WHO Drug Information Vol. 34, No. 4, 2020

WHO Drug Information Contents

Quality Assurance News

802 White Paper for the WHO International Meeting of World Pharmacopoeias – Value of Pharmacopoeial Standards for Access to Quality Medicines

809 Study Report: Proficiency testing study on a WHO/TAL-trained methodology

Consultation Documents

842 Rifampicin (rifampicinum) – Draft proposal for inclusion in The International Pharmacopoeia

846 Dolutegravir sodium (dolutegravirum natricum) – Draft proposal for inclusion in The International Pharmacopoeia

856 Dolutegravir tablets (dolutegraviri compressi) – Draft proposal for inclusion in The International Pharmacopoeia

862 Remdesivir (remdesivirum) – Draft proposal for inclusion in The International Pharmacopoeia

871 Remdesivir intravenous infusion (remdesiviri infusio intraveno) - Draft proposal for inclusion in The International Pharmacopoeia

877 WHO Guidelines on the Transfer of Technology in Pharmaceutical Manufacturing

907 Oxygen (oxygenium) - Draft proposal for inclusion in The International Pharmacopoeia

917 ATC/DDD Classification (Temporary)

923 ATC/DDD Classification (Final)

International Nonproprietary Names (INN) 929 Proposed INN List No. 124

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/) 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) WHO World Health Organization (www.who.int) WHO MHP WHO Access to Medicines and Health Products Division (www.who.int/medicines/en/) WHO RPQ WHO Regulation and Prequalification Department WHO PQT WHO Prequalification Unit (https://www.who.int/topics/prequalification/en/) WHO HPS WHO Health Product Policy and Standards Department

Note: The online version of this issue is available at www.who.int/medicines/publications/druginformation)

Quality Assurance News WHO Drug Information, Vol 34, No. 4, 2020

White Paper for the WHO International Meeting of World Pharmacopoeias Value of Pharmacopoeial Standards for Access to Quality Medicines

Introduction In healthcare systems around the world, medicines play an important role in treating illness, preventing disease, and ultimately, saving lives. In a broader sense, medicines are valuable to society as tools to protect the public health. Nowadays, medicines are complex products made from numerous ingredients sourced through the global supply chain. The quality of medicines is ensured by the control of many factors such as the quality of their components. While quality medicines are safe and effective, substandard and falsified medicines can be ineffective and even harmful.

Medicine Quality Standards: The Pharmacopoeias Because medicine quality is so important to society, standards for medicine quality have been developed and published in countries around the world. In some countries, the standards have been compiled and placed in a valuable resource called a pharmacopoeia for decades and, in some cases, for centuries. A pharmacopoeia is an official collection of quality standards and specifications for medicines and their ingredients. This information is publicly available, shared, and used by parties concerned about the quality of medicines. These different parties, known as stakeholders, include medicine manufacturers, analytical laboratories, raw material suppliers, policy makers, regulatory agencies, pharmacies and other interested groups. Traditionally, a pharmacopoeia was only contained in a book, now an increasing number of pharmacopoeias are also available online. The Pharmacopoeias constantly work to improve access to the information and enhance the user’s ability to benefit from the full range of standards, best practices, and guidance provided.

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A pharmacopoeia contains detailed, descriptive information about quality attributes of medicines and their ingredients in the form of quality standards. The information encompasses procedures for how the medicine should be tested for identity, purity, potency, and other aspects of quality before it reaches the market and throughout its shelf life. Indeed, potential impurities that need to be kept under the maximum allowable level are controlled by the quality standard. In addition to these binding quality standards, the pharmacopoeia also provides useful guidance and recommendations for laboratories and production facilities. This guidance typically describes best practices, such as the preferred techniques and procedures to use in testing the medicines, and may be in the form of non-binding chapters or other means.

The core purpose of a pharmacopoeia is to help ensure that medicines and their ingredients are safe, effective, and of appropriate quality. The standards define the specifications that pharmaceutical ingredients and products on the market must fulfill throughout their shelf life. As such, the quality standards in the pharmacopoeia serve as a benchmark for quality, underpinning the overall safety of medicines and making a vital contribution to protecting public health. Quality standards also provide a common, or shared, understanding of appropriate quality characteristics for medicines and their ingredients. This common understanding helps streamline communications between manufacturers and regulatory authorities, saving time and resources while also building confidence in medicine quality among healthcare professionals and patients.

Transparent, Unbiased Public Process Pharmacopoeias and the standards they contain are the end result of a unique collaborative effort by a range of stakeholders who work collectively to protect public health. These stakeholders are individual scientific experts who come together from regulatory agencies, academia, healthcare practice, industry, and other related areas to serve as members of pharmacopoeial committees and advisory groups. Their expertise is critical to the scientific development, review, evaluation, and approval of quality standards. Clear rules for identifying and managing potential conflicts of interest are therefore crucial. This ensures that the scientific experts on the pharmacopoeial committees are functioning as independent, impartial individuals, driven by science and acting in the best interests of public health.

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The rules for ensuring that the experts are impartial are crucial to the integrity and credibility of the pharmacopoeia. Equally critical is the transparent, well-defined public process used for developing quality standards. One aspect of transparency is that stakeholders are informed in advance of possible upcoming changes to quality standards. This ensures that a stakeholder who may have concerns about a certain quality standard will have time to provide input and participate in the standard-setting process. This practice of transparency includes opportunities to comment on proposals made about the standards. Input from stakeholders is carefully considered and may be incorporated by the pharmacopoeia’s committees of scientific experts before a standard is finalized. The process to develop quality standards is publicly available, open, and held to account, enabling stakeholders to have confidence in pharmacopoeial standards.

Data-driven and Grounded in Science Given their critical role in healthcare and public health, pharmacopoeial standards must be based on robust data and sound scientific principles. Data are mainly submitted by stakeholders who seek to support the development of a new standard. These data, from a variety of sources, are gathered and used to construct the quality standard. All the evidence is evaluated carefully by experts from multiple scientific disciplines, allowing for thorough, productive scientific discussions and decision making.

After the new standard has been finalized and published, relevant data and evidence continue to be used throughout the lifecycle of the standard to ensure that it remains fit-for-purpose and reflective of the current state of the science, resulting, where necessary, in frequent revisions of standards. The standard must continue to reflect the expected quality of the specific medicine or its ingredients over time. Robust pharmacopoeial standards are supported by appropriate validation data that confirm that the analytical procedures are suitable for the intended purpose. Feedback and input from stakeholders are collected on an ongoing basis to ensure that the standards remain appropriate and applicable to all stakeholders, most specifically the regulatory agencies or pharmaceutical industry.

Responsive to Public Health Needs Over time, the number and complexity of medicines on the market is growing. Simultaneously, quality control strategies and manufacturing paradigms are becoming more diverse. In this complex environment, quality standards are playing an increasingly relevant role in protecting public health. As part of a broader health and social care system, quality standards can help maintain a stable, affordable, accessible supply of essential medicines while also facilitating the development of new medicines1.

1 For example, a very recent US study [1] shows that pharmacopoeial standards facilitate patients’ access to quality medicines while at the same time saving the healthcare system billions (USD) annually. Additionally, findings of a new survey [2] suggest that the use of pharmacopoeial standards also reduces time and costs associated with product development for manufacturers of high-quality generic medicines. Moreover, survey respondents’ perceptions are that usage of the standards decreases the risk of rejection of the marketing approval application by the regulators, in this case FDA. While the results found are valid for the United States, it is likely that similar benefits would exist in other countries.

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In this way, quality standards represent a critical element in the safety net that protects the public’s supply of safe, effective, and affordable medicines. At the same time, the emerging public health needs of society can stimulate beneficial changes in current pharmacopoeial standards. These changes allow the standards to better reflect and respond to public health priorities as they evolve. Examples of these evolving public health priorities include addressing antimicrobial resistance, substandard or falsified medicines, and fostering access to safe, quality medicines for all2.

Whilst this article was finalized following the 10th IMWP in February 2020, the IMWP felt it was important that it address the role of the pharmacopoeias in the global healthcare response to the COVID-19 pandemic. In early March 2020, the IMWP met as a result of the initiation of the Pharmacopeial alert system with the specific goal to share knowledge and experience with regards the role that pharmacopeias can play in assuring the continued supply of quality medicines during the pandemic. Through regular communications, the IMWP has shared information with regards to maintaining operations in developing and distributing standards, engaged on strategies for the development of pharmacopeial standards for critical COVID-19 treatments, and established a public dashboard on monograph availability of COVID-19 investigated drugs in world pharmacopeias. The pharmacopoeias are resolute in their commitment to supporting the healthcare response to COVID-19 and will continue to reflect on the lessons learnt from the pandemic to improve their ability to meet public health needs.

Continuous Updates Reflect Scientific Advances The world is changing rapidly, particularly in the realm of science and technology. These changes affect many aspects of society, including quality standards for medicines. It is important to note that a pharmacopoeia must be updated continuously, as it cannot remain stagnant while technology evolves around it. Instead, pharmacopoeial standards adapt over time to better support the changing needs of users and to keep pace with technology. One example is the replacement of legacy technologies with contemporary techniques, as was the transition from thin-layer chromatography to liquid chromatography for the test for related substances. This shift in technique is just one example that illustrates how quality standards can and do respond to advances in technology and science. Therefore, scientific progress and an evolving regulatory environment are driving forces behind the need to constantly revise a pharmacopoeial standard so it can remain relevant and effective.

2 For example, Antimicrobial resistance (3), Substandard and falsified medical products (4), the Universal Health Coverage (5) and the related Sustainable Development Goals “SDGs” (6).

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Global Collaboration on Quality Standards The utility of pharmacopoeial standards relies heavily on their continued alignment with public health priorities and current, practical scientific approaches to quality. To help ensure positive outcomes, the organizations that develop pharmacopoeias collaborate with each other, industry, and regulators around the world. These stakeholders work together to ensure public health by ensuring the quality of medicines by assembling the appropriate expertise and proposing viable solutions to address public health issues related to medicines quality, including during times of public health emergencies, such as with the adulteration of heparin and glycerol with toxic contaminants, as well as the current concerns with nitrosamine impurities in sartans and other pharmaceutical products. In addition, pharmacopoeias from around the globe through a meeting hosted by WHO called the International Meeting of World Pharmacopoeias worked to develop the first ever guideline on Good Pharmacopoeial Practices (7), which was developed through a collaborative effort and based on feed back during a global consultation.

Supportive of Making Medicines Available to All Pharmacopoeias have another important function and role. Their quality standards facilitate the development, manufacture, authorization, and post-market surveillance of medicines in countries around the world. In this way, pharmacopoeias help support making medicines widely available to patients around the world. When pharmaceutical companies are developing innovative medicines to treat diseases, their scientists typically refer to the relevant quality standards in the pharmacopoeia. The awareness and understanding of standards enable the development of quality medicines and facilitates approval from regulatory agencies. Indeed, meeting the regulatory expectations for quality is critical when a company seeks approval to manufacture and market a medicine.

Moreover, when there are multiple manufacturers making the same ingredient or product for the market, the existence of common standards helps to assist all companies to achieve the expected quality. Every time a pharmacopoeial standard for a given product becomes available, it creates a level playing field for all manufacturers making the product, helping them to meet the same benchmark. Ultimately, this plays a key role in protecting patients and in assuring healthcare professionals that the medicines they prescribe or dispense are reliable, effective, and safe.

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Training and Education for Users Quality standards can only be applied successfully by informed and trained users. Training and education opportunities are available for users, particularly for supporting the effective use of new and revised standards. These opportunities include scientific events, seminars, and conferences where users can learn to correctly apply the pharmacopoeial standards and gain an understanding of the process used to develop them. Users of the standards can benefit from relevant training and education, which will support their efforts to keep pace with the rapid innovation taking place today in technology and science.

Conclusion Pharmacopoeial standards play a critical role in the overall safety net that protects public health, while enabling access to quality medicines around the world. Developed and updated through a public and open process, these science-based standards provide a common understanding of appropriate quality attributes for medicines and their ingredients to the benefit of the healthcare system and ultimately the patient. These publicly available specifications, combined with recognized principles of good manufacturing practice, represent one vital element of the quality assurance of medicines. Whenever a national or regional authority introduces pharmacopoeial standards (8) into appropriate legislation, they acquire legal status and support compliance of medicines and their ingredients with regulatory requirements and expectations for quality in relevant jurisdictions. In addition to facilitating the preparation and assessment of regulatory submissions—thus supporting market entry of quality-assured products, the pharmacopoeial standards provide a public mechanism for an independent verification of the quality of a product at any time during its shelf life, helping build confidence among healthcare professionals and patients. Resulting from a unique collaborative enterprise of a wide range of stakeholders and independent scientific experts, the distinctive value of pharmacopoeial standards is amplified by their continued alignment with public health priorities, as well as current and practical scientific approaches to quality that ensure these public standards remain relevant and effective.

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References

1. Murimi-Worstell I.B.; Ballreich J.M.; Seamans M.J.; Alexander G.C. Association between US Pharmacopeia (USP) monograph standards, generic entry and prescription drug costs, PLOS ONE 14(11) (2019): e0225109. https://doi.org/10.1371/journal.pone.0225109.

2. Warthin I.K.; Berik J.; Podolsky D.; Raghavendran V.; Reddy R.; Chang J.; Porter N.; Garito N.; Commentary on the benefits of US pharmacopeial standards: a generic pharmaceutical industry survey, Journal of Pharmaceutical Sciences (2019), doi: https://doi.org/10.1016/j.xphs.2019.10.008.

3. Follow-up to the high-level meetings of the United Nations General Assembly on health- related issues. Antimicrobial resistance. Report by the Director-General. In: Executive Board 144th session, Geneva, 30 November 2018. Geneva: World Health Organization; 2018 (EB144/9; http://apps.who.int/gb/ebwha/pdf_files/EB144/B144_19-en.pdf, accessed 17 March 2020) .

4. WHO Governing bodies on Substandard and falsified medical products (http://apps.who.int/gb/sf/, accessed 17 March 2020 ) .

5. Universal Health Coverage (https://www.who.int/health-topics/universal-health- coverage#tab=tab and https://www.who.int/news-room/events/detail/2019/09/23/default- calendar/un-high-level-meeting-on-universal-health-coverage, accessed 17 March 2020) .

6. Sustainable Development Goals Knowledge Platform. Sustainable Development Goals (https://sustainabledevelopment.un.org/sdgs, accessed 17 March 2020).

7. Good pharmacopoeial practices (GPhP): Main text published as Annex 1, WHO Technical Report Series, No. 996, 2016. Compounded preparations as Annex 6, WHO Technical Report Series, No. 1010, 2018. Herbal medicines as Annex 7, WHO Technical Report Series, No. 1010, 2018.

8. Index of world pharmacopoeias and pharmacopoeial authorities WHO Working document QAS/11.453/Rev.12 (February 2020) https://www.who.int/medicines/areas/quality_safety/quality_assurance/resources/INDEX- OF-PHARMACOPOEIAS_2020.pdf?ua=1, accessed 17 March 2020) (updated regularly).

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Study report: Proficiency testing study on a WHO/TAL-trained methodology

High Performance Anion Exchange Chromatography with Pulsed Amperometric Detection (HPAEC-PAD) for the determination of the total and free saccharide content in Haemophilus influenzae type b (Hib) liquid combined vaccines.

1. Introduction Current Haemophilus influenzae type b (Hib) vaccines are made by conjugating the capsular polysaccharide (poly ribosyl-ribitol-phosphate; PRP) to a carrier protein. This conjugated form will induce a T-dependent B-cell response in infants and will result in immune memory [1, 2].

When the native form of Hib polysaccharide is used, the polysaccharide is usually linked covalently to tetanus toxoid (TT-PRP). Some vaccines use an oligosaccharide form instead; for these vaccines, the oligosaccharide is linked to a non-toxic variant of the diphtheria toxin, the cross-reacting

material CRM197 (CRM-PRP) [3]. The Hib glycoconjugate component can be combined with different vaccine antigens such as diphtheria (D), tetanus (T), whole-cell pertussis (wP) or acellular pertussis (aP), hepatitis B (HepB) and inactivated polio vaccine (IPV). Combination with any of these antigens, as well as with adjuvants, preservatives and other excipients, can interfere with analysis of the critical parameters indicative of Hib vaccine quality and efficacy, specifically, molecular size distribution and the total and free (unconjugated) saccharide content [1].

Total and free saccharide content are two parameters that must be checked routinely by manufacturers and by national control laboratories (NCLs) as required by WHO in the guideline for production and control of Hib vaccines [4] and by the European Pharmacopoeia [5].

Pentavalent DTwP-HepB-Hib liquid vaccine is used globally and has been designated a high- priority vaccine by the WHO Prequalification Team (WHO/PQT). Quality control testing of these vaccines is performed pre-and post-prequalification [6] by WHO-contracted laboratories all of which are national, official medicines control laboratories. Furthermore, post-licensing, the vaccines are undergoing official batch release testing by the authority with regulatory oversight responsibility before release to markets.

Study Co-ordinator: Dr Ute Rosskopf – WHO / Department Regulation & Prequalification, CH Scientific Advisor: Dr Christina von Hunolstein – Istituto Superiore di Sanità (ISS), I Statistician: Dr Andrea Gaggioli – Istituto Superiore di Sanità (ISS), I

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The proficiency testing studies (PTSs) are performed to offer NCLs and manufacturers an opportunity to assess and measure their laboratory performance, based on an inter-laboratory comparison. In general, the scope of the PTS is to cover the overall performance of a laboratory, and includes the whole process starting with reception and storage of the samples, experimental work, calculations, interpretation and transcription of the data, and reporting of the results and conclusions in the recording sheets provided by study coordinators.

Once the initial test report has been submitted by a laboratory, that report cannot be modified even if the laboratory discovers a failure of one of the process steps. However, comments from the laboratories can be added to the draft final report, but tables, figures and conclusions will not be modified, unless the data submitted by the laboratories have been misinterpreted at ISS and/or clear mistakes have been made at ISS.

2. Aim of the study This PTS was organised and coordinated by the Technical Assistance & Laboratory Services (TAL) - Vaccines, Group (subsequently renamed the Laboratory Networks and Services (LNS)) within the Regulatory System Strengthening (RSS) Team, the Regulation of Medicines and Other Health Technologies (RHT) Unit, the Essential Medicines and Health Products (EMP) Department in the Health Systems and Innovation (HIS) Cluster of the World Health Organization (WHO), and was done in collaboration with the Unit of Biological and Biotechnological Products, Bacterial Vaccine Section of the Istituto Superiore di Sanità (ISS). The aim of this PTS was to assess the proficiency of the participating laboratories to quantify the total and free (unconjugated) polysaccharide (PRP) content of the Haemophilus influenzae type b (Hib) component in different liquid pentavalent vaccine (DTwP-HepB-Hib) presentations when tested according to a method using high- performance anion-exchange chromatography with pulsed amperometric detection (HPAEC- PAD). The methodology was designed to determine the PRP content in liquid vaccine combinations containing a whole-cell pertussis component [7].

3. Participation Establishment of a quality management system compliant with quality standard ISO/IEC17025: “General requirements for the competence of testing and calibration laboratories” is a requirement for laboratories in charge of vaccines’ quality control “to demonstrate that they operate competently and are able to generate valid results” [8]. Participation in proficiency testing schemes is one essential requirement for laboratories adhering to this standard.

WHO/TAL invited those NCLs and manufacturers’ quality control laboratories that had participated either in the hands-on training courses [9] and/or in the previously performed WHO collaborative study [10]. A total number of 21 laboratories registered for participation in the study; of these, twelve are NCLs and nine are quality control laboratories from vaccine manufacturers. A list of participants in alphabetical order by country is given in section 9. Herein, they are referred to by an arbitrarily allocated code number (1-21), not related to the order of listing.

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4. PTS Design 4.1 Composition of the panel of test samples Each laboratory received a panel of three pentavalent vaccines (containing D, T, wP, HepB and Hib (DTwP-HepB-Hib) active components) (Table 1). Two of the test vaccines were WHO prequalified DTwP-HepB-Hib liquid formulated vaccines, while the third test vaccine was especially prepared for the study and contained a sub-potent PRP content and a high free, unconjugated PRP content. All the vaccines were fully liquid formulations that included aluminium phosphate as adjuvant. Their content of total and free polysaccharide was not revealed to the study participants. The vaccines samples were kindly donated by different manufacturers. The samples were shipped in appropriate packaging to protect the samples during transit and under temperature-controlled conditions. Participants were asked to check the contents of the package immediately and return the completed sample arrival report to WHO indicating any problems regarding the condition of the test materials or accompanying documents. Upon receipt of the samples, participants were asked to store the vaccines at 5 °C ± 3 °C until use.

4.2 Study design and reporting of results The shipment of the samples from WHO Headquarters in Geneva to the participating laboratories was initiated in January 2019. Following the receipt of the samples, the participants were asked to submit their test data within two months after receipt of the samples as indicated in the study protocol. Due to delays in shipments (e.g., custom clearances) and test performance, the latest test report was received in December 2019.

Participants were requested to test the vaccine panel according to the analytical protocol provided; this protocol was the same as that distributed during the hands-on training courses and for the previously performed collaborative study [10].

Participants were requested to quantify the total and free PRP content of each vaccine sample in three independent runs (i.e., 3 separate testing days) by using a vaccine pool freshly prepared on each test day. Calculation of both polysaccharide contents was based on the current in-use calibration curve (i.e., either the WHO 2nd International Standard for Haemophilus influenzae polysaccharide PRP or the ribitol reference standard). Determination of the total PRP, according to the analytical protocol, does not require any pre-treatment of the vaccine sample. To test for free PRP, however, the vaccine sample must undergo several steps of preparation. The steps include pre-treatment with 5 mM phosphate buffer, pH 6.8 [10], centrifugation to eliminate the adjuvant, and application of the supernatant to a SPE C4 wide pore cartridge. The cartridge permeate was collected to recover the free PRP. Hydrolysis of the permeate (to test free PRP) and the vaccine sample (to test total PRP), was performed by adding 50 µL 6N HCl to all samples and then incubating them for 2 hours at 100 °C. In addition to the test sample, samples include the positive control, the system suitability test (SST) sample, and 1 mL of each dilution point of the calibration curve. The samples then were cooled for 10 min at 5 ± 3 °C and 400 µL of 1 M NaOH was added. Each sample was then appropriately diluted, filtered and analysed by HPAEC-PAD.

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The analytical protocol defined the chromatographic conditions to be followed. The laboratories were asked to complete a form reporting the characteristics of their HPAEC equipment, details of the ribitol used as a positive control (i.e., percent purity, moisture content, diluents, and storage time and temperature), the system suitability criteria in place, any deviations from the analytical protocol, any difficulties encountered, and any observations regarding the study protocol. An electronic data reporting sheet was provided to record the experimental data, specifically, the content, in µg per single human dose (µg/shd) of total and free saccharide (indicated in the report as total and free PRP). It was requested to report test results using two decimal places, which was applicable as well to the reporting of the free saccharide content as a percentage of the total PRP. Data from laboratories were received by WHO/TAL and ISS between February 2019 and December 2019. The original deadline date was extended to allow the acceptance of data that could not be sent on time because of the heavy workload or late sample receipt.

