WHO Drug Information · WHO Drug Informati on Vol. 32, No. 4, 2018 . 5. 15. THEME: Smart safety...

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

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

(www.ich.org) IGDRP 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/)

PRAC Pharmacovigilance Risk Assessment Committee (EMA)

PMDA Pharmaceuticals and Medical Devices Agency, Japan (www.pmda.go.jp/english/index.htm)

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 EMP WHO Essential medicines and health products (www.who.int/medicines/en/)

WHO PQT WHO Prequalification team (https://extranet.who.int/prequal/)

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

WHO Drug Information Contents

ICDRA 509 18th International Conference of Drug Regulatory

Authorities (ICDRA) Recommendations

Consultation documents 519 The International Pharmacopoeia 519 Revision of the monograph on ethinylestradiol 530 Polymorphism 538 Revision of the monograph on levofloxacin 546 Revision of the monograph on levofloxacin tablets

ATC/DDD classification

551 ATC/DDD classification (temporary) 556 ATC/DDD classification (final)

International Nonproprietary Names (INN)

559 List N° 120 of Proposed International Nonproprietary Names (INN) for Pharmaceutical Substances

http://www.ema.europa.eu/

http://www.fda.gov/

http://www.hc-sc.gc.ca/

http://www.hpra.ie/

http://www.hsa.gov.sg/

http://www.ich.org/

https://www.igdrp.com/

http://www.mhra.gov.uk/

http://www.medsafe.govt.nz/

http://apps.who.int/phint/

http://www.pmda.go.jp/english/index.htm

http://www.swissmedic.ch/

http://www.tga.gov.au/

http://www.who.int/

http://www.who.int/medicines/en/

http://www.who.int/medicines/publications/druginformation

18th ICDRA recommendations

509

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.ieInformation on past ICDRA conferences is available at:www.who.int/medicines/areas/quality_safety/regulation_legislation/icdra/en/

http://www.icdra2018.ie/

http://www.who.int/medicines/areas/quality_safety/regulation_legislation/icdra/en

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

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THEME: Regulatory collaboration, convergence and harmonization

Recommendations to WHO 1. Regulatory collaboration,

convergence and harmonizationactivities should incorporate not onlyinitial authorization but also life-cycle management andpharmacovigilance.

2. WHO should provide a toolbox withall the available options forregulatory collaboration,convergence and harmonizationand increase awareness to facilitateselection of the appropriatemechanisms by member states.

Recommendations to Member States 1. When sharing assessment or

inspection reports, Member Statesshould share unredacted reports,where possible, which is important tobuild trust and to optimize reliance onoutcomes from other regulators.

THEME: Certification of Pharmaceutical Products (CPP)

Recommendations to WHO 1. WHO should advocate for the use of an

electronic CPP template by issuing andreceiving authorities to expedite theprocess and mitigate against anyfurther need for “legalization.”

2. WHO should advocate for the CPPstandard procedure specifying thatvalue-added, unredacted documentseither accompany the CPP or areprovided upon request by any receivingagency.

3. The CPP template should be updatedto reflect current manufacturingsituations by including: (a) the sites ofmanufacture with addresses, and (b) areminder that the receiving countryshould check that the product beingshipped to it is exactly the same as theproduct being certified by the issuingcountry.


THEME: Regulatory preparedness for public health emergencies)

Recommendations to WHO 1. WHO should facilitate communication

between stakeholders (manufacturersof IVDs, vaccines and therapeutics) andregulators on needs for products,development work and risk assessmentwork. This should be facilitated by WHOsetting up a pre-Emergency Use Listingscheme.

2. WHO should encourage the use ofregulatory networks such as ICMRA inthe case of public health emergenciesand should support effective transitionfrom emergency use to in-countryapproval.

Recommendations to Member States 1. Member States should consider the

feasibility of “conditional approvals” forPHE products with strengthenedpharmacovigilance and long-termmonitoring after outbreaks.

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

Recommendations to WHO 1. WHO is asked to rapidly finalize the

good regulatory practice suite ofguidance, with a particular focus ondeveloping practical advice options,and best practices to promoteregulatory collaboration and reliancefor the whole lifecycle management ofmedical products, both for individualNational Regulatory Authorities andfor regional networks.

2. WHO is asked to use its position inthe various international regulatoryharmonization forums to help promotealignment of regulatory applicationdossier formats, including eliminationof unnecessary differences in thenational and regional CTDrequirements.

