Author byline as per print journal: Robin Thorpe, PhD, FRCPath; Elwyn Griffiths, PhD, DSc; Niklas Ekman, PhD
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Abstract: |
Submitted: 19 April 2018; Revised: 12 July 2018; Accepted: 18 July 2018; Published online first: 25 July 2018
Similar Biotherapeutic Products (SBPs or biosimilars) are being increasingly developed worldwide. The presence of this new class of biotherapeutic agent is improving access and availability to treatment for patients across the globe. However, the regulation and approval of biosimilars is not straightforward and practices differ from country to country. To ensure that biosimilars successfully enter markets and maintain the safety and efficacy achieved by their originator products, methods for their approval and regulation need to be laid out clearly.
To discuss the regulation and approval of biosimilars across the nations of Southeast Asia, the First ASEAN Educational Workshop on Regulation and Approval of Biosimilars/Similar Biotherapeutic Products took place on 23 July 2017, Bangkok, Thailand [1]. This was organized by the Generics and Biosimilars Initiative (GaBI) in collaboration with the Association of Southeast Asian Nations (ASEAN). Forty-three participants, including the speakers, attended the workshop.
This First ASEAN Educational Workshop on Regulation and Approval of Biosimilars/Similar Biotherapeutic Products was an interactive workshop that focused on the regulation and approval of biosimilars. It brought together regulators and key representatives from the ASEAN ACCSQ–PPWG (ASEAN Consultative Committee for Standards and Quality Pharmaceutical Product Working Group) Member States: Indonesia, Lao PDR, Malaysia, Myanmar, Philippines, Singapore, Thailand, Vietnam; along with academics, medical practitioners/specialists, pharmacists, and procurement specialists. These participants held discussions and exchanged information with experts from across Asia, Europe and the US.
One of the key aims of the educational workshop was to address the potential differences in quality as well as the therapeutic and immunological (immunogenicity) effects of biologicals across ASEAN nations. To facilitate this, representatives from regulatory authorities, academia and medical specialists, that are involved in biological and biosimilar development and approval in ASEAN Member States, were joined by expert speakers from other nations. The participants engaged in active discussions covering topics concerning: the principles and challenges related to manufacturing process development of biosimilars; the clinician’s experience of biocopy* erythropoietin (EPO); the regulatory experience of re-evaluating EPO; and the identification of future educational requirements.
The format of the First ASEAN Biosimilars Educational Workshop was similar to that followed in prior educational workshops as reported in GaBI Journal [2–4]. For more details of methods and case presentations, see the published report of the First Latin American educational workshop on similar biotherapeutic products [2], the First MENA educational workshop on regulation and approval of similar biotherapeutic products/biosimilars [3], and the First Turkish interactive workshop on regulation and approval of similar biotherapeutic products/biosimilars [4].
The ASEAN workshop began with presentations given by expert speakers [1]. The details of most of these presentations were updates to those given at other GaBI workshops and are summarized in their published reports [2–5].
Dr Thijs J Giezen, a hospital pharmacist at the Foundation Pharmacy for Hospitals in Haarlem, The Netherlands, and a member of the Biosimilar Medicinal Products Working Party (BMWP) of the European Medicines Agency, discussed the safety assessment and risk management of biosimilars, as reported in [2, 5]. However, in this more recent 2017 presentation, he highlighted that in many nations across the globe, patients and physicians have a knowledge gap when it comes to biosimilars. He advised that globally, further steps need to be taken to improve education and to increase trust in biosimilars.
Biocopy* EPO’s in Thailand
In addition to the presentations that have been given at previous GaBI workshops, two ASEAN-specific presentations were given. Professor Kearkiat Praditpornsilpa of Chulalongkorn University, Bangkok, Thailand gave a presentation entitled, ‘Clinician’s experience of biocopy EPO in Thailand’. Here, he discussed the well-documented immunogenicity of recombinant human erythropoietin (r-HuEPO) by subcutaneous exposure. This adverse immunological effect causes anti-r-HuEPO-associated pure red cell aplasia (PRCA). Professor Praditpornsilpa highlighted the fact that there have been increasing cases of anti-r-HuEPO-associated PRCA by subcutaneous exposure in Thailand. It is suggested that the immunogenicity may relate to human leukocyte antigen (HLA) immunogenetics, protein aggregation, stability during storage; and handling of drug products, formulation and drug product quality. Professor Praditpornsilpa and his research group have carried out extensive investigations into the unreliability of biocopy EPO’s in Thailand.
r-HuEPO’s have been licensed for the treatment of renal anaemia in Thailand and include innovator products and more than 20 biocopy products. However, there are inconsistencies in product characterization and quality which may lead to different immunogenicity and safety profiles. As such, the Prospective Immunogenicity Surveillance Registry of r-HuEPO with subcutaneous exposure in Thailand estimated the incidence rate of anti-r-HuEPO associated PRCA among subjects who had subcutaneous exposure to any currently marketed r-HuEPO product. In addition, the registry addressed the risk of anti-r-HuEPO associated PRCA and the association of product quality with adverse immunogenicity.