4.3 Statistical methods See Appendix 1 for more details on the statistical evaluation of the PTS data.

5. Results and Statistical Analysis 5.1 Study test results A total of twenty-one laboratories reported their assay results, but the data from only nineteen (19) laboratories were analysed in this report. One laboratory was excluded because it sent the results after the extended deadline (December 2019) and another laboratory was excluded because it provided results from only one test run.

Vials for PTS-1 sample were shipped to 18 laboratories only, due to limited supply of that sample. All 19 laboratories, included in the data analyses reported below, carried out three assays (test runs) for each vaccine in accordance with the study protocol.

Tables 2 A-C show a complete listing of values reported by the laboratories. The tables present the results per individual run, the geometric mean (GM) of the three runs, and the rounded GM for each test sample. The results for free saccharide content are also reported as a percentage of the total saccharide content. Grey shaded cells indicate results that were declared non-valid according to the outcome for the system suitability test. These results were retained in the analyses since they were in line with the results from the other laboratories.

In figures 1-4, results are reported using two different ways of plotting the total and free PRP content for the three PTS samples. Figures 1-3 plot, for each sample and each test, the GM and the individual test results for each of the 19 laboratories. Figures 4A-4F report the GMs for the 19 laboratories in a dot plot format (similar to the histogram plot). The central horizontal line (figures 1-3) and the vertical line in the dot plots (figures 4 A-F) represent the consensus values (see section 5.3).

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5.2 Precision of the method Precision of the method was calculated for each PTS sample for both parameters (total and free PRP content) as inter-laboratory precision, intra-laboratory precision and reproducibility. Data for the three PTS samples are reported in tables 3A, 3B and 3C.

5.3 Consensus values Consensus values were obtained based on an analysis of the raw data and an evaluation of the data distributions.

The hypothesis of normality was assessed by means of the Shapiro-Wilk Test. This is considered the most powerful normality test when there is a small sample size, as in this case of 19 laboratories. If the p-value of the Shapiro-Wilk test is less than the classical threshold of 0.05, the results indicate a significant deviation from the assumption of normality whereas Shapiro-Wilk p-values greater than 0.05 indicate no significant deviation from normality. However, for the purposes of this report, a more conservative approach was used. Specifically, a distribution was considered to be normal if normality was consistent with visual inspection of exploratory graphs of the data and if the Shapiro- Wilk p-values were greater than 0.5. When these conditions were met, the classical calculation of consensus value and standard deviation was used instead of a robust calculation. This conservative approach was adopted because the classical estimator of consensus value is very sensitive even to small deviations from normality. A complete list of the robust estimators is provided in Appendix 2 (table A-1). When the Shapiro-Wilk value was < 0.5, the consensus value was based on the robust estimator defined in “ISO 13528:2015 Statistical methods for use in proficiency testing by inter- laboratory comparison” [11].

The uncertainty of measurement [12] associated with the consensus values was determined by

pooling the uncertainty of the mean of the nLab laboratory means: i.e., the standard error:

(SLab/sqrt(nLab)), and the uncertainty associated with the homogeneity of the vials (i.e., SRun, the within-Lab standard deviation). Other potential uncertainty sources to be included in the uncertainty budget are considered negligible (i.e., less than 1/5 of the major contributor). The consensus values for all samples (derived from the geometric means of the laboratories listed in table 2) are reported in figures 3, 4 and 5, where the expanded uncertainty (U) is shown for the consensus value of all six parameters, i.e., total and free saccharide content for the three PTS samples.

In particular, the details on the approach used for the different samples are the following:

- PTS -1 sample, total PRP content: The data distribution can be considered to be normal (Shapiro-Wilk: p-value=0.927); no anomalous values were detected. Therefore, the classical calculation (i.e., arithmetic mean and SD), is used for the consensus value and the standard deviation (which equalled 1.41 µg/shd). Consensus value: 10.5 ± 1.7 µg/shd (k=2); relative U = 16.2% (k=2)

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- PTS -1 sample, free PRP content: Although the data distribution does not significantly deviate from normality (Shapiro-Wilk: p- value=0.375), a slight positive asymmetry is observed. Therefore, the robust estimate obtained using Algorithm A [11] was considered to be the consensus value and the robust estimate of the standard deviation (which equalled 0.529 µg/shd) was considered as the consensus standard deviation. Consensus value: 1.176 ± 0.337 µg/shd (k=2); relative U = 28.7% (k=2)

- PTS -2 sample, total PRP content: Although the data distribution does not deviate from normality (Shapiro-Wilk: p-value=0.108), a slight left asymmetry and an anomalous value were observed. Therefore, the robust estimate obtained by using Algorithm A [11] was considered to be the consensus value and the robust estimate of the standard deviation (which equalled 0.748 µg/shd) was considered to be the consensus standard deviation. Consensus value: 5.835 ± 1.375 µg/shd (k=2); relative U = 23.6% (k=2)

- PTS -2 sample, free PRP content: The data distribution significantly deviates from normality (Shapiro-Wilk: p-value=0.020). Visual inspection, in this case, reveals that the distribution can be considered bimodal; this means that a true consensus was not really obtained. In fact, two different groups of laboratories were observed, as illustrated in the figure of Appendix 2 (figure A-1). The minor mode makes a considerable contribution to the area of the kernel; therefore, two discrepant populations are represented in the participants’ results. Without additional independent information (e.g., further details of the participants’ analytical methods and product label claim), it is not possible to determine which of these modes is the correct one.

In this situation, two alternatives can be considered: 1) Do not attempt to determine a consensus value, and do not report for this parameter any individual laboratory performance scores. In this scenario, a repetition of the PTS would be recommended. 2) Determine the consensus value based on the principle that the higher mode is the most probable true value.

The PTS provider decided to determine a consensus value obtained by the result of the Huber robust estimator (robust standard deviation equal to 1.22 µg/shd) because it is a more suitable estimator when the data distribution is not unimodal (i.e., since it gives more weight to the higher mode). Consensus value: 3.171 ± 0.6 µg/shd (k=2); relative U = 18.9% (k=2)

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- PTS -3 sample, total PRP content: The data distribution can be assumed to be normal (Shapiro-Wilk: p-value=0.976); no anomalous values are detected. Therefore, the classical calculation (i.e., arithmetic mean and SD), was used for the consensus value and the standard deviation (which equalled 1.146 µg/shd). Consensus value: 8.19 ± 1.28 µg/shd (k=2); relative U = 15.6% (k=2)

- PTS -3 sample, free PRP content: The data distribution can be assumed to be normal (Shapiro-Wilk: p-value=0.510); no anomalous values were detected. Therefore, the classical calculation (i.e.: arithmetic mean and SD), was used for the consensus value and the consensus standard deviation (which equalled 0.607 µg/shd). Consensus value: 1.22 ± 0.37 µg/shd (k=2); relative U = 30.3% (k=2)

5.4 Z-score The performance of the participating laboratories was evaluated using the performance indicator called Z-score (see Appendix 2 for additional details). Z-score should be within the range > -2 to <+2 to declare the performance of a single laboratory as satisfactory. Table 4 reflects the Z-scores that the different laboratories achieved for each PTS sample and parameter.

The limitations induced by the high uncertainty associated with the consensus values for some of the tested parameters are not negligible, and therefore, the information content of the Z-scores will be reduced correspondingly. This means that truly questionable and unsatisfactory Z-scores could be not detected in this study. This certainly is the case for the measurements of the free PRP content for the 3 test samples; each of these showed consensus values with an associated expanded relative uncertainties (U) higher than 25%. These high U values were the result of a low reproducibility (for PTS-1 and PTS-3) or of the bimodal distribution (PTS-2). When a high uncertainty is observed, ISO 13528 ([11]) and Eurachem [13] suggest the use of Modified Z-score (i.e., z’ score = with C: 𝑥𝑥−𝐶𝐶 consensus value; u: standard uncertainty; and σ: standard deviation for proficiency assessment2 2 ), √𝑢𝑢 +𝜎𝜎 while Thomson et al. [14] offers a slightly different recommendation. In any case, Modified Z- scores tend towards values similar to standard Z-scores (data not shown).

In figures 6A-6F (for each sample and each parameter) the Z-score per laboratory in a size order within the Z- score range are reported i.e., from negative to positive value. When the bars of Z- scores are systematically on either the positive side or negative side, a systematic bias is indicated. If the bars extend more than 2 on both sides, a random bias is indicated. However, due to the variability of the results, evaluation based only on scoring is considered to be of limited value. Therefore, it did not seem appropriate to draw the conclusions regarding the proficiency of the participants’ based only on the classical criteria as presented in Appendix 1.

Similarly, it is recommended to use the Z-scores that are presented here with caution for purposes outside of this report.

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5.5 Overall assessment of performance Six different parameters have been analysed in this study: two test results (i.e., total and free PRP content) for each of the three samples. To give an overview on the performance of each participating laboratory, two different tools for data presentation have been used. The first tool is based on the Youden Plot [15]; the second is based on an attempt to pool the six different Z-scores into unique scores, specifically, Rolling Performance Indicators (RPIs) [13, 14].

5.5.1 Youden Plots Youden plots are a graphical way to represent the results obtained by the laboratories and, at the same time, to provide a critical assessment of the performances [15]. In a single graph both test results obtained for a given test sample, i.e. the total and free PRP contents, are reported. Therefore, this figure presents a combined assessment of the two parameters measured on the same sample.

The Youden plots reported in figures 7-9 are based on the raw data (in µg/shd) for each of the 3 tested samples; the scales of the axes for these plots were adapted for parameters that are not similar (i.e., total and free PRP).

Each point in the plot represents the results of one laboratory; the total PRP result is plotted on the horizontal axis and the free PRP result is plotted on the vertical axis. The centre of the circles is called the Manhattan median; this centre point represents the median values of the two test results (see Appendix 3 for additional details on construction of the Youden plots). Points outside the outer circle indicate large total error. Points that lie near the 45-degree reference line, but far from the centre of the circles, indicate large systematic error. Points that lie far from the 45-degree line indicate large random error. Thus, the plot also provides a graphical indication of the likely types of error.

Laboratories appearing in the 1st quadrant (consistently high results) or in the 3rd quadrant (consistently low results) exhibit systematic errors or bias, i.e., the further the point is from the centre of the circles, the greater is the error. If random errors are small, the points would be close to the 45° line. The lengths of perpendiculars drawn from the points to the 45° line are directly related to the random errors. Ideally, all observations should be placed on the diagonal line and inside the inner circle. Laboratories within the inner circle have a normal random variation, while laboratories outside the outer circle but near the diagonal line exhibit systematic bias.

5.5.2. Rolling Performance Indicators (RPIs) RPIs are usually computed to assess the performance of participants over a successive series of PTS studies, i.e., consecutive rounds of testing (13, 14). They can be used to assess bias and precision (systematic and random error) by pooling different results in terms of Z-scores; in case of this study for the six different parameters. There are various RPIs which can be calculated based on the obtained Z-scores: Rescaled Sum of the Z-scores, Sum of the Squared Z-scores, Rescaled Sum of the Squared Z-scores, and Absolute Rescaled Sum of the Squared Z-scores (for details, see Appendix 4).

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All the above-mentioned indicators give a unique score for each of the participants. There is a temptation to determine a single indicator of merit, that can summarize the overall performance of each laboratory within this study, based on six different tested parameters.

Although it is recognized that such RPIs may have specific applications (provided that they are based on sound statistical principles and issued with proper cautionary notice), every RPI can have its limitations (e.g., the loss of the Z-scores signs). Moreover, in this specific case, any RPI can be biased by the high uncertainty associated with the consensus values of the free PRP parameters, as highlighted above in section 5.4.

For this reason and others, the provision of combined scores is usually not recommended for inclusion in a study report for participants. Therefore, it was decided to include this information only in Appendix 4.

6. Conclusions

6.1 General comments There was a large participation in the study both by NCLs as well as manufacturers’ quality control laboratories. The goal of this PTS was reached as it provided an assessment of the proficiency of the participating laboratories to quantify the total and free (unconjugated) PRP content of the Hib component in different liquid pentavalent vaccine (DTwP-HepB-Hib) presentations when tested according to a method using HPAEC-PAD. This goal was achieved despite the limitations of the reported Z-scores (see § 5.4). For none of the participating laboratories could an unsatisfactorily performance be observed in terms of Z-scores for all six tested parameters, even though there was limited validity. In fact, no laboratory obtained Z-scores > 3 for all the 6 parameters, and therefore all the ARSSZ scores are lower than 9 (see Appendix 4).

The determination of the free PRP content was more variable for all samples than the determination of the corresponding total PRP content. This means that poor reproducibility was observed for this parameter as illustrated by the results reported in the tables for the method precision (tables 3A - 3C). Thus, for the total PRP results, the partition between intra- and inter- laboratory variabilities is as expected (i.e., inter-lab variances account for 74, 65 and 78 percent of the total variance). However, the inter-laboratory portion of the total variability represents 96 - 98 % of the total variability for the free PRP results. The observed higher variability may be related to the additional sample preparation and processing that is required for the free PRP determination whereas the determination of the total PRP requires only a dilution of the sample under test.

A PTS is performed once a method has been shown to be suitable for the intended purpose. The validity of this method has already been evaluated in small studies and in a published collaborative study [10]. It is assumed that the WHO method had been validated in-house by each participating laboratory prior to participation in the PTS. Participation in this proficiency testing scheme provided the laboratories with an objective means of assessing and demonstrating the reliability of the data being produced.

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6.2. Individual laboratory assessment and comments According to the consideration given in section 5.4, this assessment was based not only on criteria described in Appendix 1, but also on examination of Youden Plots. A decision was made to report “partially unsatisfactory” proficiency to those participants that showed a clear systematic error, and a “questionable” proficiency to those laboratories with sporadic random error. As already stated in section 5.4, the comments below are intended for information only.

Lab 1: for information only: a large intra-lab variability was observed for the total PRP content for PTS-2 sample (GCV = 31.9%). This is due to a higher value in the first run; it does not affect the overall good performance.

Lab 2: Partially unsatisfactory: a systematic bias was observed. The laboratory also tends to underestimate the true value for all the tested parameters as visible in the Youden plots (note that this is also illustrated by the high negative RPIs).

Lab 3: The laboratory was in the lower mode group for the free PRP content of PTS sample number 2.

Lab 4: No comment.

Lab 5: No comment.

Lab 6: There was a very slight tendency to underestimate the saccharide contents, both for total and free PRP. However, the size of the negative bias was very small. The bias was slightly higher for the free PRP measurements (see lower mode on free PRP for PTS-2).

Lab 7: Questionable: a questionable Z-score was observed for the free PRP content of the sample PTS-1. The laboratory tends to systematically underestimate (slightly) the total PRP content and, at the same time, to overestimate (slightly) the content of the free PRP.

Lab 8: No comment.

Lab 9: There was a slight tendency to underestimate the saccharide contents, both for total and free PRP. However, the size of the negative bias was very small. The bias was slightly higher for the free PRP measurements. The lab was in the lower mode group regarding the free PRP content of the PTS-2 sample.

Lab 10: No comment.

Lab 11: No comment.

Lab 12: No comment.

Lab 13: There was a very slight tendency to underestimate the saccharide contents, both for total and free PRP. However, the size of the negative bias was very small. The bias was slightly higher for the free PRP measurements. The lab was in the lower mode group regarding the free PRP content of the PTS-2 sample.

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Lab 14: No comment.

Lab 15: No comment.

Lab 16: No comment.

Lab 17: No comment.

Lab 18: Partially unsatisfactory: a systematic bias was observed. The laboratory tended to overestimate the true value for all the tested parameters as illustrated in the Youden plots and as highlighted by the high positive RPIs (taking into account invalid test results). The data were analysed by both including and excluding invalid test results. There were no significant changes in the final performance and assessment observed.

Lab 19: The assessment was based on only 4 parameters since the PTS-1 sample was not provided due to a limited number of samples. There was a very slight tendency to overestimate the saccharide contents. However, the size of the positive bias was very small. The bias was slightly higher for the total PRP contents, which was contrary to what was the common trend for the other laboratories.

7. References 1. Schneerson R, Barrera O, Sutton A et al. Preparation, characterization, and immunogenicity of Haemophilus influenzae type b polysaccharide protein conjugates. J Exp 1980; 152:361−6.

2. Zepp F, Schmitt HJ, Kaufhold A et al. Evidence for induction of polysaccharide specific B- cell-memory in the 1st year of life: plain Haemophilus influenzae type–PRP (Hib) boosters children primed with a tetanus-conjugate Hib-DTaP-HBV combined vaccine. Eur J Pediatr 1997; 156:18−24.

3. Frasch CE. Preparation of bacterial polysaccharide-protein conjugates: analytical and manufacturing challenges. Vaccine 2009; 27:6468−6470.

4. Recommendations for the production and control of Haemophilus influenzae type b conjugate vaccines. WHO TRS 897, 2000.

5. Haemophilus influenzae type b conjugate vaccine. Monograph 1219. Ph.Eur. Suppl. 10. Strasbourg, France; Council of Europe; 2020. 6. WHO Procedure for assessing the acceptability, in principle, of vaccines for purchase by United Nations Agencies. WHO Technical Report Series 978, Annex 6. Geneva: World Health Organization, 2010.

7. Efficient means to determine Hib component in liquid vaccine presentations, for different vaccines, produced by different manufacturers. Available from: https://www.who.int/immunization_standards/vaccine_quality/Study_Report_Vaccines_Ma y2014.pdf?ua=1; last visited 25/06/2020

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8. ISO/IEC 17025: General requirements for the competence of testing and calibration laboratories; 2017.

9. World Health Organization. Supporting countries in quality assurance for pentavalent vaccines. First WHO-ISS hands-on laboratory training course held in Rome, Italy. Geneva: World Health Organization; 2015. Available from: http://www.who.int/immunization_standards/vaccine_quality/hib_component_determinati on/en/ ; last visited 25/06/2020

10. Rosskopf U, Daas A, Terao E, von Hunolstein C. Collaborative study on saccharide quantification of the Haemophilus influenzae type b component in liquid vaccine presentations. Pharmeur Bio Sci Notes 2017; 2017:44-68.

11. ISO/13528:2015: Statistical methods for use in proficiency testing by interlaboratory comparisons.

12. ISO Guide 98-3, Uncertainty of measurement - Part 3: Guide to the expression of uncertainty in measurement (GUM)

13. Eurachem: Selection, use and interpretation of proficiency testing (PT) schemes by laboratories. 2000.

14. M. Thompson et al. IUPAC International - The International harmonized protocol for the proficiency testing of analytical chemistry laboratories (IUPAC Technical Report) - Pure Appl. Chem., 2006; 78, No.1:145–196.

15. Youden WJ. Graphical diagnosis of inter-laboratory test results. Industrial Quality Control.1959; 15: 24-28.

8. Acknowledgements The authors give sincere thanks to: • All participating laboratories for their valuable contribution to this study. • The following vaccine manufacturers (in alphabetical order) for their donation of the vaccine samples, especially the preparation of a pentavalent vaccine exclusively for the purpose of this study: - Biological E. Limited, India - PT Bio Farma (Persero), Indonesia - Serum Institute of India Limited, India. • NIBSC for donation of the WHO 2nd IS for Hib PRP Polysaccharide (12/306). • The following WHO colleagues for the preparative work and shipment of the study samples: Mr Kamel Aboudi, Mrs Tomislava Bouquet, Mr Raimundo Gomes da Silva Arbenz and colleagues, Mr Daniel Hollies as well as Ms Louise Els (consultant). • Bruce Meade for editorial review of the report.

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9. List of participants

Country Name Institution Bangladesh Dr Mohammad Mainul AHASAN Incepta Vaccine Ltd.

Belgium Dr Lorenzo TESOLIN Sciensano Dr Laure CUIGNET Quality of Vaccines and Blood Products Dr Adeline GAZAN Biochemistry team

China Dr Qiang YE National Institute for Food and Drug Control Dr Maoguang LI (NIFDC) Division of Respiratory Bacterial Vaccines

France Dr Olivier GARINOT French National Agency for Medicines and Health Products Safety (ANSM) Laboratory Controls Division

Germany Dr Wolf Hagen HOLTKAMP Paul-Ehrlich Institut (PEI) Section 3/1 Product testing of immunological medicinal products

India Dr Dipankar DAS Bharat Biotech International Ltd.

India Dr Srinivas KOSARAJU Biological E. Limited

India Dr Ravikumar RAMPA Cadila Health Care Limited Zydus Vaccine Division

India Mr Jaipal MEENA National Institute of Biologicals (NIB) Mr Ade Ajay KUMAR

India Dr Deepak MAHAJAN Panacea Biotec Ltd.

India Dr Sunil GAIROLA Serum Institute of India PVT LTD

India Dr Radhakrishnam Raju MANTENA Shantha Biotechnics Limited (A Sanofi Company)

Indonesia Dra Togi Junice HUTADJULU National Quality Control Laboratory of Drug Ms Elisabeth ARISETININGSIH and Food (NQCLDF) National Agency of Drug and Food Control

Indonesia Dr Dori UGIYADI PT Bio Farma (Persero) Ms Lin SUSANTI

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Italy Dr Cristina PEZZELLA Istituto Superiore di Sanità (ISS) Dr Luisa RALLI

Mexico Ms Imelda Rocío GUZMÁN Commission for Analytical Control and CERVANTES Expansion of Coverage (CCAYAC) Ms Laura MUNGUÍA Federal Commission for the Protection from Dr Guillermo VEGA RODRIGUEZ Sanitary Risks (COFEPRIS)

Republic of Korea Ms Helen KIM LG Chem Ltd. Dr ByoungKook HYUN

Republic of Korea Dr Naery LEE National Institute of Food and Drug Safety Dr Sun bo SHIM Evaluation (NIFDC) Vaccines Division

South Africa Dr Ruan ELLS National Control Laboratory for Biological Products (NCLBP)

Thailand Dr Supaporn PHUMIAMORN Institute of Biological Products (IBP), Mrs Wereyarmarst Department of Medical Sciences, Ministry of JAROENKUNATHUM Public Health

United Kingdom Dr Frank GAO National Institute for Biological Standards Dr Barbara BOLGIANO and Control (NIBSC) Mrs Karena Burkin Bacterial Division

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Appendix 1 – Statistical Analysis

All results were collected at ISS and the data were then analysed using the software IBM SPSS 25.0 and MS Excel 16.0. An assessment of intra-laboratory precision is provided for each of the sample vaccines and for both the total and the free saccharide measures. For laboratory assessment, Z- scores were intended to be employed.

Z-scores are performance scores for proficiency assessment. Z-scores evaluate the difference between each participant’s result and the assigned value (in this study, a consensus value based on the results from the participating labs will be used). This difference is then compared as a ratio to the overall (consensus) standard deviation. Therefore, an assigned value and standard deviation for proficiency assessment are necessary; both were derived from the results of the participating laboratories (i.e., consensus values).

