WHO Drug Information Vol. 32, No. 4, 2018

WHO Drug Information

Contents

ICDRA ATC/DDD classification

509 18th International Conference of Drug Regulatory 551 ATC/DDD classification (temporary) Authorities (ICDRA) Recommendations 556 ATC/DDD classification (final)

Consultation documents International Nonproprietary Names (INN) 519 The International Pharmacopoeia 519 Revision of the monograph on ethinylestradiol 530 Polymorphism 559 List N° 120 of Proposed International Nonproprietary 538 Revision of the monograph on levofloxacin 546 Revision of the monograph on levofloxacin tablets Names (INN) for Pharmaceutical Substances

Abbreviations and websites CHMP Committee for Medicinal Products for Human Use (EMA) EMA European Medicines Agency (www.ema.europa.eu) EU European Union FDA U.S. Food and Drug Administration (www.fda.gov) Health Canada Federal department responsible for health product regulation in Canada (www.hc-sc.gc.ca) HPRA Health Products Regulatory Authority, Ireland (www.hpra.ie ) HSA Health Sciences Authority, Singapore (www.hsa.gov.sg) ICDRA International Conference of Drug Regulatory Authorities ICH International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use IGDRP (www.ich.org) International Generic Drug Regulators Programme (https://www.igdrp.com) MHLW Ministry of Health, Labour and Welfare, Japan MHRA Medicines and Healthcare Products Regulatory Agency, United Kingdom (www.mhra.gov.uk) Medsafe New Zealand Medicines and Medical Devices Safety Authority (www.medsafe.govt.nz) Ph. Int The International Pharmacopoeia (http://apps.who.int/phint/) Pharmacovigilance Risk Assessment Committee (EMA) PRAC Pharmaceuticals and Medical Devices Agency, Japan (www.pmda.go.jp/english/index.htm) PMDA Swissmedic Swiss Agency for Therapeutic Products (www.swissmedic.ch) TGA Therapeutic Goods Administration, Australia (www.tga.gov.au) U.S. United States of America WHO World Health Organization (www.who.int) WHO Essential medicines and health products (www.who.int/medicines/en/) WHO EMP WHO Prequalification team (https://extranet.who.int/prequal/) WHO PQT Note: The online version of this issue (freely available at www.who.int/medicines/publications/druginformation) has direct clickable hyperlinks to the documents and websites referenced 18th ICDRA recommendations

ICDRA

18th International Conference of Drug Regulatory Authorities

“Smart Safety surveillance: A life-cycle approach to promoting safety of medical products”

The 18th International Conference of Drug Regulatory Authorities (ICDRA) was held in Dublin, Ireland from 3 to 7 September 2018. The event was co- hosted by the Health Products Regulatory Authority (HPRA) of Ireland and the World Health Organization (WHO).

More than 300 delegates from regulatory authorities of WHO Member States participated in the 18th ICDRA. The recommendations as presented at the end of the conference are set out on the following pages. They are reproduced here as provided by the moderators in the closing plenary sessions and finalized following the consultations with the participants. Feedback, particularly from non-participating authorities, is welcome.

Several common cross-cutting themes emerged from the discussions. These can be further grouped and consolidated and include e.g. promoting regulatory collaboration, convergence and harmonization throughout the products life cycle; improving coordination, risk-based prioritization of investments, reliance, work- sharing and use of regional networks; promoting greater transparency, awareness and communication; enabling regulatory preparedness for public health emergencies; enabling access to innovative medical products; development of international standards; and provision of technical assistance to support implementation.

WHO intends to further develop a more concise iteration of these recommendations in the form of a work plan, integrating any feedback received and ensuring greater alignment and consistency across the various work streams. This work plan will be prepared in 2019, and the outcomes of the deliverables will be presented to the 19th ICDRA in 2020.

► 18th ICDRA website: http://www.icdra2018.ie Information on past ICDRA conferences is available at: www.who.int/medicines/areas/quality_safety/regulation_legislation/icdra/en/

509 WHO Drug Information Vol. 32, No. 4, 2018 18th ICDRA recommendations

THEME: Regulatory collaboration, convergence and harmonization

Recommendations to WHO Recommendations to Member States 1. Regulatory collaboration, 1. When sharing assessment or convergence and harmonization inspection reports, Member States activities should incorporate not only should share unredacted reports, initial authorization but also life- where possible, which is important to cycle management and build trust and to optimize reliance on pharmacovigilance. outcomes from other regulators.

2. WHO should provide a toolbox with all the available options for regulatory collaboration, convergence and harmonization and increase awareness to facilitate selection of the appropriate mechanisms by member states.

THEME: Certification of Pharmaceutical Products (CPP)

Recommendations to WHO 1. WHO should advocate for the use of an electronic CPP template by issuing and receiving authorities to expedite the process and mitigate against any further need for “legalization.”

2. WHO should advocate for the CPP standard procedure specifying that value-added, unredacted documents either accompany the CPP or are provided upon request by any receiving agency.

3. The CPP template should be updated to reflect current manufacturing situations by including: (a) the sites of manufacture with addresses, and (b) a reminder that the receiving country should check that the product being shipped to it is exactly the same as the product being certified by the issuing country.

510 18th ICDRA recommendations WHO Drug Information Vol. 32, No. 4, 2018

THEME: Regulatory preparedness for public health emergencies)

Recommendations to WHO Recommendations to Member States 1. WHO should facilitate communication 1. Member States should consider the between stakeholders (manufacturers feasibility of “conditional approvals” for of IVDs, vaccines and therapeutics) and PHE products with strengthened regulators on needs for products, pharmacovigilance and long-term development work and risk assessment monitoring after outbreaks. work. This should be facilitated by WHO setting up a pre-Emergency Use Listing scheme.

2. WHO should encourage the use of regulatory networks such as ICMRA in the case of public health emergencies and should support effective transition from emergency use to in-country approval.

THEME: Enabling access to innovative medical products in resource-limited settings

Recommendations to WHO Recommendations to Member States 1. WHO is asked to rapidly finalize the 1. While fully recognizing that there are good regulatory practice suite of different languages and different guidance, with a particular focus on regulatory systems, Member States are developing practical advice options, urged to review their current application and best practices to promote dossier formats to ensure that all regulatory collaboration and reliance requirements are scientifically justified for the whole lifecycle management of and better aligned with internationally medical products, both for individual agreed harmonized standards. National Regulatory Authorities and for regional networks.

2. WHO is asked to use its position in the various international regulatory harmonization forums to help promote alignment of regulatory application dossier formats, including elimination of unnecessary differences in the national and regional CTD requirements.

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THEME: Benchmarking of Regulatory Systems: towards mature regulatory systems 4. Further clarify the role of WHO Listed Recommendations to WHO Authorities at Maturity Level 3 or 1. Continue support for regulatory Maturity Level 4 and describe how this systems strengthening to Member information can be utilized by Member States utilizing the Global States to support and advance their Benchmarking Tool which has proven regulatory work. to be effective in promoting one global standard for regulatory systems. Recommendations to Member States 1. Invest resources to strengthen 2. Support regulatory systems regulatory systems utilizing the Global strengthening to Member States at Benchmarking Tool and work towards different maturity levels in a strategic attaining at least Maturity Level 3 while manner. implementing principle of continuous improvement for all maturity levels. 3. Further develop the process for designating WHO Listed Authorities 2. Explore approaches to utilize concept of with input from Member States. reliance and collaborative decision- making to increase timely access to safe and effective medical products.

THEME: Future direction of WHO Prequalification (PQT)

Recommendations to WHO Recommendations to Member States 1. Recognizing PQP’s demonstrated 1. Member states should where possible effective contribution to UHC by take advantage of opportunities offered facilitating access to quality assured by WHO through its Prequalification medical products, WHO should expand Programme by signing up and using the the scope of products eligible for PQ collaborative registration procedures assessment and diversify the pathways and utilizing the practical training and to PQ product listing to include capacity building opportunities offered increased reliance on WLAs and on through PQT. quality assured assessments by regulatory networks.

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THEME: Regional regulatory networks: progress and challenges

Recommendations to WHO Recommendations to Member States 1. Support trust building by providing or 1. National Regulatory Authorities/regional using existing platforms for networks should engage with exchange of information to avoid stakeholders to ensure that the added having to rebuild a system for each value and strength of the network is regional network/collaborative presented and understood, and to build initiative. confidence among all National Regulatory Authorities.

THEME: Regulators role in containing antimicrobial resistance (AMR)

Recommendations to WHO Recommendations to Member States 1. Continue to support member states to 1. Regulators should consider ways that will implement Global Action Plan (GAP) in facilitate the development of new antibiotics particular, improve awareness and and diagnostic tools such as harmonized understanding of AMR and technical standards, scientific advice, monitor/support countries in accelerated pathways and incentivized implementing national action plans. research.

2. Member States/regulators should promote the implementation of national action plans including awareness and understanding of AMR, surveillance of AMR and the rational use and prescribing of medicines.

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THEME: Local production

Recommendations to WHO Recommendations to Member States 1. Maintain local production as a discussion 1. Members States are encouraged to promote topic for further ICDRAs. communication and transparency between regulators and the industry to overcome the challenges in local production of medical products in assuring quality, efficacy and safety.