Following their investigation, the registry suggested that there is an association between product quality and immunogenicity. All anti-r-HuEPO associated PRCA cases had received biocopy r-HuEPO products, resulting in the observation of a correlation between product characteristics and adverse immunogenicity. As patients’ safety is a top priority, Professor Praditpornsilpa emphasized that the approval process for biosimilars in Thailand needs to include intensive scientific regulation. The regulatory pathway for similar biological drugs must be designed to assess quality, characterization and the impurity profile of such products, including head-to-head evaluation with a reference biological product, followed by careful head-to-head evaluation of the non-clinical and clinical aspects. Pharmacovigilance studies should be the final step to ensure quality and safety and this can be assessed together with the cost-effectiveness and patient benefits that such products offer. Professor Praditpornsilpa concluded that, in light of the issues encountered with the use of biocopy r-HuEPO in Thailand, individual case-by-case review and approval of biocopy products is needed.
Re-evaluating erythropoietin’s in Thailand
Mr Pramote Akarapanon, Head of Biological Products Section at the Ministry of Public Health, Thailand, gave a presentation entitled, ‘Experience of re-evaluating erythropoietin in Thailand’. Here, he noted that in Thailand, erythropoiesis stimulating agent EPO’s have been used for the standard treatment of anaemia in patients with chronic kidney disease for some time. However, as mentioned in Professor Praditpornsilpa’s presentation, this was associated with a high prevalence of PRCA. As a result, a re-evaluation of marketed EPO’s was instigated by a Ministerial Order, whereby the importer or manufacturer of EPO is required to submit additional data (quality, non-clinical, clinical) to the Thai Food and Drug Administration (TFDA), together with a Risk Management Plan (RMP). There are two types of RMP depending on the extent of documentation already submitted for each individual product. Mr Akarapanon noted that close monitoring of RMP’s is a big challenge for TFDA.
Following the speakers presentations, there was the opportunity for discussion of the topics covered. Herein, Dr Niklas Ekman, member of the Biosimilar Medicinal Products Working Party (BMWP) of the European Medicines Agency (EMA), made it clear that EMA only evaluates biosimilars for biosimilarity, and does not evaluate the interchangeability between a biosimilar and reference product. According to the European definition, interchangeability refers to the possibility of exchanging one medicine for another medicine that is expected to have the same clinical effect [6]. He noted that interchangeability is a national concern and is to be dealt with by individual medicines regulatory agencies of the European Union Member States, most of which have published their own position papers or statements on interchangeability that are in general, aligned. He stressed that in Europe, interchangeability means that it is the prescriber that can choose between the originator and the biosimilar, but currently there is no pharmacy-level substitution.
When it comes to switching between an originator and biosimilar, Dr Giezen advised that in Europe EMA, does not require switching studies which is in contrast to the requirements of the US Food and Drug Administration (FDA). In Europe, if a biosimilar is approved it is up to the Member States to decide on interchangeability and switching, not EMA. In general, if a biosimilar and the reference product have been shown to be similar through quality characterization and this confirmed by clinical trials, they can be switched safely and efficaciously. As such, switching studies are not necessary, and are generally only carried out to provide data to show clinicians that switching is safe. Dr Giezen added that switching studies generally have limitations, particularly if the number of patients in the study is small and adverse effects are rare. The design of switching studies and the length of time over which they are carried out, also needs to be considered.
The discussion steered towards understanding how many batches of reference product are needed to establish the Quality Target Product Profile (QTPP) of a biosimilar. Here, Dr Ekman noted that the exact number of batches is not specified by EMA requirements. However, companies are recommended to analyze reference product batches over a relatively long period of time as this means that batch-to-batch variability is better understood. Furthermore, it is in the company’s interest to analyse a reasonable number of batches of the reference product as with a small number of batches the variability present in the quality attribute of the reference product cannot be appropriately estimated. Depending on the quality attribute in question, this can result in analyses of 20 or more reference product batches.
