Industrial Pharmacy Journal - Issue 73

4QUALITY BY DESIGN IN PHARMACEUTICAL FORMULATION DEVELOPMENT

by Ranjit Barshikar

10LONG COVID UPDATE

by Geraint Jones

16DIFFERENCES BETWEEN THE MANUFACTURE OF APIs AND MEDICINAL PRODUCTS

by Rainer Gnibl

3EDITORIAL COMMENT

24REGULATORY REVIEW

38BOTTLED BROWN

INDUSTRIAL PHARMACY

Issue 73 February 2023

ISSN 1741 4911

EDITOR

Luigi Martini

PRODUCTION

Sue Feather

SUBSCRIPTIONS

Jill Monk

EDITORIAL BOARD

Harblas Ahir

Michael Anisfeld

Colin Bennett

Neel Bhatt

Patrick Crowley

Harpal Dhillon

Alexander Florence

Michael Gamlen

Amira Guirguis

Ching-Yi Hsu

Ulf Janzon

Trevor M Jones

Stephen Makin

Mark McAllister

Ciara O’Brien

Mahendra Patel

Tim Sandle

Claire Thompson

Industrial Pharmacy is published quarterly by: Euromed Communications

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email address: info@euromedcommunications.com

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Views expressed in Industrial Pharmacy are those of the contributors and not necessarily endorsed by the Publisher, Editor or Editorial Board who accept no liability for the consequences of any inaccurate or misleading information

©2023 Euromed Communications

Cover photo: The cover picture shows an MRI scanner at Cardiff University which is used in the University of Oxford's 'Brain and Brainstem Basis of COVID-19 (BBBCOVID)' study, investigating Long COVID symptoms (see article on page 10)

Dear Colleagues

Welcome to the Seventy Third edition of the Industrial Pharmacy Journal – a journal we believe is essential reading for ALL pharmacists. Actually, that’s not quite correct, as the IP, as we affectionally call it is essential reading for ALL pharmacists and for ALL students who are studying pharmacy and the pharmaceutical sciences. We are therefore delighted to be working with EPSA in the knowledge that we can provide students valuable insights into Industrial Pharmacy and to the world of research and development, manufacturing, marketing, and regulation.

We know that times are difficult, and many students are on low incomes and are struggling to pay for their education. So, we at the Euromed Team are very pleased to announce a special offer for all EPSA students who can now obtain any Euromed pharmacy publication or medical e-book for just 10 euros simply by using the code EPSA10 when you order online. (See page 9 of this issue for further information). We hope that this offer will open access to a wide range of resources and educational material for many students. Material which we believe is diverse, informative, and complimentary to pharmacy curriculums across the globe.

In this issue of IP we have a variety of interesting articles. These range from our lead article on the importance of quality by design in pharmaceutical formulation development, to the differences in the manufacture of active pharmaceutical ingredients (APIs) versus medicinal products, through to an update on the impact of long COVID on people who have been badly affected by the Coronavirus. We also have our regular features – the ever popular ‘Bottled Brown’ by Malcolm Brown and the invaluable ‘Regulatory Review’ by Malcolm Holmes.

We hope you enjoy this edition and find the articles both informative and educational. We at Euromed are always delighted to receive articles and papers in the field of Industrial Pharmacy and Pharmaceutical Sciences.

With best wishes

CALL FOR ARTICLES Dear Colleague

Professor Gino Martini FRPharmS Editor, Industrial Pharmacy

We hope you enjoy Industrial Pharmacy and find it both useful and informative. We are currently seeking new articles for future issues of the journal and would like to invite you to contribute an article or review paper on any aspect of industrial pharmacy to the journal. We are also pleased to receive letters on any aspect of pharmacy or with respect to any article published in the journal. All issues of Industrial Pharmacy are indexed by both Scopus and Embase and thus are available through the listings for all other pharmacist internationally.

Quality by Design in Pharmaceutical Formulation Development

by Ranjit Barshikar

Pharmaceutical Quality by Design (QbD) is now an essential part of Formulation Development –although there is still a lot of confusion on the terminology especially in the generic industry. QbD elements include Quality Target Product Profile (QTPP) and Continual Improvement during Life Cycle Management. QbD tools and studies also include Prior Knowledge, Risk Assessment, Design of Experiments (DoE) and data analysis, and Process Analytical Technology (PAT). As the pharmaceutical industry is now implementing QbD, it has become a common terminology, and understanding the concepts and the expectations are necessary in the manufacture of new products. This understanding will facilitate better communication between those involved in riskbased drug development and ensure a better product for patients.

Dr Ranjit Barshikar is the CEO of QbD International. He is also a United Nations Adviser and an Editorial Board Member of the Journal of Generic Medicines – UK. In a career span of 51 years, he has had a rich and varied experience in the Pharmaceutical and Biotech Industry, especially in Quality Management, R&D, Mfg., Regulatory, FDA/ EU/ WHO compliances. He is an expert on Quality by Design implementation/ Data Integrity compliances/ CAPA/ Quality Culture & various other CGMP subjects. He is also an expert Auditor of “Formulations” and “API” facilities/ CRO etc. To date he has trained more than 1500 scientists in Quality by Design implementation for Formulation, API, Analytical Methods & Packaging Development. Dr Barshikar was a member of the GMP committee of DCGI –Government of India. He was also nominated for the “ICH Expert working Group-Geneva, on CTD QOS”

Introduction

Since the introduction of Qualityby-Design (QbD) concepts, it has been accepted that quality of pharmaceutical products should be designed and built into the manufacturing process. Most of subsequent quality problems are related to the way in which a pharmaceutical product was initially designed. A poorly-

designed pharmaceutical product will show poor safety and efficacy, no matter how many tests or analyses are done to verify its quality. Thus, QbD begins with the recognition that quality will not be improved by merely increasing the testing of pharmaceutical products. In other words, quality must be built into the product at the start.

Quality by Design (QbD) is one of the most important recent initiatives by the US Food and Drug Administration (FDA). At the same time the FDA issued a guideline on Process Analytical Technology (PAT) to guide the pharmaceutical industry to the advantages of PAT in real time release. This was the beginning of the journey towards implementing QbD: the concept based on enhancement of process and product understanding with the help of risk assessments, identifying critical quality attributes and critical process parameters monitored through the correct control strategy. Patients benefit through the consistency in the commercial manufacturing.

US FDA initiative on QbD and its benefits

QbD principles have been adopted by the FDA for the discovery, development, and manufacture of drugs. The FDA initiative was outlined in its 2011 report “Pharmaceutical Quality for the 21st Century: A Risk-Based Approach”1. The FDA took this initiative to guide the pharmaceutical industry on how to implement the concepts of QbD into its processes. The focus on quality has to be built into a product with an understanding of the process by which it is developed and manufactured and with knowledge of the risks involved in manufacturing the product and how best to manage these risks. This new approach results in an improvement over the traditional industry Quality by Testing (QbT) approach (see Table 1).

The FDA defines QbD as a “Systematic approach to development that begins with predefined objectives and emphasises product and process

Traditional

Pharma Development Trial & Error experiments

Mfg. Process Fixed Process

Process Controls In process checks, Offline Testing

Product specifications Primary for Quality Control – Batch Data

QbD Implementation

Systematic approach: Design Space. Multivariate experiments

Proactive to design Quality into Product

Flexible process with Design Space

PAT monitored Online Feedback

Part of Control strategy based on desired Product Performance / Predictability

Risk based controls. PAT real time monitoring Life Cycle Management Reactive actions.

Control Strategy In process Controls Quality by testing

approval

understanding and process control, based on sound science and quality risk management”.

QbD generates robust processes with the help of Quality Risk Management (ICH Q9). It is important to control the “variability” of raw materials themselves as well as in the manufacturing process by identifying critical quality attributes (CQA), critical material attributes (CMA), and critical process parameters (CPP) through a risk management process. It also helps to have a better understanding of process and product, thus helping the life cycle management of the product (LCM) as explained in Figure 1. QbD facilitates design of products and processes that enhances the product’s purity, efficacy and safety in the interest of patients.

While QbD provides design space (DS), the scale-up and commercial manufacturing experience provides knowledge about the process and the interactions of raw materials and excipients used. The FDA published a Process Validation guide in 20112 to assist companies to continually improve throughout the process lifecycle by making adaptations

to ensure that root causes of manufacturing problems are addressed (see Figure 2).

International Conference on Harmonization (ICH) Guidelines

Continuous improvement within Design Space based on Feedback / Feed forward process

Working with regulators in the European Union and Japan, the FDA has improved QbD objectives through the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. ICH introduced the following guidelines: ICH Q8

(Pharmaceutical Development), ICH Q9 (Quality Risk Management), and ICH Q10 (Pharmaceutical Quality System).3 These ICH guidelines improve the understanding to build QbD into formulation development. This ensures that Quality Risk Management and Knowledge Management are used to monitor the lifecycle management that maintain process control and product quality. The difference between QbD for new drug application (NDA) and abbreviated new drug application (ANDA) products is most apparent at the first step of the process.4

Figure 1 Understanding how variables impact on the process by way of identifying critical quality attributes (CQA) and critical process parameters(CPP) through risk assessments, and continuous improvement during life cycle management.

Table 1: Advantages of QbD Implementation over traditional ways of pharma product development.

Post

changes needed.

The FDA has already published two QbD implementation case studies:

1. Quality by Design for ANDAs: An Example for ImmediateRelease Tablets April 20125

2. Quality by Design for ANDAs: An Example for Modified Release Tablets December 20116

These FDA case studies are very good examples of “How to implement the QbD process for product development along with expected risk assessments for initial and amended risks monitoring and documentation”.

Basic Elements of QbD

The six basic elements of QbD are presented in Figure 3 and detailed as follows:

1. Quality target product profile (QTPP) that identifies critical quality attributes (CQAs) of the drug product.

2. Product design and understanding including the identification of critical material attributes (CMAs).

3. Process design and understanding including the identification of critical process parameters (CPPs) and a thorough understanding of scale-up principles, linking CMAs and CPPs to CQAs.

4. Control strategy that includes specifications for the drug substance(s), excipient(s), and drug product as well as controls for each step of the manufacturing process.

5. Process capability and continual improvement.

6. Life cycle management

By obtaining increased process and product understanding in order to identify and monitor critical sources of variability helps to achieve right first-time performance. Therefore, it is essential to shift from compliance to an improved

Figure 2: Continual Improvement / Life Cycle Management

Figure 3: QbD implementation steps

process and product understanding. This results in a QbD of an effective and efficient manufacturing process as well as real time quality assurance.

One of the important goals of QbD is to ensure that all sources of variability affecting a process are identified, explained and managed by appropriate measures (Figure 1). This enables the finished produt to consistently meet its predefined characteristics from the start to achieve ”Right First Time”. QbD focuses on the use of multivariate analysis, often in combination with modern process-analytical chemistry (PAT) methods and knowledgemanagement tools to enhance the identification and understanding of critical attributes of materials and critical parameters of the manufacturing process. This enhanced understanding of product and process is used to build quality into manufacturing and provides the basis for continuous improvement of products and processes. Knowledge gained through such process and product understanding helps monitoring the life cycle management of the product. Figure 2 explains the process and product understanding to support continual improvement.

The regulatory agencies objectives for QbD initiatives are to “Encourage early adoption of new technological advances by the pharmaceutical industry. Facilitate industry application of modern quality management techniques, including implementation of quality systems approaches, to all aspects of pharmaceutical production and quality assurance. Encourage implementation of risk-based

approaches that focus both industry and the agency attention on critical areas. Ensure regulatory review and inspection policies are based on state-of-the-art pharmaceutical science. Enhance consistency and coordination of the FDA’s drug quality regulatory programs, in part, by integrating enhanced quality systems approaches into the agency’s business processes and regulatory policies concerning review and inspection activities”7

Advantages of QbD to the Pharmaceutical Generic Industry

• Better understanding of the process and the product.

• Robust processes

• Minimum batch failures.

• Better understanding of risks involved and mitigation of these risks.