THEME: Changing procurement models (in countries transitioning from support provided by Global Health Programmes)

Recommendations to WHO Recommendations to Member States 1. WHO should develop options on how to 1. Member States should raise awareness on provide advice and support in terms of selection, prices, supply systems, sustainable strategic and practical aspects of financing and regulatory systems. adaptation of procurement practices. 2. Member States should encourage all 2. WHO should continue to stakeholders to be involved and coordinated encourage/advocate procurement agencies on national level, from industry and donors to and donors to adhere to national regulatory regulators in the process of procurement. requirements. 3. Member States should put the focus on quality-assured essential medicines and simplify the pathways for getting them to the patients.

THEME: Promoting medical products safely: supply chain integrity

Recommendations to WHO Recommendations to Member States 1. WHO should support Member States with 1. Member States should plan and implement guidelines on implementation on risk- risk-based post market surveillance based post market surveillance. programmes.

2. WHO should support the Member States 2. Member States should put in place a system to build the capacity to implement the risk- for effective response in surveillance to based post market surveillance. address serious public health threats related to Substandard and Falsified (SF) medical products.

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THEME: Smart safety surveillance – a shared responsibility

Recommendations to WHO Recommendations to Member States 1. WHO should develop guidance and a 1. Member States should further explore the toolkit to support Member States in the concept with a view towards WHO Smart implementation of the Smart Safety Safety Surveillance strategy. Surveillance strategy, one that embraces a risk-based prioritization of investments, work-sharing, joint activities and reliance for maximum return on investment for all medical products.

THEME: WHO Strategic approaches to improving access to safe medical products

Recommendations to WHO Recommendations to Member States 1. WHO RHT strategy should ensure a 1. Member States should work with comprehensive approach to improve patient harmonized systems, across product access for all medical products, including for streams, supply chains and public health blood and blood components. programmes, to ensure data are shared with the regulator, to inform policies, and for 2. WHO Coalition of Interested Partners model quality of care. should be used as a collaborative platform to advance “Smart” approaches, reliance and work-sharing among stakeholders for effective regulation.

THEME: Safety of medical products throughout the product life cycle

Recommendations to WHO Recommendations to Member States 1. Support countries to proactively assess 1. Train and prepare all policy makers and risks and benefits of medical products other stakeholders on effective throughout the product life cycle. communication of both benefits and risks of medical products, including vaccines, 2. Develop guidance and document best based on robust scientific data. practice for effective communication on risk and benefit of all medical products 2. Accumulate evidence and build evolving (including vaccines). risk management plans from early stages of medical product development.

515 WHO Drug Information Vol. 32, No. 4, 2018 18th ICDRA recommendations

THEME: Collaboration in the area of regulation of medical devices (including IVDs)

Recommendations to Member States 1. Reliance mechanisms should be developed and integrated in the medical devices regulations to avoid duplication of work.

2. Regulatory capacity for medical devices should be established in Africa to convert the Pan-African Harmonization Working Party into a continental expert working group, under the AMRH initiative, building on existing regulatory models and available guidance.

3. More efforts should be invested in medical devices post-market surveillance as a critical element of regulations.

THEME: Risk based inspections

Recommendations to Industry Recommendations to Member States 1. In support of transparency, companies 1. NRAs should embed the use of reliance should consent to the sharing of full procedures in their regulatory decision information amongst regulators and processes relating to inspections. procurement agencies on inspections. 2. NRAs should monitor foreign inspections and support desk-top assessments with defined conditions

THEME: Regulation of clinical trials: focus on patient safety

Recommendations to WHO Recommendations to Member States 1. Facilitate exchange of safety information 1. Implement any existing WHO guidance for from clinical trials and other related inclusion of vulnerable populations, children, activities at local, regional, and global level. pregnant women and women of child bearing age in clinical trials to gain knowledge of safety in these populations in a controlled setting. This will facilitate access, if benefit/risk is favourable, in these populations to important medical products.

2. Utilize opportunities for collaboration through networks such as AVAREF to assess clinical trial applications and develop processes for monitoring and follow up on safety data.

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THEME: Harmonization, work-sharing and reliance in pharmacovigilance

Recommendations to WHO Recommendations to Member States 1. WHO should coordinate Member States efforts to develop a platform for sharing best practice and emerging data in pharmacovigilance.

THEME: Regulation of advanced therapies

Recommendations to WHO Recommendations to Member States 1. WHO to develop with Member States a 1. Member States are encouraged to develop “current state of the art” document capturing national guidance and legislation on areas where agreement among advanced therapies. experienced regulatory authorities exists, noting where harmonization has yet to be achieved, and documenting existing areas of uncertainty; areas covered could include definitions, quality attributes, standards, and clinical development pathways.

THEME: Regulation of biosimilars

Recommendations to WHO Recommendations to Member States 1. WHO should keep organizing 1. Member States are encouraged to implementation workshops to accelerate collaborate, to use existing resources in more use by Member States of the WHO efficient manner and to improve transparency guidelines on biosimilars, focusing more on by making Public Assessment Reports analytical comparability than on (PARs) detailed enough, particularly on comparability in clinical data, and comparability, and publishing PAR for both emphasizing the importance of regulatory approved and rejected biotherapeutics. oversight throughout the entire life cycle of biosimilars. 2. Member States should, in accordance with their respective mandates, define prerequisites for interchangeability and substitutability of biosimilars, which is a national responsibility.

517 WHO Drug Information Vol. 32, No. 4, 2018 18th ICDRA recommendations

THEME: Safety of blood and blood products

Recommendations to WHO Recommendations to Member States 1. WHO should support the establishment of 1. Member States should take steps to national hemovigilance systems in Member establish or strengthen their national States through the facilitation of education hemovigilance system in accordance with the and training opportunities at the regional 2016 WHO guide. level. 2. Member States should engage in self- 2. WHO should take steps to ensure assessments and external assessments of standardization, harmonized terminology their national hemovigilance systems using and common good practices for national, the WHO Global Benchmarking Tool, regional and global hemovigilance integrating the WHO Assessment Criteria for database systems. National Blood Regulatory Systems.

***

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Consultation documents

The International Pharmacopoeia

REVISION OF THE MONOGRAPH ON ETHINYLESTRADIOL (ETHINYLESTRADIOLUM)

Draft proposal for inclusion in The International Pharmacopoeia (December 2018)

DRAFT FOR COMMENTS

Please send any comments you may have on the attached text to Dr Herbert Schmidt, Technical Officer, Medicines Quality Assurance, Technologies Standards and Norms ([email protected]), with a copy to Ms Sinead Jones ([email protected]) by 28 February 2019. Medicines Quality Assurance working documents will only be sent out electronically and will also be placed on the Medicines website for comment under “Current projects”. If you have not already received our draft working documents, please send your email address to [email protected] and we will add your name to our electronic mailing list.

Note from the Secretariat. It is proposed to revise the monograph on Ethinylestradiol as follows:

• Replace the existing TLC method to test for related substances with an HPLC method. • Add an alternative assay method. • Add an alternative identity test C by HPLC and revise the identity test B by TLC. • Add a transparency list to the monograph.

The proposed changes are based on information found in the European Pharmacopoeia and in Kommentar zum Europäischen Arzneibuch,Gesamtwerk mit 53. Aktualisierungslieferung 2016, Wissenschaftliche Verlagsgesellschaft Stuttgart.

Changes from the current monograph are indicated in the text by insert or delete.

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Draft proposal for inclusion in The International Pharmacopoeia REVISION OF THE MONOGRAPH ON ETHINYLESTRADIOL (ETHINYLESTRADIOLUM)

Ethinylestradiol (Ethinylestradiolum)

Molecular formula. C20H24O2

Relative molecular mass. 296.4

Graphic formula.

Chemical name. 19-Nor-17α-pregna-1,3,5(10)-trien-20-yne-3,17-diol; 17-ethynyl-estra- 1,3,5,(10)-triene-3,17β-diol; CAS Reg. No. 57-63-6.

Description. A white to slightly yellowish white, crystalline powder; odourless.

Solubility. Practically insoluble in water; freely soluble in ethanol (~750 g/l) TS; soluble in acetone R, and dioxan R and dilute alkaline solutions.

Category. Estrogen.

Storage. Ethinylestradiol should be kept in a well-closed container, protected from light.

Additional information. Ethinylestradiol may exhibit polymorphism. may exist in 2 polymorphic forms one of which melts at about 183°C, the other, metastable, at about 143°C.

Requirements

Definition. Ethinylestradiol contains not less than 97.597.0% and not more than 102.0% of C20H24O2, calculated with reference to the dried substance.

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Identity tests • Either test A or tests B and C may be applied.

A. Carry out the examination as described under 1.7 Spectrophotometry in the infrared region. The infrared absorption spectrum is concordant with the spectrum obtained from ethinylestradiol RS or with the reference spectrum of ethinylestradiol.

If the spectrum thus obtained are not concordant, repeat the test using the residues obtained by separately dissolving the test substance and ethinylestradiol RS in a small amount of methanol R and evaporating to dryness. The infrared absorption spectrum is concordant with the spectrum obtained from ethinylestradiol RS. If the spectrum obtained from the solid state of the test substance is not concordant with the spectrum obtained from the reference substance, compare the spectra of solutions in chloroform R containing 30 mg/mL, using a path length of 0.2 mm.