Recommendations to Member States 1. While fully recognizing that there are

different languages and differentregulatory systems, Member States areurged to review their current applicationdossier formats to ensure that allrequirements are scientifically justifiedand better aligned with internationallyagreed harmonized standards.

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512

THEME: Benchmarking of Regulatory Systems: towards mature regulatory systems

Recommendations to WHO 1. Continue support for regulatory

systems strengthening to MemberStates utilizing the GlobalBenchmarking Tool which has provento be effective in promoting one globalstandard for regulatory systems.

2. Support regulatory systemsstrengthening to Member States atdifferent maturity levels in a strategicmanner.

3. Further develop the process fordesignating WHO Listed Authoritieswith input from Member States.

4. Further clarify the role of WHO ListedAuthorities at Maturity Level 3 orMaturity Level 4 and describe how thisinformation can be utilized by MemberStates to support and advance theirregulatory work.

Recommendations to Member States 1. Invest resources to strengthen

regulatory systems utilizing the GlobalBenchmarking Tool and work towardsattaining at least Maturity Level 3 whileimplementing principle of continuousimprovement for all maturity levels.

2. Explore approaches to utilize concept ofreliance and collaborative decision-making to increase timely access to safeand effective medical products.

THEME: Future direction of WHO Prequalification (PQT)

Recommendations to WHO 1. Recognizing PQP’s demonstrated

effective contribution to UHC byfacilitating access to quality assuredmedical products, WHO should expandthe scope of products eligible for PQassessment and diversify the pathwaysto PQ product listing to includeincreased reliance on WLAs and onquality assured assessments byregulatory networks.

Recommendations to Member States 1. Member states should where possible

take advantage of opportunities offeredby WHO through its PrequalificationProgramme by signing up and using thecollaborative registration proceduresand utilizing the practical training andcapacity building opportunities offeredthrough PQT.


513

THEME: Regional regulatory networks: progress and challenges

Recommendations to WHO 1. Support trust building by providing or

using existing platforms forexchange of information to avoidhaving to rebuild a system for eachregional network/collaborativeinitiative.

Recommendations to Member States 1. National Regulatory Authorities/regional

networks should engage withstakeholders to ensure that the addedvalue and strength of the network ispresented and understood, and to buildconfidence among all NationalRegulatory Authorities.

THEME: Regulators role in containing antimicrobial resistance (AMR)

Recommendations to WHO 1. Continue to support member states to

implement Global Action Plan (GAP) inparticular, improve awareness andunderstanding of AMR andmonitor/support countries inimplementing national action plans.

Recommendations to Member States 1. Regulators should consider ways that will

facilitate the development of new antibioticsand diagnostic tools such as harmonizedtechnical standards, scientific advice,accelerated pathways and incentivizedresearch.

2. Member States/regulators should promotethe implementation of national action plansincluding awareness and understanding ofAMR, surveillance of AMR and the rationaluse and prescribing of medicines.


514

THEME: Local production

Recommendations to WHO 1. Maintain local production as a discussion

topic for further ICDRAs.

Recommendations to Member States 1. Members States are encouraged to promote

communication and transparency betweenregulators and the industry to overcome thechallenges in local production of medicalproducts in assuring quality, efficacy andsafety.

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

Recommendations to WHO 1. WHO should develop options on how to

provide advice and support in terms ofstrategic and practical aspects ofadaptation of procurement practices.

2. WHO should continue toencourage/advocate procurement agenciesand donors to adhere to national regulatoryrequirements.

Recommendations to Member States 1. Member States should raise awareness on

selection, prices, supply systems, sustainablefinancing and regulatory systems.

2. Member States should encourage allstakeholders to be involved and coordinatedon national level, from industry and donors toregulators in the process of procurement.

3. Member States should put the focus onquality-assured essential medicines andsimplify the pathways for getting them to thepatients.

THEME: Promoting medical products safely: supply chain integrity

Recommendations to WHO 1. WHO should support Member States with

guidelines on implementation on risk-based post market surveillance.

2. WHO should support the Member Statesto build the capacity to implement the risk-based post market surveillance.

Recommendations to Member States 1. Member States should plan and implement

risk-based post market surveillanceprogrammes.

2. Member States should put in place a systemfor effective response in surveillance toaddress serious public health threats relatedto Substandard and Falsified (SF) medicalproducts.


515

THEME: Smart safety surveillance – a shared responsibility

Recommendations to WHO 1. WHO should develop guidance and a

toolkit to support Member States in theimplementation of the Smart SafetySurveillance strategy, one that embraces arisk-based prioritization of investments,work-sharing, joint activities and reliancefor maximum return on investment for allmedical products.