Dr Ekman explained that for evaluating biosimilarity, orthogonal analytical methods should be used whenever possible. If only one method is applied for analysing a certain quality attribute this will usually add more burden on the qualification of the method. It needs to be demonstrated with high confidence that such a method is sensitive and can reliably detect minor differences between the originator and biosimilar. The use of orthogonal methods will increase trust in the biosimilar assessment. Speaker Dr Sundar Ramanan added that, in the case of glycosylation, it is very important to know what kind of enzyme reagents are used in the analysis and that it is critical to assess whether the results obtained from using these enzymes and subsequent separation methods, have the required sensitivity needed for adequate assessment.
In follow up to this, a question was asked about the charge variant analysis that should take place when evaluating a biosimilar. In response, Dr Ekman noted that differences in the charge variant often mean that there are differences between the originator and the biosimilar and it is critical to understand why these differences occur. After this, a more detailed discussion on charge variants and isoforms ensued.
During Professor Praditpornsilpa’s presentation he noted that while investigating r-HuEPOs, his research group encountered a cold chain and storage problem early on in their research. However, when they carried out their pharmacovigilance study, they made sure that the cold chain and storage problem did not interfere with their results. Professor Praditpornsilpa noted that, on inspection of their analytical data, although the human serum albumin was a better stabilizer compared to polysorbate 80, the purity of human serum albumin could be an issue for product quality. This highlights the fact that the quality of the preservation of a biological is key. Professor Praditpornsilpa also noted that he is skeptical about the quality of human serum albumin currently used in the biocopy EPOs in Thailand. He suspects that there may be some contamination but notes that carrying out analysis to confirm this is complicated. The analysis of the products by mass spectroscopy identified other human proteins and also rodent protein contamination. The human proteins could be related to the purity of human serum albumin for preservation and the rodent protein could be related to the separation of r-HuEPO from the cell culture. With regards to the immunogenicity occurring in Thailand that has led to 30 cases of PRCA in 2016, Professor Praditpornsilpa confirmed that this mostly occurred when biocopy products were used, rather than with originator products (although 1−2 cases per year are seen with originator products). He and his team believe that this issue is caused by protein aggregation and impurity of products.
Mr Pramote Akarapanon’s presentation also focused on PRCA occurring following EPO use. Due to the safety concerns surrounding this form of medication in Thailand, he noted that products associated with causing PRCA should be withdrawn from the market. However, during the discussion, Mr Akarapanon noted that there are no specific set timelines in place for product withdrawal and that products were being assessed on a case-by-case basis. In contrast, WHO Guideline on the reassessment of approved rDNA-derived biotherapeutics proposes a stepwise approach which includes timelines for undertaking the exercise. He also added that the public were aware of the safety concerns and of the fact that EPO products are under review.
Case study working sessions took place following the presentations (downloadable from the GaBI website [1]). These followed the same format as those described in [2–4], of two fictional cases of a follow-on biological therapeutic, one an erythropoietin product and the other a monoclonal antibody. The participants were divided into four discussion groups, see Table 1, where they evaluated the fictional data supplied. The group discussions are summarized in Tables 2 and 3.
Biosimilar medicines are being increasingly developed and used across Southeast Asia. Safety and efficacy issues that have surrounded the use of biocopy EPO’s in Thailand highlight the need for adequate evaluation and regulation of biosimilars across the region. The ASEAN Educational Workshop on Regulation and Approval of Biosimilars/Similar Biotherapeutic Products was successful in bringing representatives from ASEAN nations together with those from Europe and the US, to discuss the best routes forward for successful biosimilar approval, regulation and market introduction.
Speakers
Pramote Akarapanon, BSc Pharm, MA, Thailand
Niklas Ekman, PhD, Finland
Thijs J Giezen, PharmD, MSc, PhD, The Netherlands
Elwyn Griffiths, PhD, DSc, UK
Professor Andrea Laslop, MD, Austria
Professor Kearkiat Praditpornsilpa, MD, Thailand
Sundar Ramanan, PhD, USA
Robin Thorpe, PhD, FRCPath, UK
Meenu Wadhwa, PhD, UK
Moderators
Agnes Chan, Singapore
Azizah Ab Ghani, PhD, Malaysia
Associate Professor Maneewan Suksomtip, PhD, Thailand
Assistant Professor Wisit Tangkeangsirisin, PhD, Thailand
Editor’s comment
All moderators had provided the discussion/conclusion of the group discussion, read the report and revised the content of the summary discussion.