B. Carry out the test as described under 1.14.1 Thin-layer chromatography using silica gel R1 as the coating substance and a mixture of 10 volume of dehydrated ethanol R and 90 volumes of toluene R as the mobile phase. Apply separately to the plate 5 μL of each of two solutions in a mixture of 10 volumes of methanol R and 90 volumes of dichloromethane R containing (A) 1.0 mg of the test substance per mL, and (B) 1.0 mg of ethinylestradiol RS per mL. Develop the plate for a distance of 15 cm. After removing the plate from the chromatographic chamber, allow it to air dry until the solvents have evaporated, heat at 110 °C for 10 minutes, spray the hot plate with sulfuric acid/ethanol (20%) TS and heat again at 110 °C for 10 minutes. Allow to cool and examine the chromatogram in daylight and in ultraviolet light (365 nm). The principal spot obtained with solution (A) corresponds in position, appearance, and intensity with that obtained with solution (B). Carry out the test as described under 1.14.1 Thin-layer chromatography, using kieselguhr R1 as the coating substance and a mixture of 1 volume of propylene glycol R and 9 volumes of acetone R to impregnate the plate, dipping it about 5 mm beneath the surface of the liquid. After the solvent has reached a height of at least 16 cm, remove the plate from the chromatographic chamber and allow it to stand at room temperature until the solvent has completely evaporated. Use the impregnated plate within 2 hours, carrying out the chromatography in the same direction as the impregnation. Use toluene R as the mobile phase. Apply separately to the plate 2 μL of each of 2 solutions in a mixture of 9 volumes of chloroform R and 1 volume of methanol R containing (A) 1.0 mg of the test substance per mL, and (B) 1.0 mg of ethinylestradiol RS per mL. Develop the plate for a distance of 15 cm. After removing the plate from the chromatographic chamber, allow it to dry in air until the solvents have evaporated, heat at 120°C for 15 minutes, spray with 4-toluenesulfonic acid/ethanol TS, and then heat at 120°C for 5 - 10 minutes. Allow to cool, and examine the chromatogram in daylight and in ultraviolet light (365 nm). The principal spot obtained with solution A corresponds in position, appearance, and intensity with that obtained with solution B.

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C. Carry out the test as described under 1.14.4 High-performance liquid chromatography using the conditions and solutions given under “Assay”, Method A. The retention time of the principal peak in the chromatogram obtained with solution (1) corresponds to the retention time of the peak due to ethinylestradiol in the chromatogram obtained with solution (5).

Specific optical rotation. Use a 4.0 mg/mL solution in pyridine R and calculate with reference to the dried substance; = -27.0° to -30.0°.

Loss on drying. Dry to constant weight at 105°C; it loses not more than 10 mg/g.

Related substances. Carry out the test as described under 1.14.4 High-performance liquid chromatography, using a stainless steel column (25 cm × 4.6 mm) packed with end- capped particles of silica gel, the surface of which has been modified with chemically- bonded butylsilyl groups (5 μm).

Use the following conditions for gradient elution: mobile phase A: 30 volumes of acetonitrile for chromatography R and 70 volumes of water R; mobile phase B: 25 volumes of water R and 75 volumes of acetonitrile for chromatography R.

Time Mobile phase A Mobile phase B Comments (minutes) (% v/v) (% v/v) 0–35 100 0 Isocratic 35–65 100 to 0 0 to 100 Linear gradient 65–66 0 to 100 100 to 0 Return to initial composition 66–75 100 0 Re-equilibration

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Prepare the following solutions using a mixture of 40 volumes of water R and 60 volumes of acetonitrile R as diluent. For solution (1), dissolve 50.0 mg of the test substance in 30 mL of acetonitrile and dilute to 50.0 mL. For solution (2), dilute 1.0 mL of solution (1) to 100.0 mL. Dilute 1.0 mL of this solution to 10.0 mL. For solution (3), dissolve 2 mg of estrone R (impurity C) in 10.0 mL. Dilute 1.0 mL of this solution to 100.0 mL. For solution (4), dissolve the content of a vial of ethinylestradiol for system suitability RS (containing ethinylestradiol and the impurities B, F, H, I and K) in 1.0 mL of solution (3).

Operate with a flow rate of 1.5 mL per minute. As a detector, use an ultraviolet spectrophotometer set at a wavelength of 220 nm. Maintain the column temperature at 30 °C. Inject alternatively 30 µL each of solution (1), (2) and (4) and record the chromatograms.

Use the chromatogram obtained with solution (4) and the chromatogram supplied with ethinylestradiol for system suitability RS to identify the peaks due to the impurities B, C, F, H, I and K. The impurities, if present, are eluted at the following relative retention with reference to ethinylestradiol (retention time about 35 min): impurity F about 0.2; impurity H about 0.5; impurity I about 0.8; impurity B about 0.88; impurity C about 0.92; impurity K about 1.3.

The test is not valid unless in the chromatogram obtained with solution (4) the resolution between the peaks due to impurity I and B is at least 1.2.

In the chromatogram obtained with solution (1):

• the area of any peak corresponding to impurity B, when multiplied by a correction factor of 0.7, is not greater than five times the area of the peak due to ethinylestradiol in the chromatogram obtained with solution (2) (0.5 %);

• the area of any peak corresponding to impurity I, when multiplied by a correction factor of 0.4, is not greater than twice the area of the peak due to ethinylestradiol in the chromatogram obtained with solution (2) (0.2 %);

• the area of any peak corresponding to impurity H or K is not greater than twice the area of the peak due to ethinylestradiol in the chromatogram obtained with solution (2) (0.2 %);

• the area of any peak corresponding to impurity C or F is not greater than 1.5 times the area of the peak due to ethinylestradiol in the chromatogram obtained with solution (2) (0.15 %);

• the area of any other impurity peak is not greater than the area of the peak due to ethinylestradiol in the chromatogram obtained with solution (2) (0.10 %);

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• the sum of the corrected areas of any peak corresponding to impurity B and I and the areas of all other impurity peaks is not greater than eight times the area of the peak due to ethinylestradiol in the chromatogram obtained with solution (2) (0.8 %). Disregard any peak with an area less than 0.5 times the area of the peak due to ethinylestradiol in the chromatogram obtained with solution (2) (0.05 %).

Estrone. Carry out the test as described under 1.14.1 Thin-layer chromatography, using silica gel R1 as the coating substance and a mixture of 92 volumes of dichloroethane R, 8 volumes of methanol R, and 0.5 volumes of water as the mobile phase. Apply separately to the plate 5 μl of each of 2 freshly prepared solutions in a mixture of 9 volumes of chloroform R and 1 volume of methanol R containing (A) 20 mg of the test substance per mL, and (B) 0.20 mg of estrone RS per mL. After removing the plate from the chromatographic chamber, allow it to dry in air until the odour of the solvent is no longer detectable; then heat at 110°C for 10 minutes. Spray the hot plate with sulfuric acid/ethanol TS, heat again at 110°C for 10 minutes, and examine the chromatogram in ultraviolet light (365 nm). The spot obtained with solution B is more intense than any spot, corresponding in position and appearance, obtained with solution A.

Assay

• Either method A or method B may be applied.

A. Carry out the test as described under 1.14.4 High-performance liquid chromatography, using the conditions given below under “Related substances”.

Use solution (1) as described under “Related substances”. Prepare the following additional solution: for solution (5), dissolve 50.0 mg of ethinylestradiol RS in 30 mL of acetonitrile R and dilute to 50.0 mL with water R.

Inject alternately 50 μL each of solution (1) and (5) and record the chromatograms.

Measure the areas of the peaks corresponding to ethinylestradiol obtained in the chromatograms of solutions (1) and (5) and calculate the percentage content of ethinylestradiol (C20H24O2) using the declared content of C20H24O2 in ethinylestradiol RS.

B. Dissolve 50.0 mg of the test substance in sufficient dehydrated ethanol R and dilute to 100.0 mL with the same solvent. Dilute 10.0 mL of this solution to 50.0 mL with the same solvent.

Measure the absorbance of a 1 cm layer of the diluted solution at the maximum at about 281 nm. Calculate the percentage content of ethinylestradiol (C20H24O2) using % the absorptivity value of 7.1 ( = 71) 1 𝐴𝐴1 𝑐𝑐𝑐𝑐

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Dissolve about 0.05 g, accurately weighed, in sufficient dehydrated ethanol R to produce 100 mL, and dilute 10.0 mL of this solution to 50.0 mL with the same solvent. Measure the absorbance of a 1-cm layer of the diluted solution at the maximum at about 281 nm. Calculate the amount of C20H24O2 in the substance being tested by comparison with ethinylestradiol RS, similarly and concurrently examined. In an adequately calibrated spectrophotometer the absorbance of the reference solution should be 0.72 ± 0.04.