According to the ISO 13528:2005 (E) there are several recognised ways to establish the consensus value and the standard deviation for proficiency assessment in a proficiency testing scheme (e.g., algorithm A [11]).

Once the consensus value and the standard deviation have been determined, the Z-scores for each laboratory are then calculated, one score for each of the six reported parameters (i.e., total and free PRP for each of the three samples):

Lab s Result Consensus Value Z score = Consensus′ Standard Deviation − − For the purposes of performance assessment, the following classification is commonly adopted: | Z | ≤ 2.00 Satisfactory result 2.00 < | Z | ≤ 3.00 Questionable result | Z | > 3.00 Unsatisfactory result

Uncertainty associated with the consensus values is also reported. However, as already stated in the text of this report, non-negligible uncertainty exists with respect to how close the consensus values are to the true values, mainly for the free PRP parameters.

The final results of the study also are presented in the tables and graphs (e.g., histograms, descriptive individual plots, and Youden Plots) provided in this report.

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Appendix 2 – Robust Estimators

Table A-1. Consensus Values: Robust Estimators versus Mean Value Robust Estimators Shapiro-Wilk Huber's Alg_Ae Mean Sample p-value M- Tukey's Hampel's M- Andrews' (ISO 13528) Value Estimatora Biweightb Estimatorc Waved Total PRP 0.927 10.483 10.534 10.517 10.534 10.543 10.502 PTS-1 Free PRP 0.375 1.173 1.113 1.167 1.107 1.176 1.209 Total PRP 0.108 5.786 5.790 5.783 5.795 5.835 5.886 PTS- 2 Free PRP 0.020 3.171 3.380 3.194 3.380 2.857 2.856 Total PRP 0.976 8.116 8.093 8.145 8.091 8.173 8.191 PTS- 3 Free PRP 0.510 1.187 1.162 1.190 1.162 1.200 1.220 All results (except the p-values) are in µg / shd. In bold are the adopted consensus values a. The weighting constant is 1.339. b. The weighting constant is 4.685. c. The weighting constants are 1.700, 3.400, and 8.500 d. The weighting constant is 1.340*pi. e. The weighting constant is 1.483 Another robust estimator, i.e., the Median, is used and shown in the Youden Plots figures

Figure A-1. Kernel Density for free PRP in PTS-2 Sample

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Appendix 3 - Youden Plot Details

The Youden plots provide another view of the performance, using an approach which emphasizes bias. One Youden plot is created for each PTS sample (figures 7-9). They are constructed as follows: a vertical line and a horizontal line are drawn through the median values. The axes of the plot are not drawn on the same scale; instead, one standard deviation on the x-axis has the same length as one standard deviation on the y-axis.

A horizontal median line is drawn parallel to the x-axis so that there are as many points above the line as there are below it. A second median line is drawn parallel to the y-axis so that there are as many points on the left as there are on the right of this line. Outliers (according to the Tukey approach) are not used in determining the position of the median lines. The intersection of the two median lines is called the Manhattan median.

Analogous to the 45-degree reference line in the original Youden plot, a reference line is drawn which in this case represents a constant ratio of the two parameters.

Two circles are drawn that should include 95% and 99% of the laboratories, respectively, if individual constant errors could be eliminated (95% and 99% coverage probabilities).

Therefore, the radii of the two circles are calculated based on the coverage probabilities of 95% and 99%. Specifically, the radius of the circles is obtained by multiplying the quantity 2ln ( ) (with p equal to 0.05 and 0.01 for the inner and the outer circle, respectively) by the averaged intra-lab �− 𝑝𝑝 standard deviation.

Appendix 4 - Rolling Performance Indicators Approach

A list of four types of scores combination (that may be useful to assess a sequence of Z-scores) is given below (Z-score is simply denoted with z; n is the number of the tested parameters):

- RSZ - Rescaled Sum of the Z-Scores; RSZ = 𝑛𝑛 �𝑖𝑖=1 𝑧𝑧𝑖𝑖 - SSZ – Sum of the Squared Z-Scores; SSZ = √𝑛𝑛 𝑛𝑛 2 𝑖𝑖 �𝑖𝑖=1 𝑧𝑧 𝑛𝑛 - RSSZ – Rescaled Sum of the Squared Z-Scores, RSSZ = 2 𝑖𝑖 �𝑖𝑖=1 𝑧𝑧 | | - ARSSZ – Absolute Rescaled Sum of the Squared Z-Scores, 𝑛𝑛ARSSZ = 𝑛𝑛 �𝑖𝑖=1 𝑧𝑧𝑖𝑖 ∗𝑧𝑧𝑖𝑖

𝑛𝑛 In this report, only the RSZ and ARSSZ are presented (see table A-2 below), since they are considered the most informative and statistically sound indicators in this context. However, it is emphasized that there are limitations and weaknesses in any indicator that combines Z-scores from dissimilar parameters.

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Table A-2: RSZ and ARSSZ Results

Lab 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 RSZ 1.35 -4.72 -1.55 0.24 -1.72 -2.61 1.43 0.52 -2.24 1.72 -0.55 -1.73 -2.08 1.36 0.08 1.71 0.76 5.31 1.66

ARSSZ 0.54 -3.85 -0.67 0.04 -0.60 -1.40 1.33 0.11 -0.96 0.82 -0.06 -0.69 -0.90 0.43 0.02 0.53 0.17 5.33 1.16

Note: for RSZ the shading means the same as reported in table 4: for ARSSZ the shading denotes results higher than |3|, denoting partially unsatisfactory performance

The RSZ “can” be interpreted as a single Z-score, i.e., it is expected to be zero-centered with Variance = 1. This indicator has the useful property of demonstrating a persistent bias or trend, so that a sequence of satisfactory results [e.g.: 1.4, 1.8, 1.1, 1.5, 1.7, 1.7] would provide statistically significant RSZ equal to 3.0, even though each individual Z-score is less than 2. As is obvious, the main deficiency is the lost information due to large Z-scores of opposite signs.

The ARSSZ has the advantage of avoiding the cancellation of large Z-scores of opposite signs (the signs are maintained), but is less sensitive to small biases. If an ARSSZ is lower than 9, it means that there is not a systematic unsatisfactory performance (i.e., when all the six Z-scores ≥ |3|).

It is recommended that these combinations of scores should not be misused; there is a danger that such an approach can be misinterpreted or abused by non-experts, especially outside the context of the individual scores.

It is especially emphasized that there are limitations and weaknesses in any approach that combines Z-scores from dissimilar analyses. If a single score out of several produced by a laboratory were outlying, the combined score may well be not outlying. In some respects, this is a useful feature, in that a lapse in a single analysis is down weighted in the combined score. However, there is a danger that a laboratory may be consistently yield a faulty value for only a single parameter, and thus frequently report an unacceptable value for that analysis in all the tested samples. This factor may well be obscured by the combination of scores.

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TABLES

Table 1. Overview of test panel composition

Vaccine Doses per Quantity of Specification for total and free sample code container provided vials saccharide content Total: 8-12 mcg/0.5 mL PTS-1 5-dose 12 Free: < 20% of total PRP

PTS-2 10-dose 6 not applicable (inferior quality)

Total: 8-12 mcg/0.5 mL PTS-3 10-dose 6 Free: < 30% of total PRP

Table 2A. PTS-1 sample: Individual results reported by the participating laboratories

Total PRP - µg / shd (shd - 0.5 ml) Free PRP - µg / shd (shd - 0.5 ml) Free PRP - % of Total PRP Lab Run 1 Run 2 Run 3 GM GCV (%) Run 1 Run 2 Run 3 GM GCV (%) Run 1 Run 2 Run 3 GM GCV (%) 1 14.15 11.42 11.33 12.23 12.66 1.23 1.26 1.09 1.19 7.78 8.69 10.98 9.63 9.72 11.76 2 6.09 8.94 7.46 7.41 19.38 0.46 0.35 0.37 0.39 14.52 7.39 3.91 4.96 5.23 33.02 3 10.04 8.47 9.8 9.41 9.22 1.51 1.38 1.2 1.36 11.62 15.04 16.29 12.24 14.42 14.83 4 11.68 10.74 11.04 11.15 4.28 1.16 1.12 1.11 1.13 2.33 9.93 10.41 10.09 10.14 2.40 5 9.23 9.29 8.66 9.06 3.88 0.91 0.90 0.85 0.89 3.66 9.83 9.62 9.82 9.76 1.22 6 9.9 9.65 9.71 9.75 1.33 0.54 0.51 0.7 0.58 17.00 5.45 5.28 7.21 5.92 17.27 7 10.03 10.43 10.33 10.26 2.04 2.42 2.64 1.94 2.31 15.98 24.13 25.28 18.78 22.54 16.09 8 11.76 10.92 10.48 11.04 5.84 1.21 1.19 1.2 1.20 0.83 10.29 10.86 11.41 10.84 5.17 9 9.97 9.58 9.95 9.83 2.25 0.58 0.52 0.56 0.55 5.58 5.79 5.44 5.64 5.62 3.13 10 12.43 12.68 12.48 12.53 1.05 1.24 1.19 1.25 1.23 2.64 9.96 9.33 10.00 9.76 3.89 11 10.33 9.97 10.47 10.25 2.53 0.97 1.01 1.15 1.04 9.00 9.00 10.00 11.00 9.97 10.06 12 9.35 8.78 8.62 8.91 4.26 1.17 1.05 1.08 1.10 5.62 12.51 11.97 12.56 12.34 2.67 13 9.71 9.92 9.38 9.67 2.82 0.60 0.62 0.61 0.61 1.64 6.13 6.25 6.52 6.30 3.15 14 11.94 11.5 10.86 11.42 4.78 1.87 1.73 1.61 1.73 7.50 15.58 15.04 14.73 15.11 2.84 15 9.48 10.76 10.62 10.27 6.97 1.39 1.57 1.39 1.45 7.04 14.67 14.57 13.03 14.07 6.66 16 11.45 11.06 11.69 11.40 2.80 1.63 1.72 1.59 1.65 4.02 14.24 15.55 13.6 14.44 6.82 17 11.9 12.68 10.09 11.50 11.83 1.16 1.22 1.08 1.15 6.19 9.74 9.58 10.66 9.98 5.75 18 12.24 14.69 12.03 12.93 11.10 2.29 2.15 2.15 2.20 3.64 19.00 15.00 18.00 17.25 12.43 19 na na na na na na na na na na na na na na na GM 10.41 GM 1.09 GM 10.49 Ove rall Ove rall Ove rall GCV (%) 13.91 GCV (%) 50.82 GCV (%) 42.03

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Table 2B. PTS-2 sample: Individual results reported by the participating laboratories

Total PRP - µg / shd (shd - 0.5 ml) Free PRP - µg / shd (shd - 0.5 ml) Free PRP - % of Total PRP Lab Run 1 Run 2 Run 3 GM GCV% Run 1 Run 2 Run 3 GM GCV% Run 1 Run 2 Run 3 GM GCV% 1 9.17 5.48 5.23 6.41 31.93 3.67 3.61 3.69 3.66 1.14 40.46 65.88 70.60 57.31 31.05 2 3.53 4.57 3.81 3.95 13.32 0.79 0.96 1.02 0.92 13.41 22.38 20.79 26.77 23.18 13.06 3 6.41 4.36 5.45 5.34 19.53 1.69 1.60 1.13 1.45 22.09 26.37 36.70 20.73 27.17 29.28 4 6.17 5.82 5.92 5.97 3.00 3.24 3.26 3.29 3.26 0.77 52.45 56.03 55.51 54.64 3.57 5 5.12 5.16 5.16 5.14 0.42 3.04 3.10 3.14 3.09 1.63 59.23 60.57 60.86 60.22 1.45 6 4.99 5.06 5.53 5.19 5.58 0.92 1.12 1.12 1.05 11.39 18.44 22.13 20.25 20.22 9.14 7 5.82 5.32 5.56 5.57 4.49 3.55 3.75 3.72 3.67 2.96 60.90 70.37 66.83 65.92 7.33 8 6.49 5.90 6.03 6.13 5.00 2.86 2.85 2.93 2.88 1.51 44.14 48.35 48.55 46.97 5.39 9 5.51 4.92 5.50 5.30 6.49 1.46 1.34 1.47 1.42 5.16 26.43 27.21 26.68 26.77 1.48 10 6.70 6.77 6.94 6.80 1.80 3.54 3.60 3.42 3.52 2.62 52.83 53.18 49.25 51.72 4.26 11 5.44 5.57 5.81 5.60 3.33 3.10 2.89 3.19 3.05 5.09 57.00 52.00 55.00 54.63 4.63 12 5.15 4.91 4.89 4.98 2.88 2.69 2.55 2.56 2.60 2.98 52.03 52.01 52.30 52.11 0.31 13 5.70 5.42 5.33 5.48 3.49 1.24 1.33 1.29 1.29 3.51 21.71 24.55 24.06 23.41 6.60 14 6.52 6.24 5.49 6.07 8.95 3.7 3.41 3.18 3.42 7.59 56.75 54.48 57.92 56.37 3.12 15 5.27 6.14 5.82 5.73 7.76 2.95 3.69 3.17 3.26 11.46 55.97 60.06 54.36 56.75 5.13 16 6.34 6.23 7.07 6.54 6.86 3.78 3.60 3.72 3.70 2.49 59.62 57.78 52.62 56.59 6.50 17 6.41 6.83 5.36 6.17 12.62 3.75 3.73 3.27 3.57 7.78 58.41 54.59 60.86 57.90 5.49 18 9.06 8.38 8.66 8.70 3.92 4.80 4.67 4.83 4.77 1.80 53.00 56.00 56.00 54.98 3.18 19 6.60 7.12 6.59 6.77 4.43 3.47 3.78 3.81 3.68 5.19 52.64 53.16 57.77 54.48 5.11 GM 5.76 GM 2.54 GM 44.08 Ove rall Ove rall Ove rall GCV (%) 16.23 GCV (%) 53.38 GCV (%) 41.42

Table 2C. PTS-3 sample: Individual results reported by the participating laboratories

Total PRP - µg / shd (shd - 0.5 ml) Free PRP - µg / shd (shd - 0.5 ml) Free PRP - % of Total PRP Lab Run 1 Run 2 Run 3 GM GCV% Run 1 Run 2 Run 3 GM GCV% Run 1 Run 2 Run 3 GM GCV% 1 11.29 8.63 8.28 9.31 16.95 1.27 1.13 1.08 1.16 8.57 11.25 13.10 13.00 12.42 8.59 2 5.65 6.67 5.41 5.89 11.08 0.33 0.29 0.40 0.34 16.29 5.84 4.20 7.39 5.66 28.96 3 7.99 6.42 6.90 7.07 11.18 1.17 1.08 0.89 1.04 14.45 14.64 16.82 12.90 14.7 13.33 4 8.51 8.02 8.35 8.29 3.03 1.21 1.10 1.12 1.14 5.07 14.17 13.70 13.40 13.75 2.81 5 7.11 7.19 7.15 7.15 0.60 0.78 0.77 0.75 0.77 2.00 11.02 10.66 10.50 10.72 2.47 6 7.67 7.56 7.88 7.70 2.10 0.21 0.21 0.20 0.21 2.82 2.74 2.78 2.54 2.68 4.85 7 8.01 7.25 7.88 7.71 5.35 1.92 2.59 2.64 2.36 18.00 24.03 35.69 33.49 30.62 21.48 8 9.87 8.58 8.45 8.94 8.58 1.35 1.16 1.23 1.24 7.66 13.63 13.41 14.50 13.84 4.12 9 7.41 7.49 7.68 7.53 1.84 0.57 0.56 0.56 0.56 1.02 7.62 7.47 7.26 7.45 2.43 10 9.28 9.37 9.51 9.39 1.23 1.23 1.25 1.24 1.24 0.81 13.16 13.29 12.99 13.15 1.15 11 7.86 7.76 8.33 7.98 3.78 0.98 0.97 1.15 1.03 9.48 13.00 12.00 14.00 12.97 7.72 12 6.81 7.22 6.71 6.91 3.88 1.09 1.12 1.05 1.09 3.24 15.95 15.50 15.55 15.67 1.57 13 7.71 7.93 7.77 7.80 1.45 0.58 0.59 0.57 0.58 1.72 7.57 7.37 7.29 7.41 1.94 14 8.72 8.31 8.13 8.38 3.59 1.88 1.73 1.75 1.79 4.51 21.56 20.82 21.53 21.30 1.98 15 6.94 8.37 7.74 7.66 9.43 1.34 1.59 1.43 1.45 8.65 19.33 18.99 18.38 18.90 2.56 16 8.56 8.87 8.63 8.69 1.86 1.66 1.76 1.76 1.73 3.38 19.39 19.84 20.39 19.87 2.52 17 8.97 9.45 7.80 8.71 9.95 1.16 1.32 1.12 1.20 8.45 12.89 13,91 14.39 13.72 5.64 18 11.42 10.46 10.56 10.80 4.82 2.44 2.29 2.41 2.38 3.36 11.42 10.46 10.56 10.80 4.82 19 9.45 9.84 9.89 9.72 2.49 1.71 1.97 1.92 1.86 7.55 18.04 20.00 19.45 19.15 5.34 GM 8.12 GM 1.04 GM 12.38 Ove rall Ove rall Ove rall GCV (%) 14.12 GCV (%) 69.84 GCV (%) 58.78

na (not applicable): laboratory 19 did not receive PTS-1 sample and therefore no results were reported. GM: Geometric Mean. For the calibration curve, Lab 1 and Lab 2 used the WHO 2nd IS for PRP GCV: Geometric Coefficient of Variation (defined by sqrt(eω -1)*100), with ω = Sample Variance of the ln- transformed results). GCVs for each Lab are single measures of Intra-Lab Precision. These measures should be used assuming a Log-Normal distribution. Grey shaded values indicate results that were declared non-valid according to the outcome of the system suitability test.

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Table 3A. Method precision for PTS-1 sample

Total PRP Free PRP VAR VAR S RSD VAR S RSD % of tot % of tot Component Estimate (µg/shd) (%) Estimate (µg/shd) (%) Inter-Lab 1.769 SLab=1.330 74 0.277 SLab=0.527 96 (between) Intra-Lab 0.630 SRun=0.794 26 7.6 0.013 SRun=0.114 4 9.4 (within) Reproducibility 2.400 SRepr=1.549 100 14.8 0.290 SRepr=0.539 100 44.5

Table 3B. Method precision for PTS-2 sample

Total PRP Free PRP VAR VAR S RSD VAR S RSD % of tot % of tot Component Estimate (µg/shd) (%) Estimate (µg/shd) (%) Inter-Lab 0.810 SLab=0.900 65 1.189 SLab=1.090 98 (between) Intra-Lab 0.430 SRun=0.656 35 11.2 0.027 SRun=0.165 2 5.8 (within) Reproducibility 1.240 SRepr=1.113 100 18.9 1.217 SRepr=1.103 100 38.6

Table 3C. Method precision for PTS-3 sample

Total PRP Free PRP VAR VAR S RSD VAR S RSD % of tot % of tot Component Estimate (µg/shd) (%) Estimate (µg/shd) (%) Inter-Lab 1.206 SLab=1.098 78 0.367 SLab=0.606 96 (between) Intra-Lab 0.346 SRun=0.588 22 7.2 0.015 SRun=0.0122 4 10.0 (within) Reproducibility 1.552 SRepr=1.246 100 15.2 0.382 SRepr=0.618 100 50.7

VAR: Variance; S: Standard Deviation; RSD: Relative Standard Deviation

SRun: Intra-Lab (or within Lab) S; it represents the “Variability among Runs + Repeatability of the Method” It is obtained by the pooled S within the 3 Runs results, per each of the N Labs.

SLab: Inter-Lab S; it represents the variability among the participating laboratories. It is obtained by

2 with Sb: standard deviation between laboratories, and Nrun: number of Runs (i.e., 3). 2 𝑆𝑆𝑅𝑅𝑅𝑅𝑅𝑅 �𝑆𝑆𝑏𝑏 − 𝑁𝑁𝑟𝑟𝑟𝑟𝑟𝑟 SRepr is the standard deviation of “Reproducibility”; it is obtained by + . 2 2 𝑅𝑅𝑅𝑅𝑅𝑅 𝐿𝐿𝐿𝐿𝐿𝐿 �𝑆𝑆 𝑆𝑆

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Table 4. Z-scores

PTS - 1 PTS - 2 PTS - 3 Lab Total PRP Free PRP* Total PRP Free PRP^ Total PRP Free PRP* 1 1.23 0.03 0.76 0.40 0.98 -0.10 2 -2.19 -1.49 -2.53 -1.88 -2.02 -1.45 3 -0.77 0.34 -0.66 -1.43 -0.98 -0.30 4 0.46 -0.09 0.18 0.08 0.09 -0.13 5 -1.02 -0.55 -0.92 -0.06 -0.91 -0.74 6 - 0.53 -1.13 -0.86 -1.77 -0.43 -1.66 7 -0.17 2.15 -0.36 0.42 -0.42 1.88 8 0.38 0.05 0.40 -0.24 0.66 0.03 9 -0.47 -1.18 -0.71 -1.46 -0.58 -1.09 10 1.44 0.10 1.29 0.29 1.05 0.03 11 -0.17 -0.26 - 0.31 -0.10 -0.19 -0.31 12 -1.13 -0.15 -1.14 -0.48 -1.12 -0.21 13 -0.59 -1.07 -0.47 -1.57 -0.34 -1.05 14 0.66 1.05 0.31 0.21 0.17 0.94 15 -0.16 0.51 -0.14 0.07 -0.47 0.38 16 0.64 0.89 0.94 0.44 0.44 0.84 17 0.71 -0.05 0.45 0.33 0.46 -0.03 18 1.73 1.93 3.83 1.33 2.29 1.91 19 na na 1.24 0.43 1.34 1.05

* interpretation of the Z-scores should be made carefully due to the high uncertainty of measurement associated with the consensus values. ^ interpretation of the Z-scores should be made carefully due to the bimodal distribution of data results “Light grey” cells indicate |Z| > 2 and < 3; “Dark grey” cell indicates |Z| > 3.

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FIGURES

Figure 1A. PTS-1 sample, descriptive plot for total PRP

Figure 1B. PTS-1 sample, descriptive plot for free PRP

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Figure 2A. PTS-2 sample, descriptive plot for total PRP

Figure 2B. PTS-2 sample, descriptive plot for free PRP

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Figure 3A. PTS-3 sample, descriptive plot for total PRP

Figure 3B. PTS-3 sample, descriptive plot for free PRP

The central horizontal lines represent the consensus values.

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Figures 4 A-F. Dot plots of geometric means by laboratories

4A. PTS-1 sample, total PRP

4B. PTS-1 sample, free PRP

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4C. PTS-2 sample, total PRP

4D. PTS-2 sample, free PRP

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4E. PTS-3 sample, total PRP

4F. PTS-3 sample, free PRP

The vertical lines (Figures 4 A-F) represent the consensus values; numbers in the boxes indicate the code number of the laboratory.