Acknowledgement
The Generics and Biosimilars Initiative (GaBI) wishes to thank Ms Sylvia Laksmi Sardy and Ms B Lusia Herwahyu S from the ASEAN Secretariat for their support towards the coordination of the workshop with ASEAN member states; Dr Tankamol Chanprapap, Ms Charunee Krisanaphan and Mr Pramote Akarapanon of Thai FDA for their strong support through the offering of advice and information towards the preparation and organization of the workshop; the moderators in clarifying the information of the case study discussion when finalizing the meeting report; as well as Dr Robin Thorpe and Professor Andrea Laslop, chair and co-chair of the 2017 workshop; for their strong support through the offering of advice and information during the preparation of the workshop.
The authors would like to acknowledge the help of all the workshop speaker faculty and participants, each of whom contributed to the success of the workshop and the content of this report, as well as the support of the moderators and co-moderators: Ms Agnes Chan, Dr Azizah Ab Ghani, Associate Professor Maneewan Suksomtip and Assistant Professor Wisit Tangkeangsirisin in facilitating meaningful discussion during the parallel case study working sessions, presenting the discussion findings at the workshop, and contributing in the finalization of this meeting report.
Lastly, the authors wish to thank Ms Alice Rolandini Jensen, GaBI Journal Editor, in preparing and finalizing this meeting report manuscript and providing English editing support on the group summaries.
Competing interests: The workshop was sponsored by an unrestricted educational grant to GaBI from Amgen Inc.
Provenance and peer review: Not commissioned; externally peer reviewed.
Robin Thorpe, PhD, FRCPath, UK
Elwyn Griffiths, PhD, DSc, UK
Niklas Ekman, PhD, Finland
*Biocopy refers to a licensed product made as a copy of an original product but not licensed according to the now accepted international norms of a biosimilar.
References
1. Generics and Biosimilars Initiative. First ASEAN Educational Workshop on Regulation and Approval of Biosimilars/Similar Biotherapeutic Products 2017. 23 July 2017; Bangkok, Thailand. Available from: www.gabi-journal.net/about-gabi/educational-workshops/first-asean-educational-workshop-on-regulation-and-approval-of-biosimilarssimilar-biotherapeutic-products-2017
2. Walson P, Thorpe R. First Latin American educational workshop on similar biotherapeutic products, Mexico City, Mexico, 20 January 2015. Generics and Biosimilars Initiative Journal (GaBI Journal). 2015;4(3):143-8. doi:10.5639/gabij.2015.0403.031
3. Walson P, Thorpe R. First MENA educational workshop on regulation and approval of similar biotherapeutic products/biosimilars, Dubai, United Arab Emirates, 1 September 2015. Generics and Biosimilars Initiative Journal (GaBI Journal). 2015;4(4):173-7. doi:10.5639/gabij.2015.0404.039
4. First Turkish interactive workshop on regulation and approval of similar biotherapeutic products/biosimilars 2016. Generics and Biosimilars Initiative Journal (GaBI Journal). 2016;5(3):134-8. doi:10.5639/gabij.2016.0503.034
5. Roundtable on biosimilars with European regulators and medical societies, Brussels, Belgium, 12 January 2016. Generics and Biosimilars Initiative Journal (GaBI Journal). 2016;5(2):74-83. doi:10.5639/gabij. 2016.0502.019
6. European Medicines Agency. European Commission, Biosimilars in the EU. Information guide for healthcare professionals [homepage on the Internet]. [cited 2018 Jul 12]. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/Leaflet/2017/05/WC500226648.pdf
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Author for correspondence: Robin Thorpe, PhD, FRCPath, Deputy Editor-in-Chief, GaBI Journal |
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Introduction: The Association of Southeast Asian Nations (ASEAN) Overview Workshop on GMP for Biologicals and Biosimilars was co-organized with the Generics and Biosimilars Initiative (GaBI). This meeting was intended to improve the understanding of the good manufacture practice (GMP) inspection framework for biological (and biosimilar) drugs among ASEAN countries. |
Submitted: 18 February 2019; Revised: 24 July 2019; Accepted: 25 July 2019; Published online first: 6 August 2019
In collaboration with the Association of Southeast Asian Nations (ASEAN), the Generics and Biosimilars Initiative (GaBI) organized a first workshop of its kind in this region on good manufacturing practices (GMP) for biological drugs (including biosimilars).
The workshop held on 5 August 2018 focused on GMP standards and the knowledge required for effective GMP inspection of biological products. In addition, there were discussion sessions to identify common concerns in these areas.
