Who Di 33-4 PDF

WHO Drug Information Vol. 33, No.
4, 2019
WHO Drug Information

Contents
Consultation Documents
709 Environmental aspects of manufacturing for the prevention of antimicrobial resistance
713 Draft monograph on sofosbuvir tablets (sofosbuvir compressi)
721 Draft monograph on sofosbuvir (sofosbuvirum)
729 Dolutegravir sodium (dolutegravir natricum)
738 Dolutegravir tablets (dolutegravir compressi)
745 Dolutegravir, Lamivudine and Tenofovir disoproxil fumarate (dolutegraviri, lamivudine et tenofoviri
disoproxili fumarati compressi)
757 Tenofovir disoproxil fumarate (tenofoviri disoproxili fumaras)
769 Proposal to discontinue the test for undue toxicity (chapter 3.7) in The International Pharmacopoeia
773 Guideline on data integrity
794 ATC/DDD Classification (Temporary)
797 ATC/DDD Classification (Final)
International Nonproprietary Names (INN)

801 List No. 122 of Proposed International Nonproprietary 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 (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, Vol 33, No. 4, 2019 Regulation and Safety News
ENVIRONMENTAL ASPECTS OF MANUFACTURING FOR THE

PREVENTION OF ANTIMICROBIAL RESISTANCE
Antimicrobial resistance (AMR) is a global and multisectoral challenge that requires a

comprehensive One Health response to bridge human, animal, plant and environmental health.
The environment is considered as one driver/reservoir of AMR as the discharge of
antimicrobial residues and resistant microbes from health care facilities, household and farms
and pharmaceutical manufacturing can potentially increase the risk of AMR infections. 1
According to research by UN Environment, 2 growing antimicrobial resistance (AMR) linked to

the discharge of drugs and particular chemicals into the environment is one of the most
worrying health threats of today. There is an emerging evidence showing that pharmaceutical
plants can act as hotspots that release large amounts of antibiotics into the environment, which
is of particular concern in the regions without adequate monitoring and wastewater
management capacity.
The Organisation for Economic Cooperation and Development (OECD) in its latest report
“Pharmaceutical Residues in Freshwater” (November 2019), highlights the need to better
understand the effects of pharmaceutical residues in the environment, and to employ policy
instruments across the pharmaceutical life-cycle to mitigate the risks, by improvements in the
design, authorization, production, use, solid waste and wastewater treatment. A focus on
preventive options early in the pharmaceutical life-cycle, including production, may deliver the
most long-term, cost-effective and large-scale benefits 3.
1 Interagency Coordination Group on Antimicrobial Resistance. No Time to Wait: Securing the future from drug-resistant
infections. Report to the Secretary-General of the United Nations. April 2019.
https://www.who.int/antimicrobial-resistance/interagency-coordination-group/IACG_final_report_EN.pdf?ua=1
2
Antimicrobial Resistance: Investigating the Environmental Dimension. Frontiers 2017: Emerging Issues of Environmental
Concern. UN Environment Program, 2017. P.12-20 (http://tiny.cc/jyufdz)
3
World Health Organization. Critically important antimicrobials for human medicine, 6th revision, 2019.
https://www.who.int/foodsafety/publications/antimicrobials-sixth/en/
709
Regulation and Safety News WHO Drug Information, Vol 33, No. 4, 2019
Against a backdrop of rising global concern about AMR, following up on the

Expert Committee on Specifications for Pharmaceutical Preparations (ECSPP) request from
October 2018, the WHO Secretariat developed a document outlining points for manufacturers
and inspectors to consider in preventing AMR. This Points to Consider document addresses
also the November 2018 decision of the World Health Organization (WHO) Executive Board
to provide technical input to good manufacturing practices guidance on waste and wastewater
management from the production of critically important antimicrobials for human medicine.
The ECSPP at its last meeting in October 2019 adopted the text “Environmental aspects of
manufacturing for the prevention of antimicrobial resistance” that is going to be published in
spring 2020 as an Annex to the ECSPP report in the WHO Technical Report Series (TRS).
The purpose of the document is to leverage on the current WHO Good Manufacturing
Practices (GMP) with the following objectives:
• raise awareness among manufacturers, GMP inspectors and inspectorates of the
existing GMP guidance that applies to the production of antimicrobials;
• encourage Member States to establish and enforce appropriate requirements on their
local pharmaceutical production facilities; and
• consider options for reducing and mitigating the uncontrolled disposal of waste and
wastewater containing antimicrobials, with a focus on the role of GMP and inspectors
in this.
The first draft of the document (April 2019) prepared by WHO Prequalification (PQ) Team -
Inspections and the WHO Secretariat was reviewed by WHO colleagues from the
AMR Surveillance, Prevention and Control Department within the AMR Division, and then
it was mailed to the Expert Advisory Panel on the International Pharmacopoeia and
Pharmaceutical Preparations inviting their comments. The document was also posted on the
WHO website for public consultation (May-June 2019). In addition, it was discussed during
several international meetings. All the comments received were consolidated and discussed
during the Informal Consultation on Good Practices for Health Products Manufacture and
Inspection (Geneva, July 2019).
During the GMP consultation on Good Practices for Health Products Manufacture and
Inspection (Geneva, July 2019), some proposals were discussed including:
a. the potential role of GMP inspectors to tackle AMR; and
b. the need to revise the WHO GMP main text in order to specifically address this issue.
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WHO Drug Information, Vol 33, No. 3, 2019 Regulation and Safety News
The main limitations identified when considering broadening up either the current
WHO GMP scope or the role of the inspectors to encompass environmental aspects were the
following;
i. GMP inspectors may not be adequately trained for inspecting waste and wastewater
management processes on a required level and that the duration of GMP inspections,
being limited to no more than 2 to 5 days, depending on the type of site, should not be
considerably extended to cover those aspects.
ii. The competence on environmental issues is often with environmental inspectors
reporting to a different authority with specific competences and mandate.
iii. There are no WHO or government-developed thresholds (only industry ones) on the
acceptable residual limits from antimicrobial production in waste and wastewater to
perform a meaning evaluation.
iv. The knowledge on the waste and wastewater treatment is limited for most GMP
inspectors, therefore additional training in this area may be required if they are to
verify those aspects.
v. This Point to consider document focuses purely on the contamination of the
environment through production and does not attempt to address the many other
drivers of AMR and the life-cycle of managing medicines in the environment.
vi. The potential challenges to implementing the points to consider in practice and the
importance of ensuring collaboration between product and environment inspections
were also acknowledged.
After a careful reflection of the pros/cons and the stated limitations, the document was
restructured and the main changes were made to narrow the scope and structure of the initial
document by:
• including the relevant text from the GMP guidelines 4 relating to environment
protection and waste management to prevent AMR in the main body;
• elaborating on recommendations to manufacturers, including explanations on the
clauses listed to clarify the expectation of Inspectors from manufacturers in this area;
• focusing on the new target audience, namely pharmaceutical manufacturers and GMP
inspectors; and
• amending the scope: it is now drafted as a policy document for use by manufacturers
when designing and selecting their waste management processes, when performing
self-audits and also for use by both inspectors and manufacturers during GMP
inspections of pharmaceutical manufacturing sites.
4 WHO Good Manufacturing Practices for Pharmaceutical Products containing Hazardous Substances (WHO TRS No. 957,
2010, Annex 3)
WHO Good Manufacturing Practices for Pharmaceutical Products: main principles (WHO TRS No. 986, 2014, Annex 2)
WHO Good Manufacturing Practices for Active Pharmaceutical Ingredients (WHO Technical Report Series, No. 957,
2010, Annex 2)
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Regulation and Safety News WHO Drug Information, Vol 33, No. 4, 2019
The Point to Consider document discussed and adopted by the 54th ECSPP last October 2019
will be used in conjunction with a survey of waste and wastewater management practices that
will be sent to manufacturers t to raise awareness of AMR and to verify the practices currently
in use in the industry as well as the application of the recommendations made in the
newly-adopted Points to Consider for manufacturers and inspectors: Environmental aspects of
manufacturing for the prevention of antimicrobial resistance.
The WHO Prequalification (PQ) Team – Inspections is also initiating a phased approach in the
verification of the waste and wastewater management practices in use at pharmaceutical
manufacturing sites who are active in the production of antimicrobials during onsite
inspections in 2020.
Results of the survey will be presented to the 55th ECSPP in 2020.
***
712
WHO Drug Information, Vol 33, No. 4, 2019 Consultation Documents
DRAFT MONOGRAPH ON SOFOSBUVIR TABLETS

(SOFOSBUVIR COMPRESSI)
Draft proposal for inclusion in The International Pharmacopoeia
(November 2019)
DRAFT FOR COMMENTS
Please send any comments you may have on this draft working document to Dr Herbert
Schmidt, Technical Officer, Medicines Quality Assurance, Technologies Standards and Norms
(email: schmidth@who.int) by 20 February 2020.
Working documents are sent out electronically and they will also be placed on the Medicines
website for comments under “Current projects”.
http://www.who.int/medicines/areas/quality_safety/quality_assurance/guidelines/en
If you wish to receive our draft guidelines, please send your email address to
(jonessi@who.int) and your name will be added to our electronic mailing list.
713
Consultation Documents WHO Drug Information, Vol 33, No. 4, 2019
DRAFT PROPOSAL FOR INCLUSION IN

THE INTERNATIONAL PHARMACOPOEIA
SOFOSBUVIR TABLETS
(SOFOSBUVIRI COMPRESSI)
Category. Antiviral (Hepatitis C viral polymerase nucleotide inhibitor)
Storage. Sofosbuvir tablets should be kept in a well-closed container not exceeding 30 °C
Additional information. Strength in the current WHO Model List of Essential Medicines:
400 mg sofosbuvir
Requirements
Comply with the monograph for “Tablets”.
Definition. Sofosbuvir tablets contain not less than 90.0 % and not more than 110.0 % of the
amount of sofosbuvir (C22H29FN3O9P) stated on the label.
Identity tests
• Either test A alone or tests B and D or tests C and D may be applied.
A. Carry out the test as described under 1.14.4 High-performance liquid

chromatography using the conditions given under “Assay”. Record the UV
spectrum of the principle peak in the chromatograms with a diode array detector in
the range of 200 nm to 400 nm. The retention time and the UV spectrum of the
principal peak in the chromatogram obtained with solution (1) correspond to the
retention time and UV spectrum of the peak due to sofosbuvir in the
chromatogram obtained with solution (2).
714
B. 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 sofosbuvir in the chromatogram obtained
with solution (2).
C. Carry out the test as described under 1.14.1 Thin-layer chromatography, using
silica gel R21 as the coating substance and a mixture of 6 volumes of
dichloromethane R, 1 volume of methanol R, 4 volumes of ethyl acetate R and
0.1 volume of ammonia R as the mobile phase.
Apply separately to the plate 10 µL of each of the following solutions in methanol

R. For solution (A), sonicate a quantity of the powdered tablets, nominally
containing 10 mg of sofosbuvir with 10 mL of methanol, allow to cool to room
temperature and filter. For solution (B), use 1 mg of sofosbuvir RS per mL.
After removing the plate from the chromatographic chamber, allow it to dry
exhaustively in a current of air. Examine the chromatogram in ultraviolet light
(254 nm).
The principal spot obtained with solution (A) corresponds in position, appearance
and intensity to that obtained with solution (B).
D. To a quantity of the powdered tablets, nominally equivalent to 50 mg of sofosbuvir,

add 30 mL of methanol R and sonicate for 10 minutes. Allow to cool to room
temperature, dilute to 50 mL with the same solvent and filter. Dilute 1.0 mL of the
filtrate to 100.0 mL using methanol R. The absorption spectrum (1.6) of the
resulting solution, when observed between 200 and 400 nm, exhibits a maximum at
about
260 nm.
Dissolution. Carry out the test as described under 5.5 Dissolution test for solid oral dosage
forms using as dissolution medium 900 mL of dissolution buffer pH 6.8 TS. Rotate the paddle
at 75 revolutions per minute. At 15 minutes, withdraw a sample of 10 mL of the medium
through an in-line filter. Allow the filtered solution to cool down to room temperature. Dilute
5.0 mL of the filtrate to 50.0 mL with dissolution medium and use it as solution (1). For
solution (2), transfer 44.0 mg of sofosbuvir RS to a 100 mL volumetric flask. Add 4 mL of
methanol R and 70 mL of dissolution medium, sonicate for 5 minutes, cool to room
temperature and dilute to volume. Dilute 5.0 mL of this solution to 50.0 mL with dissolution
medium.
1
Silica gel on TLC Alu foils from Fluka is suitable.
715
Measure the absorbance as described under 1.6 Spectrophotometry in the visible and ultraviolet
regions of a 1 cm layer of the resulting solutions at the maximum at about 262 nm, using the
dissolution medium as the blank.
For each of the tablets tested, calculate the total amount of sofosbuvir (C22H29FN3O9P) in the
medium. Evaluate the results as described under 5.5 Dissolution test for solid oral dosage
forms, Acceptance criteria. The amount of sofosbuvir released is not less than 75% (Q) of the
amount declared on the label.
[Note from the Secretariat. It is intended to determine the absorptivity value of sofosbuvir
during the establishment of the corresponding International Chemical Reference Standard and
to use this value for the calculation of the test result.]
Related substances. Carry out the test as described under 1.14.4 High–performance liquid
chromatography, using a column (150 mm x 4.6 mm) packed with end-capped, base
deactivated particles of silica gel, the surface of which has been modified with chemically
bonded octadecylsilyl groups (3.5 μm). 2
Use the following conditions for gradient elution:

As mobile phase A, use a mixture of 21 volumes of 0.05 % phosphoric acid (~1440 g/L) TS,
77 volumes of water R and 2 volumes of acetonitrile R. As mobile phase B, use a mixture of
21 volumes of 0.05 % phosphoric acid (~1440 g/L) TS and 79 volumes of acetonitrile R.
Use the following gradient:
Time (min) Mobile phase A (% v/v) Mobile phase B (% v/v) Comments

0 - 2.5 100 0 Isocratic
2.5 - 27.4 100 to 0 0 to 100 Linear gradient
27.4 - 38 0 100 Isocratic
38 - 45 100 0 Re-equilibration
2
XSelect® C18 was found suitable.
716
Operate with a flow rate of 1.5 mL per minute. As a detector, use an ultraviolet
spectrophotometer set at a wavelength of 260 nm. Maintain the column temperature at 30 °C.
Prepare the following solutions using as diluent a mixture of 50 volumes of mobile phase A and
50 volumes of mobile phase B. Prepare solution (1) as described under “Assay”. For solution
(2), dilute 1.0 mL of solution (1) to 100.0 mL. For solution (3), dilute 5.0 mL of solution (2) to
50.0 mL. For solution (4), dissolve 1.0 mg of sofosbuvir for peak identification RS (containing
sofosbuvir and the impurities A, B, C, D and E) in 5.0 mL. For solution (5), dissolve 25.0 mg of
phenol R and dilute to 50.0 mL. Dilute 2.0 mL to of this solution to 100.0 mL. Dilute 5.0 mL of
this solution to 50.0 mL.
Inject 20 µL of solutions (3) and (4).
The test is not valid unless the peak-to-valley ratio (Hp/Hv) in the chromatogram obtained
with solution (4) is at least x3, where Hp is the height above the extrapolated baseline of the
peak due to impurity A and Hv is the height above the extrapolated baseline at the lowest point
of the curve separating this impurity from the peak due to sofosbuvir. Also, the test is not valid
unless the signal-to-noise of the peak due to sofosbuvir in the chromatogram obtained with
solution (3) is at least 10.
Inject alternately 20 µL each of solutions (1), (2) and (5).
Use the chromatograms obtained with solutions (4) and (5) and the relative retentions below to
identify the peaks due to impurities D, 1, 2, 3, 4 and 5.
The impurities, if present, are eluted at the following relative retentions with reference to
sofosbuvir (retention time about 16 minutes): impurity A about 0.98; impurity B about 1.05;
impurity C about 1.41; impurity D about 0.38; impurity E about 0.93, impurity F about 1.13;
impurity G about 1.57; impurity 1 about 0.21; impurity 2 about 0.45; impurity 3 about 0.61;
impurity 4 about 0.65; impurity 5 about 0.72.
3
A value for the Hp/Hv has to be determined based on the available sofosbuvir for peak identification RS.
717
In the chromatogram obtained with solution (1):