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Figure 5. Consensus Values for the six parameters; the error bars represent the Expanded Uncertainties (U; k=2)

Figures 6 A-F. “Size-Ordered” Histogram Plots of Z-scores

A)

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B)

C)

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D)

E)

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F)

The horizontal central line (at Z-score = 0) corresponds to the consensus values; the dotted lines represents the range from -2 to +2 and is considered a satisfactory Z-score. The solid line represents the range from -3 to +3 and is considered a questionable Z-score. A Z-score is considered unsatisfactory if it is outside the range from -3 to +3.

Figure 7. Youden Plot for PTS-1 sample, in µg/shd

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Figure 8. Youden Plot for PTS-2 sample, in µg/shd

Figure 9. Youden Plot for PTS-3 sample, in µg/shd

Note: Numbers in the graphs indicate the code number of the laboratory. ***

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RIFAMPICIN

RIFAMPICINUM

Draft proposal for revision for The International Pharmacopoeia

DRAFT FOR COMMENTS

Please send any comments you may have on this draft working document to Dr Herbert Schmidt, Technical Officer, Norms and Standards for Pharmaceuticals, Technical Standards and Specifications ([email protected]), with a copy to Ms Claire Vogel ([email protected]) by 29 January 2021.

Our working documents are sent out electronically and they will also be placed on the WHO Medicines website (https://www.who.int/teams/health-product-and-policy- standards/standards-and-specifications/pharmaceuticals/working-documents-public- consultation) for comments under the “Monographs and general texts under review/revision for inclusion in The International Pharmacopoeia”.

If you wish to receive our draft guidelines, please send your e-mail address to [email protected] and your name will be added to our electronic mailing list.

[Note from the Secretariat. Following the determination of traces of nitrosamines in some batches of rifampicin active pharmaceutical ingredient, it is proposed to revise the corresponding monograph.

Changes to the current chapter are indicated in the text by insert or delete.]

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RIFAMPICIN

RIFAMPICINUM

C43H58N4O12

Relative molecular mass. 822.9.

Chemical name. (2S,12Z,14E,16S,17S,18R,19R,20R,21S,22R,23S,24E)-5,6,9,17,19- pentahydroxy-23-methoxy-2,4,12,16,18,20,22-heptamethyl-8-[[(4-methylpiperazin-1- yl)imino]methyl]-1,11-dioxo-1,2-dihydro-2,7- (epoxypentadeca[1,11,13]trienimino)naphtho[2,1-b]furan-21-yl acetate; 3-[[(4-methyl-1- piperazinyl)imino]methyl]rifamycin; CAS Reg. No. 13292-46-1.

Other name. Rifampin.

Description. A brick-red to red-brown, crystalline powder.

Solubility. Very slightly to slightly soluble in water; soluble in methanol R; slightly soluble in acetone R, ethanol (~750 g/L) TS, and ether R.

Category. Antileprosy drug; antituberculosis drug.

Storage. Rifampicin should be kept in a tightly closed container or in an atmosphere of nitrogen, protected from light.

Additional information. Rifampicin exhibits polymorphism.

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Requirements

Definition. Rifampicin contains not less than 97.0% and not more than 102.0% of

C43H58N4O12, calculated with reference to the dried substance.

Manufacture. The production method is validated to demonstrate to the satisfaction of the responsible regulatory authority that the probably carcinogenic nitrosamine 1-nitroso-4- methyl piperazine (MeNP) is eliminated or minimized and adequately controlled in the final product.

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

B. Dissolve 50 mg in 50 mL of methanol R and dilute 1 mL of this solution to 50 mL with phosphate buffer, pH 7.4, TS. The absorption spectrum of the resulting solution, when observed between 220 nm and 500 nm, exhibits 4 maxima at about 237 nm, 254 nm, 334 nm and 475 nm; the ratio of the absorbance of a 1 cm layer at the maximum at about 334 nm to that at the maximum at about 475 nm is about 1.75.

C. Suspend 25 mg in 25 mL of water, shake for 5 minutes and filter. To 5 mL of the filtrate, add 1 mL of ammonium persulfate/phosphate buffer TS and shake for a few minutes; the colour turns from orange-yellow to violet-red without the formation of a precipitate.

Heavy metals. Place 1.0 g in a silica crucible and mix it with 4 mL of magnesium sulfate/sulfuric acid TS. Heat cautiously to ignition and continue heating until a white or, at most, greyish residue is obtained. Ignite at a temperature not exceeding 800 °C, allow to cool, and moisten the residue with a few drops of sulfuric acid (~100 g/L) TS. Evaporate, ignite again, and allow to cool. Next, dissolve the residue in hydrochloric acid (~70 g/L) TS, add, drop by drop, a solution of ammonia (~100 g/L) PbTS, until the pH of the solution is between 8 and 8.5, then add, also drop by drop, acetic acid (~60 g/L) PbTS to adjust the pH to 3–4, filter, dilute with water to 40 mL and mix. Determine the heavy metals content as described under 2.2.3 Limit test for heavy metals, according to Method A; not more than 20 μg/g.

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Sulfated ash. Not more than 1.0 mg/g.

Loss on drying. Dry at 60 °C under reduced pressure (not exceeding 0.6 kPa or about 5 mm of mercury) for 4 hours; it loses not more than 10 mg/g. pH value. Shake 0.10 g with 10 mL of carbon-dioxide-free water R; pH of the suspension, 4.5–6.5.

Related substances

Carry out the test as described under 1.14.1 Thin-layer chromatography, using silica gel R1 as the coating substance and preparing the slurry with phosphate/citrate buffer pH 6.0, TS. As the mobile phase, use a mixture of 85 volumes of chloroform R and 15 volumes of methanol R. Apply separately to the plate 20 μl of each of 4 solutions in chloroform R containing (A) 20 mg of the test substance per mL, (B) 0.10 mg of 3-formylrifamycin SV RS per mL, (C) 0.30 mg of rifampicin quinone RS per mL and (D) 0.20 mg of the test substance per mL. After removing the plate from the chromatographic chamber, allow it to dry in air and examine the chromatogram in daylight. Any coloured spots obtained with solution A, other than the principal spot, are not more intense than the corresponding spots obtained with solutions B and C. Any other spots obtained with solution A are not more intense than that obtained with solution D.

Assay

Dissolve about 0.10 g, accurately weighed, in sufficient methanol R to produce 100 mL. Dilute 2 mL of this solution to 100 mL with phosphate buffer, pH 7.4, TS. Measure the absorbance of the resulting solution in a 1 cm layer at the maximum at about 475 nm, using as the blank phosphate buffer, pH 7.4, TS. Calculate the content of C43H58N4O12, using the absorptivity value of 18.7 ( = 187).

***

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DOLUTEGRAVIR SODIUM DOLUTEGRAVIRUM NATRICUM

Draft proposal for inclusion in The International Pharmacopoeia

DRAFT FOR COMMENTS

Please send any comments you may have on this draft working document to Dr Herbert Schmidt, Technical Officer, Norms and Standards for Pharmaceuticals, Technical Standards and Specifications ([email protected]), with a copy to Ms Claire Vogel ([email protected]) by 28 February 2021.

Our working documents are sent out electronically and they will also be placed on the WHO Medicines website (https://www.who.int/teams/health-product-and-policy- standards/standards-and-specifications/pharmaceuticals/current-projects) for comments under the “Working documents in public consultation” link.

If you wish to receive our draft guidelines, please send your e-mail address to [email protected] and your name will be added to our electronic mailing list.

[Note from the Secretariat. The monograph on Dolutegravir sodium is proposed for inclusion in The International Pharmacopoeia.

Being one of the first public standard on Dolutegravir sodium, the monograph is expected to play an important role in ensuring access to quality assured dolutegravir products worldwide. Manufacturers are therefore invited to provide their feed-back on the draft monograph to help ensure that the proposed standard adequately controls the products they manufacture.]

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DOLUTEGRAVIR SODIUM DOLUTEGRAVIRUM NATRICUM

Molecular formula. C20H18F2N3NaO5

Relative molecular mass. 441.37

Graphic formula

Chemical name. (4R,12aS)-N-[(2,4-Difluorophenyl)methyl] -7-hydroxy-4-methyl-6,8- dioxo-3,4,6,8,12,12a-hexahydro-2-H-pyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazine-9- carboxamide sodium salt (IUPAC), 2H-Pyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazine-9- carboxamide, N-[(2,4-difluorophenyl)methyl]-3,4,6,8,12,12a-hexahydro-7-hydroxy-4-methyl- 6,8-dioxo-, sodium salt (1:1), (4R,12aS) (CAS); 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 strand-transfer inhibitor).

Storage. Dolutegravir sodium should be kept in a tightly closed container and protected from light.

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.

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Identity tests Either tests A, D and E or tests B, D and E or tests C, D and E 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 tests specified in B.1 or, where a diode array detector is available, test B.2. B.1 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). 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 a maximum at about 258.

B.2 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 and the UV spectrum of the principal peak in the chromatogram obtained with solution (1) corresponds to the retention time and the UV spectrum of the peak due to dolutegravir in the chromatogram obtained with solution (2).

C. 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 volumes of glacial acetic acid R as the mobile phase. Apply separately to the plate 5 μL of each of the following two test 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).

The principal spot obtained with solution (A) corresponds in position, appearance and intensity with the spot due to dolutegravir obtained with solution (B). After drying, spray the plate with basic potassium permanganate (5 g/L) TS. Examine the chromatogram in daylight. The principal spot obtained with solution (A)

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corresponds in position, appearance and intensity with the spot due to dolutegravir obtained with solution (B).

D. Carry out test D.1 or, where HPLC and the indicated chiral columns are available, test D.2. D.1 Determine the specific optical rotation (1.4) using a 2 mg/mL solution in a mixture of 9 volumes of methanol R and one volume of formic acid (~1080 g/L) TS and calculate with reference to the anhydrous substance; [ ] = –85 to –93. 25 𝐷𝐷 D.2 Carry out the test as described under 1.14.4 High-performance𝛼𝛼 liquid chromatography using the conditions and solutions given under “Impurity A (dolutegravir enantiomer), impurity B and G.” The retention time of the principal peak due to dolutegravir obtained with solution (2) correspond to the retention time of the corresponding peak in the chromatogram obtained with solution (3).

E. The test substance yields reaction A as described under 2.1 General identification tests as characteristic of sodium.

Heavy metals. Use 0.5 g for the preparation of the test solution as described under 2.2.3 Limit test for heavy metals, Procedure 5; determine the heavy metals content according to Method C; not more than 20 μg/g.

Water. Determine, as described under 2.8 Determination of water by the Karl Fischer method, Method A, using 0.300 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), impurity B and G (dolutegravir diastereomers). Perform the test in subdued light and without any prolonged interruptions, 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 particles of silica gel, the surface of which has been modified with cellulose tris (4-chloro-3-methylphenyl carbamate) (5 µm).1 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 spectrophotometer set at a wavelength of 258 nm. Maintain the column temperature at 25 °C.

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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), dissolve 5 mg of the test substance in 1 mL acetonitrile R. Add 4.5 mL water R and 4.5 mL hydrochloric acid (~ 420 g/L) TS and boil the solution under a reflux for 1 hour. Cool the solution to room temperature and dilute 1 mL of it to 10 mL with a mixture of 6 volumes of water R and 4 volumes of acetonitrile R. For solution (4) dilute 2 mg of dolutegravir impurity D RS in 5 mL of acetonitrile R. Dilute 1 mL of this solution to 10 mL. For solution (5) dilute 2 mg of dolutegravir impurity B RS in 5 mL of acetonitrile R. Dilute 1 mL of this solution to 10 mL. For solution (6) mix 1 mL of solution (4) with 1.0 mL of solution (5).

Inject 15 µL of solution (3) and (6). Record the chromatogram for about 45 minutes. Use the chromatogram obtained with solution (3) to identify the peak due to impurity H (the chromatogram usually shows two principal peaks: the peak due to dolutegravir and the peak due to impurity H).

The impurities are eluted at the following relative retentions with reference to dolutegravir (retention time about 22 minutes): impurity H and impurity G: about 0.41; impurity A: about 0.72, impurity F: about 0.88; impurity D: about 1.27 and impurity B: about 1.39; impurity C: 1.62.

The test is not valid unless, in the chromatogram obtained with solution (6), 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).

In the chromatogram obtained with solution (1): • 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%).

Measure the area of the peak corresponding to impurity H and impurity G obtained in the chromatograms of solution (1) (impurity H and impurity G co-eluate) and the area of the peak corresponding to dolutegravir obtained in the chromatograms of solution (2) and calculate the percentage content of the sum of impurity H and impurity G. Subtract the percentage content of impurity H determined using the method described under Related substances. The percentage content of impurity G is not greater than 0.15%.

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Related substances. Perform the test in subdued light and without any prolonged interruptions, 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 particles of silica gel, the surface of which has been modified with chemically-bonded octadecylsilyl and pentafluorophenyl groups (5 µm).2

Use the following conditions for gradient elution: • mobile phase A: 0.186 g of disodium edetate R in 1000 mL water R adjusted to pH 2.0 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) 0–2 60 40 Isocratic 2–32 60 to 50 40 to 50 Linear gradient 32–56 50 to 20 50 to 80 Linear gradient 56–62 20 80 Isocratic Return to initial 62–63 20 to 60 80 to 40 composition 63–70 60 40 Re-equilibration

Operate at a flow rate of 1.0 mL per minute. As a detector, use an ultraviolet spectrophotometer set at a wavelength of 258 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), 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) dilute 2 mg of dolutegravir impurity D RS in 5 mL of acetonitrile R. Dilute 1 mL of this solution to 10 mL. For solution (5), dissolve 5 mg of the test substance in 1 mL acetonitrile R. Add 4.5 mL water R and 4.5 mL hydrochloric acid (~ 420 g/L) TS and boil the solution under a reflux for 1 hour. Cool the solution to room temperature and dilute 1 mL of it to 10 mL with a mixture of 6 volumes of water R and 4 volumes of acetonitrile R. For solution (6) mix 1 mL of solution (4) with 1 mL of solution (5).

Inject alternately 10 µL each of solutions (1), (2), (3), (4), (5) and (6).

Use the chromatogram obtained with solution (4) and the chromatogram supplied with dolutegravir impurity D RS to identify the peak due to impurity D. Use the chromatogram obtained with solution (5) to identify the peak due to impurity H (the chromatogram usually shows two principal peaks: the peak due to dolutegravir and the peak due to impurity H).

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The impurities, if present, are eluted at the following relative retentions with reference to dolutegravir (retention time about 30 minutes): impurity C about 0.66; impurity F about 0.70; impurity D about 0.74; impurity H about 0.78; impurity E about 0.89; impurity J about 1.75; impurity K about 1.77; impurity L about 2.10.

The test is not valid unless, in the chromatogram obtained with solution (6), the resolution factor between the peaks due to impurity D and due to impurity H is at least 1.5. 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.

In the chromatogram obtained with solution (1): • the area of any peak corresponding to either impurities C, D, E, F, H, J, K or L 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%).

Assay. Perform the assay in subdued light and without any prolonged interruptions, 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 (25 cm x 4.6 mm) packed with particles of silica gel, the surface of which has been modified with chemically-bonded octadecylsilyl and pentafluorophenyl groups (5 µm).3 B. Use the following mobile phase: Dissolve 0.186 g of disodium edetate R in 1000 mL water R and adjust to pH 2.0 with phosphoric acid (~20 g/L) TS. Mix 420 volumes of this solution with 580 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 40 °C.

Prepare the following solutions using as the diluent a mixture of 60 volumes of water R and 40 volumes of acetonitrile R.

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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 25 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.

Impurities

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,12aS)-N-benzyl-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; desfluoro dolutegravir (synthesis-related impurity).

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CH3 O OH O F N H N N O H O D. (4R,12aS)-N-[(2-fluorophenyl)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; (2-fluoro dolutegravir) (synthesis-related impurity).

CH3 O OH O F N H N N O H O E. (4R,12aS)-N-[(4-fluorophenyl)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 (4-fluoro dolutegravir) (synthesis-related impurity).

CH3 O OH O F N H N N O H O F F. (4R,12aS)-N-[(2,6-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 (2,6-difluoro dolutegravir) (synthesis-related impurity).

CH3 O OH O F F N H N N O H O G. (4S,12aS)-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 F F N H N N HO O H. N-[(2,4-difluorophenyl)methyl]-9-hydroxy-2-[(2R)-4-hydroxybutan-2-yl]-1,8-dioxo- 2,8-dihydro-1H-pyrido[1,2-a]pyrazine-7-carboxamide (synthesis-related impurity, degradation product).

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CH3 O O O F F N H N N O H O J. (4R,12aS)-N-[(2,4-difluorophenyl)methyl]-4-methyl-6,8-dioxo-7-(phenylmethoxy)- 3,4,6,8,12,12a-hexahydro-2H-pyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazine-9- carboxamide (synthesis-related impurity).

F CH3 O OH O F F NH N H N N F O O O K (3R)-3-(7-{[(2,4-difluorophenyl)methyl]carbamoyl}-9-hydroxy-1,8-dioxo-1,8-dihydro- 2H-pyrido[1,2-a]pyrazin-2-yl)butyl [(2,4-difluorophenyl)methyl]carbamate (synthesis- related impurity). F

F

CH3 O HN O F F N H N N O H O L 4R,12aS)-N-[(2,4-difluorophenyl)methyl]-7-{[(2,4-difluorophenyl)methyl]amino}-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 (synthesis-related impurity).

International Chemical Reference Substances (ICRS) to be established: Dolutegravir sodium RS ICRS to be established.

Dolutegravir impurity D RS ICRS to be established.

Dolutegravir impurity B RS ICRS to be established.

***

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DOLUTEGRAVIR TABLETS DOLUTEGRAVIRI COMPRESSI

Draft proposal for inclusion in The International Pharmacopoeia

DRAFT FOR COMMENTS

Please send any comments you may have on this draft working document to Dr Herbert Schmidt, Technical Officer, Norms and Standards for Pharmaceuticals, Technical Standards and Specifications ([email protected]), with a copy to Ms Claire Vogel ([email protected]) by 28 February 2021.

Our working documents are sent out electronically and they will also be placed on the WHO Medicines website (https://www.who.int/teams/health-product-and-policy- standards/standards-and-specifications/pharmaceuticals/current-projects) for comments under the “Working documents in public consultation” link.

If you wish to receive our draft guidelines, please send your e-mail address to [email protected] and your name will be added to our electronic mailing list.

[Note from the Secretariat. The monograph on dolutegravir tablets is proposed for inclusion in The International Pharmacopoeia.]

Being one of the first public standard on Dolutegravir tablets, the monograph is expected to play an important role in ensuring access to quality assured dolutegravir products worldwide. Manufacturers are therefore invited to provide their feed-back on the draft monograph to help ensure that the proposed standard adequately controls the products they manufacture.]

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DOLUTEGRAVIR TABLETS

DOLUTEGRAVIRI COMPRESSI

Category. Antiretroviral (integrase strand-transfer 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.

Additional information. Strength in the current WHO Model List of Essential Medicines: 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 the tests as specified in A. 1, or where a diode array detector is available, test A.2. A1. 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 of 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 a maximum at about 258 nm.

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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 principal 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 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 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). The principal spot obtained with solution (A) corresponds in position, appearance and intensity with that obtained with solution (B).

After drying, spray the plate with basic potassium permanganate (5 g/L) TS. Examine the chromatogram in daylight. The principal spot obtained with solution (A) corresponds in position, appearance and intensity with that obtained with solution (B).

Dissolution. Carry out the test as described under 5.5 Dissolution test for 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 45 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 the filtered solution to 10.0 mL with dissolution medium. Use this solution as solution (1) Measure the absorbance as described under 1.6 Spectrophotometry in the visible and ultraviolet regions in a cuvette with an optical pathlength of 10 mm 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 using the absorptivity value of 54.0 for dolutegravir sodium ( = 540). Each mg of dolutegravir sodium is equivalent to 0.950 mg of dolutegravir. 1% 𝐴𝐴1 𝑐𝑐𝑐𝑐 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.

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Related substances. Perform the test in subdued light and without any prolonged interruptions, 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 particles of silica gel, the surface of which has been modified with chemically-bonded octadecylsilyl and pentafluorophenyl groups (5 µm).4

Use the following conditions for gradient elution: • mobile phase A: 0.186 g disodium edetate R in 1000 mL water R adjusted to pH 2.0 with phosphoric acid (~20 g/L) TS; • 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) 0–2 60 40 Isocratic 2–32 60 to 50 40 to 50 Linear gradient 32–56 50 to 20 50 to 80 Linear gradient 56–62 20 80 Isocratic Return to initial 62–63 20 to 60 80 to 40 composition 63–70 60 40 Re-equilibration

Operate at a flow rate of 1.0 mL per minute. As a detector, use an ultraviolet spectrophotometer set at a wavelength of 258 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.

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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) dilute 2 mg of dolutegravir impurity D RS in 5 mL of acetonitrile R. Dilute 1 mL of this solution to 10 mL. For solution (4), dissolve 5 mg of dolutegravir sodium RS in 1 mL acetonitrile R. Add 4.5 mL water R and 4.5 mL hydrochloric acid (~ 420 g/L) TS and boil the solution under reflux for 1 hour. Cool the solution to room temperature and dilute 1 mL of it to 10 mL with a mixture of 6 volumes of water R and 4 volumes of acetonitrile R. For solution (5) mix 1 mL of solution (3) with 1 mL of solution (4).

Inject alternately 10 µL of solutions (1), (2), (3), (4) and (5).

Use the chromatogram obtained with solution (3) and the chromatogram supplied with dolutegravir impurity D RS to identify the peak due to the impurity D. Use the chromatogram obtained with solution (4) to identify the peak due to impurity H (the chromatogram usually shows two principal peaks: the peak due to dolutegravir and the peak due to impurity H).

The impurities, if present, are eluted at the following relative retentions with reference to dolutegravir (retention time about 30 minutes): impurity C about 0.66; impurity F about 0.70; impurity D about 0.74; impurity H about 0.78; impurity E about 0.89; impurity J about 1.75; impurity K about 1.77; impurity L about 2.10.

The test is not valid unless in the chromatogram obtained with solution (5) the resolution factor between the peaks due to impurity D and due to impurity H is at least 1.5. 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.

In the chromatogram obtained with solution (1): • 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 times 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%).

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Assay. Perform the test in subdued light and without any prolonged interruptions, 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 particles of silica gel, the surface of which has been modified with octadecylsilyl and pentafluorophenyl groups (5 µm).5

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 (~20 g/L) TS. Mix 420 volumes of this solution with 580 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 40 °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), 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 53.0 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 chromatograms 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 impurities A, B and G.

International Chemical Reference Substances (ICRS) to be established: Dolutegravir sodium RS ICRS to be established.

Dolutegravir impurity D RS ICRS to be established.

Dolutegravir impurity B RS ICRS to be established.