Recommendations to Member States 1. Member States should further explore the

concept with a view towards WHO SmartSafety Surveillance strategy.

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

Recommendations to WHO 1. WHO RHT strategy should ensure a

comprehensive approach to improve patientaccess for all medical products, including forblood and blood components.

2. WHO Coalition of Interested Partners modelshould be used as a collaborative platformto advance “Smart” approaches, relianceand work-sharing among stakeholders foreffective regulation.

Recommendations to Member States 1. Member States should work with

harmonized systems, across productstreams, supply chains and public healthprogrammes, to ensure data are shared withthe regulator, to inform policies, and forquality of care.

THEME: Safety of medical products throughout the product life cycle

Recommendations to WHO 1. Support countries to proactively assess

risks and benefits of medical products throughout the product life cycle.

2. Develop guidance and document bestpractice for effective communication onrisk and benefit of all medical products(including vaccines).

Recommendations to Member States 1. Train and prepare all policy makers and

other stakeholders on effectivecommunication of both benefits and risksof medical products, including vaccines,based on robust scientific data.

2. Accumulate evidence and build evolvingrisk management plans from earlystages of medical product development.


516

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 devicesregulations to avoid duplication of work.

2. Regulatory capacity for medical devicesshould be established in Africa to convert thePan-African Harmonization Working Partyinto a continental expert working group,under the AMRH initiative, building onexisting regulatory models and availableguidance.

3. More efforts should be invested in medicaldevices post-market surveillance as a criticalelement of regulations.

THEME: Risk based inspections

Recommendations to Industry 1. In support of transparency, companies

should consent to the sharing of fullinformation amongst regulators andprocurement agencies on inspections.

Recommendations to Member States 1. NRAs should embed the use of reliance

procedures in their regulatory decisionprocesses relating to inspections.

2. NRAs should monitor foreign inspections andsupport desk-top assessments with definedconditions

THEME: Regulation of clinical trials: focus on patient safety

Recommendations to WHO 1. Facilitate exchange of safety information

from clinical trials and other relatedactivities at local, regional, and global level.

Recommendations to Member States 1. Implement any existing WHO guidance for

inclusion of vulnerable populations, children,pregnant women and women of child bearingage in clinical trials to gain knowledge ofsafety in these populations in a controlledsetting. This will facilitate access, ifbenefit/risk is favourable, in thesepopulations to important medical products.

2. Utilize opportunities for collaboration throughnetworks such as AVAREF to assess clinicaltrial applications and develop processes formonitoring and follow up on safety data.


517

THEME: Harmonization, work-sharing and reliance in pharmacovigilance

Recommendations to WHO 1. WHO should coordinate Member States

efforts to develop a platform for sharingbest practice and emerging data inpharmacovigilance.

Recommendations to Member States

THEME: Regulation of advanced therapies

Recommendations to WHO 1. WHO to develop with Member States a

“current state of the art” document capturingareas where agreement amongexperienced regulatory authorities exists,noting where harmonization has yet to beachieved, and documenting existing areasof uncertainty; areas covered could includedefinitions, quality attributes, standards,and clinical development pathways.

Recommendations to Member States 1. Member States are encouraged to develop

national guidance and legislation onadvanced therapies.

THEME: Regulation of biosimilars

Recommendations to WHO 1. WHO should keep organizing

implementation workshops to accelerateuse by Member States of the WHOguidelines on biosimilars, focusing more onanalytical comparability than oncomparability in clinical data, andemphasizing the importance of regulatoryoversight throughout the entire life cycle ofbiosimilars.

Recommendations to Member States 1. Member States are encouraged to

collaborate, to use existing resources in moreefficient manner and to improve transparencyby making Public Assessment Reports(PARs) detailed enough, particularly oncomparability, and publishing PAR for bothapproved and rejected biotherapeutics.

2. Member States should, in accordance withtheir respective mandates, defineprerequisites for interchangeability andsubstitutability of biosimilars, which is anational responsibility.


518

THEME: Safety of blood and blood products

Recommendations to WHO 1. WHO should support the establishment of

national hemovigilance systems in MemberStates through the facilitation of educationand training opportunities at the regionallevel.

2. WHO should take steps to ensurestandardization, harmonized terminologyand common good practices for national,regional and global hemovigilancedatabase systems.

***

Recommendations to Member States 1. Member States should take steps to

establish or strengthen their nationalhemovigilance system in accordance with the2016 WHO guide.