• the area of any peak corresponding to impurity D, when multiplied by a correction
factor of 0.5, is not greater than 0.2 times the area of the peak due to sofosbuvir in the
chromatogram obtained with solution (2) (0.2 %);
• the area of any peak corresponding to impurities 1, 2, 3 or 4 is not greater than 0.2 times
the area of the peak due to sofosbuvir in the chromatogram obtained with solution (2)
(0.2 %);
• the area of any peak corresponding to impurity 5 is not greater than the area of the peak
due to phenol in the chromatogram obtained with solution (5) (0.2 %).
• The sum of the corrected area of any peak corresponding to impurity D and the areas of
any peak corresponding to impurities 1, 2, 3 or 4 is not greater than the area of the peak
due to sofosbuvir in the chromatogram obtained with solution (2) (1.0 %). Disregard
any peak with an area less than the area of the peak due to sofosbuvir in the
chromatogram obtained with solution (3) (0.1%).
Assay. 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 65 volumes of mobile phase A and 35 volumes of mobile
phase B.
Prepare the following solutions using the mobile phase as diluent. For solution (1), weigh and
powder 20 tablets. Transfer a quantity of the powdered tablets, nominally containing 125.0 mg
of sofosbuvir, to a 250 mL volumetric flask. Add about 200 mL of diluent and sonicate for
10 minutes, cool to room temperature, dilute to volume and filter. For solution (2), dilute
50.0 mg of sofosbuvir RS and dilute to 100.0 mL.
Inject alternatively 20 µL each of solutions (1) and (2). Record the chromatograms for
20 minutes.
Measure the areas of the peaks corresponding to sofosbuvir obtained in the chromatograms
from solutions (1) and (2) and calculate the percentage content of sofosbuvir (C22H29FN3O9P),
using the declared content of C22H29FN3O9P in sofosbuvir RS.
718
Impurities. The impurities limited by the requirements of this monograph include the
impurities listed in the monograph for sofosbuvir and the impurities 1, 2, 3, 4 and 5.
H
O N O
O OH
P O N
HO O
CH3
HO F
1. (2'R)-2'-deoxy-2'-fluoro-2'-methyluridine 5'-(dihydrogen phosphate) (fluoro uridine

phosphate) (degradation product)
H
O N O
CH3 O OH
HO P O N
N O
H
O
CH3
HO F
2. N-[{[(2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-3-hydroxy-
4-methyloxolan-2-yl]methoxy}(hydroxy)phosphoryl]-L-alanine (uridine alanine
phosphate) (degradation product)
H
O N O
O O
P O N
HO O
CH3
HO F
3. (2'R)-2'-deoxy-2'-fluoro-5'-O-[hydroxy(phenoxy)phosphoryl)-2'-methyluridine
(uridine phenyl phosphate) (degradation product)
H
O N O
CH3 O OH
H3 C O P O N
N O
H
CH3 O
CH3
HO F
4. propan-2-yl N-[{[(2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-
fluoro-3-hydroxy-4-methyloxolan-2-yl]methoxy}(hydroxy)phosphoryl]-L-alaninate
(uridine isopropyl alanine phosphate) (degradation product)
OH
5. phenol (degradation product).
719
Reference substances invoked

Sofosbuvir RS
International Chemical Reference Substance (ICRS) to be established.
Sofosbuvir for peak identification RS (containing sofosbuvir and the impurities A, B, C, D

and E)
***
720
DRAFT MONOGRAPH ON SOFOSBUVIR

(SOFOSBUVIRUM)
(November 2019)
DRAFT FOR COMMENTS
(email: schmidth@who.int) by 15 February 2020.
721
DRAFT PROPOSAL FOR INCLUSION IN

THE INTERNATIONAL PHARMACOPOEIA
SOFOSBUVIR
(SOFOSBUVIRUM)
Molecular formula. C22H29FN3O9P
Relative molecular mass. 529.5
Graphic formula.
H
O N O
CH3 O O
H 3C O P O N
N O
H
CH3 O
HO CH3
F
Chemical name. Propan-2-yl N -[(S )-{[(2R ,3R ,4R ,5R )-5-(2,4-dioxo-3,4-dihydropyrimidin-

1(2H )-yl)-4-fluoro-3-hydroxy-4-methyloxolan-2-yl]methoxy}phenoxyphosphoryl]-L-alaninate;
CAS Reg. No. 1190307-88-0.
Description. A white to off-white powder.
Solubility. Slightly soluble in water R, freely soluble in dehydrated ethanol R and acetone R,
soluble in 2-propanol R and insoluble in heptane R.
Category. Antiviral (Hepatitis C viral polymerase nucleotide inhibitor)
Storage. Sofosbuvir should be kept in a well-closed container and stored at a temperature

below 30 °C.
Additional information. Sofosbuvir may exhibit polymorphism.
722
Definition. Sofosbuvir contains not less than 97.5 % and not more than 102.0 % of
C22H29FN3O9P with reference to the anhydrous substance.
Identity tests
• Either test A alone 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 sofosbuvir RS or with the reference spectrum of sofosbuvir.
If the spectra thus obtained are not concordant repeat the test using the residues
obtained by separately dissolving the test substance and sofosbuvir RS in a small
amount of methanol R and evaporating to dryness. The infrared absorption
spectrum is concordant with the spectrum obtained from sofosbuvir RS.
B. 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 sofosbuvir in the chromatogram obtained with
solution (2).
C. Carry out the test as described under 1.14.1 Thin-layer chromatography, using silica
gel R2 4 as the coating substance and a mixture of 6 volumes of dichloromethane R,
1 volume of methanol R, 4 volumes of ethyl acetate R and 0.1 volume of ammonia
(~260 g/L) TS as the mobile phase.
Apply separately to the plate 10 µL of each of the following solutions in methanol R.

For solution (A), use 1 mg of the test substance per mL. For solution (B), use 1 mg of
sofosbuvir RS per mL. After removing the plate from the chromatographic chamber,
allow it to dry in a current of air. Examine the chromatogram in ultraviolet light
(254 nm). The principal spot obtained with solution (A) corresponds in position,
appearance and intensity to the spot due to sofosbuvir in the chromatogram
obtained with solution (B).
4
Silica gel on TLC alu foils from Fluka are suitable.
723
Heavy metals. Use 1.0 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 20 µg/g.
Water. Carry out the test as described under 2.8 Determination of water by the Karl Fischer
method, Method A, using about 0.200 g of the substance; the water content is not more than
10 mg/g.
Related substances. Carry out the test as described under 1.14.4 High–performance liquid
chromatography, using a column (150 mm x 4.6 mm) packed with end-capped, base
deactivated particles of silica gel, the surface of which has been modified with chemically
bonded octadecylsilyl groups (3.5 μm). 5 Use the following conditions for gradient elution:
As mobile phase A, use a mixture of 21 volumes of 0.05 % phosphoric acid (~1440 g/L) TS,
77 volumes of water R and 2 volumes of acetonitrile R. As mobile phase B, use a mixture of
21 volumes of 0.05 % phosphoric acid (~1440 g/L) TS and 79 volumes of acetonitrile R.
Use the following gradient:
Time (min) Mobile phase A (% v/v) Mobile phase B (% v/v) Comments

0 - 2.5 100 0 Isocratic
2.5 - 27.4 100 to 0 0 to 100 Linear gradient
27.4 - 38 0 100 Isocratic
38 - 45 100 0 Re-equilibration
spectrophotometer set at a wavelength of 260 nm and, for impurities F and G, at 205 nm.
Maintain the column temperature at 30 °C.
Prepare the following solutions using as diluent a mixture of 50 volumes of mobile phase A and
50 volumes of mobile phase B. For solution (1), dissolve 50.0 mg of the test substance and
dilute to 100.0 mL. For solution (2), dilute 1.0 mL of solution (1) to 100.0 mL. For solution (3),
dilute 5.0 mL of solution (2) to 100.0 mL. For solution (4), dilute 1.0 mg of sofosbuvir for peak
identification RS (containing sofosbuvir and the impurities A, B, C, D and E) in 5.0 mL.
For solution (5), dissolve 30.0 mg of pentafluorophenol R and dilute to 100.0 mL. Dilute
5.0 mL of this solution to 100.0 mL. Dilute 5.0 mL of this solution to 100.0 mL.
5
XSelect C18 was found suitable.
724
Inject 20 µL each of solution (3) and (4). The test is not valid unless in the chromatogram
obtained with solution (4) the peak-to-valley ratio (Hp/Hv) is at least x6, where Hp is the height
above the extrapolated baseline of the peak due to impurity A and Hv is the height above the
extrapolated baseline at the lowest point of the curve separating this peak from the peak due to
sofosbuvir. Also, the test is not valid unless in the chromatogram obtained with solution (3) the
signal-to-noise of the peak due to sofosbuvir is at least 10.
Inject alternately 20 µL each of solutions (1), (2) and (5).
Use the chromatograms obtained with solutions (4) and (5) and the relative retentions below to
identify the impurity peaks.
sofosbuvir (retention time about 16 minutes): impurity A about 0.98; impurity B about 1.05;
impurity C about 1.41; impurity D about 0.38; impurity E about 0.93, impurity F about 1.13;
impurity G about 1.57.

• the area of any peak corresponding to either impurity A or B is not greater than
0.15 times the area of the peak due to sofosbuvir in the chromatogram obtained with
solution (2) (0.15 %);
• the area of any peak corresponding to impurity C, when multiplied by a correction
• the area of any peak corresponding to impurity D, when multiplied by a correction
• the area of any peak corresponding to impurity E is not greater than 0.3 times the area
of the peak due to sofosbuvir in the chromatogram obtained with solution (2) (0.3 %);
• the area of any peak corresponding to either impurities F or G, recorded at 205 nm, is
not greater than the area of the peak due to pentafluorophenol in the chromatogram
obtained with solution (5) and recorded at 205 nm (0.15%);
• the area of any other impurity peak is not greater than 0.1 times the area of the peak due
to sofosbuvir in the chromatogram obtained with solution (2) (0.10%).
• The sum of the corrected areas of any peak corresponding to impurities C and D and
the areas of all other impurity peaks, recorded at 260 nm, is not greater than the area of
the peak due to sofosbuvir in the chromatogram obtained with solution (2) (1.0 %).
Disregard any peak with an area less than the area of the peak due to sofosbuvir in the
chromatogram obtained with solution (3) (0.05 %).
6
* A value for the Hp/Hv has to be determined based on the available sofosbuvir for peak identification RS.
725
Assay. 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 65 volumes of mobile phase A and 35 volumes of mobile
phase B.
Prepare the following solutions using mobile phase as diluent. For solution (1), dissolve
50.0 mg of the test substance and dilute to 100.0 mL. For solution (2), dissolve 50.0 mg of
sofosbuvir RS and dilute to 100.0 mL.
Inject alternately 20 µL each of solutions (1) and (2). Record the chromatograms for
20 minutes.
Measure the areas of the peaks corresponding to sofosbuvir obtained in the chromatograms of
solutions (1) and (2) and calculate the percentage content of sofosbuvir (C22H29FN3O9P), using
the declared content of C22H29FN3O9P in sofosbuvir RS.
Impurities
H
O N O
CH3 O O
H3 C O P O N
N O
H
CH3 O
CH3
HO F
A. Propan-2-yl N-[(R)-{[(2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-
fluoro-3-hydroxy-4-methyloxolan-2-yl]methoxy}phenoxyphosphoryl]-L-alaninate (Rp
isomer) (process related impurity).
H
O N O
CH3 O O
H3 C O P O N
N O
H
CH3 O
CH3
HO Cl
B. Propan-2-yl N-[(S)-{[(2R,3R,4R,5R)-4-chloro-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-
yl)-3-hydroxy-4-methyloxolan-2-yl]methoxy}phenoxyphosphoryl]-L-alaninate (chloro
analogue) (process related impurity).
726
H
O N O
CH3 O O
H3 C O P O N
N O
H
CH3 O
CH3
O F
CH3
H3 C O P O
N
H O
CH3 O
C. Bis(propan-2-yl) P,P'-[(2'R)-2'-deoxy-2'-fluoro-2'-methyluridine-3'O,5'O-diyl]-P,P'-
diphenoxybis[(S)-N-phosphoryl-L-alininate] (phosphoramidate sofosbuvir) (process
related impurity).
H
O N O
O N
HO
CH3
HO F
D. 1-[(2R,3R,4R,5R)-3-fluoro-4-hydroxy-5-(hydroxymethyl)-3-methyloxolan-2-
yl]pyrimidine-2,4(1H,3H)-dione (fluorouridine) (process related impurity and
degradation product).
H
O N O
CH3 O O
H3 C O P O N
N O
H
O
CH3
HO F
E. Ethyl N-[(S)-{[(2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-3-
hydroxy-4-methyloxolan-2-yl]methoxy}phenoxyphosphoryl]-L-alaninate (ethyl
analogue) (process related impurity).
F
F F
HO F
F
F. Pentafluorophenol (process related impurity).
F
F F
CH3 O O
H3 C O P
N O F
H
CH3 O F
G. Propan-2-yl N-[(S)-N-(pentafluorophenoxy)(phenoxy)phosphoryl]-L-alaninate
(phosphoramidate intermediate) (process related impurity).
727
Sofosbuvir RS
Sofosbuvir for peak identification RS (containing sofosbuvir and the impurities A, B, C,