Impurities

A. 19-norpregna-1,3,5(10)-trien-20-yne-3,17-diol (17β-ethinylestradiol)

B. 19-nor-17α-pregna-1,3,5(10),9(11)-tetraen-20-yne-3,17-diol (degradation product)

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C. 3-hydroxyestra-1,3,5(10)-trien-17-one (estrone) (synthesis related impurity, degradation product)

D. estra-1,3,5(10)-triene-3,17β-diol (estradiol) (degradation product)

E. 19-nor-17α-pregna-1,3,5(10)-trien-20-yne-3,6α,17-triol (6α-hydroxy-ethinylestradiol) (degradation product)

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F. 19-nor-17α-pregna-1,3,5(10)-trien-20-yne-3,6β,17-triol (6β-hydroxy-ethinylestradiol) (degradation product)

G. 3,17-dihydroxy-19-nor-17α-pregna-1,3,5(10)-trien-20-yn-6-one (6-oxo-ethinylestradiol) (degradation product)

H. 3,17-dihydroxy-19-nor-17α-pregna-1,3,5(10)-trien-20-yn-16-one (16-oxo- ethinylestradiol)

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I. 19-nor-17α-pregna-1,3,5(10),6-tetraen-20-yne-3,17-diol

J. 1-methyl-19-nor-17α-pregna-1,3,5(10)-trien-20-yne-3,17-diol (1-methyl- ethinylestradiol)

K. 4-methyl-19-nor-17α-pregna-1,3,5(10)-trien-20-yne-3,17-diol (4-methyl- ethinylestradiol)

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L. estra-1,3,5(10)-triene-3,17α-diol (17α-estradiol)

M. 2-methyl-19-nor-17α-pregna-1,3,5(10)-trien-20-yne-3,17-diol (2-methyl- ethinylestradiol)

***

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Consultation documents

The International Pharmacopoeia

POLYMORPHISM

Draft chapter for The International Pharmacopoeia (December 2018)

DRAFT FOR COMMENTS

Please send any comments you may have on this draft to Dr Herbert Schmidt, Medicines Quality Assurance Programme, Technologies Standards and Norms, Department of Essential Medicines and Health Products, World Health Organization, 1211 Geneva 27, Switzerland; email: [email protected], with a copy to Ms Sinéad Jones (email: [email protected]) by 28 February 2019.

In order to speed up the process for receiving draft monographs and for sending comments, please send us your email address and we will add it to our electronic mailing list. Please specify if you wish to receive monographs.

Note from the Secretariat. It is proposed to publish the following chapter on Polymorphism in the Supplementary Information section under “Notes for guidance”.

The text was revised based on the comments received during the last public consultation in June – July 2018

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POLYMORPHISM 1. INTRODUCTION AND TERMINOLOGY The aim of this chapter is to provide a brief overview of:

• the terminology associated with crystal polymorphism; • some analytical techniques commonly used to characterise polymorphs; • the relevance of polymorphism for active pharmaceutical ingredients (APIs) and finished pharmaceutical products (FPPs); and • the control strategies for polymorphism employed by The International Pharmacopoeia.

APIs and excipients, in the solid phase, can be classified as either crystalline or non- crystalline solids. A crystalline structure implies that the structural units (i.e. the unit cells) are repeated in a long range order (i.e. three dimensional crystal lattice). The arrangement of atoms and/or molecules in an amorphous solid is non-ordered (i.e. does not have a long range order), or random system, analogous to the liquid state, and does not possess a distinguishable crystal lattice. Amorphous solids are classified as non-crystalline solids.

Variation in the crystallization conditions (temperature, pressure, solvent composition, concentration, rate of crystallization, seeding of the crystallization medium, presence and concentration of impurities, etc.) may cause the formation of different crystalline forms.

When a chemical element (e.g. sulfur) exists in different crystalline forms, it is referred to as allotropy, not polymorphism (1). When a chemical compound with a given chemical structure crystallizes in more than one crystalline lattice with different unit cells, these crystalline phases are called polymorphs and the phenomena is referred to as polymorphism. The difference in internal crystal structure could be attributed to differences in molecule packing arrangements and/or different molecular conformations. Polymorphic substances, having identical chemical composition, will on dissolution exhibit the same chemical behaviour in solution.

Crystals of a given chemical compound with the same internal structure may exhibit different external shapes or crystal habits. In addition, variations in crystal habit may indicate the presence of polymorphism but is not necessarily indicative of polymorphic forms (12).

Solvates are crystal forms containing stoichiometric or non-stoichiometric quantities of a solvent. When the solvent incorporated into the crystal structure of the compound is water, the molecular adduct formed is referred to as a hydrate. Hydrates can be classified as three categories based on different structural aspects: Class I represents hydrates where the water molecules exist at isolated sites; Class II hydrates are generally referred to as channel hydrates; and Class III hydrates are generally referred to as ion-coordinated site hydrates. In such systems, water molecules form ion-water bonds that are usually much stronger than hydrogen bonds (13). Solvation and hydration products are also sometimes referred to as pseudopolymorphs (2, 3, 4). However, the term “pseudopolymorphism” is ambiguous because of its use in different circumstances. It is therefore preferable to use only the terms “solvates” and “hydrates”.

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Occasionally, a compound of a given hydration/solvation composition may crystallize into more than one crystalline form; an example of such a compound is nitrofurantoin (5). Nitrofurantoin can be crystallized as two monohydrate forms (Forms I and II) and two anhydrous forms (designated polymorphs α and β) (5).

Crystal forms are said to be isostructural (also referred to as isomorphous) when they have the same overall crystal packing. Solvates, which have the same overall crystal packing, but differ only in the solvents included in their crystal structures, are termed isostructural or isomorphous solvates, e.g. hydrate and isopropanolate of hexakis(2,3,6-tri-O-acetyl)-α- cyclodextrin (6).

The term desolvated solvate (or desolvated hydrates), also referred to as isomorphous desolvates, has been used to describe a solid form obtained by removing solvent from the solvate crystal structure (or water from a hydrate) without significantly changing the crystal structure (4), as in the desolvated monohydrate of terazosin HCl (7).

Amorphous forms of APIs and excipients are of substantial interest because they are usually more soluble (also having a faster kinetic solubility) than their crystalline counterparts but are thermodynamically less stable. Solid-state properties of amorphous forms of the same chemical compound (i.e. thermal behaviour, solubility profile, density, etc.) may differ.

Co-crystals are crystalline materials composed of two or more different molecules, typically an API and co-crystal formers (“coformers”) within the same crystal lattice that are associated by nonionic and noncovalent bonds. An example of a co-crystal is the succinic acid co-crystal of fluoxetine HCl (8). Co-crystals are thus more similar to solvates, in that both contain more than one component in the lattice. However, for co-crystals the coformer is non-volatile (i.e. exists as solid material at ambient conditions) (3).

Pharmaceutical co-crystals have gained considerable attention as alternative forms in an attempt to enhance the bioavailability, stability and processability of the API in the manufacturing process. Another advantage of co-crystals is that they generate a diverse array of solid state forms for APIs that lack ionisable functional groups, which is a prerequisite for salt formation (3). Guidance and reflection papers on the use and classification of pharmaceutical co-crystals have been published (3, 9).

2. CHARACTERIZATION AND THERMODYNAMIC STABILITY OF SOLID FORMS

Crystalline and amorphous forms are characterized based on their physicochemical properties. Table 1 lists some examples of the properties that may differ among different forms (9).

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Table 1. Examples of physicochemical properties that may differ among different forms

1. Packing properties a. Molar volume and density b. Refractive index c. Conductivity (electrical and thermal) d. Hygroscopicity

2. Thermodynamic properties a. Melting and sublimation temperatures b. Internal energy (i.e. structural energy) c. Enthalpy (i.e. heat content) d. Heat capacity e. Entropy f. Free energy and chemical potential g. Thermodynamic activity h. Vapour pressure i. Solubility

3. Spectroscopic properties a. Electronic state transitions b. Vibrational state transitions c. Nuclear spin state transitions

4. Kinetic properties a. Dissolution rate b. Rates of solid state reactions c. Stability d. Solid state

5. Surface properties a. Surface-free energy b. Interfacial tensions c. Habit (i.e. shape)

6. Mechanical properties a. Hardness b. Tensile strength c. Compactibility d. Flow

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Table 2 summarizes some of the most commonly used techniques to study and/or classify different amorphous or crystalline forms. These techniques are often complementary and it is indispensable to use several of them. Demonstration of a non-equivalent structure by single crystal X-ray diffraction is currently regarded as the definitive evidence of polymorphism. X-ray powder diffraction and/or solid state NMR can also be used, as bulk techniques, to provide unequivocal proof of polymorphism (10).

Any technique(s) chosen to confirm the identity of the specific form(s) must be proven to be suitably specific for the identification of the desired form(s). Care must be taken in choosing the appropriate sample preparation technique, as heat generation, mechanical stress or exposure to elevated pressure and other environmental conditions (humidity) may trigger conversion between different forms.

Table 2. Examples of some techniques that may be used to study and/or classify different crystalline forms

1. X-ray powder diffraction* & Single crystal X-ray diffraction 2. Microcalorimetry 3. Thermal analysis (1.2.1 Melting point,* differential scanning calorimetry, thermogravimetry, thermomicroscopy) 4. Moisture sorption analysis 5. Polarized optical microscopy and electronic microscopy with diffraction capability (ex. Transmission Electron Microscopy) 6. Solid-state nuclear magnetic resonance; 7. Solubility studies 8. Spectrophotometry in the infrared region (1.7)* and Raman spectrophotometry 9. Intrinsic dissolution rate 10. Density measurement

* Methods currently employed by The International Pharmacopoeia

Using suitable analytical techniques, the thermodynamic stability of the forms should be investigated. The form with the lowest free energy is the most thermodynamically stable at a given temperature and pressure. All other forms of the given system are in a metastable state. At standard temperature and pressure, a metastable form may remain unchanged or may change to a thermodynamically more stable form. In general, the more stable the form the less soluble it is. Conversion to a thermodynamically more stable form, may cause changes in some of the physicochemical properties (see Table 1) of the compound that may result in changes to other critical properties such as bioavailability, manufacturability (also referred to as processability), etc.