2. Member States should engage in self-assessments and external assessments oftheir national hemovigilance systems usingthe WHO Global Benchmarking Tool,integrating the WHO Assessment Criteria forNational Blood Regulatory Systems.


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 HPLCmethod.

• 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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mailto:[email protected]



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

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

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 infraredregion. The infrared absorption spectrum is concordant with the spectrum obtainedfrom ethinylestradiol RS or with the reference spectrum of ethinylestradiol.

If the spectrum thus obtained are not concordant, repeat the test using the residuesobtained by separately dissolving the test substance and ethinylestradiol RS in asmall amount of methanol R and evaporating to dryness. The infrared absorptionspectrum is concordant with the spectrum obtained from ethinylestradiol RS. If thespectrum obtained from the solid state of the test substance is not concordant withthe spectrum obtained from the reference substance, compare the spectra ofsolutions 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 silicagel R1 as the coating substance and a mixture of 10 volume of dehydrated ethanol Rand 90 volumes of toluene R as the mobile phase. Apply separately to the plate 5 μLof each of two solutions in a mixture of 10 volumes of methanol R and 90 volumes ofdichloromethane R containing (A) 1.0 mg of the test substance per mL, and (B) 1.0mg of ethinylestradiol RS per mL. Develop the plate for a distance of 15 cm. Afterremoving the plate from the chromatographic chamber, allow it to air dry until thesolvents have evaporated, heat at 110 °C for 10 minutes, spray the hot plate withsulfuric acid/ethanol (20%) TS and heat again at 110 °C for 10 minutes. Allow tocool and examine the chromatogram in daylight and in ultraviolet light (365 nm). Theprincipal spot obtained with solution (A) corresponds in position, appearance, andintensity with that obtained with solution (B). Carry out the test as describedunder 1.14.1 Thin-layer chromatography, using kieselguhr R1 as the coatingsubstance and a mixture of 1 volume of propylene glycol R and 9 volumes of acetoneR 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 thechromatographic chamber and allow it to stand at room temperature until the solventhas completely evaporated. Use the impregnated plate within 2 hours, carrying outthe chromatography in the same direction as the impregnation. Use toluene R as themobile phase. Apply separately to the plate 2 μL of each of 2 solutions in a mixture of9 volumes of chloroform R and 1 volume of methanol R containing (A) 1.0 mg of thetest substance per mL, and (B) 1.0 mg of ethinylestradiol RS per mL. Develop theplate for a distance of 15 cm. After removing the plate from the chromatographicchamber, allow it to dry in air until the solvents have evaporated, heat at 120°C for 15minutes, 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 inultraviolet light (365 nm). The principal spot obtained with solution A corresponds inposition, appearance, and intensity with that obtained with solution B.

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http://apps.who.int/phint/2016/index.html#toc_1_7

http://apps.who.int/phint/2016/index.html#toc_1_7

http://apps.who.int/phint/2016/index.html#toc_1_14_1



C. Carry out the test as described under 1.14.4 High-performance liquidchromatography 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 thechromatogram 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

(minutes)

Mobile phase A

(% v/v)

Mobile phase B

(% v/v)

Comments

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 acorrection factor of 0.7, is not greater than five times the area of the peak dueto ethinylestradiol in the chromatogram obtained with solution (2) (0.5 %);

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

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

• the area of any peak corresponding to impurity C or F is not greater than1.5 times the area of the peak due to ethinylestradiol in the chromatogramobtained with solution (2) (0.15 %);

• the area of any other impurity peak is not greater than the area of the peakdue 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 Iand the areas of all other impurity peaks is not greater than eight times thearea of the peak due to ethinylestradiol in the chromatogram obtained withsolution (2) (0.8 %). Disregard any peak with an area less than 0.5 times thearea of the peak due to ethinylestradiol in the chromatogram obtained withsolution (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 liquidchromatography, using the conditions given below under “Related substances”.

Use solution (1) as described under “Related substances”. Prepare the followingadditional solution: for solution (5), dissolve 50.0 mg of ethinylestradiol RS in 30 mLof 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 thechromatograms of solutions (1) and (5) and calculate the percentage content ofethinylestradiol (C20H24O2) using the declared content of C20H24O2 in ethinylestradiolRS.

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

Measure the absorbance of a 1 cm layer of the diluted solution at the maximum atabout 281 nm. Calculate the percentage content of ethinylestradiol (C20H24O2) usingthe absorptivity value of 7.1 (𝐴𝐴1 𝑐𝑐𝑐𝑐

1 % = 71)

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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)


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


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)

528


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)

***

529



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

530




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”.