D and E)
Sofosbuvir Reference Spectrum

Reference spectrum of sofosbuvir to be established.
***
728
DOLUTEGRAVIR SODIUM
(DOLUTEGRAVIR NATRICUM)
(September 2019)
DRAFT FOR COMMENTS
(email: schmidth@who.int) by 31 October 2019.
729
DOLUTEGRAVIR SODIUM
DOLUTEGRAVIR NATRICUM
Molecular formula. C20H18F2N3NaO5
Relative molecular mass. 441.37
Graphic formula.
CH3 O O
O F F
N Na
H
N N
O
H
O
Chemical name. (4R ,12aS )-N -[(2,4-Difluorophenyl)methyl]-3,4,6,8,12,12a-hexahydro-7-

hydroxy-4-methyl-6,8-dioxo-2H -pyrido[1′,2′:4,5]pyrazino[2,1-b ][1,3]oxazine-9-carboxamide
sodium salt; CAS Reg. No. 1051375-19-9.
Description. A white to pale yellow powder.
Solubility. Slightly soluble in water R, and very slightly soluble in methanol R.
Category. Antiretroviral (integrase inhibitor).
Storage. Dolutegravir sodium should be kept in a tightly closed container.
Additional information. Dolutegravir sodium may exhibit polymorphism.
Definition. Dolutegravir sodium contains not less than 97.0% and not more than 102.0%
(“Assay”, method A) or not less than 99.0% and not more than 101.0% (“Assay”, method B) of
C20H18F2N3NaO5, calculated with reference to the anhydrous substance.
730
Identity tests
Either tests A and E or tests D and E together with any one of tests B or 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
dolutegravir sodium RS or with the reference spectrum of dolutegravir sodium.
If the spectra thus obtained are not concordant repeat the test using the residues obtained
by separately dissolving the substance to be examined and dolutegravir sodium RS in a
small amount of methanol R and evaporating to dryness. The infrared absorption
spectrum is concordant with the spectrum obtained from dolutegravir sodium RS.
B. Carry out the test as described under 1.14.4 High-performance-liquid chromatography

using the conditions 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 dolutegravir in the chromatogram obtained with solution (2).
C. Carry out test C.1 or, where UV detection is not available, test C.2.
C.1 Carry out the test as described under 1.14.1 Thin-layer chromatography using silica
gel R6, or similar, as the coating substance and a mixture of 72 volumes of ethyl
acetate R, 14 volumes of water R and 14 volume of glacial acetic acid R as the
mobile phase. Apply separately to the plate 5 μL of each of the following two
solutions in a mixture of 96 volumes of methanol R and 4 volumes of glacial acetic
acid R containing (A) 1 mg of the substance to be examined per mL and (B) 1 mg of
dolutegravir sodium RS per mL. After removing the plate from the
chromatographic chamber, allow it to dry in air or in a current of cool air. Examine
the chromatogram in ultraviolet light (254 nm).
and intensity with that obtained with solution (B).
C.2 Carry out the test as described under 1.14.1 Thin-layer chromatography using the
conditions described above under C.1 but using silica gel R5 as the coating
substance. After drying the plate, spray with basic potassium permanganate (5 g/L)
TS. Examine the chromatogram in daylight.
731
D. The absorption spectrum (1.6) of a 10 µg per mL solution of the substance to be examined

in methanol R, when observed between 220 nm and 400 nm, exhibits maxima at about
258 nm und 321 nm.
E. The test substance yields reaction A described under 2.1 General identification tests as
characteristic of sodium.
Sulfated ash (2.3 ). Not more than 1.0 mg/g. Use a platin crucible for the determination.
Heavy metals. Use 1.0 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 20 μg/g.
Water. Determine, as described under 2.8 Determination of water by the Karl Fischer method,
Method A, using 0.3000 g of the substance and a mixture of 90 volumes of methanol R and
10 volumes of glacial acetic acid R as the solvent; the water content is not more than 10 mg/g.
Impurity A (dolutegravir enantiomer) and impurity B (dolutegravir diastereomer).
Perform the test in subdued light and without any prolonged interruptions, preferably using
low-actinic glassware.
Carry out test as described under 1.14.4 High-performance liquid chromatography using a
stainless steel column (25 cm x 4.6 mm) packed with particles of silica gel, the surface of which
has been modified with cellulose tris (4-chloro-3-methylphenyl carbamate) (5 µm). 7 As the
mobile phase, use a mixture of 980 volumes of acetonitrile R, 40 volumes of water R and
2 volumes of phosphoric acid (~1440 g/L) TS.
Operate at a flow rate of 1.5 mL per minute. As a detector, use an ultraviolet

Prepare the following solutions using as the diluent a mixture of 50 volumes of acetonitrile R
and 50 volumes of water R. For solution (1), dissolve 50.0 mg of the substance to be examined
in 50.0 mL. For solution (2), dilute 5.0 mL of solution (1) to 100.0 mL. Dilute 3.0 mL of this
solution to 100.0 mL. For solution (3), use a solution containing 1 mg of dolutegravir sodium
for peak identification RS (containing dolutegravir sodium and the impurities A, B and D)
per mL.
7
A Lux Cellulose-4 column was found suitable.
732
Inject 15 µL of solution (3). Record the chromatogram for about 45 minutes.
The impurities are eluted at the following relative retentions with reference to dolutegravir
(retention time about 22 minutes): impurity A about 0.75, impurity D about 1.25 and impurity
B about 1.35.
The test is not valid unless the resolution factor between the peaks due to impurity D and due
to impurity B is at least 1.5.
Inject alternately 15 µL of solutions (1) and (2).

• the area of any peak corresponding to either impurity A or B is not greater than the area of
the peak due to dolutegravir in the chromatogram obtained with solution (2) (0.15%).
Related substances. Perform the test in subdued light and without any prolonged
interruptions, preferably using low-actinic glassware. Carry out the test as described under
1.14.4 High-performance liquid chromatography using a stainless steel column (15 cm x 4.6
mm) packed with particles of silica gel, the surface of which has been modified with chemically-
bonded pentafluorophenyl groups (5 µm). 8

• mobile phase A: 0.186 g of disodium edetate R in 1000 mL water R adjusted to pH 3.0 with
phosphoric acid (~20g/L) TS; and
• mobile phase B: 90 volumes of methanol R and 10 volumes of tetrahydrofuran R.
Time Mobile phase A Mobile phase B

Comments
(minutes) (% v/v) (% v/v)
0–1 60 40 Isocratic
1–30 60 to 50 40 to 50 Linear gradient
Return to initial
55–57 30 to 60 70 to 40
composition
57–65 60 40 Re-equilibration
8
A Kinetex F5 column or an Ascentis Express F5 column were found suitable.
733

Prepare the following solutions using as the diluent a mixture of 60 volumes of water R and
40 volumes of acetonitrile R. For solution (1), dissolve 35.0 mg of the substance to be examined
and dilute to 50.0 mL. For solution (2), dilute 1.0 mL of solution (1) to 100.0 mL. For solution
(3), dilute 5.0 mL of solution (2) to 50.0 mL. For solution (4), use a solution containing 0.5 mg
of dolutegravir sodium for system suitability RS (containing dolutegravir sodium and impurity
E) per mL. For solution (5), use a solution containing 1 mg of dolutegravir sodium for peak
identification RS (containing dolutegravir sodium and the impurities A, B and D) per mL.
Inject alternately 10 µL each of solutions (1), (2), (3), (4) and (5).
Use the chromatogram obtained with solution (4) and the chromatogram supplied with
dolutegravir sodium for system suitability RS to identify the peak due to impurity E. Use the
chromatogram obtained with solution (5) and the chromatogram supplied with dolutegravir
sodium for peak identification RS to identify the peak due to the impurity D.
dolutegravir (retention time about 27 minutes): impurity C about 0.65; impurity F about 0.72;
impurity D about 0.77; impurities E about 0.86.
The test is not valid unless, in the chromatogram obtained with solution (4), the resolution
factor between the peaks due to impurity E and due to dolutegravir is at least 3. Also, the test is
not valid unless in the chromatogram obtained with solution (3) the peak due to dolutegravir is
obtained with a signal-to-noise ratio of at least 20.

• the area of any peak corresponding to either impurities C, D, E or F is not greater than
1.5 times the area of the peak due to dolutegravir obtained with solution (3) (0.15%);
• the area of any other impurity peak is not greater than the area of the peak due to
dolutegravir obtained with solution (3) (0.10%);
• the sum of the areas of all impurity peaks is not greater than the area of the peak due to
dolutegravir obtained with solution (2) (1.0%). Disregard any peak with an area less than
0.5 times the area of the peak due to dolutegravir obtained with solution (3) (0.05%).
734
Assay. Perform the assay in subdued light and without any prolonged interruptions,
preferably using low-actinic glassware.
• Either method A or method B may be applied.

A. Carry out test as described under 1.14.4 High-performance liquid chromatography
using a stainless steel column (15 cm x 4.6 mm) packed with particles of silica gel, the
surface of which has been modified with chemically-bonded pentafluorophenyl groups
(5 µm). 9
Use the following mobile phase: Dissolve 0.186 g of disodium edetate R in 1000 mL
water R and adjust to pH 3.0 with phosphoric acid (~20g/L) TS. Mix 450 volumes of
this solution with 550 volumes of methanol R.
Operate at a flow rate of 1.0 mL/minute. As a detector, use an ultraviolet

spectrophotometer set at a wavelength of 258 nm. Maintain the column at a
temperature of 30 °C.
Prepare the following solutions using as the diluent a mixture of 60 volumes of water
R and 40 volumes of acetonitrile R.
For solution (1), dissolve 50.0 mg of the substance to be examined and dilute to
100.0 mL. Dilute 5.0 mL of this solution to 50.0 mL. For solution (2), dissolve 50.0 mg
of dolutegravir sodium RS and dilute to 100.0 mL. Dilute 5.0 mL of this solution to
50.0 mL.
Inject alternately 20 µL each of solutions (1) and (2). Record the chromatograms for
about 20 minutes.
Measure the areas of the peaks corresponding to dolutegravir obtained in the

chromatograms of solution (1) and (2) and calculate the percentage content of
dolutegravir sodium (C20H18F2N3NaO5) using the declared content of C20H18F2N3NaO5
in dolutegravir sodium RS.
B. Dissolve about 0.300 g of the substance to be examined in 30 mL of anhydrous acetic

acid R and titrate with perchloric acid (0.1 mol/L) VS as described under 2.6 Non-
aqueous titration, Method A. Each mL of perchloric acid (0.1 mol/L) VS is equivalent
to 44.14 mg of C20H18F2N3NaO5.
9
A Kinetex F5 column or an Ascentis Express F5 column were found suitable
735
Impurities
CH3 O OH
O F F
N
H
N N
O
H
O
A. (4S,12aR)-N-[(2,4-Difluorophenyl)methyl]- 7-hydroxy-4-methyl-6,8-dioxo-
3,4,6,8,12,12a-hexahydro-2H-pyrido[1′,2′:4,5]pyrazino[2,1-b][1,3]oxazine-9-
carboxamide (dolutegravir enantiomer) (synthesis-related impurity).
CH3 O OH
O F F
N
H
N N
O
H
O
B. (4R,12aR)-N-[(2,4-difluorophenyl)methyl]- 7-hydroxy-4-methyl-6,8-dioxo-
3,4,6,8,12,12a-hexahydro- -2H-pyrido[1′,2′:4,5]pyrazino[2,1-b][1,3]oxazine-9-
carboxamide (dolutegravir diastereomer)(synthesis-related impurity).
CH3 O OH
O
N
H
N N
O
H
O
C. (4R, 12αS)-N-[(phenyl)methyl]-7-hydroxy-4-methyl-6,8-dioxo-3,4,6,8,12,12α-
hexahydro-2H-pyrido[1’, 2’:4,5]pyrazino-[2,1-b][1,3] oxazine-9-carboxamide, Desfluoro
dolutegravir (synthesis-related impurity).
CH3 O OH
O F
N
H
N N
O
H
O
D. (4R, 12αS)-N-[(2-fluorophenyl)methyl]-7-hydroxy-4-methyl-6,8-dioxo-3,4,6,8,12,12α-
hexahydro-2H-pyrido[1’, 2’:4,5]pyrazino-[2,1-b][1,3] oxazine-9-carboxamide, 2-Fluoro
736
CH3 O OH
O F
N
H
N N
O
H
O
E. (4R, 12αS)-N-[(4-fluorophenyl)methyl]-7-hydroxy-4-methyl-6,8-dioxo-3,4,6,8,12,12α-
hexahydro-2H-pyrido[1’, 2’:4,5]pyrazino-[2,1-b][1,3] oxazine-9-carboxamide, 4-Fluoro
CH3 O OH
O F
N
H
N N
O
H
O F
F. (4R, 12αS)-N-[(2,6-difluorophenyl)methyl]-7-hydroxy-4-methyl-6,8-dioxo-
3,4,6,8,12,12α-hexahydro-2H-pyrido[1’, 2’:4,5]pyrazino-[2,1-b][1,3] oxazine-9-
carboxamide, 2,6-Difluoro dolutegravir (synthesis-related impurity).
Dolutegravir sodium RS.

Dolutegravir sodium for peak identification RS (containing dolutegravir sodium and

impurities A, B and D)
ICRS to be established.
Dolutegravir sodium for system suitability RS (containing dolutegravir sodium and

impurity E)
***
737
DOLUTEGRAVIR TABLETS
DOLUTEGRAVIR COMPRESSI
(September 2019)
DRAFT FOR COMMENTS
738
DOLUTEGRAVIR TABLETS
DOLUTEGRAVIR COMPRESSI
Category. Antiretroviral (integrase inhibitor).
Storage. Dolutegravir tablets should be kept in a well-closed container.
Labelling. The designation of the container should state that the active ingredient is the
sodium salt and the quantity should be indicated in terms of the equivalent amount of
dolutegravir.
50 mg dolutegravir. Strengths in the current WHO EML for children: 50 mg dolutegravir.
Requirements.
Comply with the monograph for Tablets.
Definition. Dolutegravir tablets contain Dolutegravir sodium. They contain not less than
90.0% and not more than 110.0% of the amount of dolutegravir (C20H19F2N3O5) stated on the
label.
Identity tests
• Either test A or test B may be applied.
A. Carry out test A. 1, or where a diode array detector is available, test A.2.
A.1 Carry out the test as described under 1.14.4 High-performance liquid
chromatography using the conditions and solutions 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 dolutegravir
in the chromatogram obtained with solution (2).
To a quantity of the powdered tablets, nominally equivalent to 10 mg

dolutegravir, add 40 mL methanol R, sonicate for five minutes, allow to cool
to room temperature, dilute to 50 mL and filter. Dilute 1 mL of the filtrate to
20 mL with methanol R. The absorption spectrum (1.6) of the resulting
solution, when observed between 220 nm and 400 nm, exhibits maxima at
about 258 nm und 321 nm.
739
A.2 Carry out the test as described under 1.14.4 High-performance liquid
chromatography using the conditions and solutions given under “Assay”.
Record the UV spectrum of the principle peak in the chromatograms with a
diode array detector in the range of 220 and 400 nm. The retention time and
the UV spectrum of the principal peak in the chromatogram obtained with
solution (1) correspond to the retention time and the spectrum of the peak
due to dolutegravir in the chromatogram obtained with solution (2).
B. Carry out test B.1 or, where UV detection is not available, test B.2.
B.1 Carry out test as described under 1.14.1 Thin-layer chromatography using silica gel
R6, or similar, as the coating substance and a mixture of 72 volumes of ethyl acetate
R, 14 volumes of water R and 14 volumes of glacial acetic acid R as the mobile
phase. Prepare as a solvent solution a mixture of 96 volumes of methanol R and
4 volumes of glacial acetic acid R. Apply separately to the plate 5 μL of each of the
following two solutions. For solution (A), shake a quantity of the powdered tablets
containing 10 mg of dolutegravir with 10 mL of the solvent solution and filter. For
solution (B), use a solution containing 1 mg of dolutegravir sodium RS per mL
solvent solution. After removing the plate from the chromatographic chamber,
allow it to dry in air or in a current of cool air. Examine the chromatogram in
ultraviolet light (254 nm).
B.2 Carry out the test as described under 1.14.1 Thin-layer chromatography using the
conditions described above under text A.1 but using silica gel R5 as the coating
substance. After drying the plate spray with basic potassium permanganate (5 g/L)
TS. Examine the chromatogram in daylight.
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 a solution prepared by dissolving 2.5 g of
sodium dodecyl sulfate R in 1000 mL dissolution buffer pH 6.8. Rotate the paddle at
50 revolutions per minute. At 20 minutes withdraw a sample of 10 mL of the medium through
an in-line filter. Allow the filtered solution to cool down to room temperature and dilute
5.0 mL of to 10.0 mL with dissolution medium. Use this solution as solution (1). For solution
(2), dissolve a suitable amount of dolutegravir sodium RS in dissolution medium and dilute to a
suitable volume with the same solvent.
740
Measure the absorbance as described under 1.6 Spectrophotometry in the visible and ultraviolet
regions of a 1 cm layer of the resulting solutions at the maximum at about 258 nm, using the
dissolution medium as the blank.
For each of the tablets tested, calculate the amount of dolutegravir (C20H19F2N3O5) in the
medium. Each mg of dolutegravir sodium is equivalent to 0.950 mg of dolutegravir.
Evaluate the results as described under 5.5 Dissolution test for solid oral dosage forms,
Acceptance criteria. The amount of dolutegravir 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 dolutegravir
during the establishment of dolutegravir sodium RS and to use this value for the calculation of
the test result.]
Related substances. Perform the test in subdued light and without any prolonged
interruptions, preferably using low-actinic glassware.
Carry out the test as described under 1.14.4 High-performance liquid chromatography using a
stainless steel column (15 cm x 4.6 mm) packed with particles of silica gel, the surface of which
has been modified with chemically-bonded pentafluorophenyl groups (5 µm). 10

• mobile phase A: 0.186 g disodium edetate R in 1000 mL water R adjusted to pH 3.0 with
phosphoric acid (~20 g/L) TS; and

Comments
Return to initial
55–57 30 to 60 70 to 40
composition
10
741

40 volumes of acetonitrile R.
For solution (1), transfer a quantity of the powdered tablets, nominally equivalent to 70.0 mg
dolutegravir, to a 100 mL volumetric flask. Add about 70 mL diluent and sonicate for five
minutes, cool to room temperature, dilute to volume and filter. For solution (2), dilute 1.0 mL
of solution (1) to 100.0 mL. Dilute 10.0 mL of this solution to 50.0 mL. For solution (3), use a
solution containing 0.5 mg of dolutegravir sodium for system suitability RS (containing
dolutegravir sodium and impurity E) per mL. For solution (4), use a solution containing 1 mg
of dolutegravir sodium for peak identification RS (containing dolutegravir sodium and the
impurities A, B and D) per mL.
Inject alternately 10 µL of solutions (1), (2), (3) and (4).
dolutegravir sodium for system suitability RS to identify the peak due to the impurity E.
dolutegravir sodium for peak identification RS to identify the peak due to the impurity D.
dolutegravir (retention time about 27 minutes): impurity C about 0.65; impurity F about 0.72;
impurity D about 0.77; impurities E about 0.86.
The test is not valid unless in the chromatogram obtained with solution (3) the resolution
factor between the peaks due to impurity E and dolutegravir is at least 3. Also, the test is not
valid unless in the chromatogram obtained with solution (2) the peak due to dolutegravir is
obtained with a signal-to-noise ratio of at least 20.