If there are several crystalline forms one form is thermodynamically more stable at a given temperature and pressure. A given crystalline form may constitute a phase that can reach equilibrium with other solid phases and with the liquid and gas phases.

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If each crystalline form is stable within a given temperature range the change from one form to another is reversible and is said to be enantiotropic. The change from one phase to another is a univariate equilibrium so that at a given pressure this state is characterized by a transition temperature. However, if only one of the forms is stable over the entire temperature range, the change is irreversible or monotropic (11).

3. RELEVANCE OF POLYMORPHISM FOR APIs AND FPPs

Polymorphism (and hydrate formation) of APIs and excipients are of interest as they may affect bioavailability, toxicity and processability. Also, the thermodynamic stability of the form included in the FPP is considered important as environmental conditions may compromise the stability thereof. For formulations where the API is dissolved, attention has to be paid to supersaturation with regards to different forms. A formulation might not be supersaturated regarding a metastable polymorph but supersaturated with regards to the thermodynamically stable polymorph. Control of the form by the manufacturer may be required during the processing of APIs and excipients and during the manufacturing of a dosage form to ensure the correct physicochemical characteristics thereof. The control of a specific form is especially critical in the areas where the bioavailability, stability or processability are directly impacted (4).

The form of a readily soluble API that is incorporated into a solution, for example, an injection, an oral solution or eye drops, is normally non-critical (exceptions to this statement might be if the concentration of the solution is such that it is close to the limit of solubility of one of the possible polymorphs – as mentioned above - or solvate formation is observed with one of the excipients). Similarly, if an API is processed during the manufacturing process to obtain an amorphous form (e.g. hot melt extrusion, spray-dried dispersion, etc.), the original form is considered non-critical, as long as the processability is not influenced.

The form may be critical when the material is included in a solid dosage form or as a suspension in a liquid dosage form. In such cases, the characteristics of the different polymorphs may affect the bioavailability or dissolution of the material. The polymorphic form of a biopharmaceutics classification system (BCS) class I or III API in a solid oral dosage form is normally non-critical in terms of dissolution rate or bioavailability as by definition it would be readily soluble, but confirmation thereof by the manufacturer, is recommended. The ICH Harmonised Tripartite Guideline on Specifications: Test procedures and acceptance criteria for new drug substances and new drug products: Chemical substances Q6A, provides guidance on when and how polymorphic forms should be controlled and monitored (4).

The inclusion of potentially harmful solvents in the crystal lattice, which may render APIs or excipients to be toxic or harmful to patients (i.e. solvates), should also be suitably regulated and monitored by the manufacturer.

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4. POLYMORPHISM IN THE INTERNATIONAL PHARMACOPOEIA

Where a monograph indicates that a compound shows polymorphism this may be true crystal polymorphism, occurrence of solvates/hydrates or occurrence of the amorphous form.

The International Pharmacopoeia controls the polymorphic or crystalline forms (hereafter referred to as form) of a limited number of substances by restricting it to either:

• a single form, for example, carbamazepine API (Anhydrous Form III), mebendazole API (Form C); or • by limiting the presence of unwanted forms, for example, chloramphenicol palmitate API (should contain at least 90% of polymorph B).

The control of forms specified in The International Pharmacopoeia may be achieved by:

• permitting no deviation from the infrared absorption spectrum of the reference substance prescribed (or reference spectrum supplied) – when the infrared absorption spectrum has been proven to be specific to the preferred form and able to distinguish the undesired form(s), for example, indomethacin API; • restricting the melting point range, when the melting properties of the forms are clearly distinguishable, for example, phenobarbital API; • recommending the use of any other suitable methods such as X-ray powder diffractometry, for example, carbamazepine tablets; and • limiting the incorporated solvent (in the case of solvates/hydrates) with a specific limit test, for example, nevirapine hemihydrate API.

The specific control to be used will be indicated in the applicable monograph.

When the infrared identification test is able to detect differences in forms for a specific compound (i.e. polymorphism may be present for this compound), but the control of a specific form is not required by the monograph, the user may be instructed to:

• recrystallize both the test substance and the specified reference substance, in the event where the infrared spectra are found to be not concordant, for example, fluconazole API; and/or • dry the API and/or specified reference substance to ensure that both forms are in the anhydrous or dehydrated state, for example, nevirapine hemihydrate API.

Whenever the choice of a specific form is critical with regard to bioavailability and/or stability, the method of the manufacturer of the product must be validated to consistently yield the desired polymorph in the final product at release and over its shelf life. The monograph will include a statement under the heading “Manufacturing” to draw attention to the control of a specified form during manufacturing where control is known to be critical, for example, carbamazepine oral suspension.

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It is the intention of The International Pharmacopoeia to extend the inclusion of explicit statements in monographs, where appropriate, as information on the occurrence of polymorphism becomes available. The Secretariat thus cordially invites the users of The International Pharmacopoeia and manufacturers to share any relevant information that could be included in the monographs.

References

1. Gaskell, DR. 2005. Allotropy and Polymorphism. Reference Module in Materials Science and Materials Engineering. Encyclopedia of Condensed Matter Physics, 8–17. 2. Brittain, HG. 2007. Polymorphism and Solvatomorphism 2005. Journal of Pharmaceutical Sciences, 96(4):705–728. 3. US Department of Health and Human Services, Food and Drug Administration. Center for Drug Evaluation and Research. 2013. Guidance to Industry: Regulatory Classification of Pharmaceutical Co-crystals. 4. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. 1999. ICH Q6A – Specifications: The Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances. 5. Caira, M, Pienaar, EW, Lötter, AP. 2006. Polymorphism and Pseudopolymorphism of the Antibacterial Nitrofurantoin. Molecular Crystals and Liquid Crystals, 179(1):241-264. 6. Bettineti, G., Sorrenti, M., Catenacci, L., Ferrari, F. & Rossi, S. Bettinetti, G, et al. 2006. Polymorphism, Pseudopolymorphism, and Amorphism of Peracetylated α-, β-, and γ-cyclodextrins. Journal of Pharmaceutical and Biomedical Analysis, 41:1205-1211. 7. Bauer, J, et al. 2006. Identification, Preparation and Characterization of Several Polymorphs and Solvates of Terazosin Hydrochloride. Journal of Pharmaceutical Sciences, 95(4):917-928. 8. Peterson, ML, et al. 2006. Expanding the Scope of Crystal Form Evaluation in Pharmaceutical Science. Journal of Pharmaceutical Sciences, 9(3):317-326. 9. European Medicines Agency. 2015. Reflection Paper on the Use of Co-crystals of Active Substances in Medicinal Products. 10. US Department of Health and Human Services, Food and Drug Administration. Center for Drug Evaluation and Research. 2007. Guidance to Industry: ANDAs: Pharmaceutical Solid Polymorphism. Chemistry, Manufacturing and Controls Information. 11. British Pharmacopoeia Commission. 2017. SC I B. Polymorphism. In: British Pharmacopoeia Commission. British Pharmacopoeia 2017. Supplementary chapter. London: TSO. 12. J. Bernstein. 2002. Polymorphism in Molecular Crystals, Clarendon Press, Oxford, United Kingdom volume. 13. Byrn, R.S, Zografi, G. & Chen, X. 2017. Solid state properties of pharmaceutical materials, John Wiley & Sons. Inc.

***

5 37 WHO Drug Information Vol. 32, No. 4, 2018 Consultation documents

Consultation documents

The International Pharmacopoeia

REVISION OF THE MONOGRAPH ON LEVOFLOXACIN

Draft proposal for The International Pharmacopoeia (January 2019)

DRAFT FOR COMMENTS

Please send any comments you may have on this draft to Dr Herbert Schmidt ([email protected]), Medicines Quality Assurance Programme, Technologies Standards and Norms, Department of Essential Medicines and Health Products, World Health Organization, 1211 Geneva 27, Switzerland, by 15 March 2019.

In order to speed up the process for receiving draft monographs and for sending comments, please send your email address to [email protected] and we will add it to our electronic mailing list. Please specify if you wish to receive monographs.

Note from the Secretariat. It is proposed to revise the monograph on Levofloxaxin.

The revision is based on an evaluation of information found in other pharmacopoeias, in the scientific literature and on laboratory investigations performed by a collaborating laboratory.

5 38 Consultation documents WHO Drug Information Vol. 32, No. 4, 2018

Levofloxacin (Levofloxacinum)

Molecular formula. C18H20FN3O4,½ H2O

Relative molecular mass. 370.4

Graphic formula. H H3C N O CH3 N N . ½ H2O

F CO2H O

Chemical name. (3S)-9-Fluoro-3-methyl-10-(4-methylpiperazin-1-yl)-7-oxo-2,3-dihydro- 7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid hemihydrate; CAS Reg. No. 138199-71-0.

Description. Light yellowish-white or slightly yellow powder.

Solubility. Sparingly soluble in water R, freely soluble in acetic acid (~300 g/L) TS, sparingly soluble in methanol R, and slightly soluble in dehydrated ethanol R.

Category. Antibacterial, antituberculosis.

Storage. Levofloxacin should be kept in a tightly closed container, protected from light.

Requirements

Definition. Levofloxacin contains not less than 98.0% and not more than 101.0% of levofloxacin (C18H20FN3O4) calculated with reference to the anhydrous substance.

Identity test

Either tests A and D or tests B, C and D may be applied.

