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Review of Developments in GMP and the Regulation of Medicines March 2024




Vol 29.1C
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During the last 4 weeks there have been a number of developments in the regulation of the pharmaceutical industry. This month reported issues have come from the UK, EU, USA, Australia and PIC/S regulatory authorities.

The topics covered in this edition of the “Update” include:

UK MHRA

  • Approvals for Comirnaty (Pfizer/BioNTech) and Nuvaxovid (Novavax) COVID-19 vaccines

  • Pioneering genetic biobank to start recruiting patients on stroke prevention medicines

  • Funding for game-changing tech which could destroy cancers and predict disease

  • Codeine linctus to be reclassified to a prescription-only medicine

  • Update on MHRA safety review of medicines containing pseudoephedrine  

  • First approval via the new International Recognition Procedure (IRP) in 30 days

EU

  • Progress update on pilot for academic and non-profit developers of advanced therapy medicines

  • Q&A on EMA pilot offering enhanced support to academic and non-profit developers of ATMPs

  • Final programming document 2024-2026

  • Launch of new HMA-EMA catalogues of real-world data sources and studies

  • Meeting Summary - Medicine Shortages Single Point of Contact (SPOC) Working Party  

  • Multi-agency report highlights importance of reducing antibiotic use 

  • Pseudoephedrine – Risks of posterior reversible encephalopathy syndrome (PRES) and reversible cerebral vasoconstriction syndrome (RCVS)

  • Concept paper for the development of a reflection paper on a tailored clinical approach in biosimilar development  

  • CTIS newsflash

  • Procedural advice for requests for the classification of variations not already listed in Commission Implementing Regulation.

  • Q&A on quality of herbal medicinal products/traditional herbal medicinal products.


The European Directorate for the Quality of Medicines & HealthCare (EDQM)

  • Top 10 deficiencies in New Applications for Certificates of Suitability for chemical purity 

  • Reference Standards 

USA


  • Reporting Amount of Listed Drugs and Biological Products Under Section 510(j)(3) of the FD&C Act

  • Notifying FDA of a Discontinuance or Interruption in Manufacturing of Finished Products or Active Pharmaceutical Ingredients Under Section 506C of the FD&C Act

  • Assessing COVID-19-Related Symptoms in Outpatient Adult and Adolescent Subjects in Clinical Trials of Drugs and Biological Products for COVID-19 Prevention or Treatment  


International

Australia

Therapeutic Goods Administration


  • Planned update to manufacturing principles for medicines, active pharmaceutical ingredients and sunscreens

  • Reforms to the regulation of vapes


The Pharmaceutical Inspection Co-operation Scheme (PIC/S)

  • Annex 1 Joint implementation working group and GDP Expert circle


Products

  • First oral treatment against residual haemolytic anaemia in patients with paroxysmal nocturnal haemoglobinuria

  • New treatment for rare motor neurone disease recommended for approval


Conferences

  • Webinar - Clinical Trials Information System Last Year of Transition

  • Free webinar - CEP 2.0: Fresh feedback from stakeholders


RECENT DEVELOPMENTS IN GMP AND REGULATORY REQUIREMENTS

UK

MHRA

Approvals for Comirnaty (Pfizer/BioNTech) and Nuvaxovid (Novavax) COVID-19 vaccines  

Approval of a change to the licence of Comirnaty COVID-19 vaccine will enable thawing and re-labelling of the vaccine outside of the NHS.

This new authorisation granted by the MHRA is valid in Great Britain only and was approved via the European Commission (EC) Decision Reliance Route. This is when the marketing authorisation application made by the company references the decision made by the European Medicines Agency (EMA) Committee for Medicinal Products for Human Use (CHMP).

Pioneering genetic biobank to start recruiting patients on stroke prevention medicines  

The Yellow Card Biobank has started investigating a new group of medicines known as Direct Oral Anticoagulants

This pilot launched by the MHRA and Genomics England, will investigate a new group of medicines used to prevent strokes known as Direct Oral Anticoagulants.

The Yellow Card Biobank aims to help understand how a patient’s genetic makeup can impact the safety of their medicines and forms part of a long-term vision for more personalised medicine approaches.