• the area of any impurity peak is not greater than the area of the peak due to dolutegravir in
the chromatogram obtained with solution (2) (0.2%).
• The sum of the areas of all impurity peaks is not greater than 5 time the area of the peak
due to dolutegravir in the chromatogram obtained with solution (2) (1.0%). Disregard any
peak with an area less than 0.5 times the area of the peak due to dolutegravir in the
chromatogram obtained with solution (2) (0.1%).
742
Assay. Perform the test in subdued light and without any prolonged interruptions, preferably
using low-actinic glassware. Carry out test as described under 1.14.4 High-performance liquid
chromatography using a stainless steel column (15 cm x 4.6 mm) packed with particles of silica
gel, the surface of which has been modified with pentafluorophenyl groups (5 µm). 11
Use the following mobile phase: Dissolve 0.186 g of disodium edetate R in 1000 mL water R and
adjust to pH 3.0 with phosphoric acid (~20g/L) TS. Mix 450 volumes of this solution with
550 volumes of methanol R.
Operate at a flow rate of 1.0 mL/minute. As a detector, use an ultraviolet spectrophotometer

set at a wavelength of 258 nm. For identity test A.2 use a diode array detector in the range of
220 nm to 400 nm. Maintain the column at a temperature of 30 °C.
40 volumes of acetonitrile R.
For solution (1), weigh and powder 20 tablets. Transfer a quantity of the powdered tablets,
nominally equivalent to 100.0 mg of dolutegravir, to a 100 mL volumetric flask. Add about
70 mL of diluent and sonicate for five minutes, cool to room temperature and make up to
volume with diluent. Filter and dilute 5.0 mL of the filtrate to 100.0 mL. For solution (2),
dissolve 55.0 mg of dolutegravir sodium RS and dilute to 50.0 mL. Dilute 5.0 mL of this
solution to 100.0 mL.
Inject alternately 20 µL each of solutions (1) and (2). Record the chromatogram for about
20 min.
Measure the areas of the peaks corresponding to dolutegravir obtained in the chromatograms
of solution (1) and (2) and calculate the percentage content of dolutegravir (C20H18F2N3O5) in
the tablets using the declared content of C20H18F2N3NaO5 in dolutegravir sodium RS. Each mg
of dolutegravir sodium is equivalent to 0.950 mg of dolutegravir.
Impurities. The impurities limited by the requirements of this monograph include those listed
in the monograph on Dolutegravir sodium, excluding impurity A and B.
11
743

Dolutegravir sodium RS.
Dolutegravir sodium for peak identification RS (containing dolutegravir sodium and

impurities A, B and D)
Dolutegravir sodium for system suitability RS (containing dolutegravir sodium and

impurity E)
***
744
DOLUTEGRAVIR, LAMIVUDINE AND TENOFOVIR

DISOPROXIL FUMARATE TABLETS
(DOLUTEGRAVIRI, LAMIVUDINE ET TENOFOVIRI DISOPROXILI
FUMARATI COMPRESSI)
(September 2019)
DRAFT FOR COMMENTS
745
DOLUTEGRAVIR, LAMIVUDINE AND TENOFOVIR

DISOPROXIL FUMARATE TABLETS
(DOLUTEGRAVIRI, LAMIVUDINE ET TENOFOVIRI DISOPROXILI
FUMARATI COMPRESSI)
Category. Antiretroviral (Integrase inhibitor; Nucleoside/Nucleotide reverse transcriptase

inhibitor; Nucleoside/Nucleotide reverse transcriptase inhibitor).
Storage. Dolutegravir, lamivudine and tenofovir disoproxil tablets should be kept in a tightly
closed container.
Labelling. The designation of the container should state that the active ingredient,
dolutegravir, is in sodium form and that the quantity should be indicated in terms of the
equivalent amount of dolutegravir. The quantities of the two other active ingredients should be
indicated in terms of the amounts of lamivudine and tenofovir disoproxil fumarate.
50 mg Dolutegravir, 300 mg Lamivudine and 300 mg Tenofovir disoproxil fumarate.
Requirements
Comply with the monograph for Tablets .
Definition. Dolutegravir, lamivudine and tenofovir disoproxil tablets contain Dolutegravir

sodium, Lamivudine and Tenofovir disoproxil fumarate. They contain not less than 90.0% and
not more than 110.0% of the amount of dolutegravir (C20H19F2N3O5), lamivudine (C8H11N3O3S)
and tenofovir disoproxil fumarate (C19H30N5O10P, C4H4O4) stated on the label.
Manufacture. The manufacturing process and the product packaging are designed and
controlled so as to minimize the moisture content of the tablets. They ensure that, if tested, the
tablets would comply with a water content limit of not more than 50 mg/g when determined as
described under 2.8 Determination of water by the Karl Fischer method , Method A, using
about 0.5 g of the powdered tablets.
Identity test. Carry out the test as described under 1.14.4 High-performance liquid
chromatography using the conditions and solutions given under “Assay”. The retention time
of the three principal peaks in the chromatogram obtained with solution (1) correspond to the
retention time of the corresponding peaks due to dolutegravir, lamivudine and tenofovir
disoproxil fumarate in the chromatograms obtained with solutions (2), (3) and (4).
746
Dissolution. Carry out the test described under 5.5 Dissolution test for solid oral dosage
forms, using as the dissolution medium 900 mL of dissolution buffer, pH 6.8, 0.25% SDS TS
and rotating the paddle at 60 revolutions per minute. At 30 minutes, withdraw a sample of
10 mL of the medium through an in-line filter (sample (A)). Add 10 mL of the dissolution
medium, maintained at 37.0 °C (+/- 0.5 °C), to each dissolution vessel and continue the
dissolution for a further 30 minutes. At 60 minutes withdraw again a sample of 10 mL of the
dissolution medium through an in-line filter (sample (B)). Dilute 5.0 mL each of sample (A)
and sample (B) to 25.0 mL with diluent (2), described under “Assay”, and use the obtained
solution as solution (1) and solution (2).
Measure the concentration of lamivudine and tenofovir disoproxil fumarate in solution (1) and
the concentration of dolutegravir in solution (2). Carry out the test as described under
1.14.4 High-performance liquid chromatography using the chromatographic conditions and
solutions as described under “Assay”.
For each of the tablets tested, calculate the total amount each of lamivudine, tenofovir
disoproxil fumarate and dolutegravir in the medium from the results obtained, using the
declared content of dolutegravir sodium (C20H18F2NaO5) in dolutegravir sodium RS, the
declared content of lamivudine (C8H11N3O3S) in lamivudine RS and the declared content of
tenofovir disoproxil fumarate (C19H30N5O10P.C4H4O4) in tenofovir disoproxil fumarate RS.
Each mg of dolutegravir sodium is equivalent to 0.950 mg of dolutegravir.
Evaluate the results as described under 5.5 Dissolution test for solid oral dosage forms,
Acceptance criteria. The amount of lamivudine (C8H11N3O3S) and tenofovir disoproxil
fumarate (C19H30N5O10P.C4H4O4) released after 30 minutes is not less than 80% (Q) of the
amounts declared on the label and the amount of dolutegravir (C20H18F2N3O5) released after
60 minutes is not less than 80% (Q) of the amount declared on the label.
Tests for related substances

A. Lamivudine- and tenofovir disoproxil-related substances
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 particles of silica
gel, the surface of which has been modified with chemically-bonded octadecylsilyl groups
(5 µm). 12

• mobile phase A: acetate buffer pH 4.2; and
• mobile phase B: acetonitrile R.
12
An Inertsil ODS-3v column was found suitable.
747
Prepare the acetate buffer pH 4.2 by dissolving 9.64 g of ammonium acetate R in 900 mL
of water R, adjust the pH to 4.2 (+/- 0.05) with glacial acetic acid R and dilute to 1000 mL
with water R.
Time Mobile phase A Mobile phase B Comments

62–63 25 to 100 75 to 0 Return to initial

composition
spectrophotometer set at a wavelength of 260 nm. Maintain the column temperature at
25 °C and the autosampler temperature at 6 °C.
Prepare the following solutions using water R as diluent.
For solution (1), transfer a quantity of the powdered tablets, nominally containing 225 mg
of Tenofovir disoproxil fumarate, to a 250 mL volumetric flask. Add about 175 mL of
diluent and sonicate at room temperature for about 30 minutes with intermittent shaking.
Allow to cool to room temperature, dilute to volume and filter.
For solution (2), dilute 1.0 mL of solution (1) to 100.0 mL.
For solution (3), dilute 10.0 mL of solution (2) to 100.0 mL.
For solution (4), dissolve about 1 mg of tenofovir disoproxil for system suitability
(containing tenofovir disoproxil and the impurities I and H) in 2 mL of water R.
For solution (5), dissolve 10 mg of tenofovir disoproxil fumarate RS in 10 mL of water R.
Heat the solution carefully in a boiling water-bath for 20 minutes.
748
For solution (6), use a solution containing 0.2 mg of fumaric acid R per mL of water R.
For solution (7), dissolve 5 mg of lamivudine for system suitability RS (containing
lamivudine and lamivudine impurities A and B) and dilute to 10.0 mL.
For solution (8), dissolve 25 mg of cytosine R and 25 mg of uracil R and dilute to 50.0 mL.
Dilute 1.0 mL of this solution to 100.0 mL.
For solution (9), dissolve a suitable amount of each of the excipients stated on the label in
10 mL of a suitable solvent and dilute to 100.0 mL with the diluent.
Inject alternately 10 µL each of solutions (1), (2), (3), (4), (5), (6), (7), (8) and (9).
Use the chromatogram obtained with solution (4) to identify the peak due to the
tenofovir disoproxil impurity I in the chromatogram obtained with solution (1), if
present.
Use the chromatogram obtained with solution (5) to identify the peak due to the
tenofovir disoproxil impurity A in the chromatogram obtained with solution (1), if
present.
Use the chromatogram obtained with solution (6) to identify the peak due to the fumarate
in the chromatogram obtained with solution (1), if present. The peak due to fumarate is
eluted at about 2.8 minutes and may appear as single or split peaks.
Use the chromatogram obtained with solution (8) to identify the peaks due to lamivudine
impurities E (cytosine) and F (uracil) in the chromatogram obtained with solution (1), if
present.
749
Use the chromatogram obtained with solution (9) to identify the peaks due to excipients.
tenofovir disoproxil (retention time about 48 minutes):
Relative
Impurity Impurity Classification
retention
Tenofovir disoproxil impurity N 0.33 Synthesis/Degradation
Tenofovir disoproxil impurity A 0.63 Synthesis/Degradation
Tenofovir disoproxil impurity F 0.73 Degradation
Tenofovir disoproxil impurity E 0.76 Synthesis/Degradation
0.80 and
Tenofovir disoproxil impurity B Synthesis
0.81
Tenofovir disoproxil impurity C 0.88 Synthesis
Tenofovir disoproxil impurity D 0.90 Synthesis
Tenofovir disoproxil impurity M 0.94 Synthesis
Tenofovir disoproxil impurity L 0.97 Synthesis
Tenofovir disoproxil impurity I 0.98 Synthesis/Degradation
Tenofovir disoproxil impurity H 1.01 Synthesis
Tenofovir disoproxil impurity J 1.19 Synthesis/Degradation
Lamivudine impurity E 0.09 Synthesis/Degradation
Lamivudine impurity F 0.11 Synthesis/Degradation
0.15 and
Lamivudine impurity A Synthesis
0.17
Lamivudine impurity G 0.20 Synthesis/Degradation
Lamivudine impurity H 0.21 Synthesis/Degradation
Lamivudine impurity B 0.38 Synthesis
Lamivudine 0.39 -
Lamivudine impurity J 0.45 Degradant
Lamivudine impurity C 0.54 Synthesis
750
The test is not valid unless:

• in the chromatogram obtained with solution (7), the resolution between the peaks
due to lamivudine impurity B and lamivudine is at least 1.5;
• in the chromatogram obtained with solution (3), the signal-to-noise ratios of the
peaks due to lamivudine and due to tenofovir disoproxil are at least 20;
• in the chromatogram obtained with solution (4), the resolution between the peaks
due impurity I and tenofovir disoproxil is at least 1.5 and the resolution between
the peaks due to tenofovir disoproxil and impurity H is at least 1.2;
• the area of any peak corresponding to tenofovir impurity A, when multiplied by a
correction factor of 0.79, is not greater than three times the area of the peak due to
tenofovir disoproxil in the chromatogram obtained with solution (2) (3.0%);
• the area of any peak corresponding to either tenofovir impurity F, tenofovir
impurity I or tenofovir impurity J, is not greater than 0.75 times the area of the peak
due to tenofovir disoproxil in the chromatogram obtained with solution (2)
(0.75%);
• the area of any peak corresponding to tenofovir impurity M, when multiplied by a
correction factor of 0.53, is not greater than two times the area of the peak due to
tenofovir disoproxil in the chromatogram obtained with solution (3) (0.2%);
• the area of any peak corresponding to tenofovir impurity E is not greater than two
times the area of the peak due to tenofovir disoproxil in the chromatogram
obtained with solution (3) (0.2%);
• the area of any peak corresponding to lamivudine impurity E, when multiplied by a
lamivudine in the chromatogram obtained with solution (3) (0.2%);
• the area of any peak corresponding to lamivudine impurity F, when multiplied by a
lamivudine in the chromatogram obtained with solution (3) (0.2%);
• the area of any peak corresponding to either lamivudine impurity G, lamivudine
impurity H or lamivudine impurity J, is not greater than two times the area of the
peak due to lamivudine in the chromatogram obtained with solution (3) (0.2%).
751
• Determine the sum of the areas of any peaks corresponding to lamivudine impurity
G, lamivudine impurity H and lamivudine impurity J and the corrected areas of any
peaks corresponding to lamivudine impurity E and lamivudine impurity F using
the area of the peak due to lamivudine in the chromatogram obtained with solution
(2) as a reference. Disregard any peak with an area or a corrected area of less than
0.5 times the area of the peak due to lamivudine in the chromatogram obtained
with solution (3) (0.05%). Determine the sum of the areas of any peaks
corresponding to tenofovir impurity F, tenofovir impurity E, tenofovir impurity I
and tenofovir impurity J and the corrected areas of any peaks corresponding to
tenofovir impurity M and tenofovir impurity A using the area of the peak due to
tenofovir disoproxil in the chromatogram obtained with solution (2) as a reference.
Disregard any peak with an area or a corrected area of less than 0.5 times the area of
the peak due to tenofovir disoproxil in the chromatogram obtained with solution
(3) (0.05%). The sum of the lamivudine and tenofovir disoproxil related impurities
is not greater than 5.0%.
B. Dolutegravir-related substances
Perform the test in subdued light and without any prolonged interruptions, preferably
using low-actinic glassware.
Carry out the test as described under 1.14.4 High-performance liquid chromatography
using a stainless steel column (15 cm x 4.6 mm) packed with particles of silica gel, the
surface of which has been modified with chemically-bonded pentafluorophenyl and
octadecylsilyl groups (5 µm). 13