531


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).

532


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

1. Packing propertiesa. Molar volume and densityb. Refractive indexc. Conductivity (electrical and thermal)d. Hygroscopicity

2. Thermodynamic propertiesa. Melting and sublimation temperaturesb. Internal energy (i.e. structural energy)c. Enthalpy (i.e. heat content)d. Heat capacitye. Entropyf. Free energy and chemical potentialg. Thermodynamic activityh. Vapour pressurei. Solubility

3. Spectroscopic propertiesa. Electronic state transitionsb. Vibrational state transitionsc. Nuclear spin state transitions

4. Kinetic propertiesa. Dissolution rateb. Rates of solid state reactionsc. Stabilityd. Solid state

5. Surface propertiesa. Surface-free energyb. Interfacial tensionsc. Habit (i.e. shape)

6. Mechanical propertiesa. Hardnessb. Tensile strengthc. Compactibilityd. Flow

533


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 diffraction2. Microcalorimetry3. Thermal analysis (1.2.1 Melting point,* differential scanning calorimetry,

thermogravimetry, thermomicroscopy)4. Moisture sorption analysis5. Polarized optical microscopy and electronic microscopy with diffraction capability

(ex. Transmission Electron Microscopy)6. Solid-state nuclear magnetic resonance;7. Solubility studies8. Spectrophotometry in the infrared region (1.7)* and Raman spectrophotometry9. Intrinsic dissolution rate10. 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.

534


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.

535


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), mebendazoleAPI (Form C); or

• by limiting the presence of unwanted forms, for example, chloramphenicol palmitateAPI (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 referencesubstance prescribed (or reference spectrum supplied) – when the infraredabsorption spectrum has been proven to be specific to the preferred form and able todistinguish the undesired form(s), for example, indomethacin API;

• restricting the melting point range, when the melting properties of the forms areclearly distinguishable, for example, phenobarbital API;

• recommending the use of any other suitable methods such as X-ray powderdiffractometry, for example, carbamazepine tablets; and

• limiting the incorporated solvent (in the case of solvates/hydrates) with a specific limittest, 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 theevent 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 theanhydrous 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.

536


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 MaterialsScience and Materials Engineering. Encyclopedia of Condensed Matter Physics,8–17.

2. Brittain, HG. 2007. Polymorphism and Solvatomorphism 2005. Journal ofPharmaceutical 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: RegulatoryClassification of Pharmaceutical Co-crystals.

4. International Conference on Harmonisation of Technical Requirements forRegistration of Pharmaceuticals for Human Use. 1999. ICH Q6A – Specifications:The Procedures and Acceptance Criteria for New Drug Substances and New DrugProducts: Chemical Substances.

5. Caira, M, Pienaar, EW, Lötter, AP. 2006. Polymorphism andPseudopolymorphism of the Antibacterial Nitrofurantoin. Molecular Crystals andLiquid 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 SeveralPolymorphs and Solvates of Terazosin Hydrochloride. Journal of PharmaceuticalSciences, 95(4):917-928.

8. Peterson, ML, et al. 2006. Expanding the Scope of Crystal Form Evaluation inPharmaceutical Science. Journal of Pharmaceutical Sciences, 9(3):317-326.

9. European Medicines Agency. 2015. Reflection Paper on the Use of Co-crystals ofActive 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 ControlsInformation.

11. British Pharmacopoeia Commission. 2017. SC I B. Polymorphism. In: BritishPharmacopoeia Commission. British Pharmacopoeia 2017. Supplementarychapter. 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 pharmaceuticalmaterials, John Wiley & Sons. Inc.

***

537



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.

538



Levofloxacin

(Levofloxacinum)

Molecular formula. C18H20FN3O4,½ H2O

Relative molecular mass. 370.4

Graphic formula.

N

CO2HO

F

NN

H3CO CH3

H

½ H2O.

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 theinfrared region. The infrared absorption spectrum is concordant with the spectrumobtained from levofloxacin RS or with the reference spectrum of levofloxacinhemihydrate.

B. Carry out the test as described under 1.14.1. Thin layer chromatography, usingsilica 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 mobilephase. Apply separately to the plate 5 µl of each of the following two solutions in amixture of 1 volume of methanol R and 4 volumes of dichloromethane R.

539


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) TSand dilute to 50.0 ml with the same solvent. Dilute 1.0 ml of this solution to 100.0ml using water R. The absorption spectrum (1.6) of the resulting solution, whenobserved between 210 and 350 nm, exhibits two maxima at about 227 nm and atabout 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

anhydrous substance; [ ]20Dα = -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.