Dr June Raine, the MHRA Chief Executive, said

“We are excited to launch the second phase of the Yellow Card Biobank, which demonstrates that we are at the absolute forefront of innovation in the field of drug safety monitoring. Almost a third of adverse reactions to medicines could be prevented with the introduction of genetic testing. The Yellow Card Biobank will help us move towards our goal of personalised medicine.”

Funding for game-changing tech which could destroy cancers and predict disease

£ millions invested in eight innovative companies behind lifesaving new medical technology which could destroy liver cancer tumours, detect Alzheimer’s and quickly spot those at risk of stroke.

Countless lives could be saved thanks to a multi-million-pound government investment in potential breakthrough medical devices.

As part of a £10 million funding package for boosting access to medical technology, eight innovative tech companies will be supported to bring their devices to market. It could help transform the way we treat some of the biggest causes of death and disability in the UK.

Codeine linctus to be reclassified to a prescription-only medicine

Codeine linctus, an oral solution or syrup licensed to treat dry cough in adults, is to be reclassified to a prescription-only medicine due to the risk of abuse, dependency and overdose, the MHRA announced (20 February 2024).

Codeine linctus is an opioid medicine which has previously been available to buy in pharmacies under the supervision of a pharmacist but will now only be available on prescription following an assessment by a healthcare professional.

The decision to reclassify the medicine has been made following a consultation with independent experts, healthcare professionals and patients. 992 responses were received.

The consultation was launched by the MHRA after Yellow Card reports indicated instances of the medicine being abused, rather than for its intended use as a cough suppressant.

Responses to the consultation identified the pressure pharmacists were under to provide the medicine to those suffering from addiction.

Update on MHRA safety review of medicines containing pseudoephedrine

The MHRA has reviewed the latest evidence relating to the very rare risk of Posterior reversible encephalopathy syndrome (PRES) and reversible cerebral vasoconstriction syndrome (RCVS) associated with medicines containing pseudoephedrine.

Pseudoephedrine is licensed for the symptomatic relief of nasal and sinus congestion in colds, flu, and allergies. It has been used in the UK for decades by millions of people.

Following a careful MHRA review of the latest available evidence, including the assessment of cumulative reporting of adverse drug reaction reports, the safety information of all pseudoephedrine-containing medicines will be updated to provide clearer descriptions of these risks and potential risk factors for these conditions for both patients and healthcare professionals.

This decision follows independent advice from the Pharmacovigilance Expert Advisory Group (PEAG) of the Commission on Human Medicines (CHM) To date, the MHRA has received four Yellow Card reports of suspected PRES or RCVS associated with pseudoephedrine. This is in the context of widespread usage with over 4 million packets sold in the UK in 2022 alone.

First approval via the new International Recognition Procedure (IRP) in 30 days

Launched in January 2024, IRP aims to further help bring life-saving new medicines to UK patients without delay.

A new formulation for XGEVA (denosumab), a treatment used in adults to prevent serious bone-related complications caused by bone metastasis and to treat giant cell tumour of bone in adults and adolescents, is the first product to be authorised by the MHRA via the IRP. The product was authorised in 30 days, providing UK patients with earlier access to this treatment thanks to international recognition.

The product was initially reviewed by the European Medicines Agency (EMA) and received a positive opinion from the EMA’s Committee for Medicinal Products for Human Use (CHMP) on 25 January 2024. The MHRA considered the assessment made by the European regulator as part of its own review, facilitating a rapid approval process.



Europe

European Medicines Agency (EMA)

Progress update on pilot for academic and non-profit developers of advanced therapy medicines  

Following the launch in September 2022, EMA has accepted three academic and non-profit organisations developing ATMPs into a pilot scheme, in which they benefit from enhanced support from the Agency.

The aim is to guide non-commercial developers of promising ATMPs addressing unmet medical needs through the regulatory and scientific requirements in the European Union (EU) and better understand their needs to enable them to advance the development of their medicines and eventually reach the marketing authorisation application stage.

The first participant selected to join at the start of the pilot is the Hospital Clínic de Barcelona which is developing ARI-0001, a chimeric antigen receptor (CAR) product based on patients’ own T-cells.

In a second round which finished in December 2023 a total of 11 candidates had expressed their interest to join the pilot. EMA selected two new participants, both developing gene therapy medicines. TregTacRes, a medicine based on modified T-cells, intended for use as add-on therapy after transplantation and Telethon 003 for the treatment of Wiskott-Aldrich Syndrome, a rare, life-threatening immunodeficiency.