A. Carry out the examination as described under 1.7 Spectrophotometry in the infrared region. The infrared absorption spectrum is concordant with the spectrum obtained from levofloxacin RS or with the reference spectrum of levofloxacin hemihydrate.

B. Carry out the test as described under 1.14.1. Thin layer chromatography, using silica gel R5 as the coating substance and a mixture of 4 volumes of 1-butanol R, 4 volumes of methanol R and 2 volumes of ammonia (~100 g/L) TS as the mobile phase. Apply separately to the plate 5 µl of each of the following two solutions in a mixture of 1 volume of methanol R and 4 volumes of dichloromethane R.

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For solution (A), use a solution containing 5 mg of the test substance per mL. For solution (B), use a solution containing 5 mg of levofloxacin RS per mL. After removing the plate from the chromatographic chamber, allow it to dry exhaustively in air or in a current of cool air. Examine the chromatogram in ultraviolet light (366 nm). The principal spot obtained with solution (A) corresponds in position, appearance, and intensity with the spot due to levofloxacin in the chromatogram obtained with solution (B).

C. Dissolve 25 mg of the test substance in about 20 ml of hydrochloric acid (~4 g/l) TS and dilute to 50.0 ml with the same solvent. Dilute 1.0 ml of this solution to 100.0 ml using water R. The absorption spectrum (1.6) of the resulting solution, when observed between 210 and 350 nm, exhibits two maxima at about 227 nm and at about 294 nm.

D. Carry out test D.1 or D.2. D.1 Determine the specific optical rotation (1.4) using a solution containing 5.0 mg of the test substance per mL methanol R and calculate with reference to the 20 anhydrous substance; []α D = -92 to -106. D.2 Carry out the test as described under 1.14.4 High-performance liquid chromatography using the conditions given under “Related substances”. The area of any peak corresponding to impurity A is not greater than ten times the area of the peak due to levofloxacin in the chromatogram obtained with solution (2) (1.0 %).

Heavy metals. Use 2.0 g for the preparation of the test solution as described under 2.2.3 Limit test for heavy metals, Procedure 3; determine the heavy metals content according to Method A; not more than 10 μg/g.

Sulfated ash (2.3). Not more than 1.0 mg/g.

Water. Determine as described under 2.8 Determination of water by Karl Fischer Method, Method A. Use 0.500 g of the test substance. The water content is not less than 20 mg/g and not more than 30 mg/g.

Related substances. Prepare fresh solutions protected from light and perform the test without delay. Carry out the test as described under 1.14.4 High-performance liquid chromatography using a stainless steel column (25 cm x 4.6 mm), packed with end-capped and base- deactivated particles of silica gel, the surface of which has been modified with chemically- bonded octadecylsilyl groups (5 μm).1

1 Inertsil ODS-2 or ODS-3 columns were found suitable.

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Prepare the following buffer solution. Dissolve 1.25 g of copper (II) sulfate pentahydrate R, 1.3 g of isoleucine R and 8.5 g ammonium acetate R in water R and dilute to 1000 mL with the same solvent.

As the mobile phase, use a mixture of methanol R and the buffer solution (30:70 v/v). Operate with a flow rate of 0.8 mL per minute. As a detector, use an ultraviolet spectrophotometer set at a wavelength of 360 nm. Maintain the column at a temperature of 45 °C.

Prepare the following solutions in mobile phase. For solution (1), dissolve 50.0 mg of the test substance in 50.0 mL. For solution (2), dilute 1.0 mL of solution (1) to 100.0 mL. Dilute 1.0 mL of this solution to 10.0 mL. For solution (3), use a solution containing 1.0 mg of levofloxacin for system suitability RS (containing levofloxacin and the impurities A, B and G) per mL.

Inject alternately 25 µL of solution (1), (2) and (3). Record the chromatogram for three times the retention time of levofloxacin.

Use the chromatogram obtained with solution (3) and the chromatogram supplied with levofloxacin for system suitability RS to identify the peaks due to the impurities A, B and G. The impurities are eluted, if present, at the following relative retention with reference to levofloxacin (retention time about 20 minutes); impurity B about 0.50; impurity G about 0.56; impurity A about 1.22.

The test is not valid unless, in the chromatogram obtained with solution (3), the resolution between the peaks due to impurity B and the peak due to impurity G is at least 1.5.

In the chromatogram obtained with solution (1): • the area of any peak corresponding to impurity B, when multiplied by a correction factor of 1.3, is not greater than three times the area of the peak due to levofloxacin in the chromatogram obtained with solution (2) (0.3 %);

• the area of any peak corresponding to impurity G, when multiplied by a correction factor of 1.2, is not greater than three times the area of the peak due to levofloxacin in the chromatogram obtained with solution (2) (0.3 %);

• the area of any peak corresponding to impurity A is not greater than ten times the area of the peak due to levofloxacin in the chromatogram obtained with solution (2) (1.0 %);

• the area of any other impurity peak is not greater than the area of the peak due to levofloxacin in the chromatogram obtained with solution (2) (0.10 %);

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• the sum of the corrected areas of any peak corresponding to impurity B or G and the areas of all other impurity peaks, other than any peak due to impurity A, is not greater than five times the area of the peak due to levofloxacin in the chromatogram obtained with solution (2) (0.5 %). Disregard any peak with an area less than 0.5 times the area of the peak due to levofloxacin in the chromatogram in the chromatogram obtained with solution (2) (0.05%).

Impurity F. Carry out the test as described under 1.14.4 High-performance liquid chromatography using the conditions given under “Related substances” with the following modifications.

As the mobile phase, use a mixture of methanol R and the buffer solution (50:50 v/v). As a detector, use an ultraviolet spectrophotometer set at a wavelength of 320 nm.

Prepare the following solutions in mobile phase. For solution (1), dissolve 50.0 mg of the test substance in 50.0 mL. For solution (2), dissolve 5.0 mg of levofloxacin impurity F RS and dilute to 100.0 mL. For solution (3), dilute 4.0 mL of solution (2) to 100.0 mL. For solution (4), dilute 4.0 mL of solution (2) to 10.0 mL. Dilute 1.0 ml of this solution to 10.0 mL with solution (1).

Inject alternately 25 µL of solution (1), (3) and (4). Record the chromatogram for three times the retention time of levofloxacin.

Use the chromatogram obtained with solution (3) to identify the peaks due to impurity F. Impurity F, if present, is eluted at the relative retention of 1.8 with reference to levofloxacin (retention time: about 6 minutes).

The test is not valid unless, in the chromatogram obtained with solution (4), the resolution between the peaks due to impurity F and the peak due to levofloxacin is at least 5.

Measure the areas of the peaks corresponding to impurity F obtained in the chromatograms of solution (1) and (3) and calculate the percentage content of impurity F. The concentration of impurity F is not more than 0.2%.

Assay. Prepare fresh solutions protected from light and perform the test without delay.

Dissolve about 0.300 g, accurately weighed, in 100 ml of glacial acetic acid R and titrate with perchloric acid (0.1 mol/l) VS as described under 2.6. Non-aqueous titrations, Method A determining the end point potentiometrically. Each ml of perchloric acid (0.1 mol/l) VS is equivalent to 36.14 mg of C18H20FN3O4.

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Impurities

A. (3R)-9-fluoro-3-methyl-10-(4-methylpiperazin-1-yl)-7-oxo-2,3-dihydro-7H-pyrido[1,2,3- de]-1, 4-benzoxazine-6-carboxylic acid (dextrofloxacin, synthesis-related impurity),

H

HN O CH3 N N

F CO2H O

B. (3S)-9-fluoro-3-methyl-7-oxo-10-(piperazin-1-yl)-2,3-dihydro-7H-pyrido[1,2,3-de]-1,4- benzoxazine-6-carboxylic acid (N-desmethyl levofloxacin),

O H

H3C N O CH3 N N

F CO2H O

C. 4-[(3S)-6-carboxy-9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de]-1,4- benzoxazin-10-yl]-1-methylpiperazine 1-oxide (levofloxacin N-oxide; degradation product),

H H3C N O CH3 N N

CO2H O

D. (3S)-3-methyl-10-(4-methylpiperazin-1-yl)-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de]-1,4- benzoxazine-6-carboxylic acid (9-desfluoro levofloxacin, synthesis related impurity),

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H H3C N O CH3 N N

F O

E. (3S)-9-fluoro-3-methyl-10-(4-methylpiperazin-1-yl)-2,3-dihydro-7H-pyrido[1,2,3-de]-1,4- benzoxazin-7-one (decarboxy levofloxacin, synthesis related impurity),

H

O CH3 F N

F CO2H O F. (3S)-9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6- carboxylic acid,

G. (3S)-9-fluoro-3-methyl-10-[[2-(methylamino)ethyl]amino]-7-oxo-2,3-dihydro-7H- [1,4]oxazino[2,3,4-ij]quinoline-6-carboxylic acid (diamine derivative)

H. ethyl (3R)-9-fluoro-3-methyl-10-(4-methylpiperazin-1-yl)-7-oxo-2,3-dihydro-7H- [1,4]oxazino[2,3,4-ij]quinoline-6-carboxylate

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I. (3 S)-10-fluoro-3-methyl-9-(4-methylpiperazin-1-yl)-7-oxo-2,3-dihydro-7H- [1,4]oxazino[2,3,4-ij]quinoline-6-carboxylic acid (levofloxacin 9-piperazino isomer, synthesis related impurity)

New reference substances to be established

Levofloxacin RS ICRS to be established.