540


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 levofloxacinin the chromatogram obtained with solution (2) (0.3 %);

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

• the area of any peak corresponding to impurity A is not greater than ten times thearea 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 tolevofloxacin in the chromatogram obtained with solution (2) (0.10 %);

541


• the sum of the corrected areas of any peak corresponding to impurity B or G andthe areas of all other impurity peaks, other than any peak due to impurity A, is notgreater than five times the area of the peak due to levofloxacin in thechromatogram obtained with solution (2) (0.5 %). Disregard any peak with an arealess than 0.5 times the area of the peak due to levofloxacin in the chromatogram inthe 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.

542


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),

N

CO2H

O

F

N

HN O CH3

H

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),

N

CO2H

O

F

N

N O CH3

HO

H3C

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; degradationproduct),

N

CO2H

O

N

NH3C

O CH3

H

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),

543


N

O

F

N

NH3C

O CH3

H

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),

N

CO2H

O

F

F

O CH3

H

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

544


I. (3S)-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% (driedsubstance).

***

545



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.

546



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 theexamination as described under 1.7 Spectrophotometry in the infrared region. Theinfrared absorption spectrum is concordant with the spectrum obtained fromlevofloxacin RS or with the reference spectrum of levofloxacin hemihydrate.

If the spectra thus obtained are not concordant, repeat the test using the residuesobtained by separately dissolving the test substance and levofloxacin RS in a smallamount of acetonitrile R and evaporating to dryness. The infrared absorptionspectrum 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 silicagel 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 mobilephase. Apply separately to the plate 5 µl of each of the following two solutions in amixture of 1 volume of methanol R and 4 volumes of dichloromethane R. Forsolution (A), shake a quantity of the powdered tablets, nominally equivalent to 25 mgof levofloxacin, with 5 mL, filter and use the clear filtrate. For solution (B), use asolution containing 5 mg of levofloxacin RS per mL. After removing the plate fromthe chromatographic chamber, allow it to dry exhaustively in air or in a current of coolair. Examine the chromatogram in ultraviolet light (366 nm).

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

C. Carry out the test as described under 1.14.4 High-performance liquidchromatography using the conditions given under “Assay”. The retention time of theprincipal peak in the chromatogram obtained with solution (1) corresponds to theretention time of the peak due to levofloxacin in the chromatogram obtained withsolution (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 tolevofloxacin in the chromatogram obtained solution with (2) (0.7%);

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

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

• the area of any peak corresponding to impurity G, when multiplied by a correctionfactor of 1.20, is not greater than three times the area of the peak due tolevofloxacin 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 peakdue 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 andG 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 thechromatogram obtained with solution (2) (1%). Disregard any peak with an arealess the area of the peak due to levofloxacin in the chromatogram obtained withsolution (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.

***

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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http://www.whocc.no/

ATC/DDD classification WHO Drug Information Vol. 32, No. 4, 2018

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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WHO Drug Information Vol. 32, No. 4, 2018 ATC/DDD classification

New ATC 5th level codes (continued)

ATC level name/INN ATC coderabeprazole, 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 albumin

perflutren, human albumin microspheres V08DA01

microspheres of phospholipids

perflutren, phospholipid microspheres V08DA04

perflubutane polymer microspheres

perflubutane, phospholipid microspheres V08DA06

sulfur hexafluoride sulfur hexafluoride, phospholipid microspheres

V08DA05

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


557

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, plain

Angiotensin II receptor blockers (ARBs), plain

C09C

Angiotensin II antagonists, plain

Angiotensin II receptor blockers (ARBs), plain

C09CA

Angiotensin II antagonists, combinations

Angiotensin II receptor blockers (ARBs), combinations

C09D

Angiotensin II antagonists and diuretics

Angiotensin II receptor blockers (ARBs) and diuretics

C09DA

Angiotensin II antagonists and calcium channel blockers

Angiotensin II receptor blockers (ARBs) and calcium channel blockers

C09DB

Angiotensin II antagonists, other combinations

Angiotensin II receptor blockers (ARBs), other combinations

C09DX

combinations potassium (different salts in combination) A12BA30

fluoromethylcholine (18F) fluorocholine (18F) V09IX07


558

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 (argipressin)

4 U P 40 U P H01BA01

1 refers to fosaprepitant

WHO Collaborating Centre for Drug Statistics Methodology Oslo, November 2018

***

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