Non-profit academic developers are a major contributor to the development of ATMPs, but experience has shown that navigating regulatory requirements can be challenging. While the pilot does not introduce any new regulatory tools, EMA is committed to support participants in leveraging the use of existing regulatory tools and development support measures.

The selected pilot participants will benefit from fee reductions and waivers Initial results of the pilot are expected in 2025.

Q&A on EMA pilot offering enhanced support to academic and non-profit developers of ATMPs

EMA has recently updated this document

Accelerating Clinical Trials in the EU (ACT EU) – New video released 

Interested readers may wish to watch this short explanatory video to see how EMA believe that ACT-EU is transforming the way that clinical trials are initiated, designed and run. 

Final programming document 2024-2026  

This Q&A page is developed and maintained by the CHMP Biologics Working Party (BWP) and provides agreed positions by the Biologics Working Party position on issues that can be subject to different interpretation or require clarification, typically arising from discussions or correspondence during assessment procedures of biological human medicinal products. 

In order to obtain information on a topic, please click on the topics/questions. Please note that this page has been produced to provide transparency and additional information, and should be read in conjunction with the European Pharmacopoeia, CHMP guidelines on quality and other guidance documents. 

Guideline on quality data requirements for applications for biological veterinary medicinal products intended for limited markets. 

EMA has issued this Single Programming Document (SPD) for 2024 to 2026. This document, reflecting EMA’s expected challenges and goals for the next three years, sets out the final work programme for 2024 as well as medium-and longer-term objectives.

This SPD takes into account plans for the gradual resumption of activities that had been previously suspended or reduced as a result of the public health emergency. It also takes into account the expected impact of the European Commission’s proposal to revise the existing general pharmaceutical legislation.

While EMA will continue to deliver on all its strategic priorities, in 2024 It will put particular focus on three areas:

  • to build on the focus areas for 2023. Ema will continue to use haematology and oncology products as pathfinders to reflect on how it can further improve the Agency's approaches to reviewing critical medicines and thereby help patients access treatments faster.

  • to continue efforts in translating innovation into medicines that reach patients based on better data and evidence generation. Building on the COVID-19 learnings and the revolution in technology and data science

  • to focus on preparing for the revision of the general pharmaceutical legislation and seizing the opportunity to future-proof medicines regulation in the EU, and design innovative ways for implementing changes in the legislation  

Launch of new HMA-EMA catalogues of real-world data sources and studies

EMA and the Heads of Medicines Agencies (HMA) have launched two public electronic catalogues: one for real-world data (RWD) sources and one for WD studies.

The catalogues help medicines regulators, researchers and pharmaceutical companies to identify the most suitable data sources to address specific research questions and support the assessment of study protocols and results. They aim to promote transparency, encourage the use of good practices, and build trust in research based on RWD.

The initiative builds on more than 15 years of operation of the former databases, developed by the European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (ENCePP)

EMA will host a webinar on the catalogues on 4 March 2024

For further information it is suggested that readers with an interest in this field should also access “The Innovative Devices Access Pathway (IDAP)”. (First published 19 September 2023 and last updated 15 February 2024).

This guidance pilot is designed to accelerate the development of innovative medical devices that meet an unmet clinical need in the NHS and support their integration into the UK market.

Meeting Summary - Medicine Shortages Single Point of Contact (SPOC) Working Party

EMA has published a summary of the meeting held on 14 December 2023.  

Multi-agency report highlights importance of reducing antibiotic use

Countries that have decreased their consumption of antibiotics in both animals and humans have seen a reduction in antibiotic-resistant bacteria. This is according to the fourth joint report on the integrated analysis of the consumption of antimicrobial agents and occurrence of antimicrobial resistance (AMR) in bacteria from humans and food-producing animals (JIACRA IV), published by the European Centre for Disease Prevention and Control (ECDC), the European Food Safety Authority (EFSA), and the European Medicines Agency (EMA).

Pseudoephedrine – Risks of posterior reversible encephalopathy syndrome (PRES) and reversible cerebral vasoconstriction syndrome (RCVS)

Pseudoephedrine is authorised, alone or in combination with other substances, for short-term symptomatic relief of nasal or sinus congestion caused by the common cold or allergic rhinitis <or vasomotor rhinitis><or aerotitis>.