• mobile phase A: 0.186 g disodium edetate R in 1000 mL of water R adjusted to pH
2.0 with phosphoric acid (~20 g/L) TS;

Comments
Return to initial
52–53 30 to 60 70 to 40
composition
13
An ACE 5 C18-PFP column was found suitable.
752

spectrophotometer set at a wavelength of 320 nm. Maintain the column temperature at
45 °C.
Prepare the following solutions using as the diluent a mixture of 60 volumes of water R
and 40 volumes of acetonitrile R.
For solution (1), transfer a quantity of the powdered tablets, nominally equivalent to
87.5 mg dolutegravir, to a 250 mL volumetric flask. Add about 180 mL diluent and
sonicate for five minutes, cool to room temperature, dilute to volume and filter.
For solution (2), dilute 1.0 mL of solution (1) to 100.0 mL. Dilute 10.0 mL of this solution
to 50.0 mL.
For solution (3), use a solution containing 0.5 mg of dolutegravir sodium for system
suitability RS (containing dolutegravir sodium and impurity E) per mL.
For solution (4), use a solution containing 1 mg of dolutegravir sodium for peak
identification RS (containing dolutegravir sodium and the dolutegravir impurities A, B
and D) per mL.
Inject alternately 30 µL each of solutions (1), (2), (3) and (4).
Use the chromatogram obtained with solution (3) to identify the peak due to the impurity
E. Use the chromatogram obtained with solution (4) to identify the peaks due to the
impurities B and D.
dolutegravir (retention time about 27 minutes):
Relative
Impurity Impurity Classification
retention
Dolutegravir impurity C 0.67 Synthesis
Dolutegravir impurity F 0.70 Synthesis
Dolutegravir impurity D 0.77 Synthesis
Dolutegravir impurity E 0.89 Synthesis
The test is not valid unless in the chromatogram obtained with solution (3) the resolution
factor between the peaks due to impurity E and dolutegravir is at least 3.

• the area of any peak corresponding to either dolutegravir impurities C, D, E or F is
not greater than the area of the peak due to dolutegravir in the chromatogram
obtained with solution (2) (0.2%).
753
Assay. Perform the test in subdued light and without any prolonged interruptions, preferably
using low-actinic glassware. 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 particles of silica gel, the surface of which has been modified with chemically-bonded
octylsilyl groups (5 µm). 14

• mobile phase A: A solution of 0.186 g of disodium edetate R in a mixture of 1 volume of
trifluoroacetic acid R in 1000 volumes of water R; and
• mobile phase B: Acetonitrile R.
Time Mobile phase A Mobile phase B Comments

0–10.0 98 to 50 2 to 50 Linear gradient
10.0 to 12.0 50 50 Isocratic
12.0–12.5 50 to 98 50 to 2 Return to initial
composition
12.5–18.0 98 2 Re-equilibration

Prepare a phosphate buffer pH 3.0 by dissolving 12.3 g of sodium dihydrogen phosphate R in

900 mL of water R. Adjust the pH to 3.0 (+/- 0.05) with phosphoric acid (~105 g/L) TS, mix
and dilute to 1000 mL with water R.
Prepare the following diluents. For diluent (1), mix 60 volumes of water R and 40 volumes of
acetonitrile R. For diluent (2), mix 90 volumes of the phosphate buffer pH 3.0 with 10 volumes
of acetonitrile R.
14
An Inertsil C8-3 column was found suitable.
754
Prepare the following solution. For solution (1), weigh and powder 20 tablets. Transfer a
quantity of the powdered tablets, nominally equivalent to 340.0 mg of lamivudine, to a 500 mL
volumetric flask. Add about 400 mL of diluent (1) and sonicate for about 10 minutes with
intermittent shaking. Allow to cool to room temperature, dilute to volume with diluent (1) and
filter. Dilute 5.0 mL of this solution to 50.0 mL with diluent (2). For solution (2), dissolve
28.0 mg of dolutegravir sodium RS in diluent (1) and dilute to 250.0 mL with the same solvent.
Dilute 5.0 mL of this solution to 50.0 mL with diluent (2). For solution (3), dissolve 68.0 mg of
lamivudine RS in diluent (1) and dilute to 100.0 mL with the same solvent. Dilute 5.0 mL of
this solution to 50.0 mL with diluent (2). For solution (4), dissolve 68.0 mg of tenofovir
disoproxil fumarate RS in diluent (1) and dilute to 100.0 mL with the same solvent. Dilute
5.0 mL of this solution to 50.0 mL with diluent (2).
Inject alternately 25 µL each of solutions (1), (2), (3) and (4).
Measure the areas of the peaks corresponding to dolutegravir, lamivudine and tenofovir
disoproxil obtained in the chromatograms of solutions (1), (2), (3) and (4) and calculate the
percentage content of dolutegravir (C20H18F2N3O5), lamivudine (C8H11N3O3S) and tenofovir
disoproxil fumarate (C19H30N5O10P.C4H4O4) in the tablets using the declared content of
dolutegravir sodium (C20H18F2NaO5) in dolutegravir sodium RS, the declared content of
lamivudine (C8H11N3O3S) in lamivudine RS and the declared content of tenofovir disoproxil
fumarate (C19H30N5O10P.C4H4O4) in tenofovir disoproxil fumarate RS. Each mg of dolutegravir
sodium is equivalent to 0.950 mg of dolutegravir.
Impurities. The impurities limited by the requirements of this monograph include those listed
in the monographs on Dolutegravir sodium, Lamivudine and Tenofovir disoproxil fumarate,
excluding dolutegravir impurity A and B.
755

Tenofovir disoproxil for system suitability RS (containing tenofovir disoproxil and the
impurities I and H)
International Chemical Reference Substance to be established.
Lamivudine for system suitability RS (containing lamivudine and lamivudine impurities

A and B)
Established International Chemical Reference Substance.
Tenofovir disoproxil fumarate RS

Lamivudine RS
Dolutegravir RS
International Chemical Reference Substance to be established.
***
756
TENOFOVIR DISOPROXIL FUMARATE

(TENOFOVIRI DISOPROXILI FUMARAS)
(September 2019)
DRAFT FOR COMMENTS
757
TENOFOVIR DISOPROXIL FUMARATE

(TENOFOVIRI DISOPROXILI FUMARAS)
Graphic formula
Molecular formula. C19H30N5O10P. C4H4O4
Relative molecular mass. 635.5.
Chemical names. bis(1-methylethyl) 5-{[(1R )-2-(6-amino-9H -purin-9-yl)-1-

methylethoxy]methyl}-5-oxo-2,4,6,8-tetraoxa-5-λ5-phosphanonanedioate (ester) hydrogen
(2E )-but-2-enedioate (salt); bis({[(1-methylethoxy)carbonyl]oxy}methyl) {[(1R )-2-(6-amino-
9H -purin-9-yl)-1-methylethoxy]methyl}phosphonate (ester) hydrogen (2E )-but-2-enedioate
(salt); 5-[[(1R )-2-(6-amino-9H -purin-9-yl)-1-methylethoxy]methyl]-2,4,6,8-tetraoxa-5-
phosphanonanedioic acid 1,9-bis(1-methylethyl) ester 5-oxide, (2E )-2-butenedioate (1:1);
CAS Reg. No. 202138 50 9
Description. White to almost-white, crystalline powder.
Solubility. Slightly soluble in water R, soluble in methanol R, very slightly soluble in

dichloromethane R.
Category. Antiretroviral (Nucleotide Reverse Transcriptase Inhibitor).
Storage. Tenofovir disoproxil fumarate should be kept in a tightly closed container, protected
from light and stored at a temperature between 2–8 °C.
Additional information. Tenofovir disoproxil fumarate may exhibit polymorphism.
758
Requirements
Definition. Tenofovir disoproxil fumarate contains not less than 98.5% and not more than
101.0% of tenofovir disoproxil fumarate (C19H30N5O10P.C4H4O4), calculated with reference to
the anhydrous substance.
Manufacture. The production method is validated to ensure that the substance, if tested,
would comply with a limit of not more than 5 ppm for the mutagenic impurity 9-
propenyladenine (impurity K), which may be a synthesis-related substance, using a suitable
method.
• a limit of not more than 1.0% for the tenofovir disoproxil (S)-enantiomer (impurity G)
using a suitable chiral chromatographic method.
Identity tests
Either tests A, B and C or test D may be applied.
A. Carry out test A.1 or, where UV detection is not available, test A.2.
A.1 Carry out the test as described under 1.14.1 Thin-layer chromatography using
silica gel R6 as the coating substance and a mixture of 67 volumes of
dichloromethane R, 20 volumes of acetonitrile R, 10 volumes of methanol R and
3 volumes of ammonia (~260 g/L) TS as the mobile phase. Apply separately to
the plate 5 μL of each of two solutions in methanol containing (A) 10 mg of the
test substance per mL and (B) 10 mg of tenofovir disoproxil fumarate RS
per mL. After removing the plate from the chromatographic chamber, allow it
to dry exhaustively in air or in a current of air. Examine the chromatogram in
ultraviolet light (254 nm).
The principal spot obtained with solution (A) corresponds in position,
appearance and intensity with that obtained with solution (B).
A.2 Carry out the test as described under 1.14.1 Thin-layer chromatography using
the conditions described above under test A.1 but using silica gel R5 as the
coating substance. Stain the plate with iodine vapour and examine the
chromatogram in daylight.

759
B. Carry out test B.1 or, where UV detection is not available, test B.2.
B.1 Carry out the test as described under 1.14.1 Thin-layer chromatography using
silica gel R6 as the coating substance and a mixture of 50 volumes of heptane R,
30 volumes of glacial acetic acid R and 20 volumes of dichloromethane R as the
mobile phase. Apply separately to the plate 5 μL of each of the following two
solutions in ethanol R. For solution (A), use 10 mg of the test substance per mL
and for solution (B), use 2 mg of fumaric acid R per mL. Develop the plate in an
unsaturated tank over a path of 10 cm. After removing the plate from the
chromatographic chamber, allow it to dry exhaustively in air or in a current of
air. Examine the chromatogram in ultraviolet light (254 nm).
One of the principal spots obtained with solution (A) corresponds in position,
B.2 Carry out the test as described under 1.14.1 Thin-layer chromatography using
the conditions described above under test B.1 but using silica gel R5 as the
coating substance. Spray lightly with a 16 g/L solution of potassium
permanganate R and examine the chromatogram in daylight.
C. The absorption spectrum (1.6) of a 25 µg/mL solution, when observed between 220 nm
and 320 nm, exhibits a maximum at about 261 nm; the specific absorbance ( ) is 230
to 250.
D. 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 tenofovir disoproxil fumarate RS or with the reference spectrum of tenofovir
disoproxil fumarate.
If the spectra thus obtained are not concordant, repeat the test using the residues obtained
by separately dissolving the test substance and tenofovir disoproxil fumarate RS in a small
amount of methanol R and evaporating to dryness. The infrared absorption spectrum is
concordant with the spectrum obtained from tenofovir disoproxil fumarate RS.
Specific optical rotation (1.4). Prepare a fresh solution and perform the test without delay.
Use a 10.0 mg/mL solution in hydrochloric acid (0.1 mol/l) VS and calculate with reference to
the anhydrous substance; [𝛼𝛼]20
𝐷𝐷 ＝-15 to - 20.
760
Water. Determine as described under 2.8 Determination of water by the Karl Fischer method,
Method A. Use about 1.0 g of the substance; the water content is not more than 10 mg/g.
Heavy metals. Use 1.0 g in 30 mL of methanol R for the preparation of the test solution as
described under 2.2.3 Limit test for heavy metals, Procedure 2; determine the heavy metals
content according to Method A; not more than 20 μg/g.
Sulfated ash (2.3). Not more than 2.0 mg/g.
Impurity G. Carry out test as described under 1.14.4 High-performance liquid

chromatography using a stainless steel column (25 cm x 4.6 mm) packed with particles of silica
gel, the surface of which has been modified with amylose tris (3,5-dimethylphenyl carbamate)
(5 µm). 15 As the mobile phase, use a mixture of 949 volumes of methanol R, 50 volumes of
acetonitrile R and 1 volume of triethylamine R.

Prepare the following solutions using mobile phase as the diluent. For solution (1), dissolve
40.0 mg of the test substance in 100.0 mL. For solution (2), dilute 1.0 mL of solution (1) to
100.0 mL. For solution (3), use a solution containing 0.4 mg of tenofovir disoproxil fumarate
for epimer identification RS (containing tenofovir disoproxil and the impurities G) per mL.
Inject 5 µL of solution (3). Record the chromatogram for about 15 minutes.
Impurity G is eluted at the relative retention of 1.6 with reference to tenofovir disoproxil
(retention time about 5 minutes).
The test is not valid unless the resolution factor between the peaks due to impurity G and due
to tenofovir disoproxil is at least 3.
Inject alternately 5 µL each of solutions (1) and (2).
15
A Nucleocel Alpha-RP S or a Chiralpak AD-H column were found suitable.
761

• the area of any peak corresponding to impurity G is not greater than the area of the peak
due to tenofovir disoproxil in the chromatogram obtained with solution (2) (1.0%).
Related substances. 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 base-deactivated
particles of silica gel, the surface of which has been modified with chemically-bonded
octadecylsilyl groups (5 μm).
The mobile phases for the gradient elution consist of a mixture of Mobile phase A and Mobile
phase B, using the following conditions:
• Mobile phase A: 2 volumes of acetonitrile R, 20 volumes of phosphate buffer pH 6.0 and
78 volumes of water R; and
• Mobile phase B: 65 volumes of acetonitrile R, 20 volumes of phosphate buffer pH 6.0 and
15 volumes of water R.
Prepare the phosphate buffer pH 6.0 by dissolving 3.50 g of potassium dihydrogen phosphate R
and 1.70 g of tetrabutyl ammonium hydrogen sulfate R in 800 mL of water R, adjust the pH to
6.0 by adding sodium hydroxide (1 mol/L) VS and dilute to 1000 mL with water R.

Comments
5–40 81–49 19–51 Linear gradient
40–60 49–0 51–100 Linear gradient
65–70 0–81 100–19 Return to initial composition
After preparation, keep the solutions at about 6 °C or use an injector with cooling.
Prepare the following solutions using water R as diluent. For solution (1), use 1.0 mg of the test
substance per mL. For solution (2), dilute a suitable volume of solution (1) to obtain a
concentration of 5 µg of tenofovir disoproxil fumarate per mL. For solution (3), use 0.2 mg of
fumaric acid R per mL.
762
For the system suitability test, prepare solution (4) by heating solution (1) carefully in a boiling
water-bath for 20 minutes.
spectrophotometer set at a wavelength of 260 nm.
Maintain the column temperature at 30 °C.
Inject 20 μL of solution (4). The test is not valid unless the resolution between the principal
peak (retention time about 40 minutes) and the peak due to tenofovir monosoproxil (impurity
A) (with a relative retention of about 0.5) is not less than 25.
Inject alternatively 20 μL each of solutions (1) and (2) and (3). In the chromatogram obtained
with solution (1), the following peak is eluted at the following relative retention, with reference
to tenofovir (retention time about 40 minutes): fumarate about 0.15.