***

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REMDESIVIR

REMDESIVIRUM

Draft proposal for inclusion for The International Pharmacopoeia

DRAFT FOR COMMENTS

Please send any comments you may have on this draft working document to Dr Herbert Schmidt, Technical Officer, Norms and Standards for Pharmaceuticals, Technical Standards and Specifications ([email protected]), with a copy to Ms Claire Vogel ([email protected]) by 28 February 2021.

Our working documents are sent out electronically and they will also be placed on the WHO Medicines website (https://www.who.int/teams/health-product-and-policy- standards/standards-and-specifications/pharmaceuticals/current-projects) for comments under the “Working documents in public consultation” link.

If you wish to receive our draft guidelines, please send your e-mail address to [email protected] and your name will be added to our electronic mailing list.

[Note from the Secretariat. It is proposed to include a monograph on Remdesivir in The International Pharmacopoeia. The draft monograph is based on information provided by manufacturers and on laboratory investigations.]

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REMDESIVIR

REMDESIVIRUM

Molecular formula. C27H35N6O8P

Relative molecular mass. 602.6

Graphic formula. N N NH O O 2 N H C P O 3 HN O CN H3C O CH3 HO OH O

Chemical name. 2-Ethylbutyl (2S)-2-{[(S)-{[(2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1- f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2- yl]methoxy}(phenoxy)phosphoryl]amino}propanoate or 2-Ethylbutyl N-{(S)-[2-C-(4- aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-2,5-anhydro-d-altrononitril-6-O- yl]phenoxyphosphoryl}-l-alaninate (IUPAC), l-Alanine, N-[(S)- hydroxyphenoxyphosphinyl]-, 2-ethylbutyl ester, 6-ester with 2-C-(4-aminopyrrolo[2,1- f][1,2,4]triazin-7-yl)-2,5-anhydro-d-altrononitrile (CAS); CAS Reg. No. 1809249-37-3.

Description. A white to off-white or yellow crystalline powder.

Solubility. It is soluble in ethanol (~750 g/L) TS and freely soluble in methanol R and dimethylsulfoxide R. It is practically insoluble in water R.

Category. Antiviral.

Storage. Remdesivir should be kept in tightly closed containers, protected from light and moisture.

Additional information. Remdesivir exhibit polymorphism.

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Requirements

Definition. Remdesivir contains not less than 97.0% and not more than 102.0% (“Assay”. Method A) and not less than 98.0% and not more than 101.0% (“Assay”. Method B) of

C17H35N6O8P, calculated with reference to the anhydrous substance.

Identity tests • Either test A alone or any two of tests B, C and D may be applied.

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

If the spectra thus obtained are not concordant repeat the test using the residues obtained by separately dissolving the test substance and remdesivir RS in a small amount of methanol R and evaporating to dryness. The infrared absorption spectrum is concordant with the spectrum obtained from remdesivir 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 remdesivir in the chromatogram obtained with solution (2).

C. The absorption spectrum (1.6) of a 0.03 mg per mL solution of the test substance in methanol R, when observed between 220 nm and 400 nm, exhibits a maximum at about 245 nm and at about 275 nm. Where high-performance liquid chromatography with a diode array detector is available, the spectrum may be recorded with this detector and compared with the spectrum of the reference solution.

D. Carry out the test as described under 1.14.1 Thin-layer chromatography using silica gel R6 as the coating substance and a freshly prepared mixture of ethyl acetate R, methanol R and glacial acetic acid R (90:9:1 V/V/V) as the mobile phase. Apply separately to the plate 2 µL of each of the following two solutions in methanol R, containing (A) 1 mg of the test substance per mL and (B) 1 mg of remdesivir RS per mL. After removing the plate from the chromatographic chamber allow it to dry in air or in a current of air. Examine the chromatogram under ultraviolet light (254 nm). The principal spot in the chromatogram obtained with solution (A) corresponds in position, appearance and intensity with the spot due to remdesivir in the chromatogram obtained with solution (B).

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Specific optical rotation (1.4). Use a 10 mg per mL solution of the test substance in methanol R and sonicate until the substance is dissolved. Calculate with reference to the anhydrous substance; the specific optical rotation [ ] is between -18.0 to -25.0. 20 𝛼𝛼 𝐷𝐷 Sulfated ash (2.3). Not more than 1.0 mg/g, determined on 1.0 g.

Water. Determine as described under 2.8 Determination of water by the Karl Fischer method, Method A. Use 200 mg of the test substance. The water content is not more than 50 mg/g.

Clarity and colour of the solution. A solution, containing 0.20 g of remdesivir in 20 mL of methanol R, is clear and not more intensely coloured than reference solution Y2, when compared as described under 1.11.2 Degree of coloration of liquids, Method II.

Heavy metals. Use 0.30 g for the preparation of the test solution as described under 2.2.3 Limit test for heavy metals, Procedure 5; determine the heavy metals content according to Method C; not more than 10 μg/g.

Related substances. Carry out the test as described under 1.14.4 High-performance liquid chromatography, using a stainless steel column (4.6 mm x 15 cm) packed with particles of silica gel, the surface of which has been modified with chemically-bonded octadecylsilyl groups (3 µm).6

Use the following conditions for gradient elution: mobile phase A: phosphoric acid solution; mobile phase B: use acetonitrile R.

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Prepare the phosphoric acid solution by diluting 1.2 mL of phosphoric acid (~1440 g/L) TS to 1000 mL with water R.

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

0–3 97 3 Isocratic

3–45 97 to 30 3 to 70 Linear gradient

45–53 30 70 Isocratic

53–54 30 to 97 70 to 3 Return to initial composition

54–65 97 3 Re-equilibration

Operate with a flow rate of 1.0 mL per minute. As a detector, use an ultraviolet spectrophotometer set at a wavelength of 237 nm. Maintain the column temperature at 30 °C.

Prepare as a diluent a mixture of 50 volumes of methanol R and 50 volumes of water R. Prepare the following solutions: For solution (1), dissolve 25.0 mg of the test substance in 5 mL of methanol R and dilute to 50.0 mL with the diluent. For solution (2), dilute

1.0 mL of test solution (1) to 100.0 mL with the diluent[1.0%]. For solution (3), dilute 1.0 mL of solution (2) to 10.0 mL with the diluent. For solution (4), dissolve 5 mg of remdesivir for system suitability RS (containing remdesivir and impurity A) in 1 mL of methanol R and dilute to 10 mL with the diluent.

Inject alternately 5 µL each of solutions (1), (2), (3) and (4).

The impurities are eluted, if present, at the following relative retentions with reference to remdesivir (retention time about 28 minutes): impurity E about 0.18; impurity G about 0.46; impurity H about 0.51; impurity C and impurity D about 0.84; impurity A about 0.98; impurity B about 1.03 and impurity F about 1.30.

The test is not valid unless, in the chromatogram obtained with solution (4), the resolution between the peaks due to impurity A and remdesivir is at least 1.5 Also, the test is not valid unless in the chromatogram obtained with solution (3), the peak due to remdesivir is obtained with a signal-to-noise ratio of at least 25.

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In the chromatogram obtained with solution (1): • the area of any peak corresponding to impurity E, when multiplied with a correction factor of 0.5, is not greater than 1.5 times the area of the peak due to remdesivir in the chromatogram obtained with solution (3) (0.15 %); • the area of any peak corresponding to impurity F, when multiplied with a correction factor of 1.2, is not greater than 1.5 times the area of the peak due to remdesivir in the chromatogram obtained with solution (3) (0.15 %); • the area of any peak corresponding to impurity G, when multiplied with a correction factor of 0.8, is not greater than 1.5 times the area of the peak due to remdesivir in the chromatogram obtained with solution (3) (0.15 %); • the area of any peaks corresponding to impurities A, B or H is not greater than 1.5 times the area of the peak due to remdesivir in the chromatogram obtained with solution (3) (0.15 %); • the sum of the areas of any peaks corresponding to impurities C and D (impurity C and D co-elute) is not greater than 1.5 times the area of the peak due to remdesivir in the chromatogram obtained with solution (3) (0.15 %); • the area of any other impurity peak is not greater than the area of the peak due to remdesivir in the chromatogram obtained with solution (3) (0.10 %). • The sum of the areas of all impurity peaks, including the corrected areas of any peaks corresponding to impurities E, F and G, is not greater than twice the area of the peak due to remdesivir in the chromatogram obtained with solution (2) (2.0%). Disregard all peaks with an area of less than 0.5 times the area of the peak due to remdesivir in the chromatogram obtained with solution (3) (0.05%).

Assay • Either test A or test B may be applied.

A. Carry out the test as described under 1.14.4 High-performance liquid chromatography, using a stainless steel column (4.6 mm x 25 cm) packed with end-capped particles of silica gel, the surface of which has been modified with chemically-bonded octadecylsilyl groups (5 µm).7

Prepare a phosphoric acid solution by diluting 1.2 mL of phosphoric acid (~1440 g/L) TS to 1000 mL with water R. As the mobile phase, use a mixture of 35 volumes of the phosphoric acid solution and 65 volumes of methanol R.

Operate with a flow rate of 1.0 mL per minute.

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As a detector, use an ultraviolet spectrophotometer set at a wavelength of 237 nm. Maintain the column temperature at 25 °C.

Prepare as a diluent a mixture of 50 volumes of methanol R and 50 volumes of water R. Prepare the following solutions: For solution (1), dissolve 40.0 mg of the test substance in 10 mL of methanol R, dilute to 200.0 mL with the diluent. For solution (2), dissolve 40.0 mg of remdesivir RS in 10 mL of methanol R and dilute to 200.0 mL with the diluent.

Inject alternately 5 µL each of solutions (1) and (2) and record the chromatogram for 25 minutes.

Measure the areas of the peaks corresponding to remdesivir obtained in the chromatograms of solutions (1) and (2) and calculate the percentage content of

C17H35N6O8P in the sample using the declared content of C17H35N6O8P in remdesivir RS.

B. Dissolve 0.400 g in 50 mL of glacial acetic acid R1 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 60.26 mg of C17H35N6O8P.

Impurities

A. 2-Ethylbutyl (2S)-2-{[(R)-{[(2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin- 7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2- yl]methoxy}(phenoxy)phosphoryl]amino}propanoate (remdesivir diastereomer) (synthesis related impurity),

N

N NH2 O O N H C P O 3 HN O CN H3C O CH3 HO OH O B. 2-Ethylbutyl (2S)-2-{[(S)-{[(2R,3S,4R,5S)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin- 7-yl)-5-cyano-3,4-dihydroxytetrahydrofuran-2- yl]methoxy}(phenoxy)phosphoryl]amino}propanoate (remdesivir diastereomer) (synthesis related impurity),

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N

N NH2 O O N P O HN O CN H3C O CH3 HO OH O C. Butyl (2S)-2-{[(S)-{[(2R,3S,4R,5S)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5- cyano-3,4-dihydroxytetrahydrofuran-2- yl]methoxy}(phenoxy)phosphoryl]amino}propanoate (synthesis related impurity),

N

N NH2 O O N P O HN O CN H3C O CH3 HO OH O D. Butyl (2S)-2-{[(S)-{[(2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5- cyano-3,4-dihydroxytetrahydrofuran-2- yl]methoxy}(phenoxy)phosphoryl]amino}propanoate (synthesis related impurity),

N

N NH2 N O HO CN HO OH E. (2R,3R,4S,5R)-2-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-3,4-dihydroxy-5- (hydroxymethyl)tetrahydrofuran-2-carbonitrile (synthesis related impurity, degradation product),

N

N NH2 O O N H C P O 3 HN O CN H C O 3 CH 3 O O O H3C CH3 F. 2-Ethylbutyl (2S)-2-{[(S)-{[(3aR,4R,6R,6aR)-6-(4-aminopyrrolo[2,1- f][1,2,4]triazin-7-yl)-6-cyano-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4- yl]methoxy}(phenoxy)phosphoryl]amino}propanoate (synthesis related impurity),

N

N NH2 O O N P O HO O CN HO OH G. [(2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4- dihydroxytetrahydrofuran-2-yl]methyl phenyl hydrogenphosphate (synthesis related impurity, degradation product),

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N

N NH2 N O HO CN

O O H3C CH3 H. (3aR,4R,6R,6aR)-4-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-6-(hydroxymethyl)- 2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carbonitrile (synthesis related impurity).

Reference substances to be established Remdesivir for system suitability RS (containing remdesivir and impurity A) • New International Chemical Reference Substance to be established.

Remdesivir RS • New International Chemical Reference Substance to be established.

***

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REMDESIVIR INTRAVENOUS INFUSION

REMDESIVIRI INFUSIO INTRAVENO

Draft proposal for inclusion for The International Pharmacopoeia

DRAFT FOR COMMENTS

Please send any comments you may have on this draft working document to Dr Herbert Schmidt, Technical Officer, Norms and Standards for Pharmaceuticals, Technical Standards and Specifications ([email protected]), with a copy to Ms Claire Vogel ([email protected]) by 28 February 2021.

Our working documents are sent out electronically and they will also be placed on the WHO Medicines website (https://www.who.int/teams/health-product-and-policy- standards/standards-and-specifications/pharmaceuticals/current-projects) for comments under the “Working documents in public consultation” link.

If you wish to receive our draft guidelines, please send your e-mail address to [email protected] and your name will be added to our electronic mailing list.

[Note from the Secretariat. It is proposed to include a monograph on Remdesivir intravenous infusion in The International Pharmacopoeia. The draft monograph is based on information provided by manufacturers and on laboratory investigations.]

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REMDESIVIR INTRAVENOUS INFUSION

REMDESIVIRI INFUSIO INTRAVENO

Category. Antiviral.

Requirements The intravenous infusion comply with the monograph on Parenteral preparations.

Definition. Remdesivir intravenous infusion is a sterile solution containing Remdesivir. It is prepared by reconstituting Remdesivir powder for concentrate for solution for infusion and diluting it with suitable diluents according to the manufacturer’s instructions.

Remdesivir powder for concentrate for solution for infusion Description. A white or almost white amorphous powder or cake.

Storage. Remdesivir powder for concentrate for solution for infusion should be kept in sealed container, protected from moisture and light.

Manufacture. Remdesivir powder for concentrate for solution for infusion may contain solubilizing agents, like cyclodextrins. The production method is validated to ensure that the active pharmaceutical ingredient is fully dissolved before lyophilization.

Requirements The powder for concentrate for solution for infusion comply with the monograph for Parenteral preparations.

Definition. Remdesivir powder for concentrate for solution for infusion is a sterile material consisting of Remdesivir, with or without excipients. It is supplied in a sealed container and contains not less than 90.0% and not more than 110.0% of the labelled amount of remdesivir

(C17H35N6O8P) per vial.

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Identity tests • Any two of tests A, B and C may be applied.

A. Carry out as described under 1.6 Spectrophotometry in the visible and ultraviolet regions. Use the test solution as prepared for “Assay”, Method B. The absorption spectrum of the solution, when observed between 220 nm and 400 nm, exhibits a maximum at about 245 nm and at about 275 nm. Where high-performance liquid chromatography with a diode array detector is available, the spectrum may be recorded with this detector and compared with the spectrum of the reference solution.

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 remdesivir in the chromatogram obtained with solution (2).

C. Carry out as described under 1.14.1 Thin layer chromatography using silica gel R6 as the coating substance and a freshly prepared mixture of ethyl acetate R, methanol R and glacial acetic acid R (90:9:1 V/V/V) as the mobile phase. Apply separately to the plate 2 µL of each of the following two solutions. For solution (A), add 20 mL of methanol R to a vial and re-insert the stopper. Swirl the vial content gently and then mix well by repeated inversions. Transfer the dispersion into a 100 mL volumetric flask and add 60 mL of methanol R. Sonicate the flask for 15 minutes, dilute to volume with methanol R and filtrate the dispersion. For solution (2), use a solution containing 1 mg of remdesivir RS per mL of methanol. After removing the plate from the chromatographic chamber allow it to dry in air or in a current of air. Examine the chromatogram under ultraviolet light (254 nm). The principal spot in the chromatogram obtained with solution (A) corresponds in position, appearance and intensity with the spot due to remdesivir in the chromatogram obtained with solution (2).

Clarity and colour of the solution. A solution, containing 0.10 g of remdesivir in 20 mL of water R, is clear and not more intensely coloured than reference solution BY5, when compared as described under 1.11.2 Degree of coloration of liquids, Method I.

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Related substances. Carry out the test as described under 1.14.4 High-performance liquid chromatography, using a stainless steel column (4.6 mm x 15 cm) packed with particles of silica gel, the surface of which has been modified with chemically-bonded octadecylsilyl groups (3 µm).8

Use the following conditions for gradient elution: mobile phase A: dilute 1.2 mL of phosphoric acid (~1440 g/L) TS to 1000 mL with water R; mobile phase B: use acetonitrile R.

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

0–3 97 3 Isocratic

3–45 97 to 30 3 to 70 Linear gradient

45–53 30 70 Isocratic

53–54 30 to 97 70 to 3 Return to initial composition

54–65 97 3 Re-equilibration

Operate with a flow rate of 1.0 mL per minute. As a detector, use an ultraviolet spectrophotometer set at a wavelength of 237 nm. Maintain the column temperature at 30 °C.

Prepare as a diluent a mixture of 50 volumes of methanol R and 50 volumes of water R. Prepare the following solutions. For solution (1), gently remove the stopper from a vial and retain the stopper. Add 20 mL of water R to the vial and re-insert the stopper. Swirl the vial content gently and then mix well by repeated inversions until the content of the vial is fully dissolved. Transfer the solution into a 200 mL volumetric flask and dilute to volume with the diluent..

For solution (2), dilute 1.0 mL of solution (1) to 100.0 mL with the diluent. . For solution (3), dilute 1.0 mL of solution (2) to 10.0 mL with the diluent. For solution (4), dissolve 5 mg of remdesivir for system suitability RS (containing remdesivir and impurity A) in 1 mL of methanol R and dilute to 10 mL with the diluent. Inject alternately 5 µL each of solutions (1), (2), (3) and (4).

The impurities are eluted, if present, at the following relative retentions with reference to remdesivir (retention time about 28 minutes): impurity E about 0.18; impurity G about 0.46; impurity H about 0.51; impurity C and impurity D about 0.84; impurity A about 0.98; impurity B about 1.03 and impurity F about 1.30.

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The test is not valid unless in the chromatogram obtained with solution (4), the resolution between the peaks due to impurity A and remdesivir is at least 1.5. Also, the test is not valid unless in the chromatogram obtained with solution (3), the peak due to remdesivir is obtained with a signal-to-noise ratio of at least 15.

In the chromatogram obtained with solution (1): • the area of any peak corresponding to impurity E, when multiplied with a correction factor of 0.5, is not greater than the area of the peak due to remdesivir in the chromatogram obtained with solution (2) (1.0 %); • the area of any peak corresponding to impurity F, when multiplied with a correction factor of 1.2, is not greater than 2 times the area of the peak due to remdesivir in the chromatogram obtained with solution (3) (0.2 %); • the area of any peak corresponding to impurity G, when multiplied with a correction factor of 0.8, is not greater than 1.5 times the area of the peak due to remdesivir in the chromatogram obtained with solution (2) (1.5 %); • the area of any other impurity peak is not greater than the area of the peak due to remdesivir in the chromatogram obtained with solution (3) (0.2 %). • The sum of the areas of all impurity peaks, including the corrected areas of any peaks corresponding to impurities E, F and G, is not greater than three times the area of the peak due to remdesivir in the chromatogram obtained with solution (2) (3.0%). Disregard all peaks with an area of less than the area of the peak due to remdesivir in the chromatogram obtained with solution (3) (0.1%).

Assay • Either test A or test B may be applied.

A. Carry out the test as described under 1.14.4 High-performance liquid chromatography, using a stainless steel column (4.6 mm x 25 cm) packed with end- capped particles of silica gel, the surface of which has been modified with chemically-bonded octadecylsilyl groups (5 µm).9 Prepare a phosphoric acid solution by diluting 1.2 mL of phosphoric acid (~1440 g/L) TS to 1000 mL with water R. As the mobile phase, use a mixture of 35 volumes of the phosphoric acid solution and 65 volumes of methanol R. Operate with a flow rate of 1.0 mL per minute. As a detector, use an ultraviolet spectrophotometer set at a wavelength of 237 nm. Maintain the column temperature at 25 °C.

Prepare as a diluent a mixture of 50 volumes of methanol R and 50 volumes of water R.

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Prepare the following solutions. For solution (1), gently remove the stoppers from 10 vials and retain the stoppers. Add 20 mL of water R to each vial and re-insert the stoppers. Swirl the vial contents gently and then mix well by repeated inversions until the contents of the vials are fully dissolved. Transfer the solutions into a single 500 mL volumetric flask. Add 10 mL of water R to each vial, re-insert the stoppers, mix and transfer the rinses to the volumetric flask. Dilute to volume with water R. Dilute 5.0 mL of this solution to 50.0 mL with the diluent. For solution (2), weigh 40.0 mg of remdesivir RS into a 200 mL volumetric flask. Dissolve with 10 mL of methanol R and make up to volume with water R.

Inject alternately 5 µL each of solutions (1) and (2) and record the chromatogram for 25 minutes.

Measure the areas of the peaks corresponding to remdesivir obtained in the chromatograms of solutions (1) and (2) and calculate the percentage content of

C17H35N6O8P per container, using the declared content of C17H35N6O8P in remdesivir RS.

B. Prepare solution (1) as described under “Assay”, Method A. Dilute 3.0 mL of this solution to 20.0 mL with a mixture of 50 volumes of methanol R and 50 volumes of water R. Measure the absorbance of the resulting solution as described under 1.6 Spectrophotometry in the visible and ultraviolet regions in a cuvette with an optical pathlength of 10 mm at the maximum at about 275 nm, using the diluent as the blank.

Calculate the percentage content of C17H35N6O8P per container using the absorptivity

value of 9.984 for remdesivir = 99.84. 1% 𝐴𝐴1 𝑐𝑐𝑐𝑐 Impurities The impurities limited by the requirements of this monograph include those listed in the monograph on Remdesivir.

Reference substances to be established Remdesivir for system suitability RS (containing remdesivir and impurity A) • International Chemical Reference Substance to be established.

Remdesivir RS • International Chemical Reference Substance to be established.

***

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WHO GUIDELINES ON THE TRANSFER OF TECHNOLOGY IN PHARMACEUTICAL MANUFACTURING

DRAFT FOR COMMENTS

Please send your comments to Dr Sabine Kopp, Team Lead, Norms and Standards for Pharmaceuticals, Technical Standards and Specifications ([email protected]), with a copy to Ms Claire Vogel ([email protected]) before 20 February 2021. Please use the attached “Table of Comments” document for this purpose.

Our working documents are sent out electronically and they will also be placed on the WHO Medicines website (https://www.who.int/teams/health-product-and-policy- standards/standards-and-specifications/pharmaceuticals/current-projects) for comments under the “Working documents in public consultation” link.

If you wish to receive all our draft guidelines, please send your email address to [email protected] and your name will be added to our electronic mailing list.