• Minimising variations to achieve consistency in manufacturing quality.

• An enhance QbD approach to pharmaceutical development provides opportunities for more flexible regulatory approaches, for example: manufacturing changes within the approved design space can be made without regulatory review or approval.

• Reduction of post-approval submissions.

• Greater regulator confidence of robust products.

• Innovative process validation approaches.

• More drug availability and less recalls from market.

• Improved yields, lower cost, less investigations, reduced testing, etc.

• Timely launch of products.

• Right first time and every time concept.

• Continuous improvement over the total product life cycle.

• Real time releases through PAT implementation.

• Better return on investment / cost savings.

• More efficient technology transfers.

QbD applications can be applied to drug substance development (ICH Q11), drug product development (ICH Q8), ICH Q13: continuous manufacturing of drug substances (ICH Q13)8 and analytical method development (ICH Q14)9. The FDA has strongly recommended the inclusion of QbD elements in ANDA submissions since January 2013. It should also be implemented for Biopharmaceuticals products.

Quality Culture is the foundation to QbD

• Commitment to quality: Including establishing effective pharmaceutical quality systems and maintaining, and modernising as needed, equipment and facilities.

• Adopting a “Quality Culture”: Stressing importance of product quality from the top down. Decision making with end-user / patient in mind.

• Proactively monitoring products and processes: Using risk-based approaches and modern analytical methods.

• Anticipating supply problems: Arranging for additional manufacturing capacity and developing alternate supply of components.

• Investing in quality and continual improvement: Quality can pay for itself!

Regulatory Agencies like the European Medicines Agency (EMA) have also initiated the QbD concepts implementation. The EU has also released a document for “Real Time Release”. The EMA welcomes applications that include QbD. Quality by design is an approach that aims to ensure the quality of medicines by employing statistical, analytical and riskmanagement methodology in the design, development and manufacturing of medicines.

Industry response to QbD compliance

QbD is becoming the norm. The value of QbD principles is clear and will continue to be integrated into the product development processes. QbD is already expanding its scope into new paradigms such as RTRT(Real Time Real Testing), Continuous Quality Verification, and Analytical Procedure Development. Industry expects this trend to continue. QbD will continue to grow and improve as it becomes more embedded in the pharmaceutical industry. The industry will use more prior knowledge and more risk-based

approaches while developing API, formulations, and analytical procedures. There are now many global publications regarding QbD implementations in formulations development based on US FDA initiatives and ICH Q8(R2), ICH Q9, ICH Q10, ICH Q11, ICH Q12, ICH Q13 and ICH Q14 guidelines. The pharmaceutical industry is now submitting their ANDA documents based on these QbD elements.

Summary

The characteristics of a successful formulations QbD program are as follows:

• Transition from reactive to proactive approach to achieve “Right First Time”.

• Risk based, science based approach.

• Primary focus on patient safety and product quality and efficacy.

• Improvement in product and process understanding.

• Improvement in process capability / robustness / consistency in commercial manufacturing.

•Systematic development, reducing re-working and rejections of the batches.

•Significant reduction in regulatory oversight post approval due to transparent operations.

•Driver to customer satisfaction and business benefits.

References:

1 Pharmaceutical Quality for the 21st Century: A Risk-Based Approach http:// www.fda.gov/aboutfda/centersoffices/o fficeofmedicalproductsandtobacco/cder/ ucm128080.htm 6

2 “Process Validation: General Principles and Practices” (PDF). FDA Guidance.

3 ICH Quality Guidelines 8, 9, and 10.

4 Quality by Design: Concepts for ANDAs. Lionberger RA, Lee SL, Lee LM, Andre Raw A, and Yu LX. APPS J. 2008: 10: 268-276.

5 www.fda.gov/downloads/ Drugs/… /UCM304305.pdf (Immediate Release Tab)

6 www.fda.gov/downloads/ Drugs/… /UCM286595.pdf (Modified Release Tab)

7 Best Practices for the Development, Scale-up, and Post-approval Change Control of IR and MR Dosage Forms in the Current Quality-by-Design Paradigm. AAPS Pharm SciTech (# 2014)

8 ICH Q13: Continuous Manufacturing of Drug substances and Drug Products (July 2021)

9 ICH Q14: Analytical Procedure Development (March 2022)

Long COVID Update

by Geraint Jones

Theauthor, a health-care worker at a hospital in Wales, became infected with COVID-19 in April 2020. This turned into a virulent example of Long COVID which was described in detail in an article featured in Issue 70 of IP last November. A huge number of patients, over 2 million in the UK alone, have been affected by Long COVID. In this followup article the author provides the latest research uncovering some of the debilitating and recurring symptoms that he and many other patients experience and suggesting better treatment options for both adults and children.

As we approach three years since the start of the COVID-19 pandemic, our knowledge continues to grow as we are now expected to ‘live with COVID’ – a stark contrast to the public health messaging that was broadcast in the first few months of 2020. There are worldwide collaborative efforts to try to help understand this novel virus, along with the immunity of those infected and the long-term effects of acute and continued infection. The rapid delivery of the vaccination programme has notably slowed the incidence of patients requiring admission to hospital with COVID-19; however, the risks of Long COVID still remain and many fear that the prolonged levels of disability related to the condition will become increasingly significant over the coming years. In a cross-sectional study, persistent symptoms were still present in 10.1% of infected individuals 12 months after SARSCoV-2 infection1

Given the high level of cumulative incidence of COVID-

19, the absolute prevalent number of people with persistent symptoms is a growing public health concern, and one which needs to be swiftly addressed2, including a conversation around the impact of ‘clean air’ in healthcare settings3. In November 2022, the Office of National Statistics (ONS) released an update on the number of individuals affected by Long COVID in the U.K., reporting that 2.1 million individuals were affected which equates to 3.3% of the entire population. The prevalence of Long COVID was seen to be greater in those aged between 35 and 59 years of age and 6% of respondents were employed within the social care sector, further emphasising employment as a risk-factor for being affected by Long COVID. 1.1 million people report being unwell for over a year, and 507,000 report having symptoms for two years or longer, showing the daily impact on those who contracted COVID-19 in the early stages of the pandemic. There

were also 749,000 individuals reporting symptoms of Long COVID following the Omicron variant which could be argued was likely due to the huge numbers of those infected and combined with COVID restrictions being completely withdrawn throughout the U.K.4,5 These figures also coincide with the updated NICE Guidance ‘COVID19 rapid guideline: managing the long-term effects of COVID-19’6; a much more comprehensive document than the previous year. Sadly, there are individuals who have been gaslighted by clinicians, with some minimising their symptoms or incorrectly attributing them to a mental health diagnosis. Some of those have been so affected that they felt there was no other option but to end their life7,8,9, highlighting how debilitating and isolating the illness can be. There is continued research and mounting evidence that a multitude of post-acute COVID-19 syndromes can develop after SARS-CoV-2 infection and vaccination10; a series of thorough investigations, including imaging and monitoring should be undertaken, now that clinicians are more suitably equipped with a strong evidence base.

The UK Department of Work & Pensions (DWP) have recently reported a 25-fold increase in personal independence payment (PIP) claims relating to Long COVID, with one in five successful claimants receiving the enhanced rates of both components11. The total of both components of PIP allows a payment of £156.90 a week to

Geraint Jones is an advanced pharmacist specialising in HIV and homecare at Cwm Taf Morgannwg University Health Board, Wales.

Source: https://www.nature.com/articles/s44161-022-00177-8/figures/2

the claimant, demonstrating the widespread scale of disability throughout the U.K. and the implication of this on the workforce and the economy.

As ever, the patient-support groups and communities on Twitter were instrumental in sharing guidance and providing support when there was little offered elsewhere, and it’s perhaps quite bittersweet that they remain, being a crutch for those who need that support. Facebook groups allowed strangers to share their experiences of Long COVID, and

since growing to over 50,000 members, strangers have become friends, some turning into patient advocates for the condition. As a healthcare professional, I was quite sceptical of the level of support that peergroups could provide, hearing many ‘horror stories’ where other patients have provided quite dangerous advice, but having been personally affected, my opinion is now one of complete support. Members of the group began sharing personal experiences and financial support and quickly

found themselves speaking in the media and national press, some even featuring and reviewing guidance on Long COVID, and others being accepted as Core Participants in the U.K. Public Inquiry12

It is now acknowledged that everyone, regardless of age, gender, COVID risk factors, vaccination status or comorbidities, can be affected by Long COVID13.

• World-famous popstar Billie Eilish contracted COVID-19 in

Figure 1: Post-infection odds by diagnosis. a, All patients, post-infection. b, Male patients only, post-infection. c, Female patients only, post-infection. GERD, gastroesophageal reflux disease; IDA, iron deficiency anemia.

August 2021. She spoke about her illness in December 2021 and said she was unwell with the virus and that she was still experiencing undisclosed side effects14

• Swiss 800m runner Selina Rutz-Büchel tested positive in April 2021 and has not been able to return to her training routine and in November 2022 announced her retirement from the sport15 Canadian record holder and Olympic 200m champion Andre De Grasse also struggled after testing positive in June 202216 and was not able to fully regain his fitness for the World Athletics Championships in July and was forced to withdraw.

• In November 2022, Australian radio show host Jackie O revealed on air that she is ‘struggling with this fatigue’ and received medical advice to stop working. “Ever since picking up that virus, I’ve been to the doctor several times, and he said it’s because I’ve been pushing myself every day, after the show. All I’ve been doing is sleeping, and I’m not getting better” she added17

• In August 2021, Formula 1 driver Lewis Hamilton said he had been "fighting all year" with his health, after contracting COVID-19 in December 2020. Hamilton said he hadn’t spoken to anyone about it, but that his symptoms were ‘lingering’, also reporting that his training had been ‘different’, and that ‘the levels of fatigue are different and it's a real challenge’18

I’m pleased to say that since last writing for the International

Pharmaceutical Federation (FIP) in November 2021, I’ve made substantial progress with my Long COVID and hope to be nearing the end of an illness which has had a significant impact on my professional and personal life for 32 months. However, this has not been without its challenges having seen all my routine tests throughout this period return unremarkable results. Despite being frustrating, I was determined to understand why I was remaining visibly unwell with marked symptoms, both of which had a significant impact on my day-to-day life. Since the onset of my illness, I had maintained that my body had felt somewhat inflamed and swollen. The fluctuating and wide-ranging symptoms were things that I’d never experienced before; eczema-like rashes on my arms, extreme tiredness, feeling like I’d had memories completely erased and temperature dysregulation. Combined with my gastrointestinal symptoms, cognitive dysfunction and newly diagnosed inappropriate sinus tachycardia, I began wondering how long it would be before I would recover or how long would patients need to wait before there was a test to show what was happening inside our bodies – it is quite a scary thought when you’re going through it.

I read some reports in 2021 of patients in the United States paying to undergo cytokine panels, despite their extortionate costs, with most showing levels of prolonged inflammation which could be targeted by repurposing licensed medications which exist for other conditions. Thankfully there was a small cohort of patients who could undergo these tests in the U.K. for a small fee as IncellDx began to realise

that they were on the cusp of creating the first diagnostic test designed for identifying patients with Long COVID19,20. In May 2022, I attended a private clinic to have my blood tested, and within four-weeks, my results had been analysed and returned (see Table 1). As well as the tests being validating, it also reaffirmed what I felt my body was telling me in the months prior –there was a significant level of inflammation within my body!

I was provided with a personalised treatment plan and given a thorough explanation of my results via a 30-minute video consultation with a U.S. clinician. As the clinician was not based within the U.K., he was unable to prescribe the medications required and I was advised to source them privately from a U.K. based clinician. Despite sharing my results with local clinicians, understandably, they did not feel comfortable to prescribe the medications based on the opinion of another clinician and on the back of an experimental clinical test. Despite there being vast opportunities to purchase medications from overseas (which is quite scary!), and the growing trend of ‘drug tourism’, I opted to investigate other methods of controlling the inflammation, leading me into antiinflammatory diets and further (legal) supplementation.