• the area of any peak due to tenofovir monosoproxil (impurity A) is not greater than twice
the area of the principal peak obtained with solution (2) (1.0%);
• the area of any other impurity peak is not greater than the area of the principal peak
obtained with solution (2) (0.5%), and
• the areas of not more than two such peaks are greater than 0.4 times the area of the
principal peak obtained with solution (2) (0.2%).
• The sum of the areas of all peaks, other than the principal peak, is not greater than five
times the area of the principal peak obtained with solution (2) (2.5%). Disregard any
peak corresponding to the peak obtained in the chromatogram with solution (3) and any
peak with an area less than 0.1 times the area of the principal peak in the chromatogram
obtained with solution (2) (0.05%).
Assay. Dissolve 0.40 g, accurately weighed, in 30 mL of glacial acetic acid R1 and titrate with
perchloric acid (0.1 mol/l) VS, determine the end-point potentiometrically as described under
2.6 Non-aqueous titration, Method A. Each mL of perchloric acid (0.1 mol/l) VS is equivalent
to 63.55 mg of tenofovir disoproxil fumarate (C19H30N5O10P, C4H4O4).
763
Impurities
A. (1-methylethyl) (8R)-9-(6-amino-9H-purin-9-yl)-5-hydroxy-8-methyl-5-oxo-2,4,7-
trioxa-5-λ5-phosphanonanoate (tenofovir monosoproxil), (synthesis-related impurity,
B. (1-methylethyl) (5RS,8R)-9-(6-amino-9H-purin-9-yl)-5-methoxy-8-methyl-5-oxo-2,4,7-
trioxa-5-λ5-phosphanonanoate.
C. Methyl (1-methylethyl) (5RS)-5-{[(1R)-2-(6-amino-9H-purin-9-yl)-1-

methylethoxy]methyl}-5-oxo-2,4,6,8-tetraoxa-5-λ5-phosphanonanedioate, (synthesis-
related impurity).
D. (1-methylethyl) (5RS,8R)-9-(6-amino-9H-purin-9-yl)-8-methyl-5-(1-methylethoxy)-5-
oxo-2,4,7-trioxa-5-λ5-phosphanonanoate, (synthesis-related impurity).
764
E. (1-methylethyl) (8R)-5-hydroxy-8-methyl-9-(6-{[(1-methylethoxy)carbonyl]amino}-9H-
purin-9-yl)-5-oxo-2,4,7-trioxa-5-λ5-phosphanonanoate, (synthesis-related impurity,
F. Bis(1-methylethyl) 9,9'-[methylenebis(imino-9H-purine-6,9-diyl)]bis[(8R)-5-hydroxy-8-
methyl-5-oxo-2,4,7-trioxa-5-λ5-phosphanonanoate] (tenofovir monosoproxil dimer),
(degradation product).
G. Bis(1-methylethyl) 5-{[(1S)-2-(6-amino-9H-purin-9-yl)-1-methylethoxy]methyl}-5-oxo-
2,4,6,8-tetraoxa-5-λ5-phosphanonanedioate (tenofovir disoproxil (S)-enantiomer) [see
under Manufacture].
765
H. 1-methylethyl propyl (5RS)-5-{[(1R)-2-(6-amino-9H-purin-9-yl)-1-

methylethoxy]methyl}-5-oxo-2,4,6,8-tetraoxa-5-λ5-phosphanonanedioate, (synthesis-
related impurity).
I. Bis(1-methylethyl) 5-{[(1R)-2-(6-{[({9-[(2R)-5-hydroxy-2,11-dimethyl-5,9-dioxo-
3,6,8,10-tetraoxa-5-λ5-phosphadodecyl]-9H-purin-6-yl}amino)methyl]amino}-9H-purin-
9-yl)-1-methylethoxy]methyl}-5-oxo-2,4,6,8-tetraoxa-5-λ5-phosphanonanedioate
(tenofovir di- and monosoproxil heterodimer), (synthesis-related impurity, degradation
product).
766
J. Tetrakis(1-methylethyl) 5,5'-(methylenebis{imino-9H-purine-6,9-diyl[(2R)-propane-1,2-
diyl]oxymethylene})bis[5-oxo-2,4,6,8-tetraoxa-5-λ5-phosphanonanedioate] (tenofovir
disoproxil dimer), (synthesis-related impurity, degradation product).
K. 9-(prop-1-enyl)-9H-purin-6-amine, [see under Manufacture],
KL. (1-methylethyl) (5RS)-5-{[(1R)-2-(6-amino-9H-purin-9-yl)-1-methylethoxy]methyl}-10-

methyl-5,9-dioxo-2,4,6,8-tetraoxa-10-aza-5-λ5-phosphaundecanoate, (synthesis-related
impurity).
767
LM. Ethyl 1-methylethyl (5RS)-5-{[(1R)-2-(6-amino-9H-purin-9-yl)-1-

methylethoxy]methyl}-5-oxo-2,4,6,8-tetraoxa-5-λ5-phosphanonanedioate (synthesis-
related impurity, degradation product).
MN. 9-[(R )-2-(Phosphonomethxy)propyl]adenine (synthesis-related impurity, degradation

product).
[Note from the Secretariat. The structure of impurity M will be added at a later stage.]

Tenofovir disoproxil fumarate RS.
Established International Chemical Reference Substance (ICRS).
Tenofovir disoproxil fumarate for epimer identification RS (containing tenofovir disoproxil

fumarate and impurities G)
***
768
PROPOSAL TO DISCONTINUE THE TEST FOR UNDUE TOXICITY

(CHAPTER 3.7) IN THE INTERNATIONAL PHARMACOPOEIA
(September 2019)
DRAFT FOR COMMENTS
769
PROPOSAL TO DISCONTINUE THE TEST FOR UNDUE TOXICITY

(CHAPTER 3.7) IN THE INTERNATIONAL PHARMACOPOEIA
At its Sixty-ninth meeting, held from 29 October to 02 November 2018, the World Health
Organization (WHO) Expert Committee on Biological Standardization (ECBS) recommended
to discontinue the inclusion of the innocuity test in future WHO documents on vaccines and
other biologicals to be published in the Technical Report Series (TRS) (including WHO
recommendations, guidelines and manuals). In addition, the inclusion of this test in previously
published WHO TRS documents should be disregarded:
The scientific rationale and evidence for performing the innocuity test (also called the
“abnormal toxicity test” or “general safety test”) as a measure of the safety of vaccines
and other biological products, for the purpose of marketing authorization and lot
release, were discussed by the Expert Committee. Current manufacturing processes,
which include the implementation of Good Manufacturing Practices (GMP) and
comprehensive quality control measures (including in-process controls), were
considered to be more appropriate than the innocuity test in assuring the quality and
safety of vaccines and other biological products. The Expert Committee reviewed the
historical inclusion of the innocuity test in the documents published in the WHO TRS
and concluded that its complete omission would not compromise the quality and safety
of vaccines and other biological products. Therefore, the Expert Committee
recommends the discontinuation of the inclusion of the innocuity test in all future
WHO recommendations, guidelines and manuals for biological products published in
the TRS, and that a clear indication be made in its report that the inclusion of this test in
previously published WHO TRS documents be disregarded. 16
The principle of the test consists of injecting the product under investigation into guinea pigs
and/or mice. The sample passes the test if no animal shows any signs of illness, relevant body
weight changes or dies within a certain period. The exact test design and name varies between
the different pharmacopoeias and requirements.
In The International Pharmacopoeia, the test is referred to as the test for undue toxicity
(chapter 3.7) and stipulated in the monographs on Kanamycin acid sulfate and Kanamycin
monosulfate.
16
Text reproduced from main outcomes of the meeting of the WHO Expert Committee on Biological Standardization held
from 29 October to 2 November 2018 (https://www.who.int/biologicals/expert_committee/
ECBS_Executive_Summary_final_20_NOV_2018.IK.pdf?ua=1 ).
770
Following the decision of the WHO Expert Committee on Biological Standardization (ECBS), it
is proposed to omit chapter 3.7, “Undue Toxicity” in The International Pharmacopoeia and its
reference in the monographs on Kanamycin acid sulfate and Kanamycin monosulfate (see
below: changes from the current text/monographs are indicated by insert or delete.). Users of
The International Pharmacopoeia are invited to provide their comments on this proposal.
3.7 Undue toxicity
The test is used to determine the absence of undue toxicity of antibiotics intended for parenteral
administration.
Recommended procedure
Use healthy mice of a single strain that have not previously been used for any test. Select 5 mice,
each weighing between 18 g and 22 g. Prepare the solution of the test substance as specified in
the monograph. Inject a test dose of 0.5 mL intravenously into a tail vein at a uniform rate, the
injection occupying 5 seconds. Keep the mice under observation for 48 hours after the
injection. The product meets the requirements for freedom from undue toxicity if no animal
dies within 48 hours.
If 1 or 2 mice die within the observation period, repeat the procedure once, using respectively
5 or 15 mice, healthy and not previously used for any test, each weighing between 19.5 g and
20.5 g. The product under test meets the requirements for freedom from undue toxicity if no
animal dies in the repeat test within the observation period (48 hours).
Monograph on Kanamycin acid sulfate
Manufacture
Kanamycin acid sulfate is produced by methods of manufacture designed to eliminate or

minimize substances lowering blood pressure. The method of manufacture is validated to
demonstrate that the product, if tested, would comply with the test as described under
3.7 Undue toxicity, using 0.5 mL of a solution containing 2 mg per mL.
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Monograph on Kanamycin monosulfate
Manufacture
Kanamycin monosulfate is produced by methods of manufacture designed to eliminate or

minimize substances lowering blood pressure. The method of manufacture is validated to
demonstrate that the product, if tested, would comply with the test as described under 3.7
Undue toxicity, using 0.5 mL of a solution containing 2 mg per mL.
***
772
GUIDELINE ON DATA INTEGRITY

(October 2019)
DRAFT FOR COMMENTS
Please send any comments you may have to Dr Sabine Kopp, Group Lead, Medicines Quality
Assurance, Technologies Standards and Norms (email: kopps@who.int) with a copy to
Ms Claire Vogel (vogelc@who.int) by 15 January 2020.
The new text on data integrity is intended to replace the following:

Guidance on good data and record management practices
Annex 5, WHO Technical Report Series 996, 2016
773
GUIDELINE ON DATA INTEGRITY
1. INTRODUCTION AND BACKGROUND
1.1. Data governance and data integrity (DI) are important elements in ensuring the
reliability of data and information obtained in production and control of
pharmaceutical products. The data and information should be complete as well as
being attributable, legible, contemporaneous, original and accurate, commonly referred
to as meeting “ALCOA” principles.
1.2. In recent years, the number of observations made regarding the integrity of data,
documentation and record management practices during inspections of good
manufacturing practice (GMP), good clinical practice (GCP) and good laboratory
practice (GLP) has been increasing. Possible causes for this may include (i) too much
reliance on human practices; (ii) the use of computerized systems that are not
appropriately managed and validated; and (iii) failure to adequately review and manage
original data and records.
1.3. Quality risk management (QRM), control strategies and sound scientific principles are
required to mitigate such risks. Examples of controls may include, but are not limited
to:
• the establishment and implementation of a DI policy;
• the establishment and implementation of procedures that will facilitate
compliance with DI requirements and expectations;
• adoption of a quality culture within the company that encourages personnel to
be transparent about failures which includes a reporting mechanism;
• application of QRM with identification of all areas of risk to DI through data
integrity risk assessment (DIRA) and implementation of appropriate controls to
eliminate or reduce risks to an acceptable level throughout the life cycle of the
data;
• ensuring sufficient resources to monitor compliance with DI policies and
procedures and processes, and facilitate continuous improvement;
• provision of necessary training for personnel in, for example, good practices
(GXP), computerized systems and DI;
• implementation and validation of computerized systems appropriate for their
intended use;
• definition and management of appropriate roles and responsibilities for quality
agreements and contracts entered into by contract givers and contract acceptors.
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2. SCOPE
2.1. This guideline provides information, guidance and recommendations to facilitate

compliance with DI, GXP in documentation and record keeping requirements.
2.2. The scope of this guideline is designated as ‘GXP’. It does not, however, cover medical
devices.
2.3. Where possible, this guideline has been harmonised with other published documents.
The guideline should be read with other WHO GXP guidelines and publications.
2.4. In line with the current approach in GMP, it recommends a risk-based approach over
the life cycle of data. DIRA should be carried out in order to identify and assess areas of
risk.
2.5. The principles of this guideline apply to contract givers and contract acceptors.
Contract givers are ultimately responsible for the integrity of data provided to them by
contract acceptors. Contract givers should therefore ensure that contract acceptors
comply with the principles contained in this guideline.
2.6. Efficient risk-based controls and review of data and documents should be identified and
implemented. The effectiveness of the controls should be verified.
3. GLOSSARY
(Note: This section will be updated)
The definitions given below apply to the terms used in these guidelines. They may have
different meanings in other contexts.
ALCOA.
A commonly used acronym for “attributable, legible, contemporaneous, original and
accurate”.
ALCOA+.
A commonly used acronym for “attributable, legible, contemporaneous, original and accurate”
which puts additional emphasis on the attributes of being complete, consistent, enduring and
available – implicit basic ALCOA principles.
775
archiving, archival.
Archiving is the process of storage and protecting records from the possibility of being
accessed, further altered or deleted, and storing these records under the control of independent
data management personnel throughout the required retention period. Archived records
should include, for example, associated metadata and electronic signatures.
archivist.
An independent individual designated in GLP who has been authorized by management to be
responsible for the management of the archive, i.e. for the operations and procedures for
archiving.
audit trail.
The audit trail is a form of metadata containing information associated with actions that relate
to the creation, modification or deletion of GXP records. An audit trail provides for secure
recording of life cycle details such as creation, additions, deletions or alterations of information
in a record, either paper or electronic, without obscuring or overwriting the original record.
An audit trail facilitates the reconstruction of the history of such events relating to the record
regardless of its medium, including the “who, what, when and why” of the action.
data governance.
The arrangements to ensure that data, irrespective of the format in which they are generated,
are recorded, processed, retained and used to ensure the record throughout the data life cycle.
data life cycle.

All phases of the process by which data are created, recorded, processed, modified, transmitted,
reviewed, reported, used, approved, archived and restored until destruction.
electronic signatures.
A signature in digital form (bio-metric or non-biometric) that represents the signatory. This
should be equivalent in legal terms to the handwritten signature of the signatory.
good practices (GXP).

Acronym for the group of good practice guides governing the preclinical, clinical,
manufacturing, testing, storage, distribution and post-market activities for regulated
pharmaceuticals, biologicals and medical devices, such as GLP, GCP, GMP, good
pharmacovigilance practices (GPP) and good distribution practices (GDP).
776
metadata.
Metadata are data that describe the attributes of other data and provide context and meaning
and form an integral part of original records. An audit trail record is an example of metadata.
raw data (source data).

The original record (data) which can be described as the first-capture of information, whether
recorded on paper or electronically.
routine data review.