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WHO GUIDELINES ON THE TRANSFER OF TECHNOLOGY IN PHARMACEUTICAL MANUFACTURING

1. Introduction

1.1. Production and control procedures, validation and other related activities may be transferred from one site to another site prior to obtaining a marketing authorization. In some cases, this transfer takes place after the approval of, for example, a product, by a regulatory authority. This transfer can be, for example, from drug discovery to product development; to clinical trials; or to full-scale commercialization and commercial batch manufacturing; cleaning and validation.

1.2. A technology transfer, particularly one between different companies, has legal and economic implications. If such issues, which may include intellectual property rights, royalties, pricing, conflicts of interest and confidentiality agreements, are expected to impact on the open communication of technical matters in any way, they should therefore be addressed before and during the planning and execution of the transfer.

1.3. A technology transfer requires a planned approach by trained, knowledgeable personnel working within a quality system, with documentation, data and information covering all aspects of development, production and quality control (QC), as applicable.

1.4. A technology transfer takes place between a sending unit (SU) and a receiving unit (RU). In some cases, there may be a separate unit managing the project.

1.5. The technology transfer project should fulfil the following general principles and requirements. There should be: • a documented project plan covering the relevant aspects of the project; • a detailed risk management plan; • a comprehensive technical gap analysis, including due diligence performed covering technical and regulatory aspects; • similar capabilities between the SU and RU, including but not limited to, facilities and equipment; • an adequate number of adequately trained personnel with suitable qualifications and experience; and • effective process and product knowledge management.

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1.6. A technology transfer should include relevant documentation, data, information and knowledge from the SU in order to enable the RU to effectively perform the specified process or procedure in, for example, production and QC. A successful transfer of technology should result in proof that the RU can routinely reproduce the transferred product, process or procedure against a predefined set of specifications as agreed between the SU and RU.

1.7. This document should be read in conjunction with other WHO guidelines as referenced below (2-14), as well as other regulatory guidelines which include The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Q7, Q8, Q9, Q10 and Q11. This guideline does not intend to replace any of these guidelines.

1.8. This version of the guideline provides updated requirements and expectations reflecting current good practices (GxP) in the transfer of technology and replaces the previous version published (1).

2. Scope

2.1. This document provides guiding principles on technology transfer.

2.2. This guideline should be applied when transferring the technology of processes and procedures relating to active pharmaceutical ingredients (APIs), in-process bulk materials, finished pharmaceutical products (FPPs), process validation, cleaning procedure development and validation and analytical procedures.

2.3. The guideline applies to all pharmaceutical dosage forms and may be adapted on a case-by-case basis by using risk management principles. Particular attention should be given to certain complex formulations such as, for example, sterile products and metered dose aerosols.

2.4. Although this document focuses on pharmaceutical products, the principles can also be applied to the transfer of production, related processes and controls for other products such as biopharmaceutical products, vaccines, medical devices and vector control products.

2.5. Because each transfer project is unique, the provision of a comprehensive set of guidelines specific to a product or process is beyond the scope of this document.

2.6. This document does not provide guidance on any legal, financial or commercial considerations associated with technology transfer projects.

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2.7. This document addresses the following principal areas: • organization and management of the transfer; • transfer of development information in production, including but not limited to processing and packaging; • transfer of development information and analytical procedures; • documentation, premises, equipment; • personnel qualification and training; • quality management and risk management; • life cycle approach; • control strategy; and • qualification and validation.

3. Glossary

The definitions given below apply to the terms used in these guidelines. They have been aligned as far as possible with the terminology in related WHO guidelines and Good Practices and included in the WHO Quality Assurance of Medicines Terminology Database - List of Terms and related guideline https://www.who.int/docs/default-source/medicines/norms-and- standards/guidelines/mqa-terminology-sept-2020.pdf?sfvrsn=48461cfc_5 ), but may have different meanings in other contexts. acceptance criteria. Measurable terms under which a test result will be considered acceptable. active pharmaceutical ingredient (API). Any substance or mixture of substances intended to be used in the manufacture of a pharmaceutical dosage form and that, when so used, becomes an active ingredient of that pharmaceutical dosage form. Such substances are intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment or prevention of disease, or to affect the structure and function of the body.

ALCOA+. A commonly used acronym for “attributable, legible, contemporaneous, original and accurate that puts additional emphasis on the attributes of being complete, consistent, enduring and available – implicit basic ALCOA principles. bracketing. An experimental design to test the extremes of, for example, dosage strength. The design assumes that the extremes will be representative of all the samples between the extremes.

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change control. A formal system by which qualified representatives of appropriate disciplines review proposed or actual changes that might affect a validated status. The intent is to determine the need for action that would ensure that the system is maintained in a validated state. control strategy. A planned set of controls, derived from current product and process understanding that assures process performance and product quality. The controls can include parameters and attributes related to API and finished pharmaceutical product materials and components, facility and equipment operating conditions, in-process controls, finished product specifications and the associated methods and frequency of monitoring and control. corrective action. Any action to be taken when the results of monitoring at a critical control point indicate a loss of control. critical. Having the potential to impact on product quality or performance in a significant way. critical control point. A step at which control can be applied and is essential to prevent or eliminate a pharmaceutical quality hazard or to reduce it to an acceptable level. design qualification. Documented evidence that, for example, the premises, supporting systems, utilities, equipment and processes have been designed in accordance with the requirements of good manufacturing practices (GMP). design space. The multidimensional combination and interaction of input variables (e.g. material attributes) and process parameters that have been demonstrated to provide assurance of quality. drug master file. Detailed information concerning a specific facility, process or product submitted to the medicines regulatory authority, intended for incorporation into the application for marketing authorization.

finished pharmaceutical product (FPP). A product that has undergone all stages of production, including packaging in its final container and labelling. An FPP may contain one or more active pharmaceutical ingredients (APIs). gap analysis. The identification of the critical elements of a process which are available at the sending unit (SU) but are missing from the receiving unit (RU).

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good manufacturing practices (GMP). That part of quality assurance which ensures that pharmaceutical products are consistently produced and controlled to the quality standards appropriate to their intended use and as required by the marketing authorization. in-process control (IPC). Checks performed during production in order to monitor and, if necessary, to adjust the process to ensure that the product conforms to its specifications. The control of the environment or equipment may also be regarded as a part of in-process control. installation qualification (IQ). Documented verification that the installations (such as machines equipment and instruments, computer system components, measuring devices, utilities and manufacturing) used in a processor system are appropriately selected and correctly installed, in accordance with established specifications. intercompany transfer. A transfer of technology between the sites of different companies. intracompany transfer. A transfer of technology between sites of the same group of companies. operational qualification (OQ). Documented verification that the system or subsystem performs as intended over all anticipated operating ranges. performance qualification (PQ). Documented verification that the equipment or system performs consistently and reproducibly within defined specifications and parameters in its normal operating environment (i.e. in the production environment). process validation. The collection and evaluation of data, from the process design stage through to commercial production, which establishes scientific evidence that a process is capable of continuously delivering the finished pharmaceutical product meeting its predetermined specifications and quality attributes. qualification. Documented evidence that premises, systems or equipment are able to achieve the predetermined specifications when properly installed, and/or work correctly and lead to the expected results. qualification batches. Those batches produced by the receiving unit (RU) to demonstrate its ability to reproduce the product .

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quality assurance (QA). “Quality assurance” is a wide-ranging concept covering all matters that individually or collectively influence the quality of a product. It is the totality of the arrangements made with the objective of ensuring that pharmaceutical products are of the quality required for their intended use. quality control (QC). All measures taken, including the setting of specifications, sampling, testing and analytical clearance, to ensure that starting materials, intermediates, packaging materials and finished pharmaceutical products (FPP) conform with established specifications for identity, strength, purity and other characteristics. quality planning. Part of quality management, focused on setting quality objectives and specifying necessary operational processes and related resources to fulfil the quality objectives. quality policy. A brief statement that describes the organization’s purpose, overall intentions and strategic direction; provides a framework for quality objectives; and includes a commitment to meet applicable requirements. quality risk management (QRM). A systematic process for the assessment, control, communication and review of risks to the quality of the pharmaceutical product throughout the product’s life cycle. receiving unit (RU). The involved disciplines at an organization where a designated product, process or method is expected to be transferred. sending unit (SU). The involved disciplines at an organization from where a designated product, process or method is expected to be transferred. standard operating procedure (SOP). An authorized written procedure giving instructions for performing operations, not necessarily specific to a given product or material , but of a more general nature (for example, operation of equipment, maintenance and cleaning, validation, cleaning of premises and environmental control, sampling and inspection). Certain standard operating procedures may be used to supplement product-specific master and batch production documentation. transfer of technology. A logical procedure that controls the transfer of any process, together with its documentation and professional expertise between development and manufacture or between manufacture sites. It is a systematic procedure that is followed in order to pass the documented knowledge and experience gained during development and/or commercialization to an appropriate, responsible and authorized party. technology transfer report. A documented summary of a specific technology transfer project listing procedures, acceptance criteria, results achieved and conclusions.

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validation. Action of proving and documenting that any process, procedure or method actually and consistently leads to the expected results. validation master plan (VMP). A high-level document that summarizes the manufacturer’s overall philosophy and approach, to be used for establishing performance adequacy. It provides information on the manufacturer’s qualification and validation work programme and defines details of and timelines for the work to be performed, including a statement of the responsibilities of those implementing the plan. validation protocol (VP). A document describing the activities to be performed during validation, including the acceptance criteria. validation report (VR). A document in which the records, results and evaluation of validation are documented and summarized. It should also contain a conclusion of the outcome of the validation.

4. Due diligence and gap assessments

4.1. A process of due diligence, gap assessment or audits of the SU and RU should be one of the first steps when considering a technology transfer project.

4.2. The suitability and degree of preparedness of the RU should be assessed prior to the start of the transfer. The procedure to be followed should be documented.

4.3. The assessment should be done by a team of appropriately qualified persons with knowledge and experience in the field of GxP and the activity to be transferred.

4.4. The assessment should further cover resources including personnel, premises, equipment and instruments, utilities, QC, documentation, computerized systems, qualification and validation and waste management.

4.5. The assessment to determine feasibility and readiness for technology transfer may include technical, business, regulatory and legal aspects.

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5. Organization and management

5.1. All technology transfer activities should be organized and planned.

5.2. There should be a formal agreement between the parties which specifies the responsibilities of each party before, during and after transfer. The agreement should cover, for example, data management, data integrity, documentation and validation.

5.3. All the necessary activities to be executed during the technology transfer project should be identified, organized and documented at the start of the project. Responsibilities should be defined.

5.4. The SU should provide the necessary documentation relating to the process, product or procedure to be transferred.

5.5. The SU should provide criteria and information on inherent risks, hazards and critical steps associated with the process, product or procedure to be transferred. This may serve as a basis for the risk assessment exercise.

5.6. The technology transfer should be managed by responsible persons from the SU and RU. A technology transfer team may be appointed with identified and documented responsibilities.

5.7. The team members should have the necessary qualifications and experience to manage the particular aspects of the transfer.

5.8. The SU should make all the necessary information and knowledge with regard to the product, process or procedure available in relevant documents in order to ensure a successful transfer.

5.9. A training programme should be implemented specific to the process, product or procedure to be transferred.

5.10. Any changes and adaptations made during the course of the project should be fully documented and agreed to by both parties.

5.11. The execution of the technology transfer project should be documented in a report which is supported by the relevant data.

5.12. Data should meet ALCOA+ principles.

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6. Quality management and quality risk management

6.1. The SU and RU should each have an appropriately designed, clearly defined and documented quality system.

6.2. The quality system should be adequately resourced, implemented and maintained.

6.3. The quality system should incorporate GxP which should be applied to the life cycle stages of the products and processes, including the technology transfer.

6.4. The quality system should ensure that: • responsibilities are clearly specified in writing; • operations are clearly defined in writing; • there is a system for quality risk management; and • arrangements are made for the documented technology transfer.

6.5. Quality risk management should be implemented as a systematic process for the assessment, control, communication and review of risks.

6.6. The system for quality risk management should be described in writing and cover appropriate areas such as, but not limited to, premises, equipment, materials, products, production, processes, QC, qualification, validation and the process of technology transfer.

6.7. The evaluation of the risk should be based on scientific knowledge and experience including that of the process and product.

6.8. The level of effort, formality and documentation of the quality risk management process should be commensurate with the level of risk.

6.9. The procedures and records for quality risk management should retained.

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7. Documentation

Note: A list with examples of documents commonly required in technology transfer is presented in Appendix 1.

7.1. An authorized technology transfer document should list the intended sequential phases and activities of the transfer. The document should include, for example, the following: • title; • objective; • scope; • name and addresses of the SU and RU; • names of key personnel and their responsibilities; • phases of the project and actions; • a parallel comparison of premises, equipment, instruments, materials, procedures, and methods; • experimental design, quality attributes, process parameters and acceptance criteria; • information on trial production batches, qualification batches and process validation; • change and deviation management; • arrangements for keeping retention samples of active ingredients, intermediates and finished products, and information on reference substances where applicable; and • review of the transfer, outcome, signature(s) and date of conclusion of the transfer.

7.2. Standard operating procedures (SOPs) should be followed, describing actions to be taken during the technology transfer process.

7.3. Records should be maintained for the activities performed during the technology transfer process (e.g. a technology transfer report). The report content should reflect the protocol and SOPs that were followed. The report should summarize the scope of the transfer, the critical parameters as obtained in the SU and RU, and the final conclusions of the transfer. The discrepancies and appropriate actions taken to resolve them should be recorded. Supportive documents with data, results and other relevant information should be referenced in the report and be readily available.

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8. Premises

8.1. The RU should have appropriate premises with the layout, construction and finishing to suit the intended operations. Utilities such as heating, ventilation and air conditioning, as well as gas and water systems, should be appropriate for the intended process, product or procedure to be transferred.

8.2. The SU should provide the RU with information on relevant health, safety and environmental issues, including: • inherent risks of the manufacturing processes (e.g. reactive chemical hazards, exposure limits, fire and explosion risks); • health and safety requirements to minimize operator exposure (e.g. atmospheric containment of pharmaceutical dust); • emergency planning considerations (e.g. in case of gas or dust release, spillage, fire and firewater run-off); and • identification of waste streams and provisions for re-use, recycling and/or disposal.

9. Equipment and instruments

9.1. The SU should provide a list of equipment and instruments involved in the production, filling, packing and QC testing. The list should include the makes and models of the relevant equipment and instruments.

9.2. Other relevant documentation may include, on a case-by-case basis as required, drawings; manuals; maintenance procedures and records; calibration procedures and records; as well as procedures such as equipment set-up, operation and cleaning.

9.3. A review and a side-by-side comparison of equipment and instruments of the SU and RU should be carried out in terms of their working principle, make and models.

9.4. Where the review and comparison identify any gaps or differences, appropriate action should be taken. This may include the adaptation of existing equipment or acquisition of new equipment. Such action should be taken by following a change management procedure which should be documented.

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9.5. Production volumes and batch sizes at the SU and RU should be compared. Where batch sizes are different, the impact should be assessed and the appropriate action planned and taken. Other factors relating to equipment to be reviewed may include: • minimum and maximum capacity; • material of construction of contact surfaces; • critical operating parameters; • components (e.g. filters, screens, and temperature/pressure sensors); and • range of intended use.

9.6. The impact of the potential product to be transferred, on existing products manufactured on site, should be assessed.

10. Qualification and validation

10.1. The extent of qualification and validation to be performed should be determined on the basis of risk management principles.

10.2. The qualification of premises, utilities and equipment should be done in accordance with a qualification master plan and protocols.

10.3. Validation, such as process validation, should be done in accordance with a validation master plan and protocols.

10.4. Where technology is transferred to commercial sites, the qualification of equipment and instruments should be completed prior to the actual technology transfer.

10.5. Process validation usually starts in research and development facilities either as prospective validation (traditional approach) or as stage I process validation (see references regarding the new approaches in process validation; and the life cycle approach). Note: Process validation should be done according to current guidelines as published in current WHO Technical Report Series (3).

10.6. Procedures including processing and analytical procedures, should be appropriately validated at the SU and transferred to the RU following documented procedures. Verification and validation, as appropriate, should be continued at the RU as identified and documented in the technology transfer protocol.

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10.7. For cleaning procedures, development and validation should be done in accordance with the guidelines as published in current WHO Technical Report Series (6). Points to consider when using HBEL in cleaning validation (14) should be taken into account in establishing cleaning procedures, cleanability studies and setting acceptance limits.

10.8. Analytical procedures should be validated according to the guidelines as published in current WHO Technical Report Series (7).

10.9. Qualification and validation procedures, protocols, data and results should be appropriately recorded. The documents should be retained as defined in procedures.

11. Product life cycle and project management principles

11.1. The relevant stage of the life cycle of the facility, equipment, instrument, utility, product, process or procedure to be transferred should be taken into consideration when the transfer is planned and executed.

12. Phases of a technology transfer project

12.1. The technology transfer project plan may be divided into different phases. These may include, for example: • Phase I: Project initiation; • Phase II: Project proposal; • establishing a team; • risk assessment; • project plan; • control strategy; • Phase III: Project transfer; and • Phase IV: Project review.

Phase I: Project initiation

12.2. During the initiation phase of the project, a unit should normally identify the need for the technology transfer. This may be because of lack of capacity, transfer from development to commercial site or transfer from one company to another.

12.3. The units should establish initial discussion and identify whether or not there is any interest for such a project. (See also section on due diligence above).

12.4. The RU should be able to accommodate the intended activity.

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12.5. The RU should have the necessary technical expertise, technology and capability.

12.6. A sufficient level and depth of detail to support the activity, and any further development and optimization at the RU, should be transferred.

Phase II: Project proposal

12.7. The SU and RU should jointly establish a team that will coordinate activities and execute the technology transfer exercise.

12.8. The team should perform a risk assessment based on the available data, information and knowledge of the premises, materials, products, procedures and other related information.

12.9. The team should prepare the technology transfer document. 12.10. The team should develop a control strategy which includes, for example: • risks; • material attributes; • processing steps and stages in production; • testing steps in QC; • equipment working principles and their impact on the process; • critical quality attributes (CQAs), critical process parameters (CPPs) and in- process controls; • QC instruments; • acceptance criteria and limits; • alarms and trends; • personnel requirements, such as qualification and training; and • qualification and validation.

Phase III: Project transfer

12.11. The team should execute the project in accordance with the procedures and agreed plan.

Production:

Starting materials

12.12. The specifications and relevant functional characteristics of the starting materials (APIs and excipients) to be used at the RU should be consistent with those materials used at the SU. Any properties which are likely to influence the process or product should be identified and/or characterized.

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Active pharmaceutical ingredients

12.13. The SU should provide the RU with the open part of the Drug Master File (API master file), or equivalent information, as well as any relevant additional information on the API of importance for the manufacture of the pharmaceutical product. The following are examples of the information which may typically be provided; however the information needed in each specific case should be assessed using the principles of QRM: • manufacturer and associated supply chain; • step of the API to be transferred; • flow chart of synthesis pathway outlining the process, including entry points for raw materials, critical steps, process controls and intermediates; • where relevant, definitive physical form of the API (including photomicrographs and other relevant data) and any polymorphic and solvate forms; • solubility profile; • if relevant, pH in solution; • partition coefficient, including the method of determination; • intrinsic dissolution rate, including the method of determination; • particle size and distribution, including the method of determination; • bulk physical properties, including data on bulk and tap density, surface area and porosity as appropriate; • water content and determination of hygroscopicity, including water activity data and special handling requirements; • microbiological considerations (including sterility, bacterial endotoxins and bioburden levels where the API supports microbiological growth) in accordance with national, regional or international pharmacopoeia requirements; • specifications and justification for release and end-of-life limits; • summary of stability studies conducted in conformity with current guidelines, including conclusions and recommendations on retest date; • list of potential and observed synthetic impurities, with data to support proposed specifications and typically observed levels; • information on degradants, with a list of potential and observed degradation products and data to support proposed specifications and typically observed levels; • potency factor, indicating observed purity and justification for any recommended adjustment to the input quantity of API for product manufacturing, providing example calculations; and • special considerations with implications for storage and or handling, including but not limited to, safety and environmental factors (e.g. as specified in material safety data sheets) and sensitivity to heat, light or moisture. 892

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Excipients

12.14. The specifications and relevant functional characteristics of excipients should be made available by the SU for transfer to the RU site. The following are examples of the information which may typically be provided; however, the information needed in each specific case should be assessed using the principles of QRM: • manufacturer and associated supply chain; • description of functionality, with justification for inclusion of any antioxidant, preservative or any excipient; • definitive form (particularly for solid and inhaled dosage forms); • solubility profile (particularly for inhaled and transdermal dosage forms); • partition coefficient, including the method of determination (for transdermal dosage forms); • intrinsic dissolution rate, including the method of determination (for transdermal dosage forms); • particle size and distribution, including the method of determination (for solid, inhaled and transdermal dosage forms); • bulk physical properties, including data on bulk and tap density, surface area and porosity as appropriate (for solid and inhaled dosage forms); • compaction properties (for solid dosage forms); • melting point range (for semi-solid or topical dosage forms); • pH range (for parenteral, semi-solid or topical, liquid and transdermal dosage forms); • ionic strength (for parenteral dosage forms); • specific density or gravity (for parenteral, semi-solid or topical, liquid and transdermal dosage forms); • viscosity and or viscoelasticity (for parenteral, semi-solid or topical, liquid and transdermal dosage forms); • osmolarity (for parenteral dosage forms); • water content and determination of hygroscopicity, including water activity data and special handling requirements (for solid and inhaled dosage forms); • moisture content range (for parenteral, semisolid or topical, liquid and transdermal dosage forms); • microbiological considerations (including sterility, bacterial endotoxins and bioburden levels where the excipient supports microbiological growth) in accordance with national, regional or international pharmacopoeia requirements, as applicable (for general and specific monographs); • specifications and justification for release and end-of-life limits; • information on adhesives supporting compliance with peel, sheer and adhesion design criteria (for transdermal dosage forms);

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• special considerations with implications for storage and or handling, including but not limited to, safety and environmental factors (e.g. as specified in material safety data sheets {MSDS}) and sensitivity to heat, light or moisture; and • regulatory considerations (e.g. documentation to support compliance with transmissible animal spongiform encephalopathy certification requirements, where applicable).

Information on process and finished pharmaceutical product information

Processing, packaging

12.15. Product, process and procedure knowledge should be an essential part of the transfer process from SU to RU.

12.16. The quality target product profile, critical quality attributes, critical process parameters, material attributes, control strategy and any other impacting elements on the quality of the product should be available. (See also ICH guidelines.)

12.17. The SU should provide the total product quality profile with its qualitative and quantitative composition, physical description, method of manufacture, in-process controls, control method and specifications, packaging components and configurations, and any safety and handling considerations to the RU.

12.18. The SU should provide any information on the history of process development which may be required to enable the RU to perform any further development and or process optimization after successful transfer.

