closures used for dry preparations has been deleted. Allowing the sample to stand for 16 h at room temperature proved unnecessary and this requirement has therefore been deleted from the procedure to ease the running of the test. As mentioned above, the revised chapter will come into force on 1 April 2023. Reference: EDQM News

IMPLANTS Implants are long-acting dosage forms that provide continuous release of the drug substance often for periods of months to years. They are administered by the parenteral route and are sterile. Some implants approved as animal drugs to be administered subcutaneously to the ears are not required to be sterile. Typically for systemic delivery, they may be placed subcutaneously, or for local delivery, they can be placed in a specific region in the body (e.g., in the sinus, in an artery, in the eye, in the brain). Implants are usually administered by means of a suitable injector or by surgical procedure. Polymer implants can be formed as a single-shaped mass such as a cylinder. The polymer matrix must be biocompatible (see The Biocompatibility of Materials Used in Drug Containers, Medical Devices, and Implants), but it can be either bioabsorbable or nonbioabsorbable. Shaped polymer implants are administered by means of a suitable special injector. Release kinetics are typically not zero-order, but zero-order kinetics are possible. Drug substance release can be controlled by the diffusion of the drug substance from the bulk polymer matrix or by the properties of a rate-limiting polymeric membrane coating. Polymer implants are used to deliver potent small molecules like steroids (e.g., estradiol for cattle) and large molecules like peptides [e.g., luteinizing hormone-releasing hormone (LHRH)]. Example durations of drug substance release are 2 and 3 months for bioabsorbable implants and up to 3 years for nonbioabsorbable implants. An advantage of bioabsorbable implants is that they do not require removal after the release of all drug substance content. Nonbioabsorbable polymer implants can be removed before or after a drug substance release is complete or may be left in situ. An implant can have a tab with a hole in it to facilitate suturing it in place (e.g., for an intravitreal implant for local ocular delivery). Such implants may provide a therapeutic release for periods as long as 2.5 years. Drug substance-eluting stents combine the mechanical effect of the stent to maintain arterial patency with the prolonged pharmacologic effect of the incorporated drug substance (to reduce restenosis, inhibit clot formation, or combat infection). As an example, a metal stent can be coated with a nonbioabsorbable or bioabsorbable polymer-containing drug substance. The resultant coating is a polymeric matrix that controls the extended release of the drug substance. PREPARATION Cylindrical polymeric implants are commonly made by melt extrusion of a blend of drug substance and polymer, resulting in a rod that is cut into shorter lengths. Polymer implants also can be made by injection molding. Still, other implants are assembled from metal tubes and injection-molded plastic components. Sterility can be achieved by terminal sterilization or by employing aseptic manufacturing procedures.

OTHER NONMONOGRAPHED WATERS In addition to Drinking Water, this compendium discusses waters with various other designations. These include waters of various quality levels for special uses such as, but not limited to, cleaning and testing purposes. Both General Notices and Requirements (Water in a Compendial Procedure) and Reagents, Indicators, and Solutions clearly state that where the term “water” is indicated for use in analyses without grammatical qualification or other specification, the quality of the water must be Purified Water. However, numerous such qualifications do exist. Some of these qualifications involve adjectives describing methods of preparation, ranging from specifying the primary purification step to specifying additional purification. Other qualifications call for specific attribute “absences” to be met that might otherwise interfere with analytical processes. In most of these cases, the required attribute absences are not specifically tested. Sometimes, a further “purification process” is specified that ostensibly allows the water to adequately meet this required “absence attribute”. However, preparation instructions for many reagents were carried forward from the innovator’s laboratories to the originally introduced monograph for a particular USP–NF article or general test chapter. The quality of the reagent water described in these tests may reflect the water quality designation of the innovator’s laboratory. These specific water designations may have originated without the innovator’s awareness of the requirement for Purified Water in USP–NF tests. Regardless of the original reason for the creation of these numerous special analytical waters, it is possible that the attributes of these special waters could now be met by the basic preparation steps and current specifications of Purified Water. In some cases, however, some of the cited post-processing steps are still necessary to reliably achieve the required attributes. Users are not obligated to utilize specific and perhaps archaically generated forms of analytical water where alternatives with equal or better quality, availability, or analytical performance may exist. The consistency and reliability of operations for producing these alternative analytical waters should be verified so that the desired attributes are produced. In addition, any alternative analytical water must be evaluated on an application-by-application basis by the user to ensure its suitability. The following is a summary of the various types of nonmonographed analytical waters that are cited in the USP–NF. This is not an exhaustive listing. Those listed below are used in multiple locations. Several nonmonographed analytical waters are not included below because they are only found in one or perhaps two locations within this compendium. Note that the names of many of the waters below imply a very low chemical impurity level. For example, “deionized water” implies that all the ions have been removed. However, in most cases discussed below, exposure of the water to air will result in the ingress of carbon dioxide (CO2), leading to the formation of bicarbonate and hydrogen ions. Therefore, the removal of ions cannot be completely maintained for most analytical applications. DRINKING WATER OTHER NONMONOGRAPHED WATERS AMMONIA-FREE WATER CARBON DIOXIDE-FREE WATER DISTILLED WATER FRESHLY DISTILLED WATER DEIONIZED WATER DEIONIZED DISTILLED WATER FILTERED WATER HIGH-PURITY WATER DEAERATED WATER OXYGEN-FREE WATER WATER FOR BACTERIAL ENDOTOXINS TEST