It was attended by the ASEAN Joint Sectoral Committee (JSC) on GMP inspection, other ASEAN GMP inspectors, reviewers from the ACCSQ-PPWG (ASEAN Consultative Committee for Standards and Quality-Pharmaceutical Product Working Group) Member States, academics, regulators and other experts, including from the World Health Organization (WHO). In total, 46 people attended the workshop, which included a series of presentations, each followed by a Q&A session, and parallel group discussions.
There were a number of expert speaker presentations followed by Q&A and an in-depth panel discussion. The presentations are downloadable from the GaBI website [1].
The workshop began with a welcoming speech from Mr Do Van Dong, Deputy Director General of the Drug Administration of Vietnam.
Mr Dong discussed the importance of GMP for the entire lifecycle of biological and biosimilar products. He noted that WHO has published several different versions of its guidelines on GMP practices and principles and recently updated its specific requirements. The latest version of WHO GMP for biologicals and biosimilars (WHO Technical Report Series (TRS) No. 999, Annex 2 [2]) replaces the previous version from 1992. However, Mr Dong highlighted the disproportionate input from the Western world on GMP practices. As a result, the ASEAN Member States (AMS) lack opportunities to update their GMP practices, especially for biological products. Mr Dong stated that the present workshop was an encouraging start for the development of an ongoing forum for the exchange of knowledge and experience among GMP inspectors, as well as for the promotion of consistency and harmonization of the relations among the regulatory authorities within the ASEAN community with regards to GMP for biologicals.
Chair of the ASEAN Joint Sectoral Committee on GMP Inspection, Adjunct Associate Professor Chong Hock Sia then provided a second welcome address and outlined of the workshop objectives.
Professor Sia introduced ASEAN and noted that its Member States have a combined population of 650 million people and a combined economy of US$2.5 trillion. He also discussed aspects of the ASEAN Mutual Recognition Agreement (MRA) on GMP inspection [3] but noted that this does not yet include biologicals, active pharmaceutical ingredients (APIs) or investigational medicinal products. As such, he highlighted the importance of the workshop and its objectives:
1) To understand current GMP (cGMP) inspection framework for biologicals/biosimilars based on Pharmaceutical Inspection Convention and Pharmaceutical Inspection Co-operation Scheme (PIC/S) or other equivalent cGMP standards
2) To promote active discussion amongst inspectors, reviewers and scientists from AMS concerning best practices to use when inspecting manufacturers of biologicals/biosimilars
3) To identify areas of consensus, uncertainty or disagreement concerning inspection framework on cGMP for biologicals/biosimilars.
Overall, the workshop aimed to increase the ability of participants to conduct inspection of biological/biosimilar manufacturing facilities under the cGMP framework, a critical component of the registration and licensing of pharmaceutical and biological products.
Dr Dianliang Lei, a WHO scientist in Technologies, Standards and Norms for Essential Medicines and Health Products, discussed the 2015 updated WHO GMP guidance for biologicals.
Dr Lei explained that WHO’s GMP guidelines for biologicals were first established in 1992. These have now been revised and updated in accordance with the revision principles [2], see Table 1. A number of challenges were encountered during the revision process but key changes to the guidelines have now been made. These include changes to the scope, terminology, pharmaceutical quality and risk control, starting materials, campaign production, containment, labelling and documentation. Containment and biosafety were also introduced into the GMP guideline. Measures such as segregation of live and non-live material, clothing, product and material transfer procedures, HVAC design, acquiring specific knowledge on the type of microorganisms being handled and its associated risks, environmental monitoring tailored based on the risks and characteristics of the biological products, and the use of a campaign-based production considering upstream and downstream processes are addressed in the guidelines. Terms such as reference sample and retention sample were used in the revised GMP guidelines. Reference sample is a sample of a batch of starting material, packaging material, intermediate or finished product which is stored for the purpose of being analysed should the need arise during the shelf-life of the batch concerned. Retention sample is a sample of a fully packaged unit from a batch of finished product. It is stored for identification purposes. In certain situations, both samples are exchangeable.
Dr Elwyn Griffiths, former Chairman (2010–2016) and Rapporteur (2016–2017) of the WHO Expert Committee on Biological Standardization, and workshop Chair, discussed the use of animal cells in the production of biological drugs and vaccines. Cell banks are critical to the production of modern biological medicines, Some of which were previously extracted from animal fluids or tissues, the range of cells used include microbial, animal and plant cells.
Dr Griffiths outlined some of the critical manufacturing issues in producing biological drugs from cells, including the production system; the genetic stability of the cell substrate and microbial seeds; viral safety issues and impurities caused by the host cell such as residual deoxyribonucleic acid (rDNA) from mammalian cells, see Table 2. He stressed that small process changes can have a major impact on the clinical performance and safety of a biological product, making production consistency critical.