Routine data review is a process where the raw data and metadata are reviewed for their
integrity in an individual data set.
periodic data review.
Periodic data review is a process where an audit of the data generated is done, on a periodic
basis (e.g. monthly), where data are selected on a random basis to verify the effectiveness of
existing control measures and identification of the possibility of unauthorised activity at all
interfaces
4. PRINCIPLES OF DATA INTEGRITY AND GOOD DOCUMENTATION

PRACTICES
4.1. There should be a written DI policy.
4.2. Senior management is responsible for the establishment and implementation of an

effective quality system and a data governance system. This applies to paper and
electronic generated data.
4.3. Data should be Attributable, Legible, Contemporaneous, Original, and Accurate

(ALCOA) and be Complete, Consistent, Enduring, and Available (+). This is generally
referred to as ALCOA+. (There is no difference in expectations regardless of which
acronym is used).
4.4. The quality system, including documentation such as procedures and formats for
recording data, should be appropriately designed and implemented to provide
assurance that records and data meet the principles contained in this guideline.
4.5. Data governance should address data ownership and accountability throughout the life
cycle and consider the design, operation and monitoring of processes/systems to
comply with the principles of DI, including control over intentional and unintentional
changes to data.
777
4.6. Data governance systems should include:
• training in the importance of DI principles;

• the creation of an appropriate working environment; and
• active encouragement of the reporting of errors, omissions and undesirable
results.
4.7. Senior management should be accountable for the implementation of systems and
procedures in order to minimise the potential risk to DI, and to identify the residual risk
using risk management techniques such as the principles of the International
Conference on Harmonisation (ICH) Q9.
4.8. The data governance programme should include policies and procedures addressing
data management. Elements of effective management governance should include:
• management oversight and commitment;

• application of QRM;
• good data management principles;
• quality metrics and performance indicators;
• validation;
• change management;
• security and access control;
• configuration control;
• prevention of commercial, political, financial and other organizational pressures;
• prevention of incentives that may adversely affect the quality and integrity of
work;
• adequate resources, systems;
• workload and facilities to facilitate the right environment that supports DI and
effective controls;
• monitoring;
• record keeping;
• training; and
• awareness of the importance of DI, product quality and patient safety.
4.9. There should be a system for the regular review of documents and data to identify any
DI failures. This includes paper records and electronic records in day-to-day work,
system and facility audits and self-inspections.
778
4.10. The effort and resources applied to assure the integrity of the data should be
commensurate with the risk and impact of a DI failure.
4.11. Where DI weaknesses are identified, appropriate corrective and preventive actions
(CAPA) should be implemented across all relevant activities and systems and not in
isolation.
4.12. Significant DI lapses identified should be reported to the national medicine regulatory
authority.
4.13. Changing from automated or computerised systems to paper-based manual systems or

vice-versa will not in itself remove the need for appropriate DI controls.
4.14. Good documentation practices should be followed to ensure that all records are
complete.
4.15. Records (paper and electronic) should be kept in a manner that ensures compliance
with the principles of this guideline. These include, but are not limited to:
• restricting the ability to change dates and times for recording events;
• using controlled documents and forms for recording GXP data;
• controlling the issuance of blank paper templates for data recording of GXP
activities, with reconciliation;
• defining access and privilege rights to automated systems;
• enabling audit trails;
• having automated data capture systems and printers connected to equipment
and instruments in production and quality control where possible;
• ensuring proximity of printers to sites of relevant activities; and
• ensuring access to original electronic data for personnel responsible for
reviewing and checking data.
4.16. Data and recorded media should be durable. Ink should be indelible. Temperature-
sensitive or photosensitive inks and other erasable inks should not be used, or other
means should be identified to ensure traceability of the data over their life cycle.
4.17. Paper should not be temperature-sensitive, photosensitive or easily oxidizable. If this is

not feasible or limited, then true or certified copies should be available.
4.18. Systems, procedures and methodology used to record and store data should be
periodically reviewed for effectiveness and updated, as necessary, in relation to new
technology.
779
5. QUALITY RISK MANAGEMENT
5.1. The DIRA should be documented. This should cover systems and processes that
produce data or, where data are obtained, data criticality and inherent risks.
5.2. The risk assessment should include, for example, computerised systems, supporting
personnel, training and quality systems.
5.3. Record and DI risks should be assessed, mitigated, communicated and reviewed
throughout the document and data life cycle.
5.4. Where the DIRA has highlighted areas for remediation, prioritisation of actions
(including acceptance of an appropriate level of residual risk) and controls should be
documented and communicated. Where long-term remediation actions are identified,
risk-reducing short-term measures should be implemented to provide acceptable data
governance in the interim.
5.5. Controls identified may include organizational and functional controls such as
procedures, processes, equipment, instruments and other systems to both prevent and
detect situations that may impact on DI. (Examples include appropriate content and
design of procedures, formats for recording, access control, the use of computerized
systems and other means).
5.6. Controls should cover risks to data. Risks include deletion of, changes to, and excluding
data and results from data sets without written authorisation and detection of those
activities and events.
6. MANAGEMENT REVIEW
6.1. Compliance with DI policy and procedures should be reported in the periodic
management review meetings.
6.2. The effectiveness of the controls implemented should be measured against the quality
metrics and performance indicators. These should include for example:
• The tracking and trending of data;

• lapse in DI rates;
• review of audit trails in, for example, production, quality control, GLP, case
report forms and data processing;
• routine audits and/or self-inspections including DI and computerized systems;
and
• DI lapses at outsourced facilities (contract acceptors).
780
7. OUTSOURCING
7.1. Outsourcing of activities and responsibilities of each party (contract giver and contract
accepter) should be clearly described in written agreements. Specific attention should
be given to ensuring compliance with DI requirements.
7.2. Compliance with the principles and responsibilities should be verified during periodic
site audits. This should include the review of procedures and data (including raw data
and metadata, paper records, electronic data, audit trails and other related data) held by
the contracted organization that are relevant to the contract giver’s product or services.
7.3. Where data and document retention are contracted to a third party, particular attention
should be paid to understanding the ownership and retrieval of data held under that
agreement, as well as controls to ensure the integrity of data over their life cycle.
7.4. No activity, including outsourcing databases, should be sub-contracted to a third party

without the prior approval of the contract giver.
7.5. All contracted parties should be aware of the requirements relating to data governance,
DI and data management.
8. TRAINING
8.1. Personnel should be trained in DI policies and procedures.
8.2. Personnel should agree to abide by DI principles and should be made aware of the
potential consequences in cases of non-compliance.
8.3. Personnel should be trained in good documentation practices and measures to prevent
and detect DI issues. This may require specific training in evaluating the configuration
settings and reviewing electronic data and metadata, such as audit trails, for individual
computerized systems used in the generation, processing and reporting of data.
781
9. DATA
9.1. Data may be presented by manually recording an observation, result or other data and
information on paper, or electronically recording thereof, by using equipment and
instruments including those linked to computerised systems. A combination of manual
and electronic systems may also be used.
9.2. The same considerations for DI apply for other data sets (such as photographs, videos,
DVD, imagery and chromatography plates) as for the other data sets, together with any
additional controls required for that format such as copying, photography or
digitisation. There should be a documented rationale for the selection of such a
method.
9.3. Where possible, risk-reducing supervisory measures should be implemented.
9.4. Results and data sets require independent verification if deemed necessary from the
DIRA or by another requirement.
10. DATA INTEGRITY
10.1. Data integrity (DI) is the degree to which data are complete, consistent, accurate,
trustworthy and reliable.
10.2. Risk-based system design and controls should enable the detection of errors, lapses and
omissions of results and data during the data life cycle. Controls may include
procedural controls, organizational controls and functional controls.
10.3. The DI policy should clearly define what constitutes raw data, source data, metadata
and a “complete data set”.
10.4. Data should be contemporaneously recorded, collected and maintained in a secure

manner. Controls should ensure that they are attributable, legible, original (or a true
copy) and accurate. Assuring DI requires appropriate QRM systems, including
adherence to sound scientific principles and good documentation practices.
782
10.5. Systems should be established and implemented to ensure that all data acquired,
processed and reported are in accordance with the principles in this guideline.
Data should be:
• A = attributable to the person generating the data

• L = legible and permanent
• C = contemporaneous
• O = original record (or certified true copy)
• A = accurate
10.6. Data governance measures should also ensure that data are complete, consistent,
enduring and available throughout the life cycle, where:
• Complete = the data must be whole; a complete set.

• Consistent = the data must be self-consistent.
• Enduring = durable; lasting throughout the data life cycle.
• Available = readily available for review or inspection purposes.
10.7. Original data should be reviewed, retained, complete, enduring and readily retrievable
and readable throughout the records retention period.
11. GOOD DOCUMENTATION PRACTICES

11.1. The principles contained in this guideline are applicable to paper and electronic data.
11.2. Specific controls should be identified through DIRA, to ensure the integrity of data and
results recorded on paper records. These may include, but are not limited to:
• the use of permanent, indelible ink;

• no use of pencil or erasers;
• the use of single-line cross-outs to record changes with name, date and reason
recorded (i.e. the paper equivalent to the audit trail);
• no use of correction fluid or otherwise obscuring the record;
• controlled issuance of bound, paginated notebooks;
• controlled issuance of sequentially numbered copies of blank forms; and
• archival of paper records by independent, designated personnel in secure and
controlled archives.
783
12. COMPUTERIZED SYSTEMS

(Note. This section highlights some specific aspects relating to the use of computerized
systems. It is not intended to repeat the information presented in the other WHO Guidelines
here, such as the WHO Guideline on Computerized systems, WHO Guideline on Validation,
and WHO Guideline on Good Chromatography Practices. See references.)
12.1. The computerized system selected should suitable for its intended use.
12.2. Where GXP systems are used to acquire, record, store or process data, management
should have appropriate knowledge of the risks that the system and users may have on
the data.
12.3. Suitably configured and validated software should be used where instruments and
equipment with computerised systems are used. The potential for manipulation of data
should be eliminated during the data life cycle.
12.4. Where electronic systems with no configurable software and no electronic data
retention (e.g. pH meters, balances and thermometers) are used, controls should be put
in place to prevent manipulation of data and repeat testing to achieve the desired result.
12.5. Appropriate means of detection for lapses in DI principles should be in place.

Additional means should be implemented where stand-alone systems with a user-
configurable output is used, for example, Fourier-transform infrared spectroscopy
(FTIR) and UV spectrophotometers.
12.6. All records that are defined by the data set should be reviewed and retained. Reduced
effort and/or frequency may be justifiable.
Access and privileges
12.7. There should be a documented system in place that defines the access and privileges of
users of computerized systems. The paper and electronic records should be in line with
the electronic information including the creation and deletion of users.
12.8. Access and privileges should be in accordance with the responsibility and functionality
of the individual with appropriate controls to ensure DI (e.g. no modification, deletion
or creation of data outside the application is possible).
784
12.9. A limited number of personnel, with no conflict of interest in data, should be appointed
as system administrators. Certain privileges such as data deletion, database amendment
or system configuration changes should not be assigned to administrators without
justification - and such activities should only be done with documented evidence of
authorization by another responsible person. Records should be maintained.
12.10. Unique usernames and passwords should be used for systems as appropriate.
12.11. Programmes and methods (such as acquisition and processing methods) should ensure
that data meet ALCOA principles. Where results or data are processed using a different
method/parameters than the acquisition method should be recorded. Audit trails and
details should allow reconstruction of all data processing activities.
12.12. Data transfer should not result in any changes to the content or meaning of the data.
The transfer should be tracked in the audit trail.
12.13. Data transfer should be validated.
Audit Trail
12.14. GXP systems should provide for the retention of audit trails. Audit trails should
reflect, for example, users, dates, times, original data and results, changes and reasons
for changes.
12.15. Audit trails should be enabled when software is installed, and remain enabled all
times. Proof of enabling and verification during the life cycle of data should be
maintained.
12.16. Where add-on software or legacy systems are used (with no audit trail), mitigation
measures may be taken for defined temporary periods. This should be addressed
within defined timelines.
12.17. Routine data review should include a review of audit trails. Evidence should be
maintained.
785
Electronic signatures
12.18. Each electronic signature should be appropriately controlled. An electronic signature

should be:
• validated;
• attributable to an individual;
• free from alteration and manipulation; and
• compliant with the requirements of international standards.
12.19. An inserted image of a signature or a footnote indicating that the document has been
electronically signed is not adequate.
Data review and approval
12.20. There should be a documented procedure for the routine and periodic review, as well
as approval of data.
12.21. CAPAs should be recorded where errors, discrepancies or omissions are identified.
12.22. A conclusion following the review of original data, metadata and audit trail records
should be documented, signed and dated.
Data backup, retention, and restoration
12.23. Data should be backed up and archived according to written procedures. The
validated procedures and controls should ensure the protection of data and records.
12.24. Data and records should be kept in a secure area which provides appropriate
protection. Access should be controlled.
12.25. Retention periods should be defined in authorized procedures.
12.26. Records reflecting documented reasons for the destruction of data should be
maintained.
12.27. Backup and restoration processes should be validated and periodically tested,
including verification of data size, completeness and accuracy of data and metadata.
786
13. CORRECTIVE AND PREVENTIVE ACTIONS
13.1. Where organizations use computerized systems (e.g. for GXP data acquisition,
processing, interpretation, reporting) which do not meet current GMP requirements, a
workplan towards upgrading such systems should be documented and implemented to
ensure compliance with current GMP.
13.2. When GMP lapses in DI are identified, root cause analysis, impact and risk assessment
should be carried out. Appropriate CAPAs should be established and implemented.
Health authorities and other relevant organizations should be notified if the
investigation identifies significant impact or risk to materials, products, patients,
reported information or data in application dossiers, clinical trial reports, and so on..
References and further reading

(Note: This section will be updated)
1. WHO Basic Principles in Good Manufacturing Practices
2. WHO Guideline on Validation
3. WHO Guideline on Computerized Systems
4. WHO Guideline on Good Chromatography Practices
5. Medicines and Healthcare Products Guideline
6. U.S. Food and Drug Administration Guideline
7. Pharmaceutical Inspection Convention and Pharmaceutical Inspection Co-operation

Scheme (PIC/S) Guideline
8. International Society for Pharmaceutical Engineering (ISPE) Baseline
787
ANNEX 1
EXAMPLES IN DATA INTEGRITY MANAGEMENT
This Annex reflects on some examples in data integrity (DI) management, to support the main
text on DI. It should be noted that these are examples and are intended for the purpose of
clarification only.
Example 1: Quality risk management and data integrity risk assessment
Risk management is an important part of good manufacturing practices (GMP). Risks should
be identified and assessed, control identified and implemented to assist manufacturers in
preventing possible DI lapses.
As an example, a Failure Mode and Effects Analysis (FMEA) model (or any other tool) can be
used to identify and assess the risks relating to any system where data are, for example,
acquired, processed, recorded, saved and archived. Based on severity, occurrence and detection
classification and an overall risk priority number or risk factor, corrective and preventive action
(CAPA) should be identified, implemented and assessed for its effectiveness.
Severity
O
C LOW MEDIUM HIGH
C LOW
U MEDIUM
R HIGH
R
E HIGH MEDIUM LOW
N
C
E
Detection
788
For example, if during the weighing of a sample, the entry of the date was not
contemporaneously recorded on the worksheet but the date is available on the print-out from a
weighing balance and log book for the balance for that particular activity, this is still considered
DI. The risk is however different when there is no other means of traceability for the activity.
When assessing the risk relating to the lapse in DI, the severity could be classified as “low” (the
data is available on the print-out); it does not happen on a regular basis (occurrence is “low”),
and it could easily be detected by the reviewer (detection is “high”) – therefore the overall risk
factor may be considered low. The root cause as to why the record was not made in the
analytical report at the time of weighing should still be identified and the appropriate action
taken to prevent this from happening.
Example 2: Good documentation practices in data integrity

Documentation should be managed with care. These should be appropriately designed to assist
in eliminating erroneous entries, manipulation and human error.
Paper systems
Formats
Formats should be designed and prepared to enable personnel to record the correct
information at the right time. Provision should be made for entries such as dates, time (start,
finish), signatures, initials, results, batch numbers, equipment identification numbers andso on.
The system should prompt the personnel to make the entries at the appropriate step.
Blank forms
The use of blank forms is not encouraged. Where blank forms are used (e.g. to supplement
worksheets, laboratory notebooks and master production and control records), appropriate
controls have to be in place and may include, for example, a numbered set of blank forms
issued which are reconciled upon completion. Similarly, bound paginated notebooks, stamped
or formally issued by a document control group, allow the detection of unofficial notebooks
and any gaps in notebook pages. Authorization may include two or three signatures with dates,
for example, “prepared by” or “entered by”, “reviewed by” and “approved by”.
Error in recording data