Levofloxacin impurity F RS ICRS to be established.

Levofloxacin for system suitability RS (containing levofloxacin and the impurities A, B and G) It is intended to refer to the corresponing reference substance to be established for the European Pharmacopoeia.

New reagent to be added

Ammonia (~10 g/L) TS Ammonia (~100 g/L) TS, diluted to contain about 10 g of NH3 per litre (approximately 1% (w/v)).

Copper (II) sulfate pentahydrate R CuSO4,5H2O, [7758-99-8]; blue, crystalline powder or transparent, blue crystals, content: 99.0% to 101.0%.

L-Isoleucine R (2S,3S)-2-Amino-3-methylpentanoic acid, C6H13NO2, content: 98.5% to 101.0% (dried substance).

***

5 45 WHO Drug Information Vol. 32, No. 4, 2018 Consultation documents

Consultation documents

The International Pharmacopoeia

REVISION OF THE MONOGRAPH ON LEVOFLOXACIN TABLETS

Draft proposal for The International Pharmacopoeia (January 2019)

DRAFT FOR COMMENTS

Please send any comments you may have on this draft to Dr Herbert Schmidt ([email protected]), Medicines Quality Assurance Programme, Technologies Standards and Norms, Department of Essential Medicines and Health Products, World Health Organization, 1211 Geneva 27, Switzerland, by 31 March 2019.

In order to speed up the process for receiving draft monographs and for sending comments, please send your email address to [email protected] and we will add it to our electronic mailing list. Please specify if you wish to receive monographs.

Note from the Secretariat. It is proposed to revise the monograph on Levofloxaxin tablets.

The revision is based on and evaluation of information found in other pharmacopoeias, the scientific literature and on laboratory investigations performed by a collaborating laboratory.

5 46 Consultation documents WHO Drug Information Vol. 32, No. 4, 2018

Levofloxacin tablets (Levofloxacini compressi)

Category. Antibacterial, antibuberculosis.

Storage. Levofloxacin tablets should be kept in a well closed container, protected from light.

Labelling. The designation of the container of Levofloxacin tablets should state that the active ingredient is Levofloxacin (the hemihydrate form) and the quantity should be indicated in terms of the equivalent amount of levofloxacin.

Additional information. Strengths in the current WHO Model list of essential medicines (EML): 250 mg, 500 and 750 mg. Strengths in the current WHO EML for children: 250 mg and 500 mg.

Requirements

Comply with the monograph for Tablets.

Definition. Levofloxacin tablets contain Levofloxacin. They contain not less than 90.0% and not more than 110.0% of the amount of levofloxacin (C18H20FN3O4) stated on the label.

Identity test

Either test A or tests B and C may be applied. A. To a quantity of the powdered tablets, nominally equivalent to 100 mg of levofloxacin, add 10 ml of acetonitrile R, shake, filter and evaporate to dryness. Carry out the examination as described under 1.7 Spectrophotometry in the infrared region. The infrared absorption spectrum is concordant with the spectrum obtained from levofloxacin RS or with the reference spectrum of levofloxacin hemihydrate.

If the spectra thus obtained are not concordant, repeat the test using the residues obtained by separately dissolving the test substance and levofloxacin RS in a small amount of acetonitrile R and evaporating to dryness. The infrared absorption spectrum is concordant with the spectrum obtained from levofloxaxin RS.

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B. Carry out the test as described under 1.14.1. Thin-layer chromatography, using silica gel R5 as the coating substance and a mixture of 10 volumes of dichloromethane R, 5 volumes of methanol R and 1 volume of ammonia (~10 g/L) TS as the mobile phase. Apply separately to the plate 5 µl of each of the following two solutions in a mixture of 1 volume of methanol R and 4 volumes of dichloromethane R. For solution (A), shake a quantity of the powdered tablets, nominally equivalent to 25 mg of levofloxacin, with 5 mL, filter and use the clear filtrate. For solution (B), use a solution containing 5 mg of levofloxacin RS per mL. After removing the plate from the chromatographic chamber, allow it to dry exhaustively in air or in a current of cool air. Examine the chromatogram in ultraviolet light (366 nm).

The principal spot in the chromatogram obtained with solution (A) corresponds in position, appearance and intensity with the spot due to levofloxacin in the chromatogram obtained with solution (B).

C. Carry out the test as described under 1.14.4 High-performance liquid chromatography using the conditions given under “Assay”. The retention time of the principal peak in the chromatogram obtained with solution (1) corresponds to the retention time of the peak due to levofloxacin in the chromatogram obtained with solution (2).

Dissolution. Carry out the test as described under 5.5 Dissolution test for solid oral dosage forms, using as the dissolution medium 900 ml of hydrochloric acid (~3.65 g/L) TS and rotating the basket at 100 revolutions per minute. At 30 minutes, withdraw a sample of about 10 mL of the medium through an in-line filter. Allow the filtered sample to cool to room temperature and use is as solution (1). Measure the absorbance (1.6) of a 1 cm layer of the filtered sample at about 293 nm. At the same time, measure the absorbance of a suitable solution of levofloxacin RS in hydrochloric acid (~ 4 g/l) TS using hydrochloric acid (~ 4 g/l) TS as a blank.

For each of the tablets, calculate the total amount of levofloxacin (C18H20FN3O4), in the medium. Each mg of levofloxacin hemihydrate (C18H20FN3O4,½ H2O) is equivalent to 0.976 mg of levofloxacin (C18H20FN3O4).

Evaluate the results as described under 5.5 Dissolution test for solid oral dosage forms, Acceptance criteria. The amount of levofloxacin in solution for each tablet is not less than 80% (Q) of the amount declared on the label.

[Note from the Secretariat. It is intended to determine the absorptivity value of levofloxacin hemihydrate during the establishment of levofloxacin RS. The value will then be included in the test description.]

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Related substances. Prepare fresh solutions, protected from light, and perform the test without delay.

Carry out the test as described under 1.14.4 High-performance liquid chromatography using the conditions given under “Assay”.

Prepare the following solutions in mobile phase. For solution (1), transfer a quantity of the powdered tablets, nominally equivalent to 250.0 mg of levofloxacin, into a 250 mL volumetric flask, add about 180 ml, sonicate for 5 minutes, dilute to volume, mix and filter. For solution (2), dilute 1.0 mL of solution (1) to 100.0 mL. Dilute 1.0 mL of this solution to 10.0 mL. For solution (3), dissolve 5.0 mg of levofloxacin for system suitability RS (containing levofloxacin and the impurities A, B and G) and dilute to 5.0 mL.

Inject 25 μL of solution (1), (2) and (3). Record the chromatogram for about three times the retention time of levofloxacin.

Use the chromatogram supplied with levofloxacin for system suitability RS and the chromatogram obtained with solution (3) to identify the peaks due to impurities A, B and G. The impurities, if present, are eluted at the following relative retentions with reference to levofloxacin (retention time about 20 minutes): impurity E about 0.38, impurity B about 0.50, impurity G about 0.56, impurity C about 0.63, impurity A about 1.22.

The test is not valid unless, in the chromatogram obtained with solution (3), the resolution factor between the peaks due to impurity B and impurity G is at least 1.5.

In the chromatogram obtained with solution (1): • the area of any peak corresponding to impurity B, when multiplied by a correction factor of 1.3, is not greater than seven times the area of the peak due to levofloxacin in the chromatogram obtained solution with (2) (0.7%);

• the area of any peak corresponding to impurity C, when multiplied by a correction factor of 1.47, is not greater than seven times the area of the peak due to levofloxacin in the chromatogram obtained with solution (2) (0.7%);

• the area of any peak corresponding to impurity E, when multiplied by a correction factor of 1.67, is not greater than three times the area of the peak due to levofloxacin in the chromatogram obtained with solution (2) (0.3%);

• the area of any peak corresponding to impurity G, when multiplied by a correction factor of 1.20, is not greater than three times the area of the peak due to levofloxacin in the chromatogram obtained with solution (2) (0.3%);

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• the area of any other impurity peak is not greater than twice the area of the peak due to levofloxacin in the chromatogram obtained with solution (2) (0.2%);

• the sum of the corrected areas of any peak corresponding to impurity B, C, E and G and the areas of all other impurity peaks, other than any peak due to impurity A, is not greater than ten times the area of the peak due to levofloxacin in the chromatogram obtained with solution (2) (1%). Disregard any peak with an area less the area of the peak due to levofloxacin in the chromatogram obtained with solution (2) (0.1%).

Assay. Prepare fresh solutions, protected from light and perform the test without delay.

Carry out the test as described under 1.14.4 High-performance liquid chromatography using a stainless steel column (25 cm x 4.6 mm), packed with end-capped and base- deactivated particles of silica gel, the surface of which has been modified with chemically- bonded octadecylsilyl groups (5 μm).2

Prepare the following buffer solution. Dissolve 1.25 g of copper sulfate pentahydrate R, 1.3 g of isoleucine R and 8.5 g of ammonium acetate R in water R and dilute to 1000 mL with the same solvent.

As the mobile phase, use a mixture of methanol R and buffer solution (30:70 v/v). Operate with a flow rate of 0.8 mL per minute. As a detector, use an ultraviolet spectrophotometer set at a wavelength of 360 nm. Maintain the column temperature at 45 °C.