12.19. Such information may include the following: • information on clinical development (e.g. information on the rationale for the synthesis, route and form selection, technology selection, equipment, clinical tests, and product composition); • information on scale-up activities: process optimization, statistical optimization of critical process parameters, critical quality attributes, pilot report and/or information on pilot-scale development activities indicating the number and disposition of batches manufactured; • information or report on full-scale development activities, indicating the number and disposition of batches manufactured, and deviation and change control (sometimes referred to as change management) reports which led to the current manufacturing process; • the change history and reasons (e.g. a change control log, indicating any changes to the process or primary packaging or analytical methods as a part of process optimization or improvement); and • information on investigations of problems and the outcomes of the investigations.

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12.20. The SU should provide to the RU information on any health, safety and environmental issues associated with the manufacturing processes to be transferred, and the implications thereof (e.g. need for gowning or protective clothing).

12.21. The SU should provide to the RU information on current processing and testing, including but not limited to: • a detailed description of facility requirements and equipment; • information on starting materials, applicable MSDS and storage requirements for raw materials and finished products; • description of manufacturing steps (narrative and process maps or flow charts, and/or master batch records), including qualification of in-processing hold times and conditions, order and method of raw material addition and bulk transfers between processing steps; • description of analytical methods; • identification and justification of control strategy (e.g. identification of critical performance aspects for specific dosage forms, identification of process control points, product quality attributes and qualification of critical processing parameter ranges, statistical process control {SPC} charts); • design space, in cases where this has been defined; • validation information (e.g. validation plans and reports); • annual product quality reviews; • stability information; • an authorized set of protocols and work instructions for manufacturing; and • environmental conditions or any special requirement needed for the facility or equipment depending on the nature of the product to be transferred.

12.22. During the transfer process, the RU should identify any differences in facilities, systems and capabilities and discuss these with the SU. The potential impact should be understood and satisfactorily addressed in order to assure equivalent product quality. Based on the information received from the SU, the RU should consider its own capability to manufacture and pack the product to the required standards and should develop the relevant site operating procedures and documentation before the start of routine production.

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12.23. Process development at the RU should address the following tasks: • comparison and assessment of suitability and qualification of facility and equipment; • description of manufacturing process and flow of personnel and of materials at the RU (narrative and or process maps or flow charts); • determination of critical steps in manufacture, including hold times, endpoints, sampling points and sampling techniques; • writing and approval of SOPs for all production operations (e.g. dispensing, granulation or blending or solution preparation, tablet compression, tablet coating, encapsulation, liquid filling, primary and secondary packaging and in- process QC), packaging, cleaning, testing and storage; • evaluation of stability information, with generation of site-specific stability data if required; and • compliance with regulatory requirements for any changes made (e.g. in terms of batch size).

Packaging

12.24. The transfer of packaging operations should follow the same procedural principles as those of the product processing.

12.25. Information on packaging to be transferred from the SU to the RU should include specifications for a suitable container and closure system, as well as any relevant additional information on design, packing, processing or labelling requirements and tamper-evident and anti-counterfeiting measures.

12.26. For QC testing of packaging components, specifications should be provided including drawings, artwork and material.

12.27. Based on the information provided, the RU should perform a suitability study for the initial qualification of the packaging components.

12.28. Packaging is considered suitable if it provides adequate protection (preventing degradation of the medicine due to environmental influences), safety (absence of undesirable substances released into the product), compatibility (absence of interaction possibly affecting medicine quality) and performance (functionality in terms of drug delivery).

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Quality control: analytical method transfer

12.29. Analytical methods used to test pharmaceutical products, starting materials, packaging components and cleaning (residue) samples, if applicable, should be implemented at the testing laboratory before the testing of samples for process validation studies is performed by the RU.

12.30. A protocol defining the steps should be prepared for transfer of analytical methods. The analytical methods transfer protocol should include: • a description of the objective, scope and responsibilities of the SU and the RU; • a specification of materials and methods; • the experimental design and acceptance criteria; • documentation (including information to be supplied with the results, and report forms to be used, if any); • procedure for the handling of deviations; and • details of reference samples (starting materials, intermediates and finished products).

12.31. The SU’s responsibilities for the transfer of analytical procedures are to: • provide method-specific training for analysts and other QC staff, if required; • assist in analysis of QC testing results; • define all methods to be transferred for testing a given product, starting material or cleaning sample; • define experimental design, sampling methods and acceptance criteria; • provide any validation reports for methods under transfer and demonstrate their robustness; • provide details of the equipment used, as necessary (part of validation report, if available) and any standard reference samples; • provide approved procedures used in testing; and • review and approve transfer reports.

12.32. The RU should exercise its responsibility to: • review analytical methods provided by the SU, and formally agree on acceptance criteria before execution of the transfer protocol; • ensure that the necessary equipment for QC is available and qualified at the RU site. The equipment used by the RU during the analytical transfer should meet the appropriate specifications in order to ensure the requirements of the method or specification are met; • ensure that adequately trained and experienced personnel are in place for analytical testing;

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• provide a documentation system capable of recording receipt and testing of samples to the required specification using approved test methods, and of reporting, recording and collating data and designation of status (approved, rejected, quarantine); • execute the transfer protocol; • perform the appropriate level of validation to support the implementation of the methods; and • generate and obtain approval of transfer reports.

12.33. The appropriate training should be provided and all training activities and outcomes should be documented.

12.34. Reference should be made to compendial monographs such as The International Pharmacopoeia, European Pharmacopoeia, British Pharmacopoeia and United States Pharmacopeia), where these are available.

12.35. An experimental design should be prepared which includes acceptance criteria for the main analytical testing procedures. (See Appendix 2.)

12.36. Where products are transferred from one unit to another, the applicable analytical procedures should also be transferred.

12.37. All relevant analytical procedure development and validation documentation should be made available by the SU to the RU.

12.38. The appropriate transfer protocols and procedures should be followed when analytical procedures are transferred.

12.39. The number of analysts involved in the transfer, from both SU and RU, should be defined and justified.

12.40. The parameters of the analytical procedure to be included in the validation should be defined and justified.

12.41. Acceptance criteria should be set to determine the success of the transfer. Statistical trending of results should be considered in order to show capability of the procedure.

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Cleaning

12.42. To minimize the risk of contamination and cross-contamination, adequate cleaning procedures should be followed.

12.43. Cleaning procedures and their validation should normally be site-specific. In order for the RU to define its cleaning strategy, the SU should provide information on cleaning at the SU to minimize cross-contamination due to residues from previous manufacturing steps, operator exposure and environmental impact, including: • information on solubility of active ingredients, excipients and vehicles; • minimum therapeutic doses of active ingredients; • therapeutic category and toxicological assessment; and • existing cleaning procedures.

12.44. Additional applicable information should be provided, such as: • cleaning validation reports (chemical and microbiological); • information on cleaning agents used (efficacy, evidence that they do not interfere with analytical testing for residues of APIs, removal of residual cleaning agents); and • recovery studies to validate the sampling methodology.

12.45. Before the transfer, the SU should provide information on limits for product residues and the rationale for limit selection.

12.46. Based on the information provided by the SU, cleaning procedures should be designed at the RU, taking into account relevant characteristics of the starting materials (e.g. potency, toxicity, solubility, corrosiveness and temperature sensitivity), manufacturing equipment design and configuration, cleaning agent and product residue.

Phase IV: Project review

12.47. The progress and success of the transfer of technology should be monitored and reviewed during and after completion of the project.

12.48. Compliance with the procedures and protocols should be verified. Deviations and changes should be documented and investigated where appropriate.

12.49. Where possible, data and results should be subjected to appropriate statistical calculation and evaluation to determine trends, compliance with control limits and capability studies.

12.50. A technology transfer report should be prepared, based on the data and information obtained during the project. The supportive data should be kept and be accessible.

12.51. The report, which should include a conclusion, should be authorized by the persons responsible to do so.

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References

1. WHO guidelines on the transfer of technology in pharmaceutical manufacturing. In: WHO Expert Committee on Specifications for Pharmaceutical Preparations: forty-fifth report. Geneva: World Health Organization; 2011: Annex 7 (WHO Technical Report Series, No. 961; https://www.who.int/docs/default-source/medicines/norms-and- standards/guidelines/production/trs961-annex7-transfer-technology-pharmaceutical- manufacturing.pdf?sfvrsn=2e302838_0, accessed 30 November 2020).

2. WHO guidelines on good manufacturing practices for pharmaceutical products: main principle. In: WHO Expert Committee on Specifications for Pharmaceutical Preparations: forty-eighth report. Geneva: World Health Organization; 2014: Annex 2 (WHO Technical Report Series, No. 986; https://www.who.int/medicines/areas/quality_safety/quality_assurance/TRS986annex2.pdf?ua =1, accessed 30 November 2020).

3. WHO good manufacturing practices: guidelines on validation. In: WHO Expert Committee on Specifications for Pharmaceutical Preparations: fifty-third report. Geneva: World Health Organization; 2019: Annex 3 (WHO Technical Report Series, No. 1019; https://www.who.int/medicines/areas/quality_safety/quality_assurance/WHO_TRS_1019_An nex3.pdf?ua=1, accessed 30 November 2020).

4. WHO guidelines on heating ventilation and air-conditioning systems for non-sterile pharmaceutical products and Part 2: interpretation of guidelines on heating ventilation and air-conditioning systems for non-sterile pharmaceutical products. In: WHO Expert Committee on Specifications for Pharmaceutical Preparations: fifty-third report. Geneva: World Health Organization; 2019: Annex 2 (WHO Technical Report Series, No. 1019; https://www.who.int/medicines/areas/quality_safety/quality_assurance/WHO_TRS_1019_An nex3.pdf?ua=1, accessed 20 November 2020).

5. WHO good manufacturing practices: guidelines on validation. Appendix 4. Validation of water systems for pharmaceutical use. In: WHO Expert Committee on Specifications for Pharmaceutical Preparations: fortieth report. Geneva: World Health Organization; 2006: Annex 3 (WHO Technical Report Series, No. 937; https://www.who.int/medicines/areas/quality_safety/quality_assurance/WHO_TRS_1019_An nex3.pdf?ua=1, accessed 30 November 2020).

6. WHO good manufacturing practices: guidelines on validation. Appendix 3. Cleaning validation. In: WHO Expert Committee on Specifications for Pharmaceutical Preparations: fifty-third report. Geneva: World Health Organization; 2019: Annex 3 (WHO Technical Report Series, No. 1019; https://www.who.int/medicines/areas/quality_safety/quality_assurance/WHO_TRS_1019_An nex3.pdf?ua=1, accessed 30 November 2020).

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7. WHO good manufacturing practices: guidelines on validation. Appendix 4. Analytical procedure validation. In: WHO Expert Committee on Specifications for Pharmaceutical Preparations: fifty- third report. Geneva: World Health Organization; 2019: Annex 3 (WHO Technical Report Series, No. 1019; https://www.who.int/medicines/areas/quality_safety/quality_assurance/WHO_TRS_1019_An nex3.pdf?ua=1, accessed 30 November 2020).

8. WHO good manufacturing practices: guidelines on validation. Appendix 5. Validation of computerized systems. In: WHO Expert Committee on Specifications for Pharmaceutical Preparations: fifty-third report. Geneva: World Health Organization; 2019: Annex 3 (WHO Technical Report Series, No. 1019; https://www.who.int/medicines/areas/quality_safety/quality_assurance/WHO_TRS_1019_An nex3.pdf?ua=1, accessed 30 November 2020).

9. WHO good manufacturing practices: guidelines on validation. Appendix 6. Guidelines on qualification. In: WHO Expert Committee on Specifications for Pharmaceutical Preparations: fifty-third report. Geneva: World Health Organization; 2019: Annex 3 (WHO Technical Report Series, No. 1019; https://www.who.int/medicines/areas/quality_safety/quality_assurance/WHO_TRS_1019_An nex3.pdf?ua=1, accessed 30 November 2020).

10. WHO guidelines on good manufacturing practices: validation. Appendix 7. Non-sterile process validation. In: WHO Expert Committee on Specifications for Pharmaceutical Preparations: forty-ninth report. Geneva: World Health Organization; 2015: Annex 3 (WHO Technical Report Series, No. 992; https://www.who.int/medicines/areas/quality_safety/quality_assurance/Annex3-TRS992.pdf, accessed 30 November 2020).

11. WHO guidelines on quality risk management. In: WHO Expert Committee on Specifications for Pharmaceutical Preparations: forty-seventh report. Geneva: World Health Organization; 2013: Annex 2 (WHO Technical Report Series, No. 981; http://digicollection.org/whoqapharm/documents/s20093en/s20093en.pdf, accessed 30 November 2020).

12. WHO guidance on good data and record management practices. In: WHO Expert Committee on Specifications for Pharmaceutical Preparations: fiftieth report. Geneva: World Health Organization; 2016: Annex 5 (WHO Technical Report Series, No. 996; https://www.who.int/medicines/publications/pharmprep/WHO_TRS_996_annex05.pdf, accessed 30 November 2020).

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13. WHO guideline on data integrity. Draft for comments. Geneva: World Health Organization; 2019 (working document QAS/19.819; https://www.who.int/medicines/areas/quality_safety/quality_assurance/QAS19_819_rev1_gui deline_on_data_integrity.pdf?ua=1, accessed 30 November 2020).

14. WHO points to consider when including Health Based Exposure Limits in cleaning validation. In: WHO Expert Committee on Specifications for Pharmaceutical Preparations: fifty-fifth report. Geneva: World Health Organization; 2021: Annex 2, (WHO Technical Report Series, No. xxx, 2021).

Further reading

15. Guideline on setting health-based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities. EMA, 2014 (EMA/CHMP/ CVMP/ SWP/169430/2012).

16. ISPE Baseline, Good Practice Guide. Technology Transfer. Third edition, 2018.

17. Guideline on setting health-based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities and Questions and answers on implementation of risk-based prevention of cross-contamination in production. European Medicines Agency, 2018.

18. International conference on harmonisation of technical requirements for registration of pharmaceuticals for human use. ICH harmonised tripartite guideline. Pharmaceutical development q8(r2). Current step 4 version. August 2009.

19. International conference on harmonisation of technical requirements for registration of pharmaceuticals for human use. ICH harmonised tripartite guideline. Quality risk management. Q9. Current step 4 version. 9 November 2005.

20. International conference on harmonisation of technical requirements for registration of pharmaceuticals for human use. ICH harmonised tripartite guideline. Development and manufacture of drug substances (chemical entities and biotechnological/biological entities). Q11. Current step 4 version. 1 May 2012.

21. International conference on harmonisation of technical requirements for registration of pharmaceuticals for human use. ICH harmonised tripartite guideline. Technical and regulatory considerations for pharmaceutical product life cycle management. Q12. Final version. 20 November 2019.

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Abbreviations

ALCOA+ “attributable, legible, contemporaneous, original and accurate”. API active pharmaceutical ingredient FPP finished pharmaceutical product GMP good manufacturing practices GxP good practices ICH The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human use IPC in-process control IQ installation qualification OQ operational qualification PQ performance qualification QA quality assurance QC quality control QRM quality risk management RU receiving unit SOP standard operating procedure SU sending unit TRS Technical Report Series VMP validation master plan VP validation protocol VR validation report

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Appendix 1 Example of documentation commonly required for the transfer of technology*

The table below provides an example of documentation commonly required for the transfer of technology.

Aspect Related documentation

Starting materials (API and excipients) Material Safety Data Sheets Product development report Storage conditions Stability data Forced stability data Specifications Supplier qualification References Formulation Formulation development reports Master formula Material compatibility/interaction studies Batch manufacturing Batch manufacturing document Scale up information Risk assessment Critical process parameters In-process control specification Scale up protocol and report Process validation Batch packaging Packaging material specification Batch packaging document Validation Finished product Specification

Analytical procedures Analytical test procedures Analytical method development Analytical procedure validation Standard test procedures Instrument specifications Quality control Sampling procedures (e.g. in-process control) Stability testing protocol and procedures Equipment and instruments List of equipment and instruments Calibration information Preventive maintenance information Overview of qualification

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Cleaning Overview of cleaning approach Cleaning procedure development and cleanability Cleaning procedures Health Based Exposure Level (Permitted daily exposure) information reports Analytical procedures validation for cleaning validation sample analysis Other documents Rejected batch information Bio-batch information Pilot batch information History of changes and change management Hold time protocols and reports

*Note: These are examples. All the required documents should be identified for the different tasks.

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Appendix 2 Example of possible experimental designs and acceptance criteria for analytical testing

The table below provides an example of possible experimental designs and acceptance criteria for analytical testing. The numbers in the table are given as examples only and should not be considered as recommendations. Method transfers should account for the variability and sensitivity of the method and the specifications for the quality parameter. Alternative procedures and acceptance criteria may be applied based on science and the characteristics of the analytical method and the analyte.

Test Considerations Replication Set-up Acceptance for transfer of tests criteria Statistically Direct derived

Assay for Specific At each site: Different sets Comparison Two one-sided potency methods where 2 analysts of instruments of mean and t-tests possible should × 3 lots, in and columns variability with inter-site be used triplicate differences (= 18 per site) Independent ≤2% , 95% A bracketing solution confidence approach may preparation be used for multiple strengths Content If method is At each site: Different sets Mean at RU Two one-sided uniformity equivalent to 2 analysts, of instruments within ± 3% t-tests assay method, × 1 lot and columns of mean at with inter-site separate (= 2 per site) SU; comparison differences transfer Independent of relative ≤ 3% , 95% is not usually solution standard confidence required preparation deviation

Dissolution Bracketing may 6 units Mean at RU Compare be appropriate (12, if not within ± 5% profile for multiple routine at RU, of mean (e.g. F2), or strengths and for at SU compare extended data at Q release time points, products) as for assay

***

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OXYGEN

OXYGENIUM

Draft proposal for revision in The International Pharmacopoeia

DRAFT FOR COMMENTS

Please send any comments you may have on this draft working document to Dr Herbert Schmidt, Technical Officer, Norms and Standards for Pharmaceuticals, Technical Standards and Specifications ([email protected]), with a copy to Ms Claire Vogel ([email protected]) by 26 February 2021.

Our working documents are sent out electronically and they will also be placed on the WHO Medicines website (https://www.who.int/teams/health-product-and-policy- standards/standards-and-specifications/pharmaceuticals/current-projects) for comments under the “Working documents in public consultation” link.

If you wish to receive our draft guidelines, please send your e-mail address to [email protected] and your name will be added to our electronic mailing list.

[Note from the Secretariat. It is proposed to revise the monograph on Oxygen. The draft proposed is based on a review of current pharmacopoeial requirements for oxygen. Comments are in particular sought: • on the proposal to combine quality requirements of oxygen produced by cryogenic distillation and by pressure/vacuum swing adsorption (PSA/VSA) oxygen generating plants in one monograph; • on the suitability of the proposed test methods; and • on the need to specify further impurities.

In case additional impurities would need to be added to the monograph, please also kindly provide the rational for the inclusion and suggest the test methods and limits which could be used.

Changes to the current chapter are indicated in the text by insert or delete.]

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OXYGEN

OXYGENIUM

O2

Relative molecular mass. 32.00

Chemical name. Oxygen; CAS Reg. No. 7782-44-7.

Description. A colourless gas.

Category. Gas for inhalation.

Storage. Oxygen, if stored in appropriate containers, should comply with the safety regulations of the national authority. Valves or taps should not be lubricated with oil or grease, unless they are oxygen-compatible.

Additional information. Oxygen is mentioned in the current WHO Model list of essential medicines (EML) and in the EML for Children.

This monograph does not apply to gas produced using concentrators for home care or bedside use10.

Requirements

Oxygen contains not less than 90.0 % v/v of O2.

Production. Oxygen is produced of ambient air by cryogenic distillation or by pressure/vacuum swing adsorption (PSA/VSA) oxygen generating plants11.

Identity test. Carry out the test as described under “Assay”. The sample gas complies with the limit. The paramagnetic signal exhibited confirms the presence of oxygen.

10 Specifications for concentrators for home care or bedside use can be found in: WHO-UNICEF technical specifications and guidance for oxygen therapy devices. Geneva: World Health Organization and the United Nations Children’s Fund (UNICEF), 2019 (WHO medical device technical series), (https://www.who.int/medical_devices/publications/tech_specs_oxygen_therapy_devices/en/ , accessed 3 December 2020). 11 Technical specifications for pressure swing adsorption (PSA) oxygen generating plants can be found in: Technical specifications for Pressure Swing Adsorption (PSA) Oxygen Plants, Interim guidance, 8 June 2020. Geneva: World Health Organization, 2020, (https://www.who.int/publications/i/item/technical-specifications-for-pressure-swing-adsorption(psa)- oxygen-plants , accessed 3 December 2020). 908

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Oxygen labelled as having been produced by cryogenic distillation may be exempted from the requirements of the tests for carbon monoxide and carbon dioxide. Carbon monoxide. Determine the content using a carbon monoxide detector tube according to the manufacturer’s instruction. Pass the required volume of the test gas through the tube and read the value corresponding to the length of the coloured layer or the intensity of the colour on the graduated scale; not more than 10 μl/L.

Carbon dioxide. Determine the content using a carbon dioxide detector tube according to the manufacturer’s instruction. Pass the required volume of the test gas through the tube and read the value corresponding to the length of the coloured layer or the intensity of the colour on the graduated scale; not more than 300 μl/L.

Assay. Determine the percentage content of Oxygen (O2) using a paramagnetic analyser which measures electronically the molecule's interaction with magnetic fields.

Impurities

A. CO2, carbon dioxide; B. CO, carbon monoxide.

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O2

Relative molecular mass. 32.00

Chemical name. Oxygen; CAS Reg. No. 7782-44-7.

Description. A colourless gas; odourless.

Solubility. One volume dissolves in about 32 volumes of water and in about 7 volumes of ethanol (~750 g/l) TS, both at a pressure of 101.3 kPa and 20°C.

Category. Gas for inhalation.

Storage. Oxygen should be kept as compressed gas or liquid at cryogenic temperature, in appropriate containers complying with the safety regulations of the national authority. Valves or taps should not be lubricated with oil or grease.

Labelling. An ISO standard1 requires that cylinders containing oxygen intended for medical use should bear the name of the contents in legible and permanent characters and, preferably, also the molecular formula O2. 1 International Standard 32. Gas cylinders for medical use - marking for identification of content. International Organization for Standardization, Switzerland, 1977.

Additional information. In the analysis of medicinal gases certain tests are not intended for hospital pharmacists. They are solely applicable by laboratories equipped with the specialized apparatus.

Requirements

Oxygen contains not less than 99.5% v/v of O2. • Oxygen labelled as having been produced by the air-liquefaction process may be exempted from the requirements of the tests for carbon monoxide and carbon dioxide.

Identity tests A. Place a glowing splinter of wood into the test gas; the splinter bursts into flame. B. Shake with alkaline pyrogallol TS; the test gas is absorbed and the solution becomes dark brown (distinction from Dinitrogen oxide).

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Figure 7. Apparatus for the determination of carbon monoxide in medicinal gases Measurements in mm.

Reproduced with the permission of the European Pharmacopoeia Commission, European Directorate for the Quality of Medicines, Council of Europe. • Note: For the following tests deliver the test gas at a rate of 4 litres per hour.