Cases of posterior reversible encephalopathy syndrome (PRES) and reversible cerebral vasoconstriction syndrome (RCVS), which are serious conditions affecting the cerebral blood vessels, have been reported in patients taking pseudoephedrine-containing medicines.

Following an EU-wide review of reported cases and other available data to evaluate the risks of

PRES and RCVS with pseudoephedrine-containing medicines, it has been concluded that pseudoephedrine is associated with risks of PRES and RCVS and that the product information should be updated to include information on these adverse reactions and measures to reduce the risks.

Healthcare professionals are requested to report any suspected adverse reactions associated with the use of pseudoephedrine in accordance with the national requirements via the national spontaneous reporting system

Concept paper for the development of a reflection paper on a tailored clinical approach in biosimilar development

Currently, the required comparability exercise comprised quality data (analytical comparability exercise), in vitro and in vivo non-clinical data, and comparative pharmacokinetic, pharmacodynamic, safety and efficacy studies. However, considering the advances in the analytical sciences and the extensive regulatory experience gained, in vivo non-clinical data and, at least for some less complex biologicals with a straightforward mechanism of action, the importance of dedicated clinical efficacy and safety data should be re-evaluated. Currently, the need for Comparative Efficacy Studies (CES) is increasingly questioned

CTIS newsflash

The 9 February 2024 version of this regular CTIS newsflash provides key updates on CTIS and links to useful reference materials.

Key points include:-

  • An updated version of the Q&A on protection of confidential information and personal data in CTIS is now available on the ACT EU website, including the new question 3.4 on patient-facing documents disclosure.

  • New CTIS users can consult the recently published document which includes details on transitioning trials

Procedural advice for requests for the classification of variations not already listed in Commission Implementing Regulation. 

This advice covers veterinary medicinal products that have been authorised through the centralised, mutual recognition, decentralised or purely national procedures. The request shall apply only to variations whose classification is not provided for in the Implementing Regulation or in the EMA/ Coordination group for mutual recognition and decentralised procedures for veterinary medicinal products (CMDv) guidance on variations requiring assessment. This advice does not cover “reclassification” of a variation already listed in the Implementing Regulation or in the EMA/CMDv guidance.

Article 60, paragraph 1, of Regulation (EU) 2019/6 confers on the Commission the obligation to establish a list of variations not requiring assessment.

Commission Implementing Regulation (EU) 2021/17 establishes a list of variations not requiring assessment. Article 62 of the Regulation states that where a variation is not included in the list established in accordance with Article 60(1), a variation requiring assessment shall be submitted.

Q&A on quality of herbal medicinal products/traditional herbal medicinal products.

Revision 7 Nov 2023 of this Q&A has now been published.

The European Directorate for the Quality of Medicines & HealthCare (EDQM) 

 

Top 10 deficiencies in New Applications for Certificates of Suitability for chemical purity

This document is a summary based on the content of a random sample of 30 deficiency letters selected from the year 2023.

During this period the failure of applicants to satisfactorily address some of the deficiencies described below in their application resulted in an increase in the number of questions raised during requests for additional information by EDQM along with their complexity. Consequently, the timeline for granting of the certificate of suitability was increased.

This document is intended to help applicants avoid such issues.

Reference Standards

1 new Ph. Eur. reference standard and 15 replacement batches were released in February 2024

United States of America

Reporting Amount of Listed Drugs and Biological Products Under Section 510(j)(3) of the FD&C Act

FDA is issuing this guidance to assist registrants of drug establishments in submitting reports to FDA on the amount of each listed drug manufactured, prepared, propagated, compounded, or processed for commercial distribution.

This guidance describes the process that should be used for reporting information under section 510(j)(3) by each person who registers with FDA under section 510 of the FD&C Act with regard to a listed drug (including a drug product that is in finished package form, a drug product that is not in finished package form, an active pharmaceutical ingredient (API), and other types of listed drugs, except for biological products or categories thereof exempted by an order under section 510(j)(3)(B)).4 Listed drugs subject to reporting include human drug products (including non-exempt biological products) marketed under an approved application, animal drug products marketed under an approved application, medical gases, homeopathic products, products marketed in accordance with requirements under section 505G of the FD&C Act (21 U.S.C. 355h),6 often referred to as over-the-counter monograph drugs, and animal drug products that are not approved, conditionally approved, or indexed under sections 512, 571, and 572 of the FD&C Act.