Since the very outset of becoming infected with COVID19, patients have described ‘brain fog’, mood changes, sleep disorders, along with the now common characteristic of infection, loss of taste and smell – it has been consistent throughout the pandemic that there is some level of neurological impact21. What remains uncertain, and quite

COVID LONG HAULER PANEL

LH CYTOKINE 14 PANEL

IL-29.4HIGHpg/mL<7.0

IL-4138.7HIGHpg/mL<6.2

IL-63.4HIGHpg/mL<3.0

IL-875.2HIGHpg/mL<21.0

IL-102.4HIGHpg/mL<1.0

IL-131.2NORMALpg/mL<6.1

GM-CSF6.4NORMALpg/mL<77.0

SCD40L76440.4HIGHpg/mL<9236.0

COL3 (MIP-1 ALPHA)2.4NORMALpg/mL<33.0

CCL4 (MIP-1 BETA)44.3NORMALpg/mL<93.0

CCL5 (RANTES)20000HIGHpg/mL<11800.0

TNF-ALPHA33.4HIGHpg/mL<11.0

IFN-GAMMA40.3HIGHpg/mL<3.5

VEGF359.6HIGHpg/mL<12.3

LONG HAULER INDEX1.1HIGHINDEX<0.70

concerning, is the impact of repeated COVID-1922. More than one-third of patients who have tested positive, have experienced central or peripheral nervous system involvement, while an approximately threefold higher incidence of neurological symptoms is recorded in observational studies including patient-reported data23

In July 2022, I was invited to be a participant in the Brain and Brainstem Basis of COVID-19 (BBB-COVID) study conducted by the University of Oxford, where the study used a 7 Tesla MRI scanner to look at the effects of COVID-19 on the brain, and how it may potentially predispose some people to future brain conditions. Studies have demonstrated the potential for the virus to reside at immunologically privileged sites throughout the body, which can lead to a protracted course of illness24 and inflammation which could possibly explain the

ongoing, various symptoms that patients routinely exhibit. Perhaps NICE’s term of ‘post-COVID-19 syndrome’ is factually incorrect as patients may not be ‘post’ COVID after all.

Despite experiencing gastrointestinal symptoms for over two years, a decision was made to discharge me from Secondary Care, with ongoing symptoms to be managed under my GP. I’m extremely fortunate to have had a supportive GP who has been willing to learn and understand about my symptoms, also offering emotional and mental health support during the more troublesome periods of such an isolating illness. Having spoken in length, it was agreed that perhaps a short trial of Montelukast could be beneficial having recognised its potential role in helping to control mast cell activation syndrome (MCAS)25; a possible diagnosis given my symptoms and recent results. There has been significant

interest into the role of amyloid fibrin microclots in Long COVID26,27, pioneered by South African researchers, Resia Pretorius and Jacobus Laubscher and U.K. researcher, Douglas Kell. Starting as a brief Twitter interaction between researchers and patients, it quickly became a collective effort to source many fluorescence microscopes to confirm Resia’s early findings, all in aid of finding a cure to help the millions affected by Long COVID. A hashtag, #TeamClots, formed and allowed patients to keep up-to-speed with the progress and research from all around the world. I eagerly followed the research (and having personally spoken with Douglas and Resia about their research), I discovered repeated mentions of Nattokinase28 and Serrapeptase29, proteolytic enzymes which have been studied and found to be beneficial in patients with chronic diseases . Having trialled

Table 1: Long covid cytokine readings from the author

Source: https://pubmed.ncbi.nlm.nih.gov/35198136/

many different supplements over my period of illness, I wasn’t going to let another potential ‘cure’ pass me by.

The first few days of taking Nattokinase and Serrapeptase were awful, I felt like I had relapsed. The only reasonable way I can describe it was as if someone had removed a slowing battery from within me; gradually winding down and then shutting off completely. Around ten days later, and with a lot of perseverance, I started to feel a bit more energised –the physical and mental ‘fog’ was lifting, and I really began to hope that this was the beginning of my recovery.

Currently on a combination of Ivabradine, Montelukast, Famotidine, Fluoxetine, Nattokinase, Serrapeptase, Omega-3, Vitamin D and prebiotics, I’d like to say that I’m back to about 95% pre-COVID

health (with some minor blips and minus my pre-COVID level of fitness). Despite my previous article (see IP 70) seeming one of despair, I feel that there is hope out there for those living with Long COVID and to keep the faith, even in the darkest days, as I know that there are many clinicians and researchers working tirelessly to help you.

I sincerely hope that the sufferers of myalgic encephalomyelitis and chronic fatigue syndrome (ME / CFS) will also benefit from such research, especially where there is further evidence and emergence of more previously unknown post-viral30 conditions such as postural tachycardia syndrome (PoTS)31, autonomic dysfunction32 and mast-cell activation syndrome (MCAS)33. The care, advocacy and support from curious, adventurous clinicians34 has played a critical role in many

journeys of recovery, and I truly hope they are all remembered for their heroic and vital work.

References

1 Robineau O, Zins M, Touvier M, et al Long-lasting Symptoms After an Acute COVID-19 Infection and Factors Associated With Their Resolution. JAMA Netw Open 2022; 5(11): e2240985. https://doi:10.1001/ jamanetworkopen.2022.40985

2 Neville, S. and Cocco, F. (2022) The growing evidence that covid-19 is leaving people sicker, Financial Times. Available at: https://www.ft.com/content/26e0731f15c4-4f5a-b2dc-fd8591a02aec (Accessed: December 13, 2022).

3 Bowles, C. et al. (2022) “A rapid review of supplementary air filtration systems in health service settings. September 2022.” Available at: https://doi.org/ 10.1101/2022.10.25.22281493.

4 Wise, J. (2022) “Covid-19: Long Covid Risk is lower with Omicron than Delta, researchers find,” BMJ [Preprint]. Available at: https://doi.org/10.1136/bmj.o1500.

5 Staff, Z.O.E.E. (2022) Covid: Is Omicron less severe than Delta?, COVID: Is Omicron Less Severe Than Delta? ZOE. Available at: https://joinzoe.com/learn/ covid-omicron-less-severe (Accessed: December 13, 2022).

Figure 2: Potential pathophysiological mechanisms implicated in the manifestation of acute and ‘long-COVID’ manifestations in the central nervous system (CNS).

6 Overview: Covid-19 rapid guideline: Managing the long-term effects of covid-19: Guidance (2022) NICE Available at: https://www.nice.org.uk/guidance/NG188 (Accessed: December 13, 2022).

7 My wife had long covid and killed herself. we must help others who are suffering | Nick Güthe (2022) The Guardian. Guardian News and Media. Available at: https://www.theguardian. com/commentisfree/2022/jan/12/longcovid-wife-suicide-give-others-hope (Accessed: December 13, 2022).

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11 Terry and May, C. (2022) 25 fold increase in Pip Long Covid Awards, one in five getting maximum amount, Benefits and Work. Available at: https://www.benefitsandwork.co.uk/ne ws/25-fold-increase-in-pip-long-covidawards,-one-in-five-getting-maximumamount (Accessed: December 13, 2022).

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16 Harrison, D. (2022) Andre de Grasse has Covid, won't compete this week at track and field nationals in B.C. | CBC sports, CBCnews. CBC/Radio Canada. Available at: https://www.cbc.ca/sports/ olympics/summer/trackandfield/damianwarner-withdrawal-canadianchampionship-knee-injury-1.6494866 (Accessed: December 13, 2022).

17 Cain, S. (2022) 'I'm not getting better': Jackie O steps away from radio show to recover from long covid, The Guardian. Guardian News and Media. Available at: https://www.theguardian. com/media/2022/nov/14/im-not-gettingbetter-jackie-o-steps-away-from-radioshow-to-recover-from-long-covid (Accessed: December 13, 2022).

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19 INCELLDX receives CE-IVD marking for Incellkine Long Covid diagnostic test (2022) Medical Device Network. Available at: https://www.medical device-network.com/ news/incelldx-ceivd-incellkine-long-covid/ (Accessed: December 13, 2022).

20 Patterson, B.K., Tian, J. and Buxton, T. The Need for Precision Medicine in Active and Post COVID-19, incelldx.com. Available at: https://incelldx.com/incelldx-content/ uploads/The-need-for-precisionmedicine-.pdf (Accessed: December 13, 2022).

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22 Bowe, B., Xie, Y. & Al-Aly, Z. Acute and postacute sequelae associated with SARS-CoV-2 reinfection. Nat Med 28, 2398–2405 (2022). https://doi.org/ 10.1038/s41591-022-02051-3

23 Stefanou, M.-I. et al. (2022) “Neurological manifestations of longcovid syndrome: A narrative review,” Therapeutic Advances in Chronic Disease, 13, p. 204062232210768. Available at: https://doi.org/10.1177/ 20406223221076890

24 Baig, A.M. (2021) “Chronic long‐covid syndrome: A protracted COVID‐19 illness with neurological dysfunctions,” CNS Neuroscience & Therapeutics, 27(12), pp. 1433–1436. Available at: https://doi.org/10.1111/cns.13737

25 Long COVID low histamine diet: Allergy UK: National Charity (2021) Allergy UK | National Charity. Available at: https://www.allergyuk.org/resources/res ponse-to-long-covid-mcas-and-lowhistamine-diet/ (Accessed: December 13, 2022).

26 Kell, D.B., Laubscher, G.J. and Pretorius, E. (2022) “A central role for amyloid fibrin microclots in long COVID/PASC: Origins and therapeutic implications,” Biochemical Journal, 479(4), pp. 537–559. Available at: https://doi.org/10.1042/bcj20220016

27 Grobbelaar, L.M. et al. (2022) “Relative hypercoagulopathy of the SARS-COV-2 beta and delta variants when compared to the less severe omicron variants is related to TEG parameters, the extent of fibrin amyloid microclots, and the severity of clinical illness,” Seminars in Thrombosis and Hemostasis, 48(07), pp. 858–868. Available at:

https://doi.org/10.1055/s-0042-1756306

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29 Tiwari, M. (2017) “The role of serratiopeptidase in the resolution of inflammation,” Asian Journal of Pharmaceutical Sciences, 12(3), pp. 209–215. Available at: https://doi.org/10.1016/j.ajps.2017.01.003

30 “Long covid: An opportunity to focus on post-acute infection syndromes” (2022) The Lancet Regional HealthEurope, 22, p. 100540. Available at: https://doi.org/10.1016/j.lanepe.2022.10 0540

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34 Bath expert joins scientists around the world calling for international consensus to fight covid-19 (2022) University of Bath. Available at: https://www.bath.ac.uk/announcements /bath-expert-joins-scientists-around-theworld-calling-for-internationalconsensus-to-fight-covid-19/ (Accessed: December 13, 2022).

Differences between the manufacture of APIs and medicinal products

by Rainer Gnibl

There are many parallels between the good manufacturing practice (GMP)- compliant manufacture of active pharmaceutical ingredients (APIs) and the production of medicinal products, as the comparison of EU Guidelines to GMP Part I for medicinal products and EU Guidelines to GMP Part II for APIs show. There are however also a number of important differences to be considered if manufacturers of APIs are to stay within the official requirements, thus ensuring GMP compliance.

As GMP inspector for the Government of Upper Bavaria and the EMA, Dr Rainer Gnibl (rainer.gnibl@reg-ob.bayern.de) is responsible for carrying out national and international inspections of manufacturers of medicinal products and active ingredients. He is Head of the national expert group EFG 02 GMP Inspections/GMP Guidelines, and lectures at the Friedrich-Alexander University in Erlangen-Nurnberg.

The goal of this article is not to compare, contrast or measure in detail the GMP requirements for the manufacture of APIs in accordance with the EU Guidelines to GMP Part II with those for the manufacture of medicinal products in accordance with the EU Guidelines to GMP Part I. It is rather to work out the essential differences or possible gaps for the area of APIs in contrast to the no doubt more familiar specifications for the area of medicinal products. The following remarks are guided by the structure of the EU Guidelines to GMP Part II.