Entries of data and results (electronic and paper records) should be free from mistakes. Entries
should be made with care. Where incorrect information had been recorded, this may be
corrected provided that the reason for the error is documented, the original entry remains
readable, and the correction is signed and dated.
789
Example 3: Data entry
Data entry includes examples such as sample receiving registration, sample analysis result
recording, logbook entries, registers, batch manufacturing record entries, and information in
case report forms. The recording of source data on paper records should be in indelible ink
and free from errors. Direct entry into electronic records should be done by responsible,
appropriately trained individuals. Entries should be traceable to an individual (in electronic
records thus having a unique username and password) and traceable to the date (and time,
where possible). Where appropriate, the entry should be verified by a second person or entered
through technical means such as bar-coding, where possible, for the intended use of these data.
Additional controls may include locking critical data entries after the data are verified and
review of audit trails for critical data to detect if they have been altered.
Example 4: Dataset
All data should be included in the dataset unless there is a documented, justifiable, scientific
explanation and procedure for the exclusion of any result or data. Whenever out of trend or
atypical results are obtained, they should be investigated in accordance with written
procedures. This includes investigating and determining CAPA for invalid runs, failures,
repeats and other atypical data. The review of original electronic data should include checks of
all locations where data may have been stored, including locations where voided, deleted,
invalid or rejected data may have been stored. Data and metadata should not be found in other
electronic folders or in other operating system logs. Electronic data should be archived in
accordance with a standard operating procedure. It is important to ensure that associated
metadata are archived with the relevant data set or securely traceable to the data set through
relevant documentation. It should be possible to successfully retrieve data and datasets from
the archives. This includes metadata. This should be done in accordance with a procedure and
verified at defined intervals.
Example 5: Enduring
Data and metadata should be readable during the life cycle of the data. Risks include the fading
of microfilm records, the decreasing readability of the coatings of optical media such as
compact disks (CDs) and digital versatile/video disks (DVDs), and the fact that these media
may become brittle. Similarly, historical data stored on magnetic media will also become
unreadable over time as a result of deterioration. Data and records should be stored in an
appropriate manner, under the appropriate conditions.
790
Example 6: Attributable
Data should be attributable, thus being traceable to an individual. In paper records, this could
be done through the use of initials, full handwritten signature or personal seal. In electronic
records, this could be done through the use of unique user logons that link the user to actions
that create, modify or delete data; or unique electronic signatures which can be either biometric
or non-biometric. An audit trail that captures user identification (ID), date and time stamps,
and the electronic signature must be securely and permanently linked to the signed record.
Example 7: Contemporaneous
Personnel should record data and information at the time these are generated and acquired.
For example, when a sample is weighed or prepared, the weight of the sample (date, time, name
of the person, balance identification number) should be recorded at that time and not before or
at a later stage. In the case of electronic data, these should be automatically date and time
stamped. The use of hybrid systems is discouraged but where legacy systems are awaiting
replacement, documented mitigating controls should be in place. (Replacement of hybrid
systems should be a priority with a documented CAPA plan). The use of a scribe to record an
activity on behalf of another operator should be considered only on an exceptional basis and
should only take place where, for example, the act of recording places the product or activity at
risk, such as, documenting line interventions by aseptic area operators.
Example 8: Changes
When changes are made to any result or data, the change should be traceable to the person who
made the change, the date, time and reason for the change. In electronic systems, this
traceability should be documented via computer generated audit trails or in other metadata
fields or system features that meet these requirements. Where an existing computerized system
lacks computer-generated audit trails, personnel may use alternative means such as
procedurally controlled use of log-books, change control, record version control or other
combinations of paper and electronic records to meet GXP regulatory expectations for
traceability to document the what, who, when and why of an action.
791
Example 9: Original
Original data include the first or source capture of data or information and all subsequent data
required to fully reconstruct the conduct of the GXP activity (see the definition of raw data). In
some cases, the electronic data (electronic chromatogram acquired through high-performance
liquid chromatography (HPLC)) may be the original data, and in other cases, the recording of
the temperature on a log sheet in a room - by reading the value on a data logger – may be
considered the original data. Original data should be reviewed. Proof of review should be
presented (e.g. as a signature (reviewed by:) and date of the review). For electronic records, this
is typically signified by electronically signing the electronic data set that has been reviewed and
approved. Written procedures for data review should clarify the meaning of the review and
approval signatures to ensure that the personnel concerned understand their responsibility as
reviewers and approvers to assure the integrity, accuracy, consistency and compliance with
established standards of the electronic data and metadata subject to review and approval.
Written procedures for data review should define the frequency, roles and responsibilities and
approach to review of meaningful metadata, such as audit trails. These procedures should also
describe how aberrant data are to be handled if found during the review. Personnel who
conduct such reviews should have adequate and appropriate training in the review process as
well as in the software systems containing the data subject to review.
Example 10: Controls
Based on the outcome of the data integrity risk assessment (DIRA) (which should cover all
areas of data governance and data management) – appropriate and effective controls should be
identified and implemented to assure that all data, whether in paper records or electronic
records, will meet ALCOA+ principles. Examples of controls may include, but are not limited
to:
• qualification, calibration and maintenance of equipment, such as balances and pH
meters, that generate printouts;
• validation of computerized systems that acquire, process, generate, maintain, distribute
or archive electronic records;
• validation of systems to ensure that the integrity of data will remain while transmitting
between/among computerized systems;
• validation of analytical procedures;
• validation of production processes;
• review of GXP records; and
• investigation of deviations, doubtful, out of trend and out of specifications results.
792
Points to consider for assuring accurate GXP records:
• The entry of critical data into a computer by an authorized person (e.g. entry of a
master processing formula) requires an additional check on the accuracy of the data
entered manually. This check may be done by independent verification and release for
use by a second authorized person or by validated electronic means. For example, to
detect and manage risks associated with critical data, procedures would require
verification by a second person, such as a member of the quality unit staff;
• formulae for calculations entered into spreadsheets;
• master data entered into the laboratory information management system (LIMS) such
as fields for specification ranges used to flag out of specification values on the certificate
of analysis;
• other critical master data, as appropriate. Once verified, these critical data fields should
normally be locked to prevent further modification and only be modified through a
formal change control process;
• the process of data transfer between systems should be validated;
• the migration of data into and exported from systems requires specific planned testing
and control; and
• when the activity is time-critical, printed records should display the date and time
stamp.
***
793
ATC/DDD Classification WHO Drug Information, Vol 33, No. 4, 2019
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 2019.
Comments or objections to the decisions from the meeting should be forwarded to the WHO
Collaborating Centre for Drug Statistics Methodology before 1 February 2020. If no objections
are received before this date, the new ATC codes and DDDs will be considered final and
included in the January 2021 version of the ATC/DDD Index.
New ATC 5th level codes:
ATC level name/INN ATC code

abaloparatide H05AA04
abicipar pegol S01LA07
atorvastatin, amlodipine and ramipril C10BX18
axicabtagene ciloleucel L01XX70
belantamab mafodotin L01XC39
betibeglogene autotemcel B06AX02
bremelanotide G02CX05
brimonidine S01GA07
bulevirtide J05AX28
bupivacaine and meloxicam N01BB59
caffeine D11AX26
calcifediol1) H05BX05
cefiderocol J01DI04
dostarlimab L01XC40
ebola (vesicular stomatitis virus vector live attenuated) J07BX02
enfortumab vedotin L01XC36
esflurbiprofen M02AA29
ferrous gluconate B03AD05
filgotinib L04AA45
fostemsavir J05AX29
givosiran A16AX16
golodirsen M09AX08
794
WHO Drug Information, Vol 33, No. 4, 2019 ATC/DDD Classification

imipenem, cilastatin and relebactam J01DH56
inclisiran C10AX16
isatuximab L01XC38
istradefylline N04CX01
itacitinib L04AA46
ivacaftor, tezacaftor and elexacaftor R07AX32
ketoconazole2) H02CA03
levonadifloxacin J01MA24
lobeglitazone A10BG04
luseogliflozin A10BK07
metformin and lobeglitazone A10BD26
mirogabalin N02BG11
moxetumomab pasudotox L01XC34
nimetazepam N05CD15
onasemnogene abeparvovec M09AX09
polatuzumab vedotin L01XC37
ramipril and bisoprolol C09BX05
risdiplam M09AX10
satralizumab L04AC19
sodium benzoate and sodium phenylacetate A16AX30
somapacitan H01AC07
tafasitamab L01XC35
teneligliptin A10BH08
tisagenlecleucel L01XX71
zinc sulfate B05XA18
1) Oral formulations only indicated in treatment of renal secondary hyperparathyroidism

2) Oral formulations only indicated in treatment of Cushing’s syndrome
795
New ATC level codes (other than 5th levels):
ATC level name New ATC code

Other antiparkinson drugs N04C
Other antiparkinson drugs N04CX
New DDDs:
ATC level name/INN DDD unit Adm.R ATC code

budesonide 2 mg SL A07EA06
buprenorphine 2.1 mg P N07BC01
caplacizumab 10 mg P B01AX07
lobeglitazone 0.5 mg O A10BG04
risankizumab 1.67 mg P L04AC18
tildrakizumab 1.11 mg P L04AC17
796
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 2019.
These are considered as final and will be included in the January 2020 version of the ATC/DDD
Index.
New ATC 5th level codes:

13
C-urea V04CX05
alpelisib L01XX65
belotecan L01XX68
bempedoic acid C10AX15
carbon monoxide V04CX08
Centella asiatica herba D03AX14
darunavir and ritonavir J05AR26
darvadstrocel L04AX08
econazole, combinations G01AF55
edrophonium V04CX07
elapegademase L03AX21
entrectinib L01XE56
fedratinib L01XE57
folic acid V04CX02
formoterol and tiotropium bromide R03AL10
formoterol, glycopyrronium bromide and budesonide R03AL11
fremanezumab N02CD031
hexaminolevulinate V04CX06
1) New ATC 4th level, N02CD Calcitonin gene-related peptide (CGRP) antagonists
797

homatropine methylbromide A03BB06
indacaterol and mometasone R03AK14
indacaterol, glycopyrroinium bromide and mometasone R03AL12
lamivudine, tenofovir disoproxil and dolutegravir J05AR27
lefamulin J01XX12
mannitol V04CX04
methacholine V04CX03
omadacycline J01AA15
osilodrostat H02CA02
patent blue V04CX09
remimazolam N05CD14
revefenacin R03BB08
rifamycin D06AX15
rosuvastatin and fenofibrate C10BA09
rosuvastatin and ramipril C10BX17
sarecycline J01AA14
selinexor L01XX66
tagraxofusp L01XX67
upadacitinib L04AA44
vonoprazan A02BC08
voretigene neparvovec S01XA27
798
New ATC level codes (other than 5th levels):
ATC level name New ATC code

Calcitonin gene-related peptide (CGRP) antagonists N02CD
Change of ATC level codes:
ATC-level names Previous ATC-code New ATC code

erenumab N02CX07 N02CD01
galcanezumab N02CX08 N02CD02
miltefosine L01XX09 P01CX04
Change of ATC level names:

ATC-code Previous ATC-level name New ATC-level name
A03CB04 methylhomatropine and homatropine methylbromide and
psycholeptics psycholeptics
B06AB Other hem products Heme products
B06AB01 hematin hemin
799
New DDDs:
ATC level name/INN DDD unit Adm.R ATC code

baloxavir marboxil 40 mg O J05AX25
doravirine 0.1 g O J05AG06
fexinidazole 1.44 g O P01CA03
fremanezumab1) 7.5 mg P N02CD03
galcanezumab2) 4 mg P N02CD02
lesinurad 0.2 g O M04AB05
omadacycline 0.3 g O J01AA15
0.1 g P
prasterone 6.5 mg V G03XX01
sarecycline 0.1 g O J01AA14
1) New ATC 4th level N02CD valid from January 2020.

2) ATC code altered from N02CX08. New ATC 4th level N02CD valid from January 2020.
WHO Collaborating Centre for Drug Statistics Methodology

Oslo, November 2019
800

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WHO Drug Information Vol. 33, No.

WHO Drug Information

International Nonproprietary Names (INN)

Abbreviations and websites

ENVIRONMENTAL ASPECTS OF MANUFACTURING FOR THE

Antimicrobial resistance (AMR) is a global and multisectoral challenge that requires a

According to research by UN Environment, 2 growing antimicrobial resistance (AMR) linked to

Against a backdrop of rising global concern about AMR, following up on the

Results of the survey will be presented to the 55th ECSPP in 2020.

DRAFT MONOGRAPH ON SOFOSBUVIR TABLETS

DRAFT FOR COMMENTS

DRAFT PROPOSAL FOR INCLUSION IN

Category. Antiviral (Hepatitis C viral polymerase nucleotide inhibitor)

Storage. Sofosbuvir tablets should be kept in a well-closed container not exceeding 30 °C

Comply with the monograph for “Tablets”.

A. Carry out the test as described under 1.14.4 High-performance liquid

B. Carry out the test as described under 1.14.4 High-performance liquid

Apply separately to the plate 10 µL of each of the following solutions in methanol

D. To a quantity of the powdered tablets, nominally equivalent to 50 mg of sofosbuvir,

Use the following conditions for gradient elution:

Use the following gradient:

Time (min) Mobile phase A (% v/v) Mobile phase B (% v/v) Comments

Inject 20 µL of solutions (3) and (4).

Inject alternately 20 µL each of solutions (1), (2) and (5).

In the chromatogram obtained with solution (1):

1. (2'R)-2'-deoxy-2'-fluoro-2'-methyluridine 5'-(dihydrogen phosphate) (fluoro uridine

5. phenol (degradation product).

Reference substances invoked

International Chemical Reference Substance (ICRS) to be established.

Sofosbuvir for peak identification RS (containing sofosbuvir and the impurities A, B, C, D

International Chemical Reference Substance (ICRS) to be established.

DRAFT MONOGRAPH ON SOFOSBUVIR

DRAFT FOR COMMENTS

DRAFT PROPOSAL FOR INCLUSION IN

Molecular formula. C22H29FN3O9P

Relative molecular mass. 529.5

Chemical name. Propan-2-yl N -[(S )-{[(2R ,3R ,4R ,5R )-5-(2,4-dioxo-3,4-dihydropyrimidin-

Description. A white to off-white powder.

Category. Antiviral (Hepatitis C viral polymerase nucleotide inhibitor)

Storage. Sofosbuvir should be kept in a well-closed container and stored at a temperature

Additional information. Sofosbuvir may exhibit polymorphism.

B. Carry out the test as described under 1.14.4 High-performance liquid

Apply separately to the plate 10 µL of each of the following solutions in methanol R.

Use the following gradient:

Time (min) Mobile phase A (% v/v) Mobile phase B (% v/v) Comments

Inject alternately 20 µL each of solutions (1), (2) and (5).

In the chromatogram obtained with solution (1):

F. Pentafluorophenol (process related impurity).

Reference substances invoked

International Chemical Reference Substance (ICRS) to be established.

Sofosbuvir for peak identification RS (containing sofosbuvir and the impurities A, B, C,

International Chemical Reference Substance (ICRS) to be established.

Sofosbuvir Reference Spectrum

DRAFT FOR COMMENTS

Molecular formula. C20H18F2N3NaO5

Relative molecular mass. 441.37

Chemical name. (4R ,12aS )-N -[(2,4-Difluorophenyl)methyl]-3,4,6,8,12,12a-hexahydro-7-

Description. A white to pale yellow powder.

Solubility. Slightly soluble in water R, and very slightly soluble in methanol R.