WATER FOR BACTERIAL ENDOTOXINS TEST WATER FOR BACTERIAL ENDOTOXINS TEST is also referred as Limulus Amebocyte Lysate (LAL) Reagent Water. This type of water is often Water for Injection, which may have been sterilized. It is free from a level of endotoxin that would yield any detectable reaction or interference with the LAL reagent used in the BACTERIAL ENDOTOXINS TEST Relevant Articles.... DRINKING WATER OTHER NONMONOGRAPHED WATERS AMMONIA-FREE WATER CARBON DIOXIDE-FREE WATER DISTILLED WATER FRESHLY DISTILLED WATER DEIONIZED WATER DEIONIZED DISTILLED WATER FILTERED WATER HIGH-PURITY WATER DEAERATED WATER OXYGEN-FREE WATER WATER FOR BACTERIAL ENDOTOXINS TEST

Nonmonographed Waters: In addition to the bulk monographed waters described in the article https://www.pharmaceuticalguideline.com/post/waters-used-for-pharmaceutical-manufacturing-and-testing-purposes, non-monographed waters can also be used in pharmaceutical processing steps such as cleaning and synthetic steps, and also as a starting material for further purification or testing purposes. Unless otherwise specified in the compendium, the minimum quality of water is Purified Water. [NOTE—The information in this the chapter is not an all-inclusive discussion of all non-monographed waters identified in the USP–NF.] DRINKING WATER OTHER NONMONOGRAPHED WATERS AMMONIA-FREE WATER CARBON DIOXIDE-FREE WATER DISTILLED WATER FRESHLY DISTILLED WATER DEIONIZED WATER DEIONIZED DISTILLED WATER FILTERED WATER HIGH-PURITY WATER DEAERATED WATER OXYGEN-FREE WATER WATER FOR BACTERIAL ENDOTOXINS TEST

AMMONIA FREE WATER From a functional standpoint, Ammonia Free Water must have a negligible ammonia concentration to avoid interference in tests sensitive for or to ammonia. Due to the nature of the uses of this water, Purified Water could be a reasonable alternative for these applications.

Medicated gum is a pliable dosage form that is designed to be chewed rather than swallowed. Medicated gums release the drug substance(s) into the saliva. Medicated gums can deliver therapeutic agents for local action in the mouth or for systemic absorption via the buccal or gastrointestinal routes (e.g., nicotine or aspirin). Most gums are manufactured using the conventional melting process derived from the confectionary industry or alternatively may be directly compressed from gum powder. Medicated gums are formulated from insoluble synthetic gum bases such as polyisoprene, polyisobutylene, isobutylene isoprene copolymer, styrene-butadiene rubber, polyvinyl acetate, polyethylene, ester gums, or polyterpenes. Plasticizers and softeners such as propylene glycol, glycerin, oleic acid, or processed vegetable oils are added to keep the gum base pliable and to aid in the incorporation of the drug substance(s), sweeteners, and flavoring agents. Sugars as well as artificial sweeteners and flavorings are incorporated to improve taste, and dyes may be used to enhance appearance. Some medicated gums are coated with magnesium stearate to reduce tackiness and improve handling during packaging. A preservative may be added. Preparation Melted gum: The gum base is melted at a temperature of about 115° C until it has the viscosity of thick syrup and, at that point, is filtered through a fine-mesh screen. This molten gum base is transferred to mixing tanks where the sweeteners, plasticizers, and typically the drug substance are added and mixed. Colorings, flavorings, and preservatives are added and mixed while the melted gum is cooling. The cooled mixture is shaped by extrusion or rolling and cutting. Dosage units of the desired shape and potency are packaged individually. Additional coatings such as powder coatings to reduce tackiness or film or sugar coatings may be added to improve taste or facilitate bulk packaging. Directly compressed gum: The gum base is supplied in a free-flowing granular powder form. The powder gum base is then dry blended with sweeteners, flavors, the drug substance, and lubricant. The blend is then processed through a conventional tablet press and tableted into desired shapes. The resulting medicated gum tablets can be further coated with sugar or sugar-free excipients. These tablets can be packaged in blisters or bottles as needed. Special Considerations Medicated gums are typically dispensed in unit-dose packaging. The patient instructions also may include a caution to avoid excessive heat.

OXYGEN FREE WATER Oxygen-Free Water is Purified Water that has been treated to remove or reduce dissolved oxygen. Such treatment could involve deaerating by boiling or sparging with an inert gas such as nitrogen or helium, followed by inert gas blanketing to prevent oxygen reabsorption. Any procedure used for removing oxygen should be verified as reliably producing water that is fit for use.