Objective and scope

The first difference follows directly from the scope of application of the two GMP regulations. While the EU

Guidelines to GMP Part I is clearly fully applicable from the first step in the manufacture of medicinal products, the requirements for the applicability of the EU Guidelines to GMP Part II to the production of APIs are not always clear.

The question of the point at which the requirements of the EU Guidelines to GMP are applicable to the different process steps in the manufacture of APIs depends on the type of API or the manufacturing process. A detailed overview can be found in the introduction to the EU Guidelines to GMP Part II (see Figure 1).

The manufacture of sterile APIs constitutes a special case. The definition here is that the EU Guidelines to GMP Part II is only applicable until immediately before the sterilisation step, and that sterilisation or aseptic

processing must then take place under the requirements of the EU Guidelines to GMP for medicinal products in conjunction with Annex 1. This is also consistently reflected in the scope of Annex 1.

Quality management Organisation and responsibility

The so-called quality unit as set out in Chapter 2.3 of the EU Guidelines to GMP Part II, which is independent of production, has an extended area of responsibility: it is also responsible for the quality control of the intermediates and APIs produced. This is particularly clear in Chapter 11.10 of the EU Guidelines to GMP Part II, which explicitly requires that the quality unit should have suitable laboratory facilities at its disposal. The division into the three areas of quality assurance, production and quality control traditional for medicinal products is therefore no longer applicable here. The only distinction made is between responsibilities of the quality unit and the responsibility for production activities (EU Guidelines to GMP Part II, Chapter 2.13). The responsibilities of the quality unit or units are described in detail in Chapter 2.3, and the responsibility for production activities in Chapter 2.4 of the EU Guidelines to GMP Part II.

Release to the market

The step of release to the market of APIs and intermediates must also be performed by the quality unit. In contrast to medicinal products, the release may not only be performed by qualified persons in accordance with EU

Type of ManufacturingApplication of this Guide to steps (shown in grey) used in ths type of manufacturing Chemical Production of Introduction of Production ofIsolation andPhysical Manufacturingthe API Startingthe API StartingIntermediate(s)purificationprocessing, MaterialMaterialinto processand packaging

API derived fromCollection of Cutting, mixing, Introduction of theIsolation andPhysical animal sourcesorgan, fluid, and/or initial API Starting Materialpurificaitonprocessing or tissueprocessingand packaging

API extracted fromCollection Cutting and Introduction of the Isolation andPhysical plant sourcesof plantinitial API Starting Materialpurificationprocessing, extraction(s)into processand packaging

Herbal extractsCollection

Cutting andFurtherPhysical used as APIof plantsinitialextractionprocessing extractionand packaging

API consisting ofCollection ofCutting/Physical comminuted orplants and/orcomminutingprocessing, or powdered herbscultivation and and packaging harvesting

Biotechnology:Establishment Maintenance Cell culture and/orIsolation andPhysical fermentation/of master cell of working fermentationpurificationprocesisng, cell culturebank and working cell bankand packaging cell bank

“Classical”Establishment Maintenance ofIntroduction of theIsolation andPhysical Fermentation toof cell bankthe cell bankcells into fermentationpurificationprocessing produce an API and packaging

Increasing GMP requirements

Guidelines to GMP Part I Chapter 2.6, but also by specified, authorised persons (EU Guidelines to GMP Part II, Chapter 2.14).

Product quality review

As compared to the manufacture of medicinal products, the scope of the product quality review, which must be conducted on a regular basis, is reduced in the area of APIs with regard to the qualityrelevant parameters to be assessed. The required contents are clearly defined in the EU Guidelines to GMP Part II,

Chapter 2.60. The exact wording of the guide should however not be understood to mean that the product quality review only covers the finished API, i.e. only the last stage of the synthesis process.

The product quality review should instead also extend to intermediates, possibly even the entire synthesis route. This would seem logical if only because of the fact that the reliability of a process is determined not only by the last step, but that consistent quality of the intermediate products (comparable to bulk medicinal products) is indispensable. This is

the only way to verify the validity of a process, which is indeed precisely the intention of the product quality review. For this purpose, a risk-based determination by the manufacturer is to be expected with respect to the stage of manufacture of APIs from which the product quality check is to be carried out.

Personnel Training

The following requirements are explicitly formulated for personnel engaged in API

Figure 1. Application of the EU Guide to GMP to API manufacturing.

operations (EU Guidelines to GMP Part II, Chapter 3.12).

• Regular conduct of training.

• Qualified trainers.

• Training content in accordance with the operations that the employee performs.

• GMP content in accordance with the function of the employee.

• Archiving of training documentation.

• Periodic assessment of training measures.

• Regular planning and implementation of GMP training courses in accordance with the programme.

This means that the requirements for the training of personnel in the area of APIs are not set out in as much detail as for medicinal products (EU Guidelines to GMP Part I, Chapters 2.8 to 2.12).

Health monitoring

The requirement for preventive and continuous health monitoring of employees by means of initial and follow-up medical examinations (as in medicinal product operations) can only be indirectly inferred from Chapter 3.24 of the EU Guidelines to GMP Part II. Persons suffering from an infectious disease or having open lesions on the exposed surface of the body should not engage in activities that could result in compromising the quality of APIs.

Consultants

As compared to the EU Guidelines to GMP Part I, Chapter 3.3 of Part II requires

only that API manufacturers must maintain records for external consultants advising on manufacture and control, including the following.

• Name.

• Address.

• Qualifications.

• Type of service provided.

To ensure suitability, however, qualification of the external service provider with regard to the outsourced activity, as is explicitly required for the manufacture of medicinal products, is also to be expected here.

Buildings and facilities

For buildings, facilities and process equipment, the basic requirements for manufacturing plants for APIs and medicinal products are very similar. There are however differences in some areas. For example, where the equipment itself provides adequate protection of the material (e.g. closed or contained systems), such equipment used in API operations can be located outdoors (EU Guidelines to GMP Part II, Section 4.12).

Water quality

In the manufacture of APIs, the process water must, at a minimum, meet the World Health Organization (WHO) requirements for drinking (potable) water quality. The minimum requirement here is therefore not – as required for the manufacture of medicinal products – in the specification of the European Pharmacopoeia for purified water (Aqua purificata). However, if the WHO

requirements for drinking water appear to be insufficient, the active substance manufacturer should establish tighter specifications for the following.

• Physical and chemical attributes.

• Total microbial counts.

• Objectionable organisms.

• Endotoxins.

If a non-sterile API is to be used for sterile medicinal products, water used in the final isolation and purification steps should be monitored and controlled for the following (EU Guidelines to GMP Part II, Chapter 4.3).

• Total microbial counts.

• Objectionable organisms.

• Endotoxins.

More detailed specifications on the water quality to be used in the production of active substances are set out in the European Medicines Agency (EMA) Guideline on the Quality of Water for Pharmaceutical Use (EMA/CHMP/CVMP/QWP/49687 3/2018).

Containment

With the amendment of Chapters 3 and 5 of the EU Guidelinese to GMP Part I, a further difference to the manufacture of medicinal products follows. The decisionmaking basis for determining whether production must be carried out in dedicated facilities or whether production can be carried out in shared facilities, and how in the case of shared facilities the technical and organisational measures to avoid cross- contamination are to be

established is now set out in much greater detail for medicinal products. In this context, the calculation of the acceptance criterion for cleaning validation should also be mentioned. According to the International Council for Harmonisation (ICH) questions and answers paper on ICH Q7, an alternative calculation basis for the Maximum Allowable Carryover by means of the Occupational Exposure Limit is also acceptable in the area of APIs, whereas only the Permitted Daily Exposure is accepted for the area of medicinal products. In addition, for the production of highly sensitising active substances (such as penicillins or cephalosporins), dedicated production areas are still categorically required. In the case of APIs, this should also be considered for products of an infectious nature or high pharmacological activity or toxicity.

Sewage and refuse

In contrast to the manufacture of medicinal products, sewage and refuse are explicitly considered in Chapter 4.6 of the EU Guidelines to GMP Part II. Sewage, refuse and other waste (e.g. solids, liquids or gaseous by-products from manufacturing) in and from buildings and the immediate surrounding area should be disposed of in a safe, timely and sanitary manner. Containers and/or pipes for waste material should be clearly identified.

Process equipment

Computerised systems

Computerised systems are covered in a separate chapter of

the EU Guidelines to GMP Part II (Chapter 5.4), where they are dealt with in much greater detail than in Part I for the manufacture of medicinal products, as the then valid version of Annex 11 to the EU Guidelines to GMP, “Computerized Systems”, was no longer consistent with the best available science and technology at that time. However, with the implementation of the revised Annex 11 on 30 June 2011, it now also fully covers the requirements set out in Chapter 5.4 of the EU Guidelines to GMP Part II.

Documentation and records

Archiving periods

The archiving period for batch and distribution records for APIs is formulated differently than in the area of medicinal products. For example, all production, control and distribution records should be retained for at least 1 year after the expiry date of the batch. For APIs with retest dates, records should be retained for at least 3 years after the batch is completely distributed (EU Guidelines to GMP Part II, Chapter 6.13). Note: There are APIs that have an expiry date and there are APIs that have a retest date. Both are possible and the decision is left to the API manufacturer.

Materials management

With regard to materials management (EU Guidelines to GMP Part II, Section 7), the following special features should be noted.

• If the supplier of a critical material is not the manufacturer of that material, the name and address of the original manufacturer should be known to the supplier (Chapter 7.13).

• Before incoming materials are mixed with existing stocks (e.g. solvents or stocks in silos), they should be identified as correct, tested, if appropriate, and released. A procedure should be available to prevent discharging incoming materials wrongly into the existing stock (Chapter 7.21).

• If bulk deliveries are made in non-dedicated tankers, there should be assurance of no cross- contamination from the tanker. Means of providing this assurance could include certificates of cleaning, testing for trace impurities or audits of the supplier (Chapter 7.22).

• Supplier approval for materials for production should include an evaluation that provides adequate evidence (e.g. past quality history) that the manufacturer can consistently provide material meeting the relevant specifications. Before reducing in-house testing, full analyses should be conducted on at least three batches. However, as a minimum, a full analysis should be performed at appropriate intervals and compared with the Certificates of Analysis (CoA). The reliability of CoA should be checked at regular intervals (Chapter 7.31).

Production and in-process controls

Out-of-specification results

As compared to the production of medicinal products, it is clearly established for the production of APIs that investigations of out-ofspecification test results are not normally needed for in-process controls in accordance with the master batch record that are performed for the purpose of monitoring and/or adjusting the process (EU Guidelines to GMP Part II, Chapter 8.36).

Blending of batches

The blending of batches is a special feature of the manufacture of APIs that is dealt with in Chapter 8.4 of the EU Guidelines to GMP Part II, where blending is defined as the process of combining materials within the same specification with the goal of producing a homogeneous intermediate or API.

By contrast, combining fractions of a single batch or combining fractions from several batches for further processing is considered to be part of the production process. For the purposes of blending, each individual batch must comply with the specification and its compliance must have been tested. Blending can thus be used for example to increase batch size or to combine tailings (i.e. relatively small quantities of isolated material) from batches of the same intermediate or API to form a single batch. For blending, the following requirements apply.

• The blended batch should be fully tested with regard to the product specification.

• If necessary, additional stability samples should be created.

• The expiry or retest date should be determined on the basis of the oldest batch.

• The documentation of the blending process should ensure traceability back to the individual batches used.

• If the API has critical physical attributes (e.g. particle size distribution, bulk or tap density), the blending process should be validated.

Handling of residual materials

If there is adequate control, the carryover of residual materials into successive batches of the same intermediate or API is expressly permitted. Examples of this include residues on the walls of a microniser, a centrifuge or a vessel (EU Guidelines to GMP Part II, Chapter 8.50). The maximum permissible campaign length or batch number within a campaign must be observed.

Packaging and labelling

In API operations, there are a number of special features to be noted for packaging for shipment. Intermediate or API containers that are transported outside of the manufacturer’s control should be sealed in a manner such that, if the seal is breached or missing, the recipient can detect a damaged or missing seal and be alerted to the possibility that the contents may have been altered (EU Guidelines to GMP Part II, Chapter 9.46).

