The editors and publisher wish to express their gratitude to the colleagues listed below for their valuable contribution to the peer review process for the Generics and Biosimilars Initiative Journal (GaBI Journal) in 2020.
Dr Adel AL Harf, Saudi Arabia
Professor Alain Astier, France
Professor Moses SS Chow, USA
Dr Alessandro Curto, Italy
Professor Theodor Dingermann, Germany
Dr Brian Godman, UK
Dr Elwyn Griffiths, UK
Ms Raquel Herrera Comoglio, Argentina
Dr Lyna Irawati, Malaysia
Dr Hye-Na Kang, Switzerland
Dr Bhuvan KC, Malaysia
Professor Tore Kristian Kvien, Norway
Dr Dianliang Lei, Switzerland
Dr Frits Lekkerkerker, The Netherlands
Mr Vimal Sachdeva, Switzerland
Dr Bradley J Scott, Canada
Professor Yoshiya Tanaka, Japan
Dr Robin Thorpe, UK
Dr Jean Vigneron, France
Professor Philip D Walson, USA/Germany
Dr Keith Watson, UK
Dr Andrés F Zuluaga, Colombia
The articles in this first issue contain a large volume of useful information on the global development, approval, manufacturing, marketing, and uptake of biosimilars.
The first Original Research by Dr Hye-Na Kang et al. from the World Health Organization (WHO) presents an extensive listing of data on the status of approved similar biotherapeutic products. While, as the authors acknowledge at the end of the manuscript, not all the products listed meet the GaBI’s definition of a true biosimilar, the data demonstrate the gratifying growth in the quantity and impact of such products on the availability and affordability of such products. Increasing availability of biosimilar monoclonal antibodies has been especially noteworthy. However, much remains to be done before the wish that the, ‘adoption of biosimilars will allow affordable health care and greater patient access to important medicinal products’ can become a reality. As noted by the authors, for this to happen, ‘Regulators need to reassess such products to ensure whether they meet the current requirements and to identify the inappropriate labelling of non-innovator and copy-version products (approved when regulatory procedures were not well defined) as biosimilars’.
The second Original Research (the result of work done for a doctoral thesis) by Marzieh Zargaran et al. present data on some potentially, negative, ‘unintended consequences’ of the introduction of follow-on biological products in Iran. While the authors found a ‘downward trend’ in the cost of medications and an increase in product availability, not all six trends in the consumption of locally produced products they observed were positive. There was an increase in consumption of both some ‘domestically produced’ and originator, higher-priced imported products (Pattern 3) as well as some drugs for which there was increased sales of imported medications (Pattern 4) along with decreased sales of domestically produced products. This suggests that the availability of lower-priced products did not always produce the savings expected. The ability to extrapolate these results beyond Iran is limited by Iran’s current economic situation as well as by the definitions used in the data collection. While few other countries are dealing with similar crippling economic sanctions, the concerning trends reported could also occur elsewhere. The definitions used must also be considered when evaluating the data. The authors considered all products manufactured in Iran, whether using imported or only locally produced ingredients, to be ‘domestically produced’. Despite these limitations, the possibility that increased availability of lower-priced biologicals could result in increased rather than decreased overall healthcare costs in other countries should be studied.
The middle section of this issue contains a description of scope of GaBI Journal as well as our Instructions for Authors. Readers are encouraged to read both carefully when submitting manuscripts and comments.
The final Review Article by Adjunct Associate Professor Sia Chong Hock et al. discusses the benefits, opportunities and challenges of the continuous manufacturing (CM) process for both manufacturers and regulators. The authors present a detailed analysis of the challenges that remain to the more wide-spread pharmaceutical industry implementation and regulatory approval of CM processes. Unfortunately, perhaps because the products manufactured to date using CM have been oral solid dosing forms, the authors did not discuss how the use of CM might have impacted the ingredient related shortages of COVID-19 vaccine, monoclonal antibody, corticosteroid, antibiotic and antiviral treatments that have occurred. These authors, as well as all GaBI Journal readers, are encouraged to comment on how the use of CM processes rather than more traditional batch manufacturing might have affected these shortages.
The new year has begun with increasing hope for some easing of the many negative, pandemic-related changes to all our lives that we are experiencing. There is growing appreciation that much of this hope would not be possible without the dedication, sacrifices and efforts of all those people who provide the critically important health, security, services and support to all peoples of this world. It has also never been so obvious how important innovative regulatory and pharmaceutical science, as well as science-based governance are for the people of this world to have a healthier and happier new year.
Professor Philip D Walson, MD Editor-in-Chief, GaBI Journal
Disclosure of Conflict of Interest Statement is available upon request.
Permission granted to reproduce for personal and non-commercial use only. All other reproduction, copy or reprinting of all or part of any ‘Content’ found on this website is strictly prohibited without the prior consent of the publisher. Contact the publisher to obtain permission before redistributing.
Author byline as per print journal: Marzieh Zargaran1, PharmD, PhD Candidate; Abdol Majid Cheraghali 2,3, PharmD, PhD; Fatemeh Soleymani1,2, PharmD, MPH, PhD; Rajabali Daroudi4, BSc, MSc, PhD; Ali Akbari Sari4, MD, PhD; Professor Shekoufeh Nikfar1,2, PharmD, MPH, PhD
Background: Enacting national policies which empower the local production of medications is a promising way to improve the accessibility and affordability of medications, but this can also have unintended consequences. A number of such policies have been adopted by the Iranian government. This study was designed to examine the changes in the consumption of a number of selected pharmaceuticals which occurred in the years after these selected products began to be domestically produced. The implications of these changes were then evaluated for their potential to suggest possible policy changes. Methods: A 10-year trend study was conducted to identify changes which occurred between 2007 and 2017 in the consumption of 28 selected, imported medications after they began to be domestically produced. Results: Six different medication consumption patterns were observed after the development of domestic medication production. In addition, a downward trend in the cost of medications was observed, specifically due to the introduction of domestic pharmaceuticals. Discussion: Examination of the observed changes in the consumption patterns revealed that various factors affect consumption patterns of imported medications. Significant increases in certain domestically manufactured medications indicated that local production might result in the irrational use of medications. In addition, the competitiveness of Iranian products, in terms of quality and accessibility should be considered. Conclusion: New considerations are needed for health policymakers to support domestic production of viable alternative medications. However, increased accessibility of domestically produced medications may result in greater unreasonable use of medications.
Submitted: 28 February 2020; Revised: 29 December 2020; Accepted: 2 January 2021; Published online first: 15 January 2021
Introduction/Background
The domestic production of medications in developing countries can motivate and empower pharmaceutical industries and can enhance the accessibility of medications [1]. After the 1979 Islamic revolution in Iran, a comprehensive generic drug-based system was developed through the Iranian national drug policy (NDP), to promote affordable access to various types of medications [2]. To support the domestic production of generic medications and vaccines, the creation of a national pharmaceutical industry and national self-sufficiency in vaccine production were key aspects of the policy [3].
With 60 years’ experience in domestic medication production, the Iranian government has placed great emphasis on empowering the domestic pharmaceutical industry in recent decades [4, 5]. According to clause 28 of the health regulations laid out in the sixth Iranian development plan, at least 10% of National Development Fund resources have been deposited into domestic banks to promote the infrastructure of the health system, including that required for the production of pharmaceutical materials and products. In addition, to accomplish self-sufficiency of the pharmaceutical industry, clause 29 of the document obliges the Iranian Ministry of Health (MoH) to support and endorse domestic pharmaceutical plants.
A number of policies have been implemented to encourage Iranian pharmaceutical manufactures to develop their production capacity. High tariffs are imposed on imported medications, and in many cases imported medications are substituted with similar domestically produced alternatives present on the national reimbursement list (a list of medicinal products which are reimbursed through public health insurance), both of these policies reduce or prevent the import of certain foreign medications [2, 5].