Weigh and powder 20 tablets. For solution (1), transfer a quantity of the powdered tablets, nominally equivalent to 50.0 mg of levofloxacin, into a 250 mL volumetric flask, add about 180 mL of the mobile phase, shake for 30 minutes, dilute to volume, mix and filter. For solution (2), dissolve 20.0 mg of levofloxacin RS in mobile phase and dilute to 100.0 mL using the same solvent. Inject alternately 10 μL each of solution (1) and (2) and record the chromatograms for about two times the retention time of levofloxacin.

Measure the areas of the peaks corresponding to levofloxacin obtained in the chromatograms of solutions (1) and (2) and calculate the percentage content of levofloxacin (C18H20FN3O4) in the tablets, using the declared content of C18H20FN3O4 in levofloxacin RS.

Impurities. The impurities limited by the requirements of this monograph include those listed in the monograph for Levofloxacin.

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2 Inertsil ODS-2 or ODS-3 columns were found suitable.

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ATC/DDD classification

The Anatomical Therapeutic Chemical (ATC) classification system and the Defined Daily Dose (DDD) as a measuring unit are tools for exchanging and comparing data on drug use at international, national or local levels. The ATC/ DDD system has become the gold standard for international drug utilization research. It is maintained by the WHO Collaborating Centre for Drug Statistics Methodology in Oslo, Norway. Visit www.whocc.no/ for more information.

ATC/DDD classification (temporary)

The following ATC codes and DDDs were agreed at the meeting of the WHO International Working Group for Drug Statistics Methodology in October 2018.

Comments or objections to the decisions from the meeting should be forwarded to the WHO Collaborating Centre for Drug Statistics Methodology before 1 February 2019. If no objections are received before this date, the new ATC codes and DDDs will be considered final and included in the January 2020 version of the ATC/DDD Index.

New ATC 5th level codes ATC level name/INN ATC code acalabrutinib L01XE51 amenamevir J05AX26 amlodipine and celecoxib C08CA51 arginine and lysine V03AF11 atorvastatin and omega-3 fatty acids C10BA08 baloxavir marboxil J05AX25 betrixaban B01AF04 brolucizumab S01LA06 cemiplimab L01XC33 crizanlizumab B06AX01 daclatasvir, asunaprevir and beclabuvir J05AP58 darolutamide L02BB06 elagolix H01CC03 elbasvir J05AP10 entinostat L01XX64 Continued

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New ATC 5th level codes (continued)

ATC level name/INN ATC code enviomycin J04AB06 esketamine N06AX271) favipiravir J05AX27 ferrous sodium citrate B03AA12 fimasartan and amlodipine C09DB09 fremanezumab N02CX09 gilteritinib L01XE54 glasdegib L01XX63 glycopyrronium D11AA01 grazoprevir J05AP11 imlifidase L04AA41 inotersen N07XX15 irbesartan, amlodipine and hydrochlorothiazide C09DX07 ivosidenib L01XX62 lamivudine and dolutegravir J05AR25 laninamivir J05AH04 larotrectinib L01XE53 latanoprost and netarsudil S01EE51 latanoprostene bunod S01EE06 luspatercept B03XA06 methionine (11C) V09IX13 mosapride A03FA09 moxidectin P02CX03 opinercept L04AB07 pegvaliase A16AB19 perindopril, bisoprolol and amlodipine C09BX04 plazomicin J01GB14 quizartinib L01XE52 rabeprazole, amoxicillin and clarithromycin A02BD12 Continued

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New ATC 5th level codes (continued)

ATC level name/INN ATC code rabeprazole, amoxicillin and metronidazole A02BD13 ravulizumab L04AA43 rifamycin A07AA13 risankizumab L04AC18 rosuvastatin and fimasartan C10BX16 rosuvastatin and omega-3 fatty acids C10BA07 siponimod L04AA42 solriamfetol N06BA14 sotagliflozin A10BK06 tafenoquine P01BA07 tamsulosin and tadalafil G04CA54 tecovirimat J05AX24 ulinastatin B02AB05 vancomycin S01AA28 vonoprazan, amoxicillin and clarithromycin A02BD14 vonoprazan, amoxicillin and metronidazole A02BD15

1 Nasal formulations indicated for major depressive disorders. Parenteral formulations are classified in N01AX14

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New ATC level codes (other than 5th levels): Other hematological agents B06AX

Changes of ATC level names

Previous New ATC code lactobacillus fermentum lactobacillus G01AX14 microspheres of human perflutren, human albumin microspheres V08DA01 albumin microspheres of perflutren, phospholipid microspheres V08DA04 phospholipids perflubutane polymer perflubutane, phospholipid microspheres V08DA06 microspheres sulfur hexafluoride sulfur hexafluoride, phospholipid V08DA05 microspheres

New DDDs ATC level name/INN DDD unit Adm.R* ATC code amenamevir 0.4 g O J05AX26 apalutamide 0.24 g O L02BB05 asunaprevir 0.2 g O J05AP06 brodalumab 15 mg P L04AC12 calcium aminosalicylate 15 g O J04AA03 cerliponase alfa 21 mg P A16AB17 elbasvir 50 mg O J05AP10 enviomycin 1 g P J04AB06 erenumab 2.5 mg P N02CX07 favipiravir 1.6 g O J05AX27 glycerol phenylbutyrate 15 g O A16AX09 grazoprevir 0.1 g O J05AP11 laninamivir 40 mg Inhal.powder J05AH04 levofloxacin 0.24 g Inhal.solution J01MA12 nabilone 3 mg O A04AD11 Continued

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New DDDs (continued)

ATC level name/INN DDD unit Adm.R* ATC code opinercept 7 mg P L04AB07 pentosan polysulfate sodium 0.3 g O G04BX15 peramivir 0.6 g P J05AH03 pridinol 6 mg O M03BX03 semaglutide 0.11 mg P A10BJ06 sodium zirconium cyclosilicate 7.5 g O V03AE10 vidarabine 0.7 g P J05AB03

Changes of DDDs ATC level name/INN Previous DDD New DDD ATC code

liraglutide 1.2 mg P 1.5 mg P A10BJ02

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ATC/DDD classification (final)

The following ATC codes and DDDs were agreed at the meeting of the WHO International Working Group for Drug Statistics Methodology in March 2018.

These are considered as final and will be included in the January 2019 version of the ATC/DDD Index.

New ATC 5th level codes

ATC level name/INN ATC code abemaciclib L01XE50 angiotensin II C01CX09 apalutamide L02BB05 avatrombopag B02BX08 candesartan, amlodipine and hydrochlorothiazide C09DX06 cannabidiol N03AX24 cefpodoxime and beta-lactamase inhibitor J01DD64 copanlisib L01XX61 doravirine J05AG06 edaravone N07XX14 fexinidazole P01CA03 fostamatinib B02BX09 gemigliptin and rosuvastatin A10BH52 hydrogen peroxide D11AX25 ibalizumab J05AX23 lamivudine, tenofovir disoproxil and doravirine J05AR24 leuprorelin and bicalutamide L02AE51 metformin, saxagliptin and dapagliflozin A10BD25 omidenepag S01EX06 prasterone G03XX01 talazoparib L01XX60 telotristat A16AX15 trifarotene D10AD06

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New ATC level codes (other than 5th levels):

Other sex hormones and modulators of the genital system G03XX

Change of ATC codes: ATC level name/INN Previous ATC New ATC

dimethyl fumarate N07XX09 L04AX07

Changes of ATC level names Previous New ATC code Angiotensin II antagonists, Angiotensin II receptor blockers (ARBs), C09C plain plain Angiotensin II antagonists, Angiotensin II receptor blockers (ARBs), C09CA plain plain Angiotensin II antagonists, Angiotensin II receptor blockers (ARBs), C09D combinations combinations Angiotensin II antagonists and Angiotensin II receptor blockers (ARBs) C09DA diuretics and diuretics Angiotensin II antagonists and Angiotensin II receptor blockers (ARBs) C09DB calcium channel blockers and calcium channel blockers Angiotensin II antagonists, Angiotensin II receptor blockers (ARBs), C09DX other combinations other combinations combinations potassium (different salts in combination) A12BA30

fluoromethylcholine (18F) fluorocholine (18F) V09IX07

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New DDDs ATC level name/INN DDD unit Adm.R* ATC code artemether 0.28 g R P01BE02 artesunate 0.28 g R P01BE03 benralizumab 0.54 mg P R03DX10 chenodeoxycholic acid 1 g O A05AA01 cladribine 0.34 mg O L04AA40 dupilumab 21.4 mg P D11AH05 emicizumab 15 mg P B02BX06 ertugliflozin 10 mg O A10BK04 guselkumab 1.79 mg P L04AC16 letermovir 0.48 g O,P J05AX18 ocrelizumab 3.29 mg P L04AA36 patiromer calcium 8.4 g O V03AE09 rolapitant 0.18 g O A04AD14 telotristat 0.75 g O A16AX15 * Administration Route: O = oral; P= parenteral.

Change of DDD ATC level name/INN Previous DDD New DDD ATC code

aprepitant 95 mg O 165 mg O A04AD12 aprepitant1 95 mg P 150 mg P A04AD12 temocillin 2 g P 4 g P J01CA17 vasopressin 4 U P 40 U P H01BA01 (argipressin)

1 refers to fosaprepitant

WHO Collaborating Centre for Drug Statistics Methodology Oslo, November 2018

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