Laboratory controls

Impurity profile

The impurity profile should be regarded as an essential quality characteristic for intermediates and APIs. An impurity profile describing the identified and unidentified impurities present in a typical batch produced by a specific controlled production process should normally be established for each API. It should include the identity or some qualitative analytical designation (e.g. retention time), the range of each impurity observed, and classification of each identified impurity (e.g. inorganic, organic, solvent). The impurity profile is normally dependent upon the manufacturing process in question and is therefore to some extent characteristic of the manufacturer and thus of the origin of the API. It should be compared at appropriate intervals against the impurity profile in the regulatory submission or compared against historical data in order to detect changes to the API resulting from modifications in starting materials, equipment operating parameters, or the production process. The acceptable impurity profile should be adapted to the current state of knowledge about the manufacturing process. Impurity profiles are normally not necessary for APIs from herbal or animal tissue origin (EU Guidelines to GMP Part II, Chapters 11.21 and 11.22).

Certificate of Analysis

The impurity profile is therefore part of the CoA which, as a whole, documents the quality of the intermediate or API and identifies both the specified

acceptance criteria and the actual results of analysis. The CoA should be signed by an authorised person of the quality unit and should identify the original manufacturer. This means that the original manufacturer of the product can be identified at any time, including for a repacker or reprocessor. If new CoAs have been issued as a result of new testing, the laboratory should also be indicated on the CoA. A copy of the original CoA should be enclosed with the new CoA (EU Guidelines to GMP Part II, Chapter 11.4).

Retest date

In contrast to medicinal products, APIs are not usually assigned an expiry date, but rather a retest date based on the results of stability testing (EU Guidelines to GMP Part II, Chapter 11.61). However, a successful retest after expiry of the initially declared retest date qualifies only for direct use of the batch in the production of medicinal products, and expressly not for extension of the retest date by the initial validity period. Reprocessing in order to extend the retest date or to define a new date of manufacture after batch release is also not GMP-compliant and is therefore not acceptable.

Retention periods for reserve/retention samples

The stipulation for the archiving period for reserve/retention samples is that they should be retained, properly labelled for each batch, for 1 year after the expiry date assigned by the manufacturer or for 3 years after distribution of the batch. The

longer period in each case is applicable. For APIs with retest dates, similar reserve samples should be retained for 3 years after the batch is completely distributed by the manufacturer (EU Guidelines to GMP Part II, Chapter 11.71).

Validation

Validation and qualification are the subject of a separate section in the EU Guidelines to GMP Part II (Section 12). In contrast, the requirements in this regard for the production of medicinal products in Part I are scattered across various sections. However, if their contents are compared while at the same time taking account of Annex 15 of the EU Guidelines to GMP “Qualification and Validation”, there are no significant differences in the basic strategy, implementation and documentation of qualification and validation activities. With regard to the extent and scope of validation measures, however, and, in particular, process and cleaning validation in the area of the manufacture of APIs, there may well be differences to the manufacture of medicinal products. For example, in the manufacture of medicinal products, application of the EMA Guideline on Setting Health Based Exposure Limits for Use in Risk Identification in the Manufacture of Different Medicinal Products in Shared Facilities should be considered obligatory for calculation of the acceptance criterion for cleaning validation.

Change control

One real difference to the information set out in the EU

Guidelines to GMP Part I for medicinal products is Section 13 of Part II “Change Control”, where the change control system to be implemented as part of the quality assurance system is dealt with in much greater detail than in Part I in Sections 13.10 to 13.17.

Rejection and re-use

The requirements for the reprocessing and reworking of intermediates or APIs that do not meet the specification provided are specific to the API.

Reprocessing

Where the issue at hand here is only repetition of a process step that is part of the routine process and thus of the master batch record, the term used is reprocessing. Examples of reprocessing include repetitions of crystallisation, distillation, filtration, chromatography or milling. Introducing unreacted material back into a process and repeating a chemical synthesis step is also considered to be reprocessing, unless it is part of the established process in the master batch record. Against the background of quality considerations, however, a careful evaluation with regard to the formation of by-products and over-reacted materials should be carried out and documented prospectively. However, the continuation of a process step if the in-process control test has shown that the desired end point has not yet been reached is not to be considered reprocessing. Reprocessing is generally acceptable, but should be included in the master batch record if it is used on a regular

basis (EU Guidelines to GMP Part II, Chapters 14.20 to 14.22).

Reworking

If a material that does not conform to the specification is subjected to a new process step that is not part of the routine manufacturing process and therefore not part of the master batch record, the term used is reworking. This must be documented in a report, subjected to appropriate evaluation and provided with additional tests and stability samples to ensure that it is of equivalent quality to the routine process. A comparison of the impurity profiles for the reworked and routine product must also be taken into account. Concurrent validation is recommended for reworking. The cause of the deviation from the specification should also be investigated before any reworking is initiated (EU Guidelines to GMP Part II, Chapters 14.30 to 14.32).

Recovery

The recovery of reactants, intermediates, APIs or solvents is also acceptable under defined conditions and is probably more specific for the production of

APIs than for the manufacture of medicinal products. Remarks on the requirements made by the authorities and to be fulfilled by the manufacturer can be found in Chapters 14.40 to 14.43 of the EU Guidelines to GMP Part II.

Agents, brokers, traders, distributors, repackers and relabellers

Section 17 of the EU Guidelines to GMP Part II sets out GMP requirements for agents, brokers, traders, distributors, repackers and relabellers of intermediates and APIs. Here again, this topic primarily characterises the area of APIs rather than medicinal products. The relevant provisions apply to any party other than the original manufacturer who may trade and/or take possession, repack, relabel, manipulate, distribute or store an API or intermediate. In addition, the EU good distribution practice requirements specific to APIs in accordance with the Guidelines on Principles of Good Distribution Practice of Active Substances for Medicinal Products for Human Use should also be taken into account.

APIs for clinical trials

The 19th and final section of the EU Guidelines to GMP Part II sets out provisions governing the production of APIs for use in clinical trials. There is no comparable section in the EU Guidelines to GMP Part I, as the relevant requirements for medicinal products are set out in Annex 13 to the EU Guidelines to GMP “Investigational Medicinal Products”.

GMP-Verlag Peither AG specialises in providing current GMP information. GMP-Verlag Peither serves as a platform for GMP knowledge and has become a trusted partner for all GMPrelated questions and publications. The main product is the GMP Compliance Adviser (https://www.gmppublishing.com/en/gmpcompliance-adviser/). This paper is an extract of the extensive advice provided in GMP Compliance Adviser.

regulatory review

International

UK Medicines & Healthcare products Regulatory Agency (MHRA) Return to International GMP Inspections

International travel is now becoming easier to organise and less likely to suffer unexpected disruption

Since April 2022, GMP Inspectors have been taking part in a pilot programme to evaluate a potential return to international onsite GMP inspections. Considerations include whether the risk to inspectors is acceptable, and whether we can make efficient use of our inspectors’ time.

MHRA are pleased to announce that the pilot was successful, and it is now resuming its programme of international onsite GMP inspections.

There will still be restrictions on the countries that MHRA are able to travel to, particularly those that still have a requirement for international travellers to quarantine on arrival, so that we can make the most efficient use of limited inspection time.

MHRA will be adopting a riskbased approach, prioritising inspections with the greatest

impact on UK public health and patient safety. MHRA will do this in conjunction with its product licence assessors and using existing risk-based inspection (RBI) tools. Whilst implementing this return to international inspections, MHRA asks that sites do not contact them asking to arrange a routine inspection or to enquire about when they can expect their inspection to be; MHRA will make contact when it is able to arrange each inspection.

European Commission Decision Reliance Procedure (ECDRP) available until 31 Dec, 2023

The ECDRP allows a company to submit a product that has received approval from the EMA to the MHRA. The MHRA can grant a licence with a lighter touch review than they would normally conduct for that medicinal product, relying on the EMA’s decision.

The MHRA has extended the ECDRP to apply until 31 December 2023, the continuation of the EC DRP includes variations and extensions.

Horizon Scanning Case Study: Developing standards for Adenoassociated virus gene therapies

Horizon scanning at the MHRA leads to external funding being secured, helping our scientists work in a new area of standardisation that will support developers and manufacturers of AAV gene therapies. Horizon scanning identified a need for

standardisation of AAV products to support developers and manufacturers of these therapies, and to enable patients to access these innovative products but to also ensure they are regulated appropriately and are safe and effective. Together with colleagues at the UK Cell & Gene Therapy Catapult CGTC, MHRA secured funding from the Regulators Pioneer Fund (RPF).

The CGTC produced and purified a batch of AAV2 material using their new state of the art bioreactors and facilities at Braintree.

The materials are now being evaluated by multiple external collaborators, from industrial stakeholders to academic laboratories, and its ‘fitness for use’ as a reference material is being assessed.

MHRA appoints first new UK Approved Body to certify medical devices since Brexit MHRA has confirmed that DEKRA Certification UK Ltd has now joined the three current UK Approved Bodies, increasing the UK’s capacity to process conformity assessments for medical devices.

There are a further six organisations who are currently in the assessment process and there is active engagement with several further organisations who are preparing to submit their initial submission.

Medical devices: guidance for manufacturers on vigilance

The manufacturer, UK Responsible Person or Authorised Representative shall notify the MHRA about incidents and field safety corrective actions (FSCAs) which meet the reporting criteria; this includes Periodic Summary Reports (PSR) and Trend Reports.

The manufacturer has the responsibility for investigating

The current review period has seen a number of changes in the regulation of medicines and regulatory guidance in the UK, EU, USA and certain

markets.

incidents and for taking any corrective action necessary.

The manufacturer should also ensure that these guidelines are made known to their UK Responsible Person or Authorised Representative, to enable their UK Responsible Person or Authorised Representative to fulfil their obligations.

Department for Business, Energy & Industrial Strategy (BEIS)

funding to unlock digital, data and scientific regulatory innovation

MHRA has received a total of £970,688 from BEIS’ Regulators’ Pioneer Fund for three projects that aim to unlock cutting edge regulatory innovation, to drive real world benefits for patients, the healthcare sector and clinical research.

The first project has been awarded £750,387 to tackle the challenges of finding control groups for clinical trials, through the development of alternative synthetic datasets.

The second project

(£167,863) aims to address the issue of how to safely introduce complex ‘black-box’ AI products into clinical settings, so that clinicians can be confident that the decision from the AI device is appropriate and suitable in that specific context.

The third project has been awarded £52,438 to explore the development of guidelines around regulating microbiome therapeutics and diagnostics, a rapidly emerging field that poses a challenge for regulators and companies due to its novel and complex nature.

The US Food and Drug Administration (USFDA) Planning for the Effects of High Absenteeism to Ensure Availability of Medically Necessary Drug Products. The guidance encourages manufacturers of medically necessary drug products (MNPs) and components to develop production plans in the event of an emergency that results in high absenteeism at one or more production facilities. The purpose of the guidance is to provide to industry considerations for developing plans for these types of emergencies, as well as to discuss the Center for Drug Evaluation and Research's (CDER's) intended approach to assist in avoiding drug product shortages that may have a negative impact on the national public health during such emergencies.

Size, Shape, and Other Physical Attributes of Generic Tablets and Capsules

Tablets and capsules are widely manufactured and prescribed and may provide a number of advantages over other dosage forms, including ease of storage, portability, ease of administration, and accuracy in dosing. While generic formulations of these drug products are required to be both pharmaceutically and therapeutically equivalent to a reference listed drug (RLD),2 we are concerned that differences in physical characteristics (e.g., size and shape of the tablet or capsule) may affect patient compliance and acceptability of medication regimens or could lead to medication errors. FDA

believes these patient safety concerns are important, and is recommending that generic drug manufacturers consider physical attributes when they develop quality target product profiles (QTPPs) for their generic product candidates.