An establishment engaged in the manufacture of a drug in the United States is required to be registered with FDA. Likewise, any establishment within a foreign country engaged in the manufacture of a drug that is imported or offered for import into the United States is also required to be registered with the FDA.

Further, domestic and foreign registrants are required to list with FDA all the drugs being manufactured by their registered establishments for commercial distribution. Each registrant must provide certain information for each listed drug it manufactures for commercial distribution, including unfinished drugs and APIs.

These obligations pertain to the registrant (e.g., manufacturers, including contract). Unless the application holder is also the registrant, these obligations do not pertain to the application holder of an approved drug.

In addition, the CARES Act included authorities to enhance FDA’s ability to assess, prevent, and mitigate possible drug shortages by, improving FDA’s visibility into drug supply chains. Section 3112(e) of the CARES Act added section 510(j)(3) of the FD&C Act, which requires that each person (including repackers and relabelers) who registers with FDA under section 510 of the FD&C Act with regard to a drug must report to FDA annually on the amount of each listed drug that was manufactured by such person for commercial distribution.

With earlier awareness of persistent or emerging supply chain challenges, FDA is better informed and able to take more targeted and timely actions to promote stronger supply chains and reduce drug shortage risks.

Notifying FDA of a Discontinuance or Interruption in Manufacturing of Finished Products or Active Pharmaceutical Ingredients Under Section 506C of the FD&C Act

FDA is announcing the availability of a draft guidance for industry entitled “Notification of a Permanent Discontinuance or Interruption in Manufacturing Under Section 506C of the FD&C Act.” The draft guidance is intended to assist applicants and manufacturers in providing FDA timely, informative notifications about changes in the production of certain finished drugs and biological products as well as certain active pharmaceutical ingredients (API) that may, in turn, help the Agency in its efforts to prevent or mitigate shortages. The draft guidance also explains how FDA communicates information about products in shortage to the public.

Assessing COVID-19-Related Symptoms in Outpatient Adult and Adolescent Subjects in Clinical Trials of Drugs and Biological Products for COVID-19 Prevention or Treatment

This final guidance provides sponsors and investigators with considerations for approaches on how common symptoms related to the Coronavirus Disease 2019 (COVID-19) can be measured and analyzed in clinical trials evaluating drugs or biological products2 for the prevention or treatment of COVID-19 in outpatient adult and adolescent3 subjects.4 This guidance is not intended for development programs evaluating products to treat or prevent postinfectious COVID-1922 conditions (e.g., long COVID, multisystem inflammatory syndrome) in children and adults, or development programs for preventative vaccines. This guidance does not address considerations for clinical trial design other than those pertaining to the measurement and analysis of COVID-19 related symptoms among outpatients. Considerations for patients with COVID-19 who require hospitalization are out of scope for this guidance.

FDA is implementing this guidance without prior public comment because the Agency has determined that prior public participation is not feasible or appropriate. FDA made this determination because although the COVID-19-related public health emergency under section 319 of the Public Health Services Act has expired, SARS-CoV-2 continues to circulate, COVID-19 remains a serious health risk for some individuals, and there is a need to ensure that sponsors are aware of FDA’s recommendations to facilitate timely development of drugs and biological products for treatment and prevention of COVID-19. This guidance supersedes the guidance of the same name issued on September 29, 2020.


 

International

Australia

Planned update to manufacturing principles for medicines, active pharmaceutical ingredients and sunscreens

Australia’s current Manufacturing Principles for the manufacture of medicines, active pharmaceutical ingredients and sunscreens is the PIC/S Guide to Good Manufacturing Practice (GMP) – 1 May 2021, PE009-15, except for its Annexes 4, 5, and 14. This version of the PIC/S Guide was adopted on 1 July 2022.

This notification is to advise that TGA is moving to a more recent version and will be adopting the PIC/S Guide to GMP 1 Feb 2022 PE009-16, except for Annexes 4, 5 and 14 on 3 June 2024.

Reforms to the regulation of vapes

Reforms to the regulation of vapes seek to address the significant public health issues caused by vaping, particularly among young people.