Carbon monoxide • Either test A or test B may be applied.

A. The apparatus (Fig. 7) consists of the following parts connected in series: - a U-tube (U1) containing desiccant silica gel R impregnated with chromium trioxide R; - a wash bottle (F1) containing 100 mL of potassium hydroxide (~400 g/l) TS; - a U-tube (U2) containing pellets of potassium hydroxide R; - a U-tube (U3) containing phosphorus pentoxide R dispersed on previously granulated, fused pumice; - a U-tube (U4) containing 30 g of recrystallized iodine pentoxide R in granules, previously dried at 200 °C and kept at a temperature of 120°C (T) during the test. The iodine pentoxide is packed in the tube in 1-cm columns separated by 1-cm columns of glass wool to give an effective length of 5 cm; - a reaction tube (F2) containing 2.0 mL of potassium iodide (160 g/l) TS and 0.15 mL of starch TS.

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Flush the apparatus with 5.0 litres of argon R. If necessary, discharge the blue colour in tube F2 containing potassium iodide (160 g/l) TS by adding a sufficient volume of freshly prepared sodium thiosulfate (0.002 mol/l) VS. Continue flushing with argon R until not more than 0.045 mL of sodium thiosulfate (0.002 mol/l) VS is required after the passage of 5.0 litres of argon R. Pass 7.5 litres of the test gas from the container through the apparatus. Flush the last traces of liberated iodine into the reaction tube by passing 1.0 litre of argon R through the apparatus. Titrate the liberated iodine with sodium thiosulfate (0.002 mol/l) VS. Repeat the procedure using 7.5 litres of argon R.

B. Determine the content using a carbon monoxide detector tube. Pass the required volume of the test gas through the tube, the calibration of which is verified according to the manufacturer's instructions.

The gas supply is connected to a pressure regulator and needle valve. Connect the flexible tubing fitted with a Y-piece to the valve and adjust the flow of the test gas to purge the tubing to an appropriate flow. Fit the carbon monoxide detector tube to the metering pump following the manufacturer's instructions. Connect the open end of the tube to the short leg of the tubing and operate the pump sufficiently to pass a suitable volume of the test gas through the tube. Read the value corresponding to the length of the coloured layer or the intensity of the colour on the graduated scale; not more than 5 μl/l.

Note: For the following tests - "Carbon dioxide", "Oxidizing substances", and "Acidity and alkalinity" - pass the test gas through the appropriate reagent contained in a hermetically closed flat-bottomed glass cylinder (with dimensions such that 50 mL of liquid reaches a height of 12-14 cm) that is fitted with (a) a delivery tube terminated by a capillary 1 mm in internal diameter and placed within 2 mm of the bottom of the cylinder; and (b) an outlet tube.

Prepare the reference solutions in identical cylinders.

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Carbon dioxide • Either test A or test B may be applied. A. Pass 1.0 litre of the test gas through 50 mL of a clear solution of barium hydroxide (0.15 mol/l) VS. Similarly prepare a reference solution by adding 1.0 mL of a 1.1 mg/mL solution of sodium hydrogen carbonate R in carbon-dioxidefree water R to 50 mL of barium hydroxide (0.15 mol/l) VS.

Any turbidity in the solution after the passage of the test gas is not more intense than that of the reference solution (300 μl/l).

B. Determine the content using a carbon dioxide detector tube. Pass the required volume of the test gas through the tube, the calibration of which is verified according to the manufacturer's instructions.

The gas supply is connected to a suitable pressure regulator and needle valve. Connect the flexible tubing fitted with a Y-piece to the valve and adjust the flow of the test gas to purge the tubing to an appropriate flow. Fit the carbon dioxide detector tube to the metering pump following the manufacturer's instructions. Connect the open end of the tube to the short leg of the tubing and operate the pump sufficiently to pass a suitable volume of the test gas through the tube. Read the value corresponding to the length of the coloured layer or the intensity of the colour on the graduated scale; not more than 300 μl/l.

Oxidizing substances. To two cylinders add 50 mL of freshly prepared potassium iodide/starch TS1 and about 0.2 mL of glacial acetic acid R. Protect the cylinders from light. Pass 5.0 litres of the test gas into one of the solutions and compare the colour produced. The solutions in both cylinders remain colourless.

Water • Either test A or test B may be applied. A. The apparatus consists either of an electrolytic hygrometer as described below, an appropriate humidity detector tube, or a capacity hygrometer.

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The measuring cell consists of a thin film of phosphoric anhydride placed between two coiled platinum wires that act as electrodes. The water vapour in the test gas is absorbed by the phosphoric anhydride to form phosphoric acid, which acts as an electrical conductor. Before introducing the test gas into the device, allow the gas to stabilize at room temperature and make sure that the temperature is constant throughout the apparatus. Apply a continuous voltage across the electrodes to produce electrolysis of the water and regeneration of phosphoric anhydride. Measure the resulting electrical current, which is proportional to the water content in the test gas. (This is a self-calibrating system that obeys Faraday's law.) Calculate the content of water; not more than 60 μg/l.

B. Determine the content using a water vapour detector tube. Pass the required volume of the test gas through the tube, the calibration of which is verified according to the manufacturer's instructions.

The gas supply is connected to a pressure regulator and needle valve. Connect the flexible tubing fitted with a Y-piece to the valve and adjust the flow of the test gas to purge the tubing to an appropriate flow. Fit the water vapour detector tube to the metering pump following the manufacturer's instructions. Connect the open end of the tube to the short leg of the tubing and operate the pump sufficiently to pass a suitable volume of the test gas through the tube. Read the value corresponding to the length of the coloured layer or the intensity of the colour on the graduated scale; not more than 60 μl/l.

Acidity and alkalinity. Pass 2.0 litres of the test gas through a mixture of 0.10 mL of hydrochloric acid (0.01 mol/l) VS and 50 mL of carbon-dioxide-free water R. For reference solution 1, use 50 mL of carbon-dioxide-free water R. For reference solution 2, use a mixture of 0.20 mL of hydrochloric acid (0.01 mol/l) VS and 50 mL of carbon-dioxide- free water R.

To each solution add 0.1 mL of methyl red/ethanol TS; the intensity of the colour in the solution of the test gas is between those of reference solutions 1 and 2.

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Assay • Either method A or method B may be applied. A. For the determination use a 25-mL capacity gas burette (Fig. 8) in the form of a chamber with at its upper end, a tube graduated in 0.2% between 95 and 100, and isolated at each end by a tap with a conical barrel. The lower tap is joined to a tube with an olive-shaped nozzle and is used to introduce the test gas into the apparatus. A cylindrical funnel above the upper tap is used to introduce the absorbent solution. Wash the burette with water and dry. Open the two taps. Connect the nozzle to the container of the test gas and set the flow rate to 1 litre per minute. Flush the burette by passing the gas through it for 1 minute. Close the upper tap of the burette and immediately afterwards the lower tap. Rapidly disconnect the burette from the container of the test gas, and give a half turn to the upper tap to eliminate any excess pressure in the burette. Keeping the burette vertical, fill the funnel with a freshly prepared mixture of 21 mL of potassium hydroxide (~560 g/l) TS and 130 mL of sodium dithionite (200 g/l) TS. Open the upper tap slowly. The solution absorbs the oxygen and enters the burette. Allow to stand for 10 minutes without shaking.

Read the level of the liquid meniscus on the graduated part of the burette; the figure represents the content of oxygen as a percentage in v/v.

B. Oxygen in medicinal gases can also be determined using a paramagnetic analyser, which measures electronically the molecule's interaction with magnetic fields.

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Figure 8. Burette used for the assay of oxygen Measurements in mm. Reproduced with the permission of the European Pharmacopoeia Commission, European Directorate for the Quality of Medicines, Council of Europe.

Carry out the method according to the instrument manufacturer's instructions.

***

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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 2020.

Comments or objections to the decisions from the meeting should be forwarded to the WHO Collaborating Centre for Drug Statistics Methodology before 1 February 2021. If no objections are received before this date, the new ATC codes and DDDs will be considered final and included in the January 2022 version of the ATC/DDD Index.

New ATC 5th level codes:

ATC level name/INN ATC code abametapir P03AX07 abrocitinib D11AH08 aducanumab N06DX03 ammonia (13N) V09GX05 anifrolumab L04AA51 artemisinin and naphthoquine P01BF08 artemisinin and piperaquine P01BF07 artesunate, sulfadoxine and pyrimethamine P01BF09 asciminib L01EA06 belumosudil L04AA48 berotralstat B06AC06 bevacizumab S01LA08 bimekizumab L04AC21 cefixime and ornidazole J01RA15 cetirizine S01GX12 chloroquine and proguanil P01BB52 clascoterone D10AX06 covid-19 vaccines J07BX03 daprodustat B03XA07 deutetrabenazine N07XX16

917 ATC/DDD Classification WHO Drug Information, Vol 34, No. 4, 2020

diroximel fumarate L04AX09 eptinezumab N02CD05 evinacumab C10AX17 fosdenopterin A16AX19 gallium (68Ga) PSMA-11 V09IX14 haemophilus influenza B, combinations with meningococcus J07AG54 C,Y, conjugated imeglimin A10BX15 lasmiditan N02CC08 lemborexant N05CM21 levamlodipine C08CA17 lonafarnib A16AX20 lumateperone N05AD10 maralixibat chloride A05AX04 metformin, linagliptin and empagliflozin A10BD27 metronidazole and diloxanide P01AB52 netakimab L04AC20 norfloxacin and metronidazole J01RA14 odevixibat A05AX05 ofatumumab L04AA52 oteseconazole J02AC06 pamiparib L01XK06 peficitinib L04AA49 pegunigalsidase alfa A16AB20 ponesimod L04AA50 pralsetinib L01EX23 pravastatin and ezetimibe C10BA11 prolgolimab L01XC42 remdesivir J05AB16 rimegepant N02CD06 ripasudil S01EX07 selpercatinib L01EX22 setmelanotide A08AA12 sodium phosphate V03AG05

918 WHO Drug Information, Vol 34, No. 4, 2020 ATC/DDD Classification sotorasib L01XX73 tanezumab N02BG12 tazemetostat L01XX72 tegoprazan A02BC09 teprotumumab L04AA53 tezepelumab R03DX11 tilbroquinol and tiliquinol P01AA30 tilidine and naloxone N02AX51 trafermin D03AX15 trilaciclib V03AF12 ubrogepant N02CD04 vadadustat B03XA08 viltolarsen M09AX12 volanesorsen C10AX18 vosoritide M05BX07 voxelotor B06AX03

Change of ATC level codes:

ATC level names Previous ATC-code New ATC code and name diphenhydramine R06AA021 R06AA11 dimenhydrinate

1: Splitting of ATC code. Products containing dimenhydrinate (rINN)/diphenhydramine teoclate are moved to the new code. Product containing diphenhydramine chloride will remain in R06AA02.

Change of ATC level names:

ATC code Previous ATC-level name New ATC-level name J02AC triazole derivatives triazole and tetrazole derivatives P01AB51 metronidazole, combinations metronidazole and furazolidone P01BB51 proguanil, combinations proguanil and atovaquone

919 ATC/DDD Classification WHO Drug Information, Vol 34, No. 4, 2020

New DDDs:

ATC level name/INN DDD unit Adm.R ATC code abemaciclib 0.3 g O L01EF03 acalabrutinib 0.2 g O L01EL02 afatinib 40 mg O L01EB03 alectinib 1.2 g O L01ED03 alpelisib 0.3 g O L01EM03 amisulpride 7.5 mg P N05AL05 avapritinib 0.3 g O L01EX18 axitinib 10 mg O L01EK01 binimetinib 90 mg O L01EE03 bosutinib 0.4 g O L01EA04 brigatinib 0.18 g O L01ED04 cabozantinib 60 mg O L01EX07 cannabidiol 0.7 g O N03AX24 capmatinib 0.8 g O L01EX17 ceritinib 0.45 g O L01ED02 cobimetinib 45 mg O L01EE02 copanlisib 6.43 mg O L01EM02 crizotinib 0.5 g O L01ED01 dabrafenib 0.3 g O L01EC02 dacomitinib 45 mg O L01EB07 darolutamide 1.2 g O L02BB06 dasatinib 0.1 g O L01EA02 duvelisib 50 mg O L01EM04 encorafenib 0.45 g O L01EC03 entrectinib 0.6 g O L01EX14 erdafitinib 9 mg O L01EX16 erlotinib 0.15 g O L01EB02 esketamine 8 mg N N06AX27 everolimus 10 mg O L01EG02 fedratinib 0.4 g O L01EJ02 gefitinib 0.25 g O L01EB01 gemifloxacin 0.2 g P J01MA15

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gilteritinib 0.12 g O L01EX13 ibrutinib 0.42 g O L01EL01 idelalisib 0.3 g O L01EM01 imatinib 0.4 g O L01EA01 lapatinib 1.25 g O L01EH01 larotrectinib 0.2 g O L01EX12 lenvatinib 18 mg O L01EX08 lorlatinib 0.1 g O L01ED05 luspatercept 3.33 mg P B03XA06 midostaurin 0.1 g O L01EX10 mirogabalin 25 mg O N02BG11 neratinib 0.24 g O L01EH02 nilotinib 0.6 g O L01EA03 nintedanib 0.38 g O L01EX09 osimertinib 80 mg O L01EB04 ozanimod 0.92 mg O L04AA38 palbociclib 94 mg O L01EF01 pazopanib 0.8 g O L01EX03 pemigatinib 9 mg O L01EX20 perhexiline 0.2 g O C08EX02 pexidartinib 0.8 g O L01EX15 ponatinib 45 mg O L01EA05 pralsetinib 0.4 g O L01EX23 regorafenib 0.12 g O L01EX05 remdesivir 0.1 g P J05AB16 ribociclib 0.45 g O L01EF02 ripretinib 0.15 g O L01EX19 ruxolitinib 30 mg O L01EJ01 selpercatinib 0.32 g O L01EX22 semaglutide 10.5 mg O A10BJ06 sodium phosphate 8 g O V03AG05

921 ATC/DDD Classification WHO Drug Information, Vol 34, No. 4, 2020

sorafenib 0.8 g O L01EX02 sunitinib 33 mg O L01EX01 temsirolimus 3.57 mg P L01EG01 tivozanib 1 mg O L01EK03 trametinib 2 mg O L01EE01 tucatinib 0.6 g O L01EH03 vandetanib 0.3 g O L01EX04 velmanase alfa 10 mg P A16AB15 vemurafenib 1.92 g O L01EC01 zanamivir 1.2 g P J05AH01 zanubrutinib 0.32 g O L01EL03

WHO Collaborating Centre for Drug Statistics Methodology Oslo, November 2020

922 WHO Drug Information, Vol 34, No. 4, 2020 ATC/DDD Classification

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 April 2020.

These are considered as final and will be included in the January 2021 version of the ATC/DDD Index.

New ATC 5th level codes:

ATC level name/INN ATC code avapritinib L01EX18 beinaglutide A10BJ07 bempedoic acid and ezetimibe1 C10BA10 cabotegravir2 J05AJ04 capmatinib L01EX17 cenobamate N03AX25 drospirenone and estetrol G03AA18 duvelisib L01EM04 ebola vaccines J07BX02 erdafitinib L01EX16 fenfluramine N03AX26 fosravuconazole D01BA03 inebilizumab L04AA47 influenza, virus like particles J07BB04 lascufloxacin J01MA25 lumasiran A16AX18 lurbinectedin L01XX69 menthae piperitae aetheroleum A03AX15 metadoxine A05BA09 minocycline D10AF07 mometasone, combinations R01AD59 oxymorphone N02AA11 palovarotene M09AX11 pemigatinib L01EX20 pertuzumab and trastuzumab L01XY02 pexidartinib L01EX15 pretomanid J04AK08

923 ATC/DDD Classification WHO Drug Information, Vol 34, No. 4, 2020

relugolix, estradiol and norethisterone H01CC54 ripretinib L01EX19 selumetinib L01EE04 tazarotene and ulobetasol D05AX55 tenapanor A06AX08 tepotinib L01EX21 tirbanibulin D06BX03 tralokinumab D11AH07 trastuzumab deruxtecan L01XC41 triheptanoin A16AX17 tucatinib L01EH03 veliparib L01XK05 vericiguat C01DX22 zanubrutinib L01EL03

1: Alteration of ATC 4th level name to C10BA Combinations of various lipid modifying agents 2: New ATC 4th level J05AJ Integrase inhibitors valid from January 2021

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

ATC level name New ATC code Anaplastic lymphoma kinase (ALK) inhibitors L01ED BCR-ABL tyrosine kinase inhibitors L01EA B-Raf serine-threonine kinase (BRAF) inhibitors L01EC Bruton's tyrosine kinase (BTK) inhibitors L01EL Cyclin-dependent kinase (CDK) inhibitors L01EF Epidermal growth factor receptor (EGFR) tyrosine kinase L01EB inhibitors Hedgehog pathway inhibitors L01XJ Histone deacetylase (HDAC) inhibitors L01XH Human epidermal growth factor receptor 2 (HER2) tyrosine L01EH kinase inhibitors Integrase inhibitors J05AJ Janus-associated kinase (JAK) inhibitors L01EJ Mammalian target of rapamycin (mTOR) kinase inhibitors L01EG Mitogen-activated protein kinase (MEK) inhibitors L01EE Other protein kinase inhibitors L01EX

924 WHO Drug Information, Vol 34, No. 4, 2020 ATC/DDD Classification

Phosphatidylinositol-3-kinase (Pi3K) inhibitors L01EM Poly (ADP-ribose) polymerase (PARP) inhibitors L01XK Proteasome inhibitors L01XG Protein kinase inhibitors L01E Retinoids for cancer treatment L01XF Topoisomerase 1 (TOP1) inhibitors L01CE Vascular endothelial growth factor receptor (VEGFR) tyrosine L01EK kinase inhibitors

Change of ATC level codes:

Alterations as a consequence of new ATC 3rd and 4th levels to be implemented in the ATC Index 2021: J05AJ Integrase inhibitors, L01CE Topoisomerase 1 inhibitors, L01E Protein kinase inhibitors with 4th levels, and 4th levels in L01X Other antineoplastic agents, see list of new ATC level codes (other than 5th levels), see above:

ATC level names Previous ATC-code New ATC code abemaciclib L01XE50 L01EF03 acalabrutinib L01XE51 L01EL02 afatinib L01XE13 L01EB03 alectinib L01XE36 L01ED03 alitretinoin L01XX22 L01XF02 alpelisib L01XX65 L01EM03 axitinib L01XE17 L01EK01 belinostat L01XX49 L01XH04 belotecan L01XX68 L01CE04 bexarotene L01XX25 L01XF03 binimetinib L01XE41 L01EE03 bortezomib L01XX32 L01XG01 bosutinib L01XE14 L01EA04 brigatinib L01XE43 L01ED04 cabozantinib L01XE26 L01EX07

925 ATC/DDD Classification WHO Drug Information, Vol 34, No. 4, 2020

carfilzomib L01XX45 L01XG02 cediranib L01XE32 L01EK02 ceritinib L01XE28 L01ED02 cobimetinib L01XE38 L01EE02 copanlisib L01XX61 L01EM02 crizotinib L01XE16 L01ED01 dabrafenib L01XE23 L01EC02 dacomitinib L01XE47 L01EB07 dasatinib L01XE06 L01EA02 dolutegravir J05AX12 J05AJ03 elvitegravir J05AX11 J05AJ02 encorafenib L01XE46 L01EC03 entinostat L01XX64 L01XH05 entrectinib L01XE56 L01EX14 erlotinib L01XE03 L01EB02 etirinotecan pegol L01XX56 L01CE03 everolimus L01XE10 L01EG02 fedratinib L01XE57 L01EJ02 gefitinib L01XE02 L01EB01 gilteritinib L01XE54 L01EX13 glasdegib L01XX63 L01XJ03 ibrutinib L01XE27 L01EL01 icotinib L01XE48 L01EB08 idelalisib L01XX47 L01EM01 imatinib L01XE01 L01EA01 irinotecan L01XX19 L01CE02 ixazomib L01XX50 L01XG03 lapatinib L01XE07 L01EH01 larotrectinib L01XE53 L01EX12 lenvatinib L01XE29 L01EX08 lorlatinib L01XE44 L01ED05 masitinib L01XE22 L01EX06

926 WHO Drug Information, Vol 34, No. 4, 2020 ATC/DDD Classification

midostaurin L01XE39 L01EX10 neratinib L01XE45 L01EH02 nilotinib L01XE08 L01EA03 nintedanib L01XE31 L01EX09 niraparib L01XX54 L01XK02 olaparib L01XX46 L01XK01 olmutinib L01XE40 L01EB06 osimertinib L01XE35 L01EB04 palbociclib L01XE33 L01EF01 panobinostat L01XX42 L01XH03 pazopanib L01XE11 L01EX03 ponatinib L01XE24 L01EA05 Protein kinase inhibitors L01XE Deleted quizartinib L01XE52 L01EX11 raltegravir J05AX08 J05AJ01 regorafenib L01XE21 L01EX05 ribociclib L01XE42 L01EF02 ridaforolimus L01XE19 L01EG03 rociletinib L01XE37 L01EB05 romidepsin L01XX39 L01XH02 rucaparib L01XX55 L01XK03 ruxolitinib L01XE18 L01EJ01 sonidegib L01XX48 L01XJ02 sorafenib L01XE05 L01EX02 sunitinib L01XE04 L01EX01 talazoparib L01XX60 L01XK04 temsirolimus L01XE09 L01EG01 tivozanib L01XE34 L01EK03 topotecan L01XX17 L01CE01 trametinib L01XE25 L01EE01 tretinoin L01XX14 L01XF01 vandetanib L01XE12 L01EX04 vemurafenib L01XE15 L01EC01 vismodegib L01XX43 L01XJ01 vorinostat L01XX38 L01XH01

927 ATC/DDD Classification WHO Drug Information, Vol 34, No. 4, 2020

Change of ATC level names:

ATC code Previous ATC-level name New ATC-level name C10BA HMG CoA reductase inhibitors Combinations of various lipid modifying in combination with other lipid agents modifying agents C10BX HMG CoA reductase inhibitors, Lipid modifying agents in combination with other combinations other drugs J07BX01 smallpox, live attenuated smallpox vaccines

New DDDs:

ATC level ATC DDD Unit Adm.R Note name/INN code cenobamate N03AX25 0.2 g O ferric maltol B03AB10 60 mg O Fe3+ fosravuconazole D01BA03 0.1 g O expressed as ravuconazole glucagon H04AA01 3 mg N imipenem, J01DH56 2 g P refers to imipenem cilastatin and relebactam lanadelumab B06AC05 21.4 mg P lascufloxacin J01MA25 75 mg O meropenem and J01DH52 3 g P refers to meropenem vaborbactam midazolam N05CD08 5 mg N 10 mg SL trientine A16AX12 0.45 g O expressed as trientine

WHO Collaborating Centre for Drug Statistics Methodology Oslo, November 2020

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