The recommendations in this guidance apply to abbreviated new drug applications (ANDAs) and their supplements for additional strengths that are submitted to the Office of Generic Drugs (OGD).

This guidance does not apply to approved ANDAs (generic drugs) already on the market. However, if the Agency determines that an approved product should be modified because the size or shape of a product poses a risk to public health, it will notify the holder of the ANDA.

This guidance revises the guidance of the same name issued in June 2015 to clarify that the largest dimension of a tablet should not exceed 22 mm and that capsules should not exceed a standard 00 size.

Physicochemical and Structural (Q3) Characterization of Topical Drug Products Submitted in ANDAs

This guidance is intended to assist applicants who are submitting abbreviated new drug applications (ANDAs) for liquid-based and/or other semisolid products applied to the skin, including integumentary and mucosal (e.g., vaginal) membranes, which are hereinafter called topical products.

Because of the complex route of delivery associated with these products, which are typically locally acting, and the potential complexity of certain

formulations, topical products (other than topical solutions) are classified as complex products.

This guidance provides recommendations for physicochemical and structural (collectively, Q3) characterizations that can be used to identify the dosage form of a proposed generic (test) topical product and to describe properties of the drug product that may be critical to its performance (to support a demonstration of bioequivalence (BE).

In Vitro Release Test Studies for Topical Drug Products Submitted in ANDAs

This guidance is intended to assist applicants who are submitting ANDAs for liquidbased and/or other semisolid products applied to the skin, including integumentary and mucosal (e.g., vaginal) membranes, which are hereinafter called topical products. Because of the complex route of delivery associated with these products, which are typically locally acting, and the potential complexity of certain formulations, topical products (other than topical solutions) are classified as complex products. This guidance provides recommendations for in vitro release test (IVRT) studies that can be used to compare a proposed generic (test) topical product and its reference standard (RS) for the purpose of supporting a demonstration of bioequivalence (BE) to the reference listed drug (RLD).

In Vitro Permeation Test Studies for Topical Drug Products Submitted in ANDAs

This guidance provides recommendations for in vitro

permeation test (IVPT) studies comparing a proposed generic (test) topical product and its reference standard (RS) for the purpose of supporting a demonstration of bioequivalence (BE) to the reference listed drug (RLD).

Failure to Respond to an ANDA Complete Response Letter Within the Regulatory Timeframe Guidance for Industry

This guidance is intended to assist applicants of abbreviated new drug applications (ANDAs), which were submitted under section 505(j) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) (21 U.S.C. 355(j)), in responding to complete response letters (CRLs) from FDA. As described in regulation, ANDA applicants are required to take action after receiving a CRL. The guidance revises the guidance of the same title issued in July 2022. This revision is being issued to incorporate the performance goals outlined in the Generic Drug User Fee Amendments Reauthorization Performance Goals and Program Enhancements Fiscal Years 20232027 (GDUFA III commitment letter). This guidance provides information and recommendations regarding potential courses of action for an ANDA applicant after issuance of a CRL, as well as the actions that FDA may take if the applicant fails to respond to that CRL.

Review of Drug Master Files in Advance of Certain ANDA Submissions Under GDUFA

This draft guidance is intended for holders of Type II active pharmaceutical ingredient (API) drug master files (DMFs) that will be referenced in an abbreviated new drug application (ANDA), or

a prior approval supplement (PAS) to an ANDA.

Specifically, this guidance describes instances when an early assessment, or “DMF prior assessment,” could be requested by a DMF holder and the circumstances under which FDA would commence an early assessment of Type II API DMFs 6 months prior to an ANDA or PAS submission referencing the DMF. It also provides recommendations for such DMF holders when making a request.

Facility Readiness: Goal Date Decisions Under GDUFA

This guidance provides information to applicants on how FDA intends to assign a goal date based on a facility’s readiness for inspection as certified on Form FDA 356h, submitted as part of an original abbreviated new drug application (ANDA) under section 505(j) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) (21 U.S.C. 355(j)).

Competitive Generic Therapies

The FDA Reauthorization Act of 2017, or FDARA, created a pathway by which FDA may, at the request of the applicant, designate a drug with “inadequate generic competition” as a competitive generic therapy (CGT). At the request of the applicant, FDA may also expedite the development and review of an abbreviated new drug application (ANDA) for a drug designated as a CGT. This guidance provides a description of the process that applicants should follow to request designation of a drug as a CGT and the criteria for designating a drug as a CGT. It also includes information on the

actions FDA may take to expedite the development and review of ANDAs for drugs designated as CGTs. Finally, it provides information on how FDA implements the statutory provision for a 180-day exclusivity period for certain first approved applicants that submit ANDAs for CGTs.

including a biological product, as these factors may relate to the safety or effectiveness of the product.

ANDAs: Pre-Submission Facility Correspondence Related to Prioritized Generic Drug Submissions

FDA and ANDA Applicants of Complex Products Under GDUFA

Formal Meetings Between

This guidance describes an enhanced pathway for discussions between FDA and a prospective applicant preparing to submit to FDA or an applicant that has submitted to FDA an ANDA for a complex product, as defined in this guidance. Specifically, this guidance provides information on requesting and conducting product development meetings, pre-submission meetings, midcycle review meetings, enhanced mid-cycle review meetings, and post-complete response letter scientific meetings with FDA.

This guidance revises the guidance issued in November 2020.

Comparability Protocols for Postapproval Changes to the Chemistry, Manufacturing, and Controls(CMC) Information in an NDA, ANDA, or BLA

This final guidance is intended to assist original applicants and holders of NDAs, ANDAs, and BLAs with implementing a CMC postapproval change through the use of a comparability protocol (CP). A CP is a comprehensive, prospectively written plan for assessing the effect of proposed postapproval CMC change(s) on the identity, strength, quality, purity, and potency of a drug product,

FDA is issuing this revised draft guidance to incorporate program enhancements related to the content, timing, and assessment of a pre-submission facility correspondence within the abbreviated new drug application (ANDA) assessment program agreed upon by the Agency and industry as part of the reauthorization of the Generic Drug User Fee Amendments (GDUFA III). This guidance replaces the November 2017 draft guidance for industry

Controlled Correspondence Related to Generic Drug Development

This guidance provides information regarding the process by which generic drug manufacturers and related industry or their representatives can submit to FDA controlled correspondence requesting information related to generic drug development. This guidance also describes the Agency’s process for providing communications related to such correspondence.

Compounding Certain Beta-Lactam products in shortage under section 503a of the federal FD&C act

This guidance describes the FDA regulation and enforcement priorities regarding preparation of beta-lactam oral antibiotic suspension products that appear on FDA’s drug shortage list by a licensed pharmacist in a Statelicensed pharmacy or Federal

facility. There is currently an acute shortage of amoxicillin oral antibiotic powder for suspension. Amoxicillin oral antibiotic powder for suspension products currently appear on FDA’s drug shortage list. Amoxicillin is widely used for the treatment of bacterial upper and lower respiratory infections in the pediatric population, among other uses. As a result of this shortage, there is an urgent need to increase the supply of these beta-lactam oral suspension products. FDA has received a number of reports related to increased demand for amoxicillin oral antibiotic suspension products in particular. FDA has also received requests for clarification about preparation of compounded versions of those products from FDA-approved tablets and capsules.

This guidance is being implemented without prior public comment because FDA has determined that prior public participation for this guidance is not feasible or appropriate. This guidance document is being implemented immediately because of the public health need for amoxicillin oral antibiotic suspension products, but it remains subject to comment in accordance with the Agency’s good guidance practices.

[‘Interesting’ risk based decision making by the FDA- but make sure you read the whole document MBH]

Cross Labeling Oncology Drugs in Combination Regimens

Drug approvals in oncology often build on treatment effects by adding drugs to current regimens or by combining investigational drug products in a combination

regimen, creating new regimens with greater efficacy.

The purpose of this guidance is to describe the FDA’s current recommendations about including relevant information in labeling for oncology drugs approved for use in a combination regimen, including important considerations for cross labeling of these drugs.

Applicants proposing cross labeling for oncology drug combination regimens should contact the review division for information on cross labeling of their individual products.

This guidance does not address circumstances in which a drug product and a biological product packaged separately constitute a cross-labeled combination product as defined in 21 CFR 3.2(e).

Sameness Evaluations in an ANDA — Active Ingredients

This draft guidance is intended to assist applicants preparing an abbreviated new drug application (ANDA) by providing recommendations on demonstrating sameness between the active ingredient in a proposed generic drug product and its reference listed drug (RLD)

Statistical Approaches to Establishing Bioequivalence

Requirements for submitting bioavailability (BA) and bioequivalence (BE) data in investigational new drugs (INDs), new drug applications (NDAs), abbreviated new drug applications (ANDAs), and supplements; the definitions of BA and BE; and the types of in vitro and in vivo studies that are appropriate to measure BA and establish BE are set forth in part 320 (21 CFR part 320). This guidance provides

recommendations on how to meet provisions of part 320 for all drug products.

Q5A(R2) Viral Safety Evaluation of

biotechnology products

derived

from cell lines of human or animal origin

This guideline concerns the testing and evaluation of the viral safety of biotechnology products, and it outlines what data should be submitted in marketing application and registration packages for those products. Biotechnology products include biotherapeutics and certain biological products derived from cell cultures initiated from characterised cell banks of human or animal origin (e.g., mammalian, avian, insect). In this document, the term “virus” excludes non-conventional transmissible agents like those associated with mammalian prions (e.g., bovine spongiform encephalopathy, scrapie). Applicants are encouraged to discuss bovine spongiform encephalopathy-associated issues with the appropriate regulatory authorities.

Hypertension Indication: Drug Labeling for Cardiovascular Outcome Claims

This guidance is intended to assist applicants in developing labeling for cardiovascular outcome claims for drugs that are indicated to treat hypertension. With few exceptions, current labeling for antihypertensive drugs includes only the information that these drugs are indicated to reduce blood pressure; the labeling does not include information on the clinical benefits related to cardiovascular outcomes expected from such blood pressure reduction.

FDA believes that the appropriate use of these drugs can be encouraged by making the connection between lower blood pressure and improved cardiovascular outcomes more explicit in labeling. This guidance recommends standard labeling for antihypertensive drugs except where differences in labeling are supported by clinical data.

European Union

European Commission (EC) European Directorate for the Quality of Medicines (EDQM) Joint EDQM–EPAA event on the future of pyrogenicity testing: phasing out the rabbit pyrogen test

In June 2021, the Ph. Eur. Commission took the decision to engage on a path that should ultimately lead to the complete replacement of the rabbit pyrogen test (RPT) in the Ph. Eur. within approximately 5 years. There are a number of Ph. Eur. texts – covering a variety of topics, including vaccines for human use, blood products, antibiotics, radiopharmaceuticals and containers – that refer to the RPT and will be affected by this decision.

The Ph. Eur. Commission is committed, for all these texts, to replacing the test for pyrogens with a suitable in vitro alternative, leading to the complete elimination of the RPT.

A three-day event, from 14 to 16 February 2023, in Brussels, Belgium, will focus on the future of pyrogenicity testing.

Thefts, losses & diversions of medicinal products

The Committee of Experts on Minimising Public Health Risks Posed by Falsification of Medical Products and Similar Crimes

(CD-P-PH/CMED) has prepared a Council of Europe (CoE) Recommendation on reporting of unaccounted disappearances of medicinal products for human and veterinary use from the legal supply chain. To better formulate this recommendation a CoE-wide survey was carried out in 2021 targeting health regulatory authorities to get their views on the situation.

The goal of this project is to draft a Committee of Ministers recommendation to member states in order to involve health authorities at an early stage by obliging stakeholders to report thefts, losses or diversions of medicines to them; to provide guidance on how authorities should deal with the information they receive and the follow-up action to be taken; and to promote international cooperation.

How CEP holders can avoid the rejection of notifications.