Between 2010 and 2017, there was a significant increase (from 89 to 167) in the number of companies engaged in the production of pharmaceuticals in Iran. In addition, the number of companies importing pharmaceuticals during this time reduced from 207 to 93. There was also 1,213% growth in the price of the domestic pharmaceutical products between 1997 and 2010 [6]. However, it is noted that, despite the efforts of the Iranian government to support their national pharmaceutical industry, it is not yet comprehensively self-sufficient [2]. Due to the administration of the Health Sector Evolution Plan (HSEP) in 2014, and new approaches of MoH to support the national pharmaceutical industry, the annual pharmaceutical importation cost reduced from US$1 billion in 2013 to US$450 in 2014 [7].
Improvements in access to domestically produced pharmaceutical preparations can lead to additional changes in consumption patterns in some cases. The lower prices and greater affordability of domestically produced medications increases their availability and accessibility which can have some unintended consequences, such as their inappropriate and irrational consumption.
As such, comprehensive investigations on the management of national production and importation of pharmaceutical sciences are required. Identifying patterns of change in the consumption of medications associated with improvements in national pharmaceutical production will reveal future trends in the pharmaceutical market and help inform the decisions of policymakers.
This paper provides a 10-year overview of medication sales in terms of volume and value of imported medications after the development of domestic production lines in Iran. The main aim is to conduct a study to assess the trends in medication consumption after the initiation of domestic production. It also hopes to shed light on the unintended consequences of increased accessibility and affordability of medications brought about by increased domestic production, to help health policymakers in their future decision-making.
Finally, this review also aims to investigate the price of different selected medications.
Methods
Comprehensive literature review A literature review was conducted to determine the best methods to assess the trends associated with domestically produced medications and relevant policies. ISI/Web of Science, PubMed/MEDLINE, Scopus, Google Scholar, as well as Iranian databases such as Irandoc, Scientific Information Database (SID), Magiran and the grey literature, were used to find studies, both in English and Persian, that contained the following Medical Subject Headings (MeSH) keywords: local production, pharmaceutical market trends, pharmaceutical industry, health policy, and pharmaceutical policy. The publications found were not constrained to a specific time period.
Medication selection The method used to select the medications to be investigated was approved by Iranian Food and Drug Administration (IFDA) experts. This used data from Iranian pharmaceutical statistical datasheets which contain pharmaceutical sale statistics collected by IFDA from lists published annually by medication distribution companies. The sales volume and sales value of medications are reported in these data sheets and this is the most reliable data on medication consumption estimations in Iran. However, due to changes in IFDA policy, these datasheets are only available up to and including 2017. It is thought that new statistical datasheets will become available in the future.
In this study, pharmaceutical statistical datasheets between 2007 and 2017 were employed to find medications meeting the following requirements:
During the 10-year time period, they must have had a minimum of three years import history, followed by a minimum of two years of domestic Iranian production.
Figure 1 demonstrates the selection process and the sale history of 277 medications in the available statistical datasheets during the specified time period. For more than 80% of the medications, national pharmaceutical companies were able to domestically produce those which had been previously imported within three years of their introduction to the Iranian market. In addition, despite some medications being available in different strengths and dosage forms, each strength and dosage form of a particular medication were considered together.
The two-year period of domestic production was selected to ensure adequate follow up could be pursued and to ensure good comparisons between imported and domestic products could be made.
Consumption data collection Data from the IFDA pharmaceutical statistical datasheets on the annual sales volume and value of the medications identified for study, was investigated. Although, the sales volume and value of both imported and domestically produced medications were scrutinized separately, the overall consumption trend of each medication was also investigated. At this stage, 108 graphs were analysed to determine the exact pattern of changes within the selected time period.
Price data collection The price of pharmaceutical preparations is defined by the IFDA pricing committee and data on this is available on the IFDA website for free [8], however, the price of some preparations was not found which led to their exclusion from the study. In addition, due to the existence of various medication strengths, the price of each strength was separately reviewed. Thirteen medications were reviewed between 2014–2017 and the prices were calculated through converting Iranian Rials to USD in each respective year. Rial/USD conversion rate varied in successive years. All the exchange rates were obtained from the Central Bank of Iran, which was selected as the most reliable reference [9].
Inter-rate reliability was evaluated through checking the data by three members of the research team (for sales and price data) and the staff of IFDA (for price data).
Results
Literature review findings The findings of the literature review indicate that there is no applicable method to appraise the trends of domestic Iranian pharmaceutical production that is in accordance with IFDA policies frameworks.
Consumption data analysis During the 10-year period, only 28 of the 3,252 reviewed medications, that were either imported or domestically produced, were identified as eligible for inclusion in this study; having at least three years import history followed by a minimum of two years of domestic production. Considering all the strengths of each dosage form of the selected medications, a total of 57 preparations were scrutinized. The sales volume and value of these preparations in the respective years demonstrated various patterns of change in consumption of the imported medications after initiation of domestic production. Medications with similar changes in consumption pattern were categorized in separate groups.
Findings of this study revealed six patterns of change in consumption of the domestically produced medications which had been previously imported:
Pattern 1: Increased sales of domestically produced medications along with an elimination of imported products.
Pattern 2: Increased sales of domestically produced medications along with a reduction in the sales of imported products.
Pattern 3: Increased sales of both domestically produced and imported medications, with more domestically produced medications being sold (and consumed) than those that were imported.
Pattern 4: Increased sales of both domestically produced and imported medications, with more imported medications being sold (and consumed) than those that were domestically produced.
Pattern 5: Reduced sales of domestically produced medications along with an increase in the sales of imported products.
Pattern 6: Reduced sales of domestically produced medications along with a reduction in the sales of imported products.
Table 1 contains the 28 selected medications and their patterns of change during the time period of the investigation. The results show that medications of the same category can have various patterns of change.
According to IFDA reports, there was no unapproved importation, and all the imported medications were registered in the pharmaceutical statistical datasheets.
Price data analysis Thirteen medications were reviewed between 2010 and 2014. Documents showed that after 2014, the registered prices of the selected medications have fluctuated less than the previous years, and in most of the cases the prices in Rial did not vary. Given the annual reduction of the exchange rate in recent years with respect to the Iranian Rial and USD, the price of medications in USD exhibited a downward trend.
Figures 2 and 3 present the prices of the domestically produced and imported medications in USD.
Discussion
Background After resolution 61.21 of the World Health Assembly (WHA) was drawn up in 2008, many policies aiming to improve the domestic production of medications and to promote innovation and improvement in drug accessibility were designed in developing countries [10]. The aim of achieving self-sufficiency in pharmaceuticals production is considered one of the most important health system policies [11].
Recently, empowering domestic production of medications through policy implementation has also been occurring in low/middle income countries. The development of national pharmaceutical industries that produce generic drug products leads to lower prices, greater affordability and increased availability of medications [12]. This is seen in China, where domestic production of pharmaceutical products has been promoted through regulatory processes that are designed to facilitate the appraisal of new domestically produced medications [13]. Indian incentive policies have also dramatically affected the emergence of a successful pharmaceutical manufacturing sector. These include the establishment of Special Economic Zones (SEZs), modification of taxation system and price control [14]. In addition, developing countries have created some reforms to help implement self-sufficiency in pharmaceutical production, these include investment in developmental research and improvement of scientific capabilities [15].
The Iranian MoH has also adopted a domestic drug development approach to improve the availability and affordability of medications [16]. Since the implementation of HSEP in 2014, the Iranian government has supported the national production of medications through various strategies, such as imposing high tariffs on the imported medications, banning import of products similar to domestically produced preparations, supporting production of copy biopharmaceuticals produced by domestic industries, and substituting imported medications with similar domestically manufactured products present on the reimbursement lists [2, 5].
Medication consumption trends in Iran In this study, products consisting of ingredients produced domestically and those containing imported ingredients to make the finished product are classified as domestically produced medications. It is important to note that there is no documented report that outlines how much pharmaceutical importation pertains to the importation of active pharmaceutical ingredients (APIs), rather than finished products. As such, the ratio of imported active ingredient to imported finished product has been considered.
When it comes to follow-on biologicals, all steps of the production of follow-on biologicals occurs in Iran. Cell line and cell culture processing are the first steps of the manufacturing of follow-on biologicals and the approval of domestically produced follow-on biologicals requires comparative experiments, as well as preclinical and clinical studies. Proving the similarity of physicochemical and biological characteristics of a reference product and the domestically produced preparation, is one of the most important steps of the follow-on biologicals product approval pathway [8].
Vaccines are domestically produced in Iran; however, they were excluded from this study as they are not under supervision of IFDA
Although there is no appropriate method for evaluating the trends in domestic production in the Iranian context, the data collecting/selecting method of this study has been approved by IFDA experts. Based on the designed method, only 28 preparations met the required criteria for further analysis.
This is the first study to characterize medication consumption trends in Iran. Further complementary studies to evaluate the assumptions made in this study may be required.
Medication consumption patterns The findings of this study reveal various changes in the medication consumption patterns after the development of domestic production.
As shown in Table 1, medications classified in Patterns 1 and 2 were those with halted or reduced imports following the initiation of domestic production. Fourteen medications in different therapeutic categories exhibited these patterns, highlighting the domestically produced medications’ capability to reduce to the market share of imported medications.
However, the products that exhibit Pattern 3 indicate that in some cases, domestically produced medications fail to lower the market share of the imported products which leads to an increase in the total consumption rate of the medication regardless its origin (whether imported or domestically produced). The increase in the consumption rate of medications classified in Pattern 3 was rational in most cases. Here, non-communicable diseases have become more commonly diagnosed and treated in recent years, as such, related medications are also more commonly prescribed. Therefore, it is likely that increasing the total consumption rate now meets previously unmet demands.
In patterns 3 and 4 there is increased sales of domestically produced medications together with an increase in the sales of imported medications, however in Pattern 3 there are higher sales of domestically produced medications when compared to imported, and in Pattern 4 the sales of domestically produced medication are lower than imported. The difference between medications categorized in Patterns 3 and 4, is associated with the reduced market share of the imported medications following the domestic production of the medications in Pattern 4. However, the consumption of both imported and domestically manufactured medications significantly increased over the target years of the review.
Pattern 5 also addresses domestically produced medications which have failed to compete with imported products.
Only one of the selected medications belongs to Pattern 6, which indicates that despite the efforts of national industries to produce medications domestically, in some cases, reduction in the consumption rate occurred.
It is thought that determining the exact reasons that lead to the creation of the various medication consumption patterns can help Iranian health policymakers’ future decision-making. Understanding what lies behind the patterns will facilitate predicting the future path of other medications with similar charac-teristics.
These patterns demonstrate that the Iranian health system has been successfully supporting the domestic production of medications to increase accessibility and empower the domestic pharmaceutical industry. In 19 of the selected medications (67.8% of the medications), importation has been halted, reduced or increased (Pattern 3) after the empowering of national pharmaceutical industries which is indicative of the successful implementation of the policies supporting domestic production.
Sales value and volume of medications Figure 4 highlights that there is an observed reduction in the sales value proportion of imported medications when compared to those that are domestically produced. Regression equations of the sales value trend charts showed similar gradients of the sales value proportions of imported and domestically produced medications when compared to total medication consumption, both when increasing and decreasing.
According to the regression equations of the trend lines shown in Figure 5, since 2014, there has been an increase in the sales volume of domestically produced medications compared with the total medication consumption (of those included in the study).
Figures 6 and 7 show a significant increase in the sales value and sales volume consumption of certain domestically produced medications after the increased production of national products. For example, after three years of rosuvastatin tablet imports, the importation of this medication has been discontinued. Additionally, in the second year of domestic production, the annual average growth rate (AAGR) of the sales value and volume was approximately 3,160 % and 5,063 %, respectively, indicating a significant increase in both the sales volume and sales value of domestically produced rosuvastatin tablets.
In some cases, the evolution of the annual market in terms of the total sales of each medication did not correspond with, and was greater than, the respective year’s population growth. Here, Iranian health policymakers face great challenges when it comes to explaining the multi-fold consumption of certain medications following the initiation of domestic production. Increased consumption of medications is associated with the irrational use of these medications in approved indications and the unreasonable use in off-label and unapproved indications, which may occur due to lower prices or greater availability of domestically produced medications. Moreover, physicians are allowed to prescribe the medications for off-label indications in accordance with their diagnosis, however off-label use is not included in reimbursement in Iran.
Increasing the consumption rate of some medications could potentially meet previously unmet demands brought about due to a lack of access to medicines; this assumption can be confirmed through further investigation.
Medication price Of the 28 selected medicines with varieties of strength, only 13 medicines were reviewed in term of price, due to a lack of data on other medicines. The selection was not random or specific for a few medical classes. All the existing data on prices of medicine was reviewed.
Price analysis of the selected medications shows that since 2014, most of the selected domestically produced medications had a constant price in Rials. Due to the reduced exchange rate in recent years, domestic products have been presented at lower prices in USD. Comparisons of the trends in Figures 2 and 3 show that the price of the imported medications has increased more freely, therefore, importer companies experienced fewer price reductions when compared with manufacturers of the same products in Iran.
Based on the overall results of this investigation it is evident that, despite the government’s encouragement to support domestic manufacturers, in certain cases, domestically produced medications have failed to become viable competitors against imported products. According to Table 1, approximately 30% of the selected imported medications exceeded domestically produced medications in terms of volume over a period of at least two years.
Policy implications In general, the domestic production of pharmaceuticals can be evaluated from two perspectives. On one hand, for industrial stakeholders, increasing the market share through development of products is very important for domestic production. On the other hand, increasing accessibility of medications is the most important factor for health policymakers [17].
In many countries, the domestic production of pharmaceutical preparations may increase medication consumption and increase money spent on the pharmaceutical industry. Encouraging approaches that aim to increase domestic production in developing countries is in accordance with national pharmaceutical policy goals [6]. However, studies have not yet shown a clear and strong relationship between the domestic production of pharmaceuticals and increased accessibility of medications [18].
Empowering the pharmaceutical industry to enhance the availability and affordability of pharmaceutical products has been the focus of the Iranian government. Supporting domestic employment, self-sufficiency and saving money on the foreign exchange are among other objectives of the Iranian health sector authorities.
This study has demonstrated that insistence upon strengthening domestic production policies for improvements of medication accessibility might be in contrary to the NDP goals, leading to the irrational use of medications and an increased financial burden on the health system.
Another controversial challenge is the lack of a viable and permanent alternative for domestically produced medications. Despite the high cost of these medications, domestically manufactured medications may not always be a proper substitute for imported products. In these cases, discontinuing the import of similar products can lead to reduced accessibility of desirable and adequate medication.
It should be mentioned that all domestically produced medicines in Iran pass specific qualification examinations prior to market release and as such, there are no perceived differences in quality of medicines that could influence specific product selection. However, it is often seen that patients tend to opt for branded originator medications.
In addition, the Iranian government requires detailed policies to prioritize the medications requiring investments for national pharmaceutical industry advances. In other words, the most appropriate medications need to be selected for domestic production as sustainable substitutes for imported ones.
This study is the first investigation of the consumption trends of pharmaceuticals in Iran and addresses the challenges encountered by the health system policymakers. The findings of this study suggest that further challenges in developing countries by the health policymakers need to be discussed.
Study limitations The limitations of this study include the absence of similar research in this area due to the novelty of the topic, and inevitable errors in the data registration of statistical datasheets impacting on the outcomes of this study.
Pharmaceutical statistical datasheets based on distribution data are the only reliable references for estimating the sales of medications in Iran. Another important limitation of this research was that it assumed the medicine distribution data to be equal to medicine consumption or sales, although this may not be quite true. In addition, a lack of price data for some of the selected medications was the final limitation of this study.
Conclusion
From a health policy perspective, increasing domestic production of medications can have negative and unintended consequences. For example, increased accessibility following domestic production of medications may lead to greater unreasonable or irrational use of medications. Policymakers should be aware of such considerations and try to design reliable plans of medication selection for the domestic production of medications.
Acknowledgement
This research is part of a submitted doctoral dissertation in the faculty of pharmacy at Tehran University of Medical Sciences.
The authors are grateful to Dr Fatemeh Teymouri for her valuable assistance in some data collections.
The authors also thank Dr Marzieh Daniali for her ongoing collaboration in the English editing of this paper, and Ms Alice Rolandini Jensen, GaBI Journal editor, for English editing of the final version of this manuscript.
Competing interests: The authors have no conflicts of interest to declare.
Provenance and peer review: Not commissioned; externally peer reviewed
1Pharmacoeconomics and Pharmaceutical Administration Department, Faculty of Pharmacy, Tehran University of Medical Sciences, 16th Azar Street, Keshavarz Boulevard, 1417614411 Tehran, Iran 2Pharmaceutical Management and Economic Research Center, The Institute of Pharmaceutical Sciences (TIPS), Tehran University of Medical Sciences, Tehran, Iran 3Faculty of Pharmacy, BMS University, Tehran, Iran 4School of Public Health, Tehran University of Medical Sciences, Poorsina Avenue, Keshavarz Boulevard, 1417613151 Tehran, Iran
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Author for correspondence: Professor Shekoufeh Nikfar, PharmD, MPH, PhD, Pharmacoeconomics and Pharmaceutical Administration Department, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
Disclosure of Conflict of Interest Statement is available upon request.
Permission granted to reproduce for personal and non-commercial use only. All other reproduction, copy or reprinting of all or part of any ‘Content’ found on this website is strictly prohibited without the prior consent of the publisher. Contact the publisher to obtain permission before redistributing.
Author byline as per print journal: Adjunct Associate Professor Sia Chong Hock, BSc (Pharm), MSc; Teh Kee Siang, BSc (Pharm)(Hon); Associate Professor Chan Lai Wah, BSc (Pharm)(Hon), PhD
Continuous manufacturing (CM) is the integration of a series of unit operations, processing materials continually to produce the final pharmaceutical product. In recent years, CM of pharmaceuticals has transformed from buzzword to reality, with at least eight currently approved drugs produced by CM. Propelled by various driving forces, manufacturers and regulators have recognized the benefits of CM and are awaiting the completion of the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Q13, a harmonized guideline on CM that would be implemented by ICH members. Although significant progress is evident, the uptake of CM is still sluggish in the pharmaceutical industry due to many existing challenges that have hindered manufacturers from adopting this technology. The top two barriers that manufacturers currently face are regulatory uncertainties and high initial cost. These issues are crucial in unleashing the untapped potential of CM, which has significant implications on patients’ access to life-saving medicines, while mutually benefitting manufacturers and regulators. Despite numerous studies, there have been few existing publications that review current regulatory guidelines, highlight the latest challenges extensively and propose recommendations that are applicable for all pharmaceuticals and biopharmaceuticals. Therefore, this critical review aims to present the recent progress and existing challenges to provide greater clarity for manufacturers on CM. This review also proposes vital recommendations and future perspectives. These include regulatory harmonization, managing financial risks, hybrid processes, capacity building, a culture of quality and Pharma 4.0. While regulators and the industry work towards creating a harmonized guideline on CM, manufacturers should focus on overcoming existing cost, technical and cultural challenges to facilitate the implementation of CM.
Submitted: 30 November 2020; Revised: 20 December 2020; Accepted: 21 December 2020; Published online first: 6 January 2021
Introduction
Continuous manufacturing (CM) is the integration of a series of unit operations, processing materials continually to produce the final pharmaceutical product. This CM technology started in the eighteenth century during the first Industrial Revolution and has since been adopted by many industries [1]. However, it is only in recent years that CM of pharmaceuticals has transformed from buzzword to reality.
To date, there has been no standardized definition of CM, and the terms ‘continuous manufacturing’, ‘continuous production’ and ‘continuous processing’ are often intermingled [2]. Nonetheless, these terms are not interchangeable as they have different nuances. As the name suggests, ‘continuous production’ refers to a production schedule operating continually for 24 hours, seven days a week [2]. On the other hand, ‘continuous processing’ refers to a single unit operation where raw materials are continuously being loaded, processed, and unloaded without interruption [2].
There are many interpretations of CM and its related terminologies. However, end-to-end CM according to the US Food and Drug Administration (FDA), refers to an approach where the drug substance and drug product process steps are fully integrated into a single continuous system [3]. On the other hand, the hybrid approach is a combination of batch and continuous processing steps [3]. The pharmaceutical industry is increasingly adopting hybrid systems as it combines the advantages of batch and continuous processes [4–6].
Although significant progress is evident, the uptake of CM in the pharmaceutical industry remains sluggish due to various challenges [5–8]. Moreover, a lack of harmonized regulatory guidelines on CM has resulted in uncertain regulatory expectations by different regulatory authorities (RAs) [8]. To overcome the regulatory challenges and to reconcile CM-related concepts, the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) is developing a new quality guideline, ICH Q13: Continuous Manufacturing of Drug Substances and Drug Products [9].
At present, multiple studies have elaborated on significant technical and regulatory challenges for the CM of specific dosage forms, while others have conducted economic analyses on CM [10–14]. For example, Lee et al. [10] reviewed the benefits of CM, emphasized prime quality considerations and proposed solutions to address them. Additionally, a recent review by Vanhoorne and Vervaet [11] presented an overview of the technical aspects of CM and discussed regulatory guidelines on CM, specifically for oral solid dosages (OSDs). Despite many studies, to date, there have been few publications that review existing regulatory guidelines, highlight the latest challenges or make recommendations that are applicable for all pharmaceutical and biopharmaceutical products.
As portrayed in Figure 1, the implementation of CM is attributed to many factors. Therefore, this review aims to identify the benefits and opportunities of CM, assess the current extent of implementation, review existing regulatory guidelines and comprehensively highlight the existing challenges. The review also includes recommendations to facilitate the implementation of CM. The general concepts discussed in this review apply to all pharmaceutical dosage forms and biopharmaceutical products.
Overview of continuous manufacturing
CM is a combined process consisting of a sequence of more than one unit operation, developed to process materials continually to produce the final product [3]. As shown in Figure 2, CM is the integration of individual continuous unit operations with process analytical technology (PAT) which monitors and controls the critical process parameters (CPPs), critical material attributes (CMAs) and critical quality attributes (CQAs) [10]. Furthermore, CM streamlines manufacturing processes by eliminating work-up unit operations [10]. As such, CM equipment is typically smaller and is located within a single facility [10]. Batch manufacturing (BM), on the other hand, involves discrete unit processes with off-line quality testing and storage before each step [10]. Moreover, BM involves shipping of intermediates from one facility to another.
QbD and PAT CM can improve pharmaceutical manufacturing with an enhanced development approach of Quality by Design (QbD) and the use of PAT [3, 10, 11]. As depicted in Figure 3, a comprehensive QbD approach allows for continuous improvement through product and process understanding to ensure better product quality [11, 15–17].
PAT is necessary for highly automated processes and continuous processing, as it fulfils quality requirements, such as residence time distribution (RTD) [18–21]. RTD refers to the distribution of time that materials remain in a unit operation; thus, it is critical for material characterization [21]. PAT uses multiple data sources for real-time product quality monitoring and control to achieve an integrated QbD quality system [10, 22]. CQAs such as the percentage of active pharmaceutical ingredient (API), particle-size distribution, granule size, and many others can be monitored with PAT [23]. As PAT and QbD tools can also be used in BM, manufacturers would be able to gain a better understanding of these processes, thereby facilitating a smoother transition to CM [22].
Benefits of CM
As listed in Table 1, there are various benefits of CM, which have been recognized for more than a decade [24].
In contrast to BM, CM provides greater scale flexibility in terms of its ability to scale-up production without any hindrance [10, 34, 35]. As depicted in Figure 2, CM eliminates the need for off-line testing and storage, thereby reducing the number of manufacturing steps [24, 29, 36]. Therefore, CM is more efficient than BM, as it reduces the processing time from raw materials to finished drug products, potentially by several months.
Also, CM has a greater response capacity to supply chain disruptions and drug shortages [10, 30]. This benefit of CM is accentuated in pandemics such as COVID-19, where ramped-up production of vaccines is required [29, 37]. As a result, there could be vast implications on global health and recovery of economies. On the other hand, it is difficult to adjust the production schedule of BM to meet changing demands [31], as building a new BM line in response to crises takes several months [10].
Benefits and opportunities for generics manufacturers Realistically, generic manufacturers operate on low-profit margins and need to constantly take measures to keep drug prices low [38]. With increased processing speed and control from CM, it will lower the cost of production and grant tremendous cost advantages, especially with high-volume production [39]. Furthermore, as CMAs and CPPs are kept constant, there would be lower batch-to-batch variability [10]. Hence, CM allows generic manufacturers to match the narrow process variability of branded drugs [38]. Therefore, adopting CM is an opportunity for generics manufacturers to be prepared for new drug products from originator manufacturers [38]. At present, generics companies such as Dr Reddy’s Laboratories, Mylan Pharmaceuticals and Aurobindo are developing CM lines in India [4], while Lupin Pharmaceuticals is developing a continuous purification process for a biosimilar monoclonal antibody drug [40]. Therefore, CM is beneficial for both brand-name and generics manufacturers.
Driving forces of CM The principal driving force for the implementation of CM is its potential to cut production costs, as manufacturers seek to maximize profits [14, 41]. Pharmaceutical companies are facing a threat to their earnings due to competition from generics and biosimilars manufacturers, increasing research and development costs, a forecasted low growth rate in developed economies, and greater demand for the affordability of drugs for patients [42]. As such, manufacturers are exploring the use of CM as it has proven to reduce operating expenses and capital expenditure [18].
Secondly, there is an increasing demand for speed to market for breakthrough therapies [14, 24, 31, 43]. CM can accelerate product development, delivering life-saving medicines to patients more quickly [31] without compromising product quality [11, 14, 24].
Thirdly, the pharmaceutical industry is transiting from large volume blockbuster drugs towards the production of personalized medicines [24]. This requires a shift from the current BM system towards CM, which is flexible in volume output and product variety [24, 31]. This feature is beneficial for the production of personalized medicines.
Lastly, environmental conservation will be a point of contention in the coming years, mounting greater external pressure on manufacturers. As CM supports greener processes and is proven to have reduced environmental footprint [11, 25, 28, 44, 45], the Pharmaceutical Roundtable recommends CM as the top priority in green engineering research [46]. These external trends, coupled with its compelling benefits, serve as fundamental driving forces for the adoption of CM.
Initiatives by international organizations to advance CM Furthermore, there are various initiatives taken by international organizations to advance CM. In particular, the International Society for Pharmaceutical Engineering (ISPE) organized the 2020 ISPE Continuous Manufacturing Virtual Workshop, whilst the Massachusetts Institute of Technology (MIT) and the Continuous Manufacturing and Crystallisation Consortium (CMAC) organized the International Symposium on Continuous Manufacturing of Pharmaceuticals (ISCMP), which brought together various stakeholders and culminated in white papers on CM [47]. As listed in Table 2, there is an increasing number of global consortia collaborating to develop and share knowledge on advanced manufacturing technology [48]. Undeniably, these initiatives would accelerate the transition from BM to CM.
Extent of implementation of CM
From the first approval of drug products manufactured by CM in 2015, there have been a total of at least eight drug products approved. However, all of the currently approved drugs are OSDs. Hence, further development of CM for API, biopharmaceuticals and other pharmaceutical dosage forms is imperative.
The approved drugs in Table 3 utilize separately produced APIs [52]. At present, while there is a development of end-to-end CM that integrates continuous API production with drug product processes, there are none that comply with the current good manufacturing practice (cGMP) standards as of yet [25, 56]. This owes to the fact that there are more technical challenges in continuous processes for drug substances compared to drug products [25, 52, 57, 58]. Continuous API manufacturing is more complicated due to longer residence time [25, 52], higher quantity and diversity of unit operations [25, 57, 58], and intractably greater complexity of distinguished key molecules [57]. !However, many organizations are developing continuous flow processes for APIs [44, 52, 58-64]. For example, the Novartis-MIT collaboration has demonstrated that there are opportunities for integration of API and drug product processes with their end-to-end CM of aliskiren hemifumarate tablets [25]. Hence, cGMP-compliant end-to-end CM would most likely be realized in the future.
Similar to the CM of APIs, there is currently no fully continuous bioprocessing facility [13]. As today’s continuous downstream unit operations are still in their nascent stage of development, hybrid systems are expected to be implemented before end-to-end systems [30]. Nonetheless, the development of continuous bioprocessing is also gaining momentum [58]. Therefore, drugs in various pharmaceutical dosage forms would likely be approved in the coming years as development of CM progresses.
Existing regulatory guidelines on CM
Currently, there are three main regulatory guidelines on CM from ICH, FDA and ASTM International. As stated in Table 4, ICH Q13 and FDA guidance are still a work-in-progress. Other RAs and international organizations such as the World Health Organization (WHO), the Pharmaceutical Inspection Co-operation Scheme (PIC/S), and the Association of Southeast Asian Nations (ASEAN) do not have established guidelines on CM. As a result of this regulatory uncertainty, manufacturers would unlikely take the risk to implement CM as adopting new technology may lead to delays in regulatory approval, and consequently delays in delivering drug products to patients.
Nonetheless, the regulatory expectations for both BM and CM are essentially the same [3, 7]. Regardless of the mode of production, manufacturers are expected to have technically sound and risk-based processes to produce quality products [7]. For existing products manufactured by BM, filing for a post-approval change for the implementation of CM is a requirement by most RAs [3].
Notably, a key difference among the guidelines is that FDA draft guidance does not apply to biopharmaceuticals and APIs. Many stakeholders have expressed concern about these differences and expect FDA guidance to be aligned with ICH Q13 to ensure global harmonization [67]. Harmonization can be achieved through ICH Guidelines, since ICH is well-represented by regulatory and industry members [68].
While ICH guidelines are not mandated by law, ICH members are expected to implement ICH guidelines in Step 5 of ICH Procedure, as illustrated in Figure 4 [69]. Therefore, with the implementation of the harmonized ICH guidelines by RAs around the world, manufacturers will have greater clarity on the regulatory expectations of the various countries.
Challenges and opportunities in implementing CM
Although there is some progress, there is still considerable traction in the uptake of CM in the pharmaceutical industry. As listed in Table 5, there are various shortcomings of CM which may hinder manufacturers from adopting this technology.
Regulatory challenges In multiple studies, the authors concur that the top barrier for implementation of CM is the regulatory challenges stemming from a lack of a globally harmonized regulatory guideline on CM [11, 23, 29, 70, 71]. Harmonization is crucial; otherwise, manufacturers must obtain approval from different RAs to market their products in various countries [72]. Historically, RAs tended to suppress post-approval changes to drug products, inadvertently ingraining a fixed mindset of batch processes in manufacturers’ production philosophy [76]. Furthermore, fear of regulatory delays has hindered the adoption of CM by manufacturers [72].
Nonetheless, regulatory support for CM has grown in recent years. FDA, EMA and PMDA have established specialized teams to promote the adoption of CM. Established in 2014, FDA Emerging Technology Programme (ETP) aims to help manufacturers overcome implementation challenges [77, 78]. Furthermore, regulatory guidelines on key prerequisites of CM has been published to aid in the implementation. Guidelines include the definition of a ‘batch’ [3], process validation [3, 79], continuous process verification [80, 81], and PAT [19]. Also, with the implementation of ICH Q12 guideline in 2019 [82], unnecessary post-approval applications are reduced to promote manufacturing innovations [83]. Therefore, while regulatory uncertainty is currently the top barrier, it is plausible that ICH Q13 will address this challenge once the guideline is implemented.
High initial cost of investment The development of continuous processes is costly, owing to the use of PAT and automation software [38]. The high initial cost is another crucial barrier for manufacturers in adopting CM [41], due to the difficulty in justifying the case for new equipment as existing batch equipment is still functional with established regulatory approval [49, 73]. Hence, investing in CM is not a priority for most manufacturers [49]. In particular, this is a significant barrier for generics manufacturers operating on low-profit margins [4, 84]. Unpredictable demand for generic drugs would further deter a generics manufacturer from investing in CM [85].
Despite the high initial capital investment required for CM equipment, manufacturers can expect to reap economic benefits, especially with high-volume production. In multiple studies, CM has proven to reduce the cost of production [6, 18, 25–28]. An analysis conducted by the Novartis-MIT Center for Continuous Manufacturing showed a significant reduction in labour cost, in-process inventory and energy consumption, resulting in more substantial cost savings [18].
Nonetheless, economic analyses for the CM of biopharmaceuticals show conflicting results. Studies conducted by Pollock et al. [86] and Klutz et al. [43] on continuous antibody production affirm that the hybrid approach is more economically favourable than end-to-end CM [43, 86]. However, Hammerschmidt et al. [87] contend that fully continuous processes allow for the most significant cost savings. The differences in findings are possibly due to the complexity of a myriad of factors in biopharmaceutical production [88]. Nevertheless, most economic analyses maintain that BM is the least economically favourable approach compared to CM [13, 43, 86, 87, 89]. Research has shown that the cost savings could outweigh the high initial cost of implementation [90]. Therefore, CM is an opportunity for manufacturers to generate long-term profits [91].
Quality, safety and technical considerations Material traceability is a key quality concern as characterization of raw materials and intermediate properties are more complex in CM. It is difficult to define the start and end of each batch of product in CM processes [10, 70, 72, 92, 93]. This is exceptionally challenging in low-volume and low-dose drug products due to the high amount of excipients used [70]. To overcome this obstacle, RTD monitored by PAT is a potential solution to ensure material traceability by determining the time taken for the material to pass through each unit operation [70, 93–95].
Additionally, advanced process control strategies are critical for CM to assure process performance and product quality [80, 96]. According to ICH Q8(R2) and Q10 [80, 96], control strategies include material and product attributes, operating conditions, product specifications, and process control. ICH Q8(R2), Q9 and Q10 quality trio provide guidance on developing control strategies that incorporate QbD [80] and risk management [97]. As part of the control strategy, real-time process management segregates any non-conforming material, thereby ensuring the high quality of the drug product [73]. Also, start-up and shutdown can be minimized to reduce material loss and cost incurred [92].
Although CM is generally safer than BM in that there are fewer transition steps [15], still it presents critical safety considerations. Manufacturers need to prevent overfilling of material, over-pressurization of the system, and other potential hazards not found in BM [72]. In recent years, some publications have addressed these technical issues on CM [10, 73]. Moreover, many equipment manufacturers are collaborating with the pharmaceutical industry to overcome the technical challenges of CM. Therefore, technical challenges are not necessarily substantial barriers for manufacturers. As opined by Janet Woodcock, Director of FDA CDER, making the business case is a greater barrier than technical issues for biopharmaceuticals [29].
Equipment and technological challenges There is currently a shortage of available CM equipment [14, 72]. Smaller manufacturers lacking such capabilities have to outsource their production to a limited number of contract manufacturing organizations (CMOs) with CM equipment [11, 49]. In this regard, manufacturers should also consider the risk of material cross-contamination and data security when engaging CMOs [98].
Apart from the lack of CM equipment, research on CM technology was initiated mainly by academic institutions and equipment manufacturers, without active involvement from the pharmaceutical industry [11]. Consequently, this led to late-stage adjustments to the equipment by pharmaceutical manufacturers, further delaying the adoption of CM [11]. The slow implementation by pharmaceutical manufacturers has decelerated the rate of innovation by equipment vendors [72, 99].
In addition, as asserted by several studies [33, 73], batch unit operations involve discrete equipment that can be easily rearranged to enable multiple manufacturing routes. However, discrete batch unit operations come at the expense of lower plant and equipment productivity [33]. While CM is currently less flexible in this aspect, ‘plug-and-play’ continuous equipment comprising distinct reconfigurable unit processes are being developed [23, 100].
Therefore, this challenge will presumably become a stumbling block of the past, as interest in CM is escalating amongst pharmaceutical manufacturers, spurring greater involvement in the innovation process. Biopharmaceutical manufacturers are also collaborating with equipment vendors to innovate new CM technologies for biopharmaceuticals [99].
Knowledge and skills gap Highly skilled personnel are required to develop and implement CM technology in cGMP facilities [41]. As CM is still in its infancy in the pharmaceutical industry, there is a lack of personnel with the relevant skills and knowledge [41, 49, 57, 70, 72]. This is a hurdle for both manufacturers and regulators as continuous systems require statistically trained personnel to understand the data generated [72]. Although training has been conducted, addressing the knowledge gap would require greater multidisciplinary collaboration [41] and commitment from all relevant stakeholders [72].
Inevitably, the adoption of CM will also cause some manual jobs to become obsolete due primarily to automation [74]. However, since there is a need for highly skilled personnel, CM presents an opportunity to create new jobs in R & D and testing [74]. Additionally, reduction in labour intensity will also produce less human errors [4]. Therefore, there would be an increase in new job openings requiring highly competent workers.
Business, operational and cultural challenges Optimally, CM should be implemented in the early phases of drug development [92] to eliminate regulatory requirements needed to prove equivalence to current batch processes [77]. Correspondingly for biopharmaceuticals, it is more effective to implement CM at the clinical stages rather than modifying existing batch processes [77]. This is because biopharmaceuticals are inherently more complex and highly process-dependent [77]. However, the steep learning curve for the CM of a new drug product may encumber a tight launch timeline [77]. Therefore, aligning the manufacturing innovation with a clinical trial timeline is an uphill task and may require structural changes within the organization [72].
Furthermore, regulatory uncertainty has led to a conservative culture in the industry, delaying the adoption of new technologies [57]. Hence, mindset and cultural changes are needed within the pharmaceutical industry to shift its production philosophy of BM [72, 73]. Additionally, new technologies need to have significant proven benefits before they are implemented widely in the pharmaceutical industry [72, 92]. Hence, it is paramount for international organizations to publish success stories of CM to build confidence amongst manufacturers [57].
Challenges for pharmaceutical and biopharmaceutical products As presented in Table 3, all of the approved drugs manufactured by CM are OSDs. Tablets represent the majority of pharmaceutical dosage forms [73, 92], and there are existing technologies for the CM of OSD. Also, FDA draft guidance is tailored towards small-molecule OSD [3]. These factors enable manufacturers to implement CM for OSDs with greater ease. Nonetheless, a one-size-fits-all approach would not be feasible for all dosage forms. Off-the-shelf equipment made for small-molecule drug production is not applicable for biopharmaceuticals [13, 101, 102]. In light of the complexity of biopharmaceutical manufacturing processes and products, CM of biopharmaceuticals is more technically challenging than OSDs. Furthermore, in the manufacture of biological vaccines, there is a need to develop continuous processes for viral inactivation, ultrafiltration and diafiltration [103]. Therefore, more research and investments into biopharmaceutical CM are required to actualize it [90].
Nevertheless, there is promising progress in the development of CM for newer dosage forms. At present, PAT tools are available for formulations such as suspensions [104, 105], liquids [104, 106] and emulsions [104, 107]. Also, as reported by Worsham et al. [12], there are economical and quality benefits for the CM of liposomal drug products. Therefore, CM for various pharmaceutical dosage forms and biopharmaceuticals is gaining momentum and is expected to become more prevalent in the future.
Recommendations and future perspectives
Despite the challenges faced by manufacturers and regulators, progress towards the transition to CM is evident. In this section, key recommendations are proposed to facilitate the implementation of CM.
Regulatory harmonization As emphasized throughout this review, regulatory harmonization is imperative to address the current regulatory uncertainty in the industry. Without harmonization, implementation will remain sluggish as regulators endeavour to understand new CM technologies [58]. This issue would be addressed in the upcoming ICH Q13, expected to be completed in 2022. With the ICH Q13, there would be harmonised expectations for dossier approval and lifecycle management [108]. Consistent regulatory assessment and oversight would likely speed up the adoption of CM [49, 65]. The benefits of harmonized regulations include process improvements, development of new manufacturing methods to produce new molecules, and ultimately improvement in the access of medicines to patients [65]. Currently, many of the major regulators are working on ICH Q13 as members of ICH. While ICH guidelines are not mandatory, it is still worthwhile for regulators that are not part of ICH to use the published guidelines as a reference to create their specific guidelines on CM. Assuredly, with global regulatory harmonization, implementation of CM would substantially increase, as manufacturers will have greater clarity on the regulatory requirements.
Management of financial risks Industry-wide pre-competitive initiatives such as efforts by global consortia could be organized to de-risk investments [24]. Also, CM technology that is applicable for multiple products will reduce the investment risk [33]. It is also essential to conduct a comprehensive analysis on the functions, costs and benefits of new technology [33]. Currently, most economic analyses are performed on finished drug products, but not on APIs [57]. Hence, there is still a need to develop a business case for the CM of APIs [109, 110].
Sustained financial investments from the government will also alleviate the high initial cost [72]. Historically, tax and regulatory incentives have led to industry-wide advancements [49]. Tax incentives, namely in Ireland, Singapore, and Puerto Rico allowed pharmaceutical manufacturing hubs to thrive [49]. As CM would ultimately benefit patients with improved access to medicines [65], governments should provide tax incentives for CM [49]. Today, government support for CM technology is steadily increasing [58, 111].
In addition, regulators should consider granting regulatory incentives to manufacturers for implementing CM, to expedite the approval process and grant a patent exclusivity period for drugs manufactured via CM [49]. With these incentives, manufacturers would be motivated to adopt CM as they would have the opportunity to break even faster and make greater profits.
Hybrid processes Implementing the full end-to-end continuum of CM might be a quantum leap for manufacturers given the myriad of challenges. To overcome this hurdle, manufacturers can employ hybrid approaches to implement CM in a stepwise and progressive manner [33]. By combining the advantages of batch and continuous processes [112], manufacturers can leverage on hybrid processes to generate revenue to offset the high initial cost [39], increase output [36], and gain experience with continuous unit processes. Hybrid approaches are also economically favourable in the production of antibodies [43, 86]. Through this approach, manufacturers can assess the benefits of continuous processes and progressively transition towards end-to-end CM, thereby reaping all the benefits of CM for both small-molecule drugs and biopharmaceuticals [13, 41].
Capacity building, collaboration and publication Training programmes must be conducted to address the lack of skilled workers in CM technology [67, 75, 113]. Currently, there are training programmes organized by various organizations, including ISPE, C-SOPS and the United States Pharmacopoeia (USP). The pharmaceutical industry can also learn from other industries that have implemented CM and adapt the processes for their products [57, 73, 75]. Implementation of CM also requires cross-departmental collaboration and institutional partnerships [24]. Manufacturers should engage in constant communication with regulators and industry experts [7, 84]. Global conferences, such as ISCMP [47] and national initiatives such as the ‘Pharma Innovation Programme Singapore’ [63] are cornerstones for fostering collaboration to drive innovation forward.
In addition, the publication of success stories and challenges of CM would build confidence in the industry and establish best practice standards [57]. Training programmes and publications are equally indispensable to ensure that the industry is well-equipped with the knowledge and skills needed to implement CM [49, 70].
Culture of quality For decades, the pharmaceutical industry has been utilizing BM, steadily instilling a narrow mindset and conservative culture within manufacturing organizations [37, 57]. In a published interview, Jayjock [114] asserts that shifting organization mindsets is the most challenging issue of adopting CM. In recent years, however, manufacturers are growing in receptivity towards CM, and are adopting pharmaceutical quality systems (PQS) which are crucial for CM [96]. Nonetheless, PQS has its limitations as quality outcomes are contingent on people making quality choices [115]. Hence, manufacturers need to embrace a culture of quality to produce quality products via CM [116]. Organizations can also adopt Kaizen or Lean Six Sigma principles to develop cross-functional continuous improvement of quality [115, 117].
Industry 4.0 and Pharma 4.0 At present, there is an astounding amount of data collected in the pharmaceutical industry that is underutilized [117], with data integrity still being a pressing issue [20]. These issues would likely be exacerbated in CM due to an increase in data collection from systems such as PAT [117].
Nonetheless, the pharmaceutical industry is progressing towards Industry 4.0 to overcome the challenges highlighted above. Pharma 4.0, modelled after Industry 4.0, is driven by technological advancements, such as big data, Artificial Intelligence (AI) and cloud-computing [20]. These technologies process, store and convert data into useful knowledge [22]. For instance, cloud computing [21] and deep neural networks (DNN) [118] can support the implementation of PAT in CM systems. With the support of guidelines [119] and pharmacopoeias [120] on computerized systems, uptake of these technologies has been rapid. Organizations are also working with regulators to integrate AI into CM to enable real-time release [121].
With time, Industry 4.0 would cause a paradigm shift in pharmaceutical manufacturing. As technology advances, machine learning and predictive analytics may even enable preventative maintenance without shutting down continuous processes [122]. Though CM aligns with Pharma 4.0 objectives [90], manufacturers should conduct more research in integrating new technologies into CM, as data security processes must be robust to prevent cyber threats [122]. Also, manufacturers are advised to start with minimal cGMP impact processes [117].
Conclusion
The pharmaceutical industry and regulators have recognized the benefits and opportunities of CM. Propelled by various driving forces, several manufacturers have successfully adopted this technology. Since the CM of pharmaceuticals is an emerging field, there are still significant challenges that need to be overcome. However, with the implementation of ICH Q13, regulators would have specific guidelines on CM, thereby eliminating the top barrier to implementation. Thereafter, the implementation of CM would substantially increase with regulatory harmonization. Nonetheless, due to the complexity of pharmaceutical processes and products, there is no one-size-fits-all solution. Therefore, it must be emphasized that while regulators work towards creating a harmonized guideline on CM, manufacturers should work on overcoming existing cost, technical, and cultural challenges.
Perhaps these challenges could be seen as opportunities for growth. Other industries have paved the way forward towards an optimistic future. Now it is time for the pharmaceutical industry to rise to the challenge, seize the opportunities and revolutionise pharmaceutical manufacturing with CM. Ultimately, the world would benefit from greater response capacities to drug shortages and pandemics, while contributing to environmental conservation. Closer to heart, individual patients’ lives would be improved with greater access to life-saving medicines.
Competing interests: None.
Provenance and peer review: Not commissioned; externally peer reviewed.
Authors
Adjunct Associate Professor Sia Chong Hock, BSc (Pharm), MSc Teh Kee Siang, BSc (Pharm)(Hon) Associate Professor Chan Lai Wah, BSc (Pharm)(Hon), PhD Department of Pharmacy, National University of Singapore, 18 Science Drive 4, Singapore 117543
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Author for correspondence: Adjunct Associate Professor Sia Chong Hock, BSc (Pharm), MSc, Senior Consultant (Audit and Licensing) and Director (Quality Assurance), Health Products Regulation Group, Health Sciences Authority Singapore, 11 Biopolis Way, #11-01 Helios, Singapore 138667
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Author byline as per print journal: Hye-Na Kang1, PhD; Robin Thorpe2, PhD; Ivana Knezevic1, PhD; Daehyun Baek3, PhD; Parichard Chirachanakul4; Hui Ming Chua5; Dina Dalili6, PhD; Freddie Foo7, MSc; Kai Gao8, PhD; Suna Habahbeh9, PhD; Hugo Hamel10, PhD; Edwin Nkansah11, PhD; Maria Savkina12, PhD; Oleh Semeniuk13; Shraddha Srivastava14; João Tavares Neto15, PhD; Meenu Wadhwa16, PhD; Teruhide Yamaguchi17, PhD
The World Health Organization (WHO) has provided specific guidance for biosimilar products to assist regulators, manufacturers and other professionals involved in the development and evaluation of these products. The development and approval of biosimilars are important for health care, as they allow the marketing of safe, efficacious and affordable biological products. Since the first biosimilars were approved in the EU in 2006, a series of biosimilars have been approved in many countries/geographical regions. This manuscript provides the figures on the status of approved biosimilars in 16 countries based on the information from regulatory experts and from publicly available data. It is clear that increasing numbers of biosimilars are now available in many countries and provide more options for treatments. It is expected that adoption of biosimilars will allow affordable health care and greater patient access to important medicinal products. It will also contribute to the overall WHO goal recognized by the World Health Assembly in 2014 by adopting a resolution on access to biotherapeutic products including biosimilars and on ensuring their quality, safety and efficacy.
Submitted: 12 October 2020; Revised: 25 November 2020; Accepted: 25 November 2020; Published online first: 14 December 2020
Introduction
Development of biosimilars is important for health care as it allows the marketing of safe, efficacious and affordable biological products. The European Medicines Agency (EMA) was the first regulatory agency to establish a process for the approval of biosimilars and approved the first biosimilars in 2006.
Since then, there has been much progress in establishing the regulatory pathway for biosimilars and a wide range of biosimilars have been approved for marketing in many countries/geographical regions [1]. An extensive number of biosimilars are now being used globally and are contributing considerably to widening patient access to appropriate biological medicines at reduced costs.
The World Health Organization (WHO) has taken a lead in the biosimilar field at the global level and has developed specific guidance for biosimilar development and approval as well as a number of other pertinent guidelines [2-4]. WHO has also organized a number of implementation workshops to assist regional regulatory agencies and manufacturers in the biosimilars area. As part of these workshops, surveys have been conducted to understand the current situation with biosimilars in the participants’ countries [1, 5, 6]. These surveys provide a unique opportunity to establish the situation with currently marketed biosimilars/similar biotherapeutic products in 16 countries. This publication presents this information.
Methods
The survey was conducted as previously described [1], but the information was updated and confirmed in July 2020. The information contained in this survey report is from participants of 15 countries who agreed for their information to be disclosed. The feedback from the UK refers to the situation in the European Union (EU) rather than specifically for the UK. Information from the US was not derived from the survey, but from the website of the US Food and Drug Administration (FDA). It should be noted that biological products in Table 1 have been approved as biosimilars in the countries as surveyed, but biosimilars approved in certain countries might not have been approved following a strict comparative regulatory process as recommended by WHO guidelines. The term ‘approval’ used in the manuscript is referring to the approval by the national regulatory authority. WHO did not conduct assessment of these products nor of the procedure for regulatory evaluation conducted by the national regulatory authorities as a basis for the ‘approval’.
Results
Table 1 shows a breakdown of information received which includes country participating (in survey), International Nonproprietary Name (INN), brand name and manufacturer/company name of product, the location of the producer of the product, the clinical indications approved, the reference product used and its manufacturer and the date the biosimilar/similar biotherapeutic products was approved. Table 2 shows the numbers of biosimilars/similar biotherapeutic products approved by regulatory authorities in the 16 countries (updated July 2020) specified by product type.
Discussion/Conclusions
Following the EU’s lead after their first biosimilar approvals in 2006, other countries have approved biosimilars/similar biotherapeutic products not only with increasing numbers but also with expanding the available product classes. ‘Big pharma’, e.g. in the EU and the US, continues to dominate the biosimilar market, but local manufacturers have played a significant role in producing biosimilars/similar biotherapeutic products in some countries, e.g. in China, India, Iran, Japan, Republic of Korea.
When compared with the situation in August 2019 [1], the major biosimilar products being approved as of July 2020 are monoclonal antibodies. For example, six and seven monoclonal antibody similar biotherapeutic products/biosimilars have been approved in Brazil and in Canada, respectively, during the updating period.
The quality of similar biotherapeutic products/biosimilars approved in some countries is still an issue for concern. Some products in certain countries were approved prior to adoption of regulations or guidelines for biosimilar evaluation, see Table 1. As mentioned above, EMA was the first agency to adopt the biosimilar concept in 2006, so products called ‘biosimilars’ approved before 2006 are unlikely to be biosimilars [1]. Regulators need to reassess such products to ensure whether they meet the current requirements and to identify the inappropriate labelling of non-innovator and copy-version products (approved when regulatory procedures were not well defined) as biosimilars [7-9].
It is clear that increasing numbers of biosimilars are now available in many countries and provide more options for treatments. In certain countries, the availability of various product classes has been expanded by approval of biosimilars for which product classes were not available on the market previously. This is important for relatively expensive products, e.g. monoclonal antibodies. It is expected that adoption of biosimilars will allow affordable health care and greater patient access to important medicinal products [1].
Disclaimer
The authors alone are responsible for the views expressed in this manuscript and they do not necessarily represent the views, decisions or policies of the institutions with which they are affiliated. The survey participants are listed in alphabetical order in the author section after the three primary authors.
The information in this manuscript provided based on the categorization of biosimilars by each national regulatory authority. Thus, biosimilars approved in certain countries might not have been approved following as strict a regulatory process as is required by WHO guidelines. Indications in Table 1 also as reported by survey participants; not necessarily representing WHO approval of these.
The World Health Organization retains copyright and all other rights (CC BY 3.0 IGO) in the manuscript of this article as submitted for publication.
Funding sources
The Ministry of Health and Welfare of Republic of Korea provided the fund to WHO for this project through a voluntary contribution for the period of 1 December 2018–30 September 2021.
Competing interests: The authors have disclosed no potential conflicts of interests.
Provenance and peer review: Not commissioned; externally peer reviewed.
Authors
Hye-Na Kang1, PhD Robin Thorpe2, PhD Ivana Knezevic1, PhD Daehyun Baek3, PhD Parichard Chirachanakul4 Hui Ming Chua5 Dina Dalili6, PhD Freddie Foo7, MSc Kai Gao8, PhD Suna Habahbeh9, PhD Hugo Hamel10, PhD Edwin Nkansah11, PhD Maria Savkina12, PhD Oleh Semeniuk13 Shraddha Srivastava14 João Tavares Neto15, PhD Meenu Wadhwa16, PhD Teruhide Yamaguchi17, PhD
1World Health Organization, Department of Health Product Policy and Standards, 20 Avenue Appia, CH-1211 Geneva, Switzerland 2Independent expert, Welwyn, UK 3Ministry of Food and Drug Safety, Osong, Republic of Korea 4Food and Drug Administration, Nonthaburi, Thailand 5National Pharmaceutical Regulatory Agency, Selangor, Malaysia 6Iran Food and Drug Administration, Tehran, Iran 7Health Sciences Authority, Singapore 8Shanghai University, Shanghai, People’s Republic of China 9Jordan Food and Drug Administration, Amman, Jordan 10Health Canada, Ottawa, Canada 11Food and Drugs Authority, Accra, Ghana 12Centre for Evaluation and Control of Medicinal Immunobiological Products of the FSBI «SCEEMP» of the Ministry of Health of Russia, Moscow, Russian Federation 13Ministry of Health of Ukraine, Kyiv, Ukraine 14Central Drug Standards Control Organization (CDSCO), Ministry of Health & Family Welfare, New Delhi, India 15Brazilian Health Regulatory Agency (ANVISA), Brasilia, Brazil 16National Institute for Biological Standards and Control, Medicines and Healthcare products Regulatory Agency, Potters Bar, UK 17Pharmaceuticals and Medical Devices Agency, Tokyo, Japan
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Author for correspondence: Hye-Na Kang, PhD, World Health Organization, Department of Health Product Policy and Standards, 20 Avenue Appia, CH-1211 Geneva, Switzerland
Disclosure of Conflict of Interest Statement is available upon request.
Permission granted to reproduce for personal and non-commercial use only. All other reproduction, copy or reprinting of all or part of any ‘Content’ found on this website is strictly prohibited without the prior consent of the publisher. Contact the publisher to obtain permission before redistributing.
GaBI Journal is an independent and peer reviewed academic journal. GaBI Journal encompasses all aspects of generic and biosimilar medicines development and use, from fundamental research up to clinical application and policies.