He noted that continuous mammalian cell lines are the substrate of choice for many rDNA products as they can be transfected and engineered to grow rapidly and produce glycosylated products. He outlined the three major concerns associated with using these cells to produce biological drugs:
1) Genetic stability of cell lines
2) Residual host cell DNA, which might cause cancer
3) Viruses in animal cells, including re-troviruses
Dr Griffiths introduced the concept of a Master Cell Bank (MCB, cells derived from a cell seed and frozen) and Working Cell Bank (WCB, derived from the MCB and used to provide cells for manufacturing) which provide a standardized source of production cells and are now used for all cell lines. To prevent viral contamination, WHO encourages production based on cryopreserved cell banks exhaustively screened for virus contamination; control of raw material used in production; closed systems of cell culture; testing each cell culture for contamination, and validation of viral removal/inactivation by downstream processing.
Dr Griffiths noted that cell banks require highly specialized expertise and infrastructure, and this is often contracted out to specialized testing organizations. He described good cell culture practice, including ensuring the donor is free of transmissible diseases, and confirming the absence of viral and microbial contamination. The MCB, WCB and all cell culture processes are key to consistently producing safe and effective biologicals.
Focusing on fermentation, Dr Dinesh Khokal of Amgen Singapore, first described the upstream and downstream processes for biological manufacturing, see Figure 1.
Dr Khokal explained the importance of process control during fermentation. He noted that cell culture contamination is the most common problem associated with fermentation. This may arise due to impurities in the source materials or biological contaminants such as unwanted bacteria, viruses or moulds. To reduce the risk of contamination, he made recommendations including:
Dr Khokal also emphasized the importance of control of the source materials in order to reduce the risk of adventitious agent contamination and other serious loss of quality and safety. It is important to ensure the origin and quality of source materials according to GMP principles and use a sampling, testing and monitoring programme. He also recommended aseptic manufacturing processes and controlled transportation of critical materials to manufacturing sites.
Finally, Dr Khokal explained that even slight changes to the culture conditions can impact culture performance, productivity and product quality, see Figure 2. He added that fermentation processes (including sterile practices, control of source materials and culture conditions) should be risk-based, science-based and in accordance with WHO GMP guidelines for biological products.
Commercial Research Manager of Indian biotechnology firm Protaccine Biotec, Dr Anil Kumar Chawla, discussed how to purify biological drugs, including vaccines. He began by explaining that the first step in the manufacturing process — the harvesting/purification of a protein from the reactor — introduces a significant risk of product degradation, bioburden concerns and/or process errors, see Table 3.
He outlined the two major techniques for purification, which aim to generate a highly pure active drug substance free of all possible impurities:
1) Cell disruption
2) Separation of soluble products
In conclusion, Dr Chawla highlighted the importance of quality risk management (QRM) and made some critical observations on WHO inspections. He noted that manufacturers should control the bioburden during purification, carefully store purification equipment, use disposable accessories wherever possible, monitor clean room parameters, replace aseptic processes with sterile filtration and improve the purification process based on historical data.
Dr Yusdy Pan, Principal Scientist for Process Development for Amgen Singapore, outlined the harvest process for biological drugs, including new harvest technologies for high density cell culture.
Dr Pan outlined the differences between mammalian and microbial cell expression systems, see Figure 3.
He also noted that mammalian cell expression systems offer a simple antibody recovery system, which is what is harvested. The conventional harvest process for mammalian cell culture involves a combination of centrifugation and filtration and is suitable for a cell density of a maximum of 10 million cells per mL, see Figure 4.
To meet the industrial demand for new high-density cell culture techniques, which can involve culturing over 10 million cells and a solid content of over 15%, alternative technologies are needed. The conventional platform process is unsuitable for this due to limited centrifuge bowl capacity and depth filter surface area. Alternative technologies include:
Mr Vimal Sachdeva, Senior Inspector in the WHO Prequalification Team, explained the WHO Prequalification of Medicines Programme.
He introduced the quality management system (QMS) as important to facilitate innovation and continual improvement and to strengthen the link between pharmaceutical development and manufacturing activities. He said a streamlined structure enables compliance and operational efficiency and the flexibility to incorporate different modalities.
With regards to this, WHO states that all biological products must be manufactured in accordance with pharmaceutical quality system (PQS) requirements, as defined in WHO GMP. QRM principles must also be used to develop control strategy across all stages of the manufacturing process, which should involve ongoing trend analysis and periodic review, starting material control and change control. It is also important to design monitoring systems and a control strategy to manage any identified risks. The International Council for Harmonization (ICH) Q10 pharmaceutical quality system aims to promote a move away from discrete GMP compliance procedures to a comprehensive quality systems approach, across the whole lifecycle of the product.