In order to facilitate the acceptance of proposed changes in a timely manner, CEP holders are reminded that the European Directorate for the Quality of Medicines & HealthCare (EDQM) Guideline on requirements for revision/renewal of Certificates of Suitability to the European Pharmacopoeia Monographs (PA/PH/CEP (04) 2, 7R corr) lists different notifications and associated conditions, and that any change not classified as a notification or a major change should be classified as a minor change by default (with the exception of editorial changes for which specific guidance is given in the policy document). If the change cannot be classified by the document and specifically as a notification, a minor revision (by default) should be submitted.

Any submission of a notification which includes changes not classifiable as a notification will be rejected and the changes will then need to be resubmitted using the correct classificationwith associated documentation and fee.

[give it a read and avoid delay and duplication of effort for both regulator and applicant. MBH]

“CEP of the future”: second project update

Since conducting a wide public survey on the Certification of suitability to the European Pharmacopoeia monographs (CEP), EDQM has been working on the design of the CEP of the future.

Different aspects were presented to stakeholders at three targeted consultation workshops in September 2022. The EDQM’s CEP of the future project team will analyse the feedback received during these discussions with the decisionmaking bodies to fine tune the design of the CEP of the future. The EDQM will then initiate a large communication campaign to explain the proposed changes.

CEP holders invited to comment on draft monographs

Holders of CEPs are requested to consult the list of substances for which draft revised monographs of the European Pharmacopoeia (Ph. Eur.) have been published in Pharmeuropa 34.4. The substances affected by these revisions and for which a CEP has been granted are:Acamprosate calcium (1585), Aluminium oxide, hydrated (0311), Calcitriol (0883), Mefloquine hydrochloride (1241), Oxytetracycline dihydrate (0199) and Suxamethonium chloride (0248)

Changes to CEP policy regarding chemical applications for polymorphs

EDQM has recently modified its policy on chemical applications for polymorphs. A request for a CEP for a specific polymorphic form (as a grade) is now possible even if the statement “the substance shows polymorphism” is not mentioned in the “Characters” section of the corresponding individual monograph in the Ph. Eur.

Agreement expanding the scope of co-operation in the field of substances of human origin

The Council of Europe (EDQM) and the European Union (EU), through the European Commission, have concluded a new contribution agreement, with equal financing, which will run until 2024. This agreement further enhances their already well-established co-operation in the field of substances of human origin (SoHO).

SoHO, such as blood, organs, tissues and cells, are used in essential therapies that save lives and improve the quality of life of millions of Europeans every year.

The agreement will contribute to providing all Council of Europe member states, including the EU 27, with a coherent European regulatory SoHO framework and to supporting professionals of the sector in implementing this framework and in strengthening their SoHO systems.

General chapter 2.2.46. Chromatographic separation techniques: comparison of requirements in the Ph. Eur. 10th and 11th Editions

A new document has been added to the knowledge Database page for revised general chapter 2.2.46, under

Additional Information. This document provides a useful and easy reference guide to the main changes made to the general chapter recently published in the 11th Edition of the Ph.Eur (PDG harmonised chapter) versus the 10th Edition version.

New FAQs on the application of revised general chapter 2.2.46 (11.0) have been added to the existing series of FAQs.

Ph. Eur. publishes Cannabis flos draft monograph in Pharmeuropa for comment

The draft text covers the herbal drug defined as dried, whole or fragmented, fully developed shoot apices of female cultivars of Cannabis sativa L. It is to be read in conjunction with the general monograph Herbal drugs (1433), which includes additional requirements that are applicable unless otherwise stated in the Cannabis flos draft.

Joint EDQM–EPAA event on the future of pyrogenicity testing: phasing out the rabbit pyrogen test

In June 2021, the Ph. Eur. Commission took the decision to engage on a path that should ultimately lead to the complete replacement of the rabbit pyrogen test (RPT) in the Ph. Eur. within approximately 5 years. There are a number of Ph. Eur. texts – covering a variety of topics, including vaccines for human use, blood products, antibiotics, radiopharmaceuticals and containers – that refer to the RPT and will be affected by this decision.

The Ph. Eur. Commission is committed, for all these texts, to replacing the test for pyrogens with a suitable in vitro alternative, leading to the complete elimination of the RPT.

A three-day event, from 14 to 16 February 2023, in Brussels, Belgium, will focus on the future of pyrogenicity testing.

Please also note that new FAQs on the application of revised general chapter 2.2.46 (11.0) have been added to the existing series of FAQs.

Reference standards

EDQM has announced the release of 12 new and 26 replacement batches of Ph. Eur. reference standards. It also announces immediate and or future removal of several other reference standards.

European Paediatric Formulary: Chloral Hydrate Oral Solution monograph open for public consultation in Pharmeuropa PaedForm

EDQM has just released Issue 5 of Pharmeuropa PaedForm, in which the draft text for Chloral hydrate 100 mg/mL Oral Solution is published for public consultation prior to its inclusion in the European Paediatric Formulary. The deadline for comments on the text in Pharmeuropa PaedForm is 31 March 2023.

The European Paediatric Formulary gathers together, at European level, monographs on formulations for extemporaneous preparations that are either described in national formularies or well established in Europe. Once these monographs (which are not legally binding) have been approved by the European Pharmacopoeia Commission and adopted by the European Committee on Pharmaceuticals and Pharmaceutical Care, they are made available to pharmacists and clinicians to help them prepare paediatric

medicines when no authorised alternative is available.

European Paediatric Formulary: Revised Phosphate Oral Solution monograph published

EDQM has published the revised monograph Phosphate 60 mg/mL Oral Solution in the European Paediatric Formulary (PaedForm). This revised monograph (the first PaedForm text to undergo revision) was published in Issue 4 of Pharmeuropa PaedForm, approved by the European Pharmacopoeia Commission (EPC) and recently adopted by the European Committee on Pharmaceuticals and Pharmaceutical Care (CD-P-PH).

European Medicines Agency (EMA)

Concept Paper on the revision of EU-PIC/S GMP Annex 11 (Computerised Systems)

See the entry in the international section of this Update report under PIC/S.

DARWIN EU® welcomes first data partners

EMA has selected the first set of data partners to collaborate with DARWIN EU®, the Data Analysis and Real-World Interrogation Network. The data available to these partners will be used for studies to generate real-world evidence that will support scientific evaluations and regulatory decision making. Real-world evidence refers to information derived from analysis of real-world data, which is routinely collected data about a patient’s health status or delivery of healthcare from a variety of sources other than traditional clinical trials.

The selected partners include both public and private

institutions. The common feature is that they all have access to real-world healthcare data from one or more sources such as hospitals, primary care, health insurance, biobanks, or disease-specific patient registries. The data partners will provide the DARWIN EU® Coordination Centre with results of analyses of these data.

With the onboarding of data partners, EMA has initiated the launch of the first three studies to be provided by DARWIN EU®. One study will focus on the epidemiology of rare blood cancers to inform on their prevalence in Europe. The second study is on drug use of valproate and the third one is looking at the use of antibiotics to inform future work on antimicrobial resistance.

New Quality Innovation Expert Group (QIG) supports medicine innovation

EMA has established a Quality Innovation Expert Group (QIG) to support innovative approaches for the development, manufacture, and quality control of medicines for the benefit of patients in the European Union (EU). These include, but are not limited to, new technologies, digitalisation, novel materials and novel devices, in line with the priorities highlighted in EMA’s Regulatory Science Strategy to 2025.

The role of the QIG is to ensure that the European medicines regulatory network keeps pace with innovation, identifies and addresses gaps in the regulatory framework and increases predictability for developers of innovative technologies. The group will also be a forum for exchange and interaction within the EU

regulatory network, as well as between EU regulators and stakeholders such as academia and industry. Considering that development and manufacturing of medicines is global in nature, the QIG also aims to establish close collaboration with international partners to facilitate global regulatory convergence.

Sales of antibiotics for animal use have almost halved between 2011-2021

EMA’s annual report on the European surveillance of veterinary antimicrobial consumption (ESVAC) shows that, since 2011, European countries have substantially reduced sales of veterinary antibiotics in animals. According to data from 25 countries that continuously provided input for the full 2011-2021 period, overall sales of veterinary antibiotics decreased by 47% in this interval, reaching the lowest value ever reported.

Sales of antibiotic classes considered critically important in human also decreased noticeably between 2011 and 2021 and accounted for only 5.5% of total sales in 2021. Sales of third and fourth generation cephalosporins dropped by 38%, polymyxins by 80%, fluoroquinolones by 14% and sales of other quinolones dropped by 83%. These antibiotics should be used prudently and responsibly to preserve their effectiveness and mitigate the potential risk to public health, as indicated in the Antimicrobial Ad Hoc Expert Group (AMEG) categorisation.

“The positive results reflect the efforts of veterinarians, farmers and pharmaceutical industry to reduce the use of antibiotics to prevent

antimicrobial resistance. It also shows that European Union (EU) policy initiatives and national campaigns promoting prudent use of antibiotics in animals are having a positive impact,” said Ivo Claassen, Head of EMA’s Veterinary Medicines Division.

Reflection paper on the application of Article 40(5) of Regulation (EU) 2019/6 for certain categories of variations Recital 33 of Regulation (EU) 2019/61 reasons that “Tests, pre-clinical studies and clinical trials represent a major investment for companies...” which “should be protected in order to stimulate research and innovation...” and “similar protection of investments should be applied to studies supporting a new pharmaceutical form, administration route or dosage that reduces the antimicrobial or antiparasitic resistance or improves the benefit-risk balance”. For variations involving a change to the pharmaceutical form, administration route or dosage, Article 40(5) of Regulation (EU) 2019/6, building on this highlevel objective, envisages four years of protection of technical documentation to the results of the concerned pre-clinical studies or clinical trials assessed to have demonstrated:

a) a reduction in the antimicrobial or antiparasitic resistance, or

b) an improvement of the benefit-risk balance of the veterinary medicinal product (VMP).

Whereas Article 40(5) provides the abovementioned high-level criteria (a) and (b), it will be necessary to elaborate more

detailed scientific criteria to ensure a clear and consistent interpretation.

This reflection paper aims to provide an overview of the CVMP’s considerations to date, taking into account the comments received during the public consultation of the concept paper preceding this reflection paper (20 July to 21 September 2020), as well as during a workshop with stakeholders held by the EMA on 15 October 2020. Closing date for comments is 28 Feb 2023.

IRIS guide for Parallel Distribution applicants

This guide has been produced to help individuals using the IRIS | Regulatory & Scientific Information Management platform understand how to use the portal to submit a notification for parallel distribution.

High-quality data to empower data-driven medicines regulation in the European Union

EMA and the Heads of Medicines Agencies (HMA) in the EU Member States are moving ahead with their ambitious agenda to increase access and improve the quality of the data that underpin decision-making on the benefits and risks of medicines in the European Union (EU).

The draft Data Quality

Framework for EU medicine regulation, sets out quality criteria for data used in medicine regulation to ensure they are fit for purpose to support benefitrisk decisions. The framework addresses principles and procedures that apply across data types and across regulatory activities. It also provides considerations on data quality, definitions for data dimensions

and sub-dimensions, as well as their characterisation and related metrics.

The second document is a draft good practice guide for the use of the EU metadata catalogue of real-world data sources. The guide provides recommendations on how to use the catalogue of real-world metadata that is currently being built and in late 2023 will replace the existing catalogue.

The public consultation ended 16 November 2022.

International Australia Therapeutic

Goods Association (TGA)

Standard for serialisation and data matrix codes commences 1 January 2023

If you include data matrix codes or serialisation on your medicines, you need to be ready for the requirements set out in TGO 106.

TGO 106 was introduced in 2021 to give clarity for adopters of serialisation and data matrix codes on medicines supplied in Australia.

TGO 106 aligns with global standards to give consistency for sponsors and manufacturers operating in multiple jurisdictions and to allow international interoperability. Both the standard and guidance were developed with stakeholder input and incorporated feedback received during consultation.

The International

Coalition of

Medicines Regulatory

Authorities

(ICMRA) Best practices to fight antimicrobial resistance

The ICMRA highlights successful regulatory and non-regulatory

interventions used in different countries to address the growing public health problem of antimicrobial resistance (AMR) in a new report.