Vapes include vaping substances, vaping accessories and vaping devices.


Pharmaceutical Inspection Co-operation Scheme (PIC/S)  

Two recent brief summaries of important meetings have recently been published as News items by PIC/s. [Unfortunately PIC/s has not released any detail of the discussions, other than a very vague / broad summary. Industry, I am sure, would be very much interested to see more detail of the issues / discussions – Particularly those relating to Annex 1 MBH])

  • PIC/S-EMA-WHO Joint Implementation Working Group on Revised Annex 1 (manufacture of sterile medicinal products)

19 January 2024 marked the inaugural kickoff meeting of the PIC/S-EMA-WHO Joint Implementation Working Group, bringing together experts from WHO, EMA, and PIC/S Participating Authorities. The goal is to achieve harmonized interpretation of the newly released PIC/S-EU GMP Annex 1 on Sterile Manufacturing.

  • 6th PIC/S Expert Circle Meeting on Good Distribution Practice (GDP)

The latest meeting included discussions on contemporary issues and latest developments in the field of GDP and supply chain integrity; consolidating lessons learnt during COVID to support uninterrupted supply chain of medicine; sharing experiences between inspectors to improve consistency among inspectors in the field of GDP; and exchanging ideas and fostering collaboration among inspectorates.


Products

First oral treatment against residual haemolytic anaemia in patients with paroxysmal nocturnal haemoglobinuria

EMA has recommended granting a marketing authorisation in the European Union (EU) for Voydeya, the first oral treatment for patients with paroxysmal nocturnal haemoglobinuria (PNH) who continue to have haemolytic anaemia (low levels of red blood cells) despite treatment with a C5 complement inhibitor (eculizumab or ravulizumab).

New treatment for rare motor neurone disease recommended for approval

EMA has recommended granting a marketing authorisation in the European Union for a new therapy for the treatment of adult patients with amyotrophic lateral sclerosis (ALS), a rare and often fatal disease that causes muscles to become weak and leads to paralysis.

Qalsody (tofersen) is indicated for the treatment of adults with ALS, who have a mutation in the superoxide dismutase 1 (SOD1) gene.

Currently, there is only one treatment for ALS (riluzole) authorised in the EU. Patients are offered supportive treatment to relieve the symptoms of the disease, such as physical, occupational or speech therapy and breathing support. There is a large unmet medical need for effective therapies that preserve muscle function and prolong the life of patients with ALS.


Conferences

Webinar - Clinical Trials Information System Last Year of Transition

Monday, 25 March 2024, 13:00 - 17:30 (CET)

The Clinical Trials Information System (CTIS) was launched on 31 January 2022, starting the clock for the three-year transition period from the Clinical Trials Directive to the Clinical Trials Regulation.

Since 31 January 2023, it is mandatory for sponsors to submit all initial clinical trial applications via CTIS. In less than a year, from 31 January 2025 onwards sponsors will need to comply with their obligations under the CTR and its Delegated Acts.

The European Medicines Agency (EMA) is organising this open event to provide:

  • reflection on the implementation of the Clinical Trials Regulation;

  • reflection on transitional trials and how they are updated in CTIS;

  • update on the current status of CTIS.

This EMA-hosted webinar is open to all sponsor organisations, including pharmaceutical companies, contract research organisations, small and medium-sized enterprises (SMEs) and academic organisations.

Free webinar - CEP 2.0: Fresh feedback from stakeholders

09 April 202413:00 to 14:30 (CEST)

The CEP 2.0 was rolled-out in September 2023 to better meet the current needs of stakeholders (enhanced user-friendliness and greater transparency of the information conveyed).

The EDQM invites CEP holders and users to participate in a public webinar to share their experiences on the use of CEP 2.0.

The aim of this webinar is to discuss the benefits, but also the difficulties encountered after implementation and the subsequent changes to submissions.

09 April 202413:00 to 14:30 (CEST, Paris, France)

This webinar is free of charge. However, places are limited, so sign up early.


 

And finally… 

Further information on these and other topics can be found in recent versions of the “Regulatory Update” on the PHSS website (members area) by utilising the hyperlink within that particular Update.

We hope that our readers find our reviews to be both informative and helpful in keeping up to date with pharmaceutical legislation and regulatory guidance.







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