Mr Sachdeva gave examples of effective QRM and examples where the implementation of QMS had failed. He then concluded that biological quality objectives should be clearly linked to business objectives and strategy and the QMS should be clear and establish the link between quality policies and their implementation on the ground. To adapt to changes in regulation and incorporate site-specific nuances, the QMS should be flexible. Manufacturers need to ensure that all elements of the QMS are well connected and use contract manufacturing organizations where necessary; and use knowledge to improve processes. Finally, he noted that there should be an effective, proactive QRM process including internal audits and product quality reviews, see Table 4 on the general principles of a good QRM.
Dr Dinesh Khokal spoke about the removal of viral contamination from biological products. This is an important issue as viral contamination is a risk to all biological drugs. Contamination can arise from the original source of the cell lines, or from the adventitious introduction of a virus during production. A number of biological drugs have been contaminated in the past and only identified years after manufacture, causing great potential risk to patients. For the manufacturer, this can lead to facility shutdowns and significant business impact, see Figure 5 on the potential source of virus contamination.
There are many viral risk mitigation strategies, but none of these alone can provide a high enough level of assurance so they must be used in combination. Furthermore, because no single test can test for all known viruses, validation of the process for viral removal or inactivation is essential in establishing product safety. Methods to achieve this include viral inactivation and viral removal. These methods must be validated.
Dr Khokal discussed the importance of choosing which viruses should be used in viral clearance studies, including relevant viruses and model viruses. He also described the various assay types and noted that any assay must produce accurate measures of the viral load (usually expressed with 95% confidence limit, around 5% log of the mean).
Dr Khokal concluded by explaining that validation of the bioanalytical method used is important to assess that the method is fit-for-purpose, to ensure that the data are reliable to support the safety and effectiveness of the biological and critical for the quantitation of analytes (including biological products) and biomarkers in biological samples. There are several important method validation parameters, see Table 5. He noted that the US Food and Drug Administration (FDA) offers guidance on bioanalytical method validation, which outlines in depth the parameters required for chromatographic and ligand binding assays.
Dr Anil Kumar Chawla discussed the process of batching bulk biological products. Biological products can be manufactured in sublots and pooled as one batch, which means the bulk batch can be packed differently in terms of volume/concentration. He explained that the batch number should be recorded according to quantity, manufacturing date, expiry date, strength and excipient(s). Here, Dr Chawla noted that traceability is the key concern.
He also said the batch numbering standard operating procedure (SOP) should identify risks such as from inadequate numbering and mix-ups, clearly differentiable batch numbers should be used and risk scores should be calculated for each batch numbering system.
Dr Chawla outlined a number of critical criteria for bulk batching during WHO inspections, including:
Moving on to the storage of bulk products, Dr Chawla explained that the primary container should protect the bulk product from the external environment, keep it stable and be of appropriate material. He outlined the necessary aspects of storage conditions which included temperature, material, location and sanitation. He also outlined the requirements for distribution and the monitoring of transportation. And he concluded by noting the importance of monitoring extreme environmental conditions, specifically that special temperature monitoring systems and alert mechanisms should be used.
Mr Vimal Sachdeva introduced the importance of data integrity in biological production, with reference to WHO guidance on this issue.
He noted that data integrity means ensuring data are recorded as intended and the same in content and meaning as when it was originally recorded at all times, as well as preventing unintended or unauthorised changes to data. Data integrity is the degree to which a collection of data is Attributable Legible Contemporaneous Original and Accurate (ALCOA).
Accurate scientific data are critical as the basis of risk/benefit decisions regarding the selection and use of drugs. This is vital to avoid harm to patients and retain trust in the effectiveness of products and those that supply them.
He quoted WHO’s expectations on data management, which state that ‘good data and record management are critical elements of the pharmaceutical quality system and a systematic approach should be implemented to provide a high level of assurance that across the product life-cycle all GMP records and data are accurate, consistent, trustworthy and reliable’. Many data regulations exist across the globe.
Mr Sachdeva gave multiple examples of real-life data integrity breaches, including one case where plates recorded and reported as negative by quality control (QC) personnel were actually positive for contamination. He noted that there can be various causes of data integrity breaches, that include human error, system level issues and technology issues.
Overall, the presentation suggested that data integrity issues are increasing, see Figure 6. Often, inspections reveal deficiencies due to non-compliance with GMP. Mr Sachdeva concluded that data integrity issues are corrosive to science and trust, which – once lost – cannot be restored.
Speaking for a second time, Dr Dianliang Lei presented the WHO’s requirements for the cells used to manufacture biologicals, which can affect the characteristics and safety of biological products.
The potential risks of using cell substrates include viruses and other infectious agents, cellular DNA and ribonucleic acid (RNA), and growth promoting (oncogenic) proteins. A two-tiered cell bank system can be used to avoid genetic drift and limit the number of paths necessary. Dr Lei outlined the different types of animal cell substrates and their advantages and disadvantages, they are primary cell culture, diploid cell lines and continuous cell lines.
When developing cell cultures, fundamental features include authenticity (identity/provenance), the absence of contamination (with another cell line/microbes) and stability. GMP provides guidance on establishment of the cell bank, traceability to the originator cell line, storage, handling, cross-contamination and adventitious agent contamination. WHO requirements on cell banks include GMP for Biologicals (TRS 999), GMP for APIs (TRS 957) which is the specific guidance for APIs manufactured by cell culture or fermentations, recommendations for cell substrates (TRS 978) and other product specific recommendations. WHO’s recommendations for cell substrates is limited to animal cells but does consider novel substrates, including cells of avian, canine and insect origin. Issues related to stem cell lines for biological production are included, but not stem cells for therapy by transplantation.
Dr Lei ended by noting that the appropriateness of continuous cell lines for the biological product must be considered, and the MCB and WCB must be fully characterized. Cell bank characterization should include preliminary evaluation (such as for oncogenicity). WHO provides a summary of testing for the evaluation and characterization of the MCB and WCB in its revised draft recommendations, based on input from manufacturers (TRS 978 Annex 3).
Chair Dr Elwyn Griffiths closed the session by providing two case studies to illustrate the importance of following GMP in biologicals production. He noted that consistency of production is critical and depends on factors including the cell substrate, cell production system and separation/purification method.
Viral contamination is a key issue in the safety of biological products. Dr Griffiths noted that guidelines, e.g. WHO recommendations for the evaluation of animal cell cultures as substrates for the manufacture of biological products and for the characterization of cell banks, consider the possible viral contamination of live viral vaccines and rDNA products produced in any mammalian cell as a major issue. Guidance is regularly updated to account for new scientific information and technologies.
He also noted that the MCB and WCB should be exhaustively screened for viral contamination and the raw material used in production including growth media and enzymes should be controlled. Closed systems of growth and testing of each cell culture lot should be employed. Finally, validation of viral removal/inactivation by downstream processing is key. In cases where viral contamination does occur, how it is handled is critical.
To illustrate this last point, he gave two real-world examples of viral contamination, with opposing outcomes. The Genentech’s contamination by minute virus of mice (MVM) in 1993 and 1994 and Genzyme’s Vesivirus contamination in the early 2000s. One situation led to global drug supply being compromised and to the near collapse of the company, demonstrating the seriousness of viral contamination. The other was handled successfully.
In conclusion, Dr Griffiths reiterated that manufacturers must deal promptly with any suspected contamination. National regulatory authorities have a critical role in overseeing these developments, but ultimately the continued vigilance of manufacturers is essential.
After the presentations, there was the opportunity for discussion about the topics covered. The key discussion points are summarized below.
WHO GMP for biologicals: input into the process and specificity of guidelines
Following the discussion of revised WHO GMP for biological products, it was emphasized that the guidance is developed not only by WHO but also based on global consultation and significant input from industry and regulators. The guidelines also refer to other compatible guidelines, such as those from FDA, the European Medicines Agency (EMA) and also PIC/S.
There was a further question about extending the guidelines, as biological products are wide-ranging including, for example, recombinant products, vaccines, monoclonal antibodies, yet current GMP standards are not specific to each individual category of product. An audience member suggested this can make it difficult for a manufacturer to navigate the guidelines as they need to look for supplementary guidelines/annexes specific to their product.
The idea of an ‘aide memoir’ for different product categories was discussed, to help remind inspectors which areas to cover during an inspection. However, it was also acknowledged that there are many different ways of carrying out an inspection. A WHO ‘Questions and Answers’ document was also mentioned, which helps to clarify certain aspects of the GMP guidelines.
Host-cell impurities
Following Dr Elwyn Griffiths presentation on the characterization and testing of animal cell substrates, a question was asked regarding host cell-related impurity – as well as DNA which has a limit of 10 ng/dose, the host cell protein can also be problematic because it can cause allergic reactions