Tackling AMR is one of ICMRA’s strategic priorities. ICMRA recognises that AMR is a complex, multifaceted problem and calls for better coordination across all sectors, including public health, animal health and the environment, through a ‘One Health’ approach. A concerted and collaborative effort is essential to address this threat to global health, economies and security effectively.

The report presents case studies on best practices from different countries that were developed in line with the ‘One Health’ approach.

The Pharmaceutical Inspection Co-operation Scheme (PIC/S) Concept Paper on the revision of EU-PIC/S GMP Annex 11 (Computerised Systems)

A dedicated European Medicines Agency (EMA) Drafting Group, in which PIC/S is represented has developed a concept paper on the revision of Annex 11 (computerised systems) of the EU-PIC/S GMP Guide.

This concept paper is submitted to a joint PIC/S-EMA public consultation from 16 November 2022 until 16 January 2023 and can be downloaded on the PIC/S website.

The current version was issued in 2011 and does not give sufficient guidance within a number of areas already covered, and other areas, which are becoming increasingly important to GMP, are not covered at all. The revised text will expand the guidance given in the document and embrace the application of new

technologies which have gained momentum since the release of the existing version.

If possible, the revised document will include guidelines for acceptance of AI/ML algorithms used in critical GMP applications. This is an area where regulatory guidance is highly needed as this is not covered by any existing regulatory guidance in the pharmaceutical industry and as pharma companies are already implementing such algorithms.

Switzerland Agreement with the USA in the field of GMP for pharmaceuticals

On December 16 2022 the Federal Council approved the agreement between Switzerland and the USA on the mutual recognition of inspections in the field of GMP for pharmaceuticals. The agreement aims to facilitate trade in pharmaceuticals and reduce the administrative burden for the industry. The agreement is expected to come into force in the course of 2023. According to the applicable requirements in Switzerland and the USA, pharmaceuticals must be manufactured in accordance with internationally agreed rules of GMP. Compliance with these rules during manufacture is inspected on site by the national authorities. These inspections are a prerequisite for the approval of medicinal products in many countries - including Switzerland and the USA. Swissmedic is the competent authority in Switzerland and the US FDA.

In the absence of an agreement, pharmaceutical production sites are usually inspected not only by national authorities but also by the

authorities of the importing countries. Between Switzerland and the USA, the authority of the importing country should now be able to rely on the inspection of the partner authority based on the present agreement. The approval of medicinal products will continue to be assessed independently by the national authorities.

In order for the agreement to take effect, a corresponding assessment of whether the domestic requirements are met by the other authority must be completed. Completion of this assessment is expected in mid2023.

[It is really good to see another MRA getting under way. MBH]

World Health Organization (WHO) Substandard (contaminated) paediatric medicines

This WHO Medical Product Alert refers to four substandard products, identified in The Gambia and reported to WHO in September 2022.

The four products are Promethazine Oral Solution, Kofexmalin Baby Cough Syrup, Makoff Baby Cough Syrup and Magrip N Cold Syrup. The stated manufacturer of these products is Maiden Pharmaceuticals Limited (Haryana, India). To date, the stated manufacturer has not provided guarantees to WHO on the safety and quality of these products.

Laboratory analysis of samples of each of the four products confirms that they contain unacceptable amounts of diethylene glycol and ethylene glycol as contaminants. To date, these four products have been identified in The Gambia, but may have been distributed, through informal markets, to other countries or regions.

[Tragic incidents such as this involving diethylene glycol and ethylene glycol (anti freeze) as contaminants particularly in children’s cough syrups amazingly continue to be an ongoing issue despite the problem being well known. It is long past time it was stopped.

For a harrowing read from US FDA look up “Taste of Raspberries, Taste of Death: The 1937 Elixir Sulfanilamide Incident”.

[There have been several repeat incidents resulting in multiple child deaths since that time MBH]

Products

New vaccine to protect people in the EU and worldwide against dengue

EMA’s human medicines committee (CHMP) has adopted a positive opinion for Dengue Tetravalent Vaccine (live, attenuated) Takeda, used to prevent disease caused by dengue virus serotypes 1, 2, 3 and 4 in people from four years of age.

According to WHO, there are approximately 390 million dengue infections per year worldwide, with an estimated death rate of 20,000 to 25,000 per year, primarily in children. Before 1970, only nine countries had experienced severe dengue epidemics, while today the disease is endemic in more than 100 countries, including in Europe. It is the second mostdiagnosed cause of fever after malaria among travellers returning from low- and middleincome countries.

This is the first time the CHMP simultaneously reviews a medicinal product meant for the European Union (EU) market, under the centralised procedure and non-EU countries, under the ‘EU-medicines for all’ programme

– or EU-M4all. EMA's initiative to support parallel aplications for the EU-M4all opinion and the centralised procedure aims to make innovative or generic medicines and vaccines that address unmet medical needs or are of major public health interest available in Europe and globally faster, while avoiding duplication of efforts from regulators.

[Another example of regulators working together in a faster / smarter way to bring about early benefit to patients. MBH]

First gene therapy to treat haemophilia B

EMA has recommended granting a conditional marketing authorisation in the European Union (EU) for Hemgenix (etranacogene dezaparvovec) for the treatment of severe and moderately severe haemophilia B in adults who do not have factor IX inhibitors (auto-antibodies produced by the immune system which make factor IX medicines less effective).Hemgenix is the first gene therapy to treat haemophilia B. It is delivered as a single infusion. Etranacogene dezaparvovec, the active substance in Hemgenix, is based on a virus (adeno-associated virus or AAV) which has been modified to not cause disease in humans. The virus contains copies of the gene responsible for producing factor IX. When injected into the patient's vein, the virus is carried to the liver where the gene will be taken up into the patient's liver cells and start producing factor IX, thereby limiting bleeding episodes. EMA’s recommendation is based on the results of two prospective, openlabel, single dose, single-arm studies, in which 57 adult male patients with moderately severe

or severe haemophilia B were enrolled. In the first study, the three patients sustained positive treatment effects up to three years following the infusion. In the second study, 52 patients sustained positive treatment effects up to two years following the infusion. It is yet unknown how long the benefits of this one-time treatment will last.

First therapy to treat transplant patients with post-transplant lymphoproliferative disease

EMA has recommended a marketing authorisation EU for Ebvallo (tabelecleucel) for the treatment of adult and paediatric patients who experience a serious complication following solid organ transplantation (SOT) or bone marrow transplantation (hematopoietic cell transplantHCT) called EBV+ PTLD. This is one of the most important malignancies after transplantation. It is a result of the immunosuppression caused by the medication required to reduce the possibility of rejection of the transplanted organ or cells and the most common form of this condition is associated with the Epstein-Barr virus. Ebvallo is indicated in patients after a transplant and who have received at least one prior therapy when the symptoms of the disease come back after treatment (relapsed) or when the treatment does not work (refractory).

ETF warns that monoclonal antibodies may not be effective against emerging strains of SARSCoV-2

EMA’s Emergency Task force (ETF) has cautioned that monoclonal antibodies currently authorised for COVID-19 are unlikely to be effective against

emerging strains of SARS-CoV-2.

These monoclonal antibodies are designed to neutralise the virus by binding to the spike protein on its surface. However, emerging strains have mutations in this protein which can reduce the ability of the antibodies to bind to them.

Recent laboratory studies show that monoclonal antibodies targeting the spike protein are poorly effective at neutralising Omicron strains BA.4.6, BA.2.75.2 and XBB. The data also show that these monoclonal antibodies do not significantly neutralise BQ.1 and BQ.1.1, which are expected to become the dominant strains in the EU in the coming weeks.

Antiviral treatments such as Paxlovid (nirmatrelvir / ritonavir) and Veklury (remdesivir), which have different mechanisms of action, are expected to retain their activity against the emerging strains. These treatments are approved in the EU for patients with COVID-19 who do not require supplemental oxygen and are at increased risk of their disease progressing to severe COVID-19.

The ETF therefore encourages EU Member States to ensure that healthcare professionals have access to these antiviral treatments for patients at increased risk of severe COVID- 19.

This review is produced by Malcolm Holmes an independent pharmaceutical consultant. For further information on these and other topics we suggest you refer to the websites of relevant regulatory bodies

bottled brown

Aristocrat of work

You have probably gained various qualifications as a scientist or technologist in production, quality assurance, research or whatever. Being clever was not enough; sweat, putting in extra effort, was also needed. You may think you deserve even greater rewards but are far from starving. It is unlikely that you got there by force, such as by the sword, or venality, bribery being one example, or nepotism, say by meteoritic promotion in the family firm. Admittedly, if one or more parents were highly educated, some of their “intellectual capital” may have been transmitted in one way or another.

What you are, like the label or not, is a meritocrat. The sociologist Michael Young satirised meritocracy in a dystopia in 1958. Disadvantages exist. This article will return to them.

Gold, anyone?

Plato argued for a meritocracy around 375 BC. Individuals were of three grades (like Olympic medals). Gold were the intellectual elite: the thinkers. Maybe today they would be the chief executives and so on. Next down were the silver. They would be for example middle managers. Bronze were the lowest, today maybe the manual workers who actually made things such as medicines. Where are you? I am mingled, you may retort. In defence, it is a simplistic

interpretation from an age before many ways of ruling (“ … ocracies) were studied. Then, the notion that grade depended on your ability (and not on who your parents were) was explosive. Ability determining grade means equal opportunities for all: a goal broadly accepted today.

Grade results from two components. The first is IQ: performance at examinations, where you fit into your cohort in the normal distribution bell curve. Political historian Adrian Wooldridge (2021) in “The Aristocracy of Talent” noted that in Singapore, students erect shrines to the Bell Curve God, the omnipresent inscrutable force that governs all our lives. The second is capacity, how much determination you invest. Applying this to industrial pharmacy, say vaccine manufacture, scientists with high credentials and training develop the medicines while other but similar scientists make, test and regulate those medicines. Those who are health professionals, such as pharmacists, perceive themselves with the extra merit of having gazed upon patients so presume an extra appreciation of their vulnerability, despite health professionals not having a monopoly of caring. Some workers strive harder, have more fire in their bellies, than others. The crucial point is that (theoretically) in our meritocracy anybody can rise to any grade.

Given limitations imposed by national laws and so on, individuals

can also offer their talents anywhere. Increase in teleworking has made working for other countries easier. Interestingly, the historian Jan Lucassen in “The Story of Work” (2021) comments that the most advanced technology passes like a baton between countries. Venice city-state passed to the Low Countries to England (17th century) and then to the USA / Germany / France / Italy / Switzerland. That baton will pass, he suggests, to China and India. Presumably, that includes the pharmaceutical industry.

Backlash

Non-cognitive talents may be valued more. The sociologists Young and Willmott (1956) found that manual labourers such as builders, who made things, valued, graded themselves, compared with non-productive office workers, higher. They seemed to just push pens and look in books. Bravery, dexterity, beauty and so on in sports, entertainment, cooking — and hot-dog-eating — also offer ample rewards.

You may have studied and studied, worked harder than was required and appreciate that you enjoy expenses, influence, high income and other rewards. You may think, “I am worth it”. Guard against being perceived as a smug technocrat, a plutocrat oozing entitlement.

Malcolm E Brown

EPSA Science Day 20th April 2023

The EPSA Science Day is back!

This year's Science Day is taking place in Podcetrtek, Slovenia on 20th April as part of the 44th EPSA Annual Congress 17-23 April 2023

The EPSA Science Day is a scientific competition that aims to bring together students with professionals and fellow scientists. Students will have the opportunity to present their research projects as oral presentations, poster presentations, or both.

All participants will receive feedback from renowned European scientists and will also receive certificates for their participation.

The Winner of the science day competition, either through a poster or an oral presentation session, will be honoured with an award from the world of science.

To participate in Science Day you need to:

1.Register to attend EPSA's Annual Congress 2023

2.Prepare a 300-words abstract of your research

3.Register by filling out the form at https://lnkd.in/d_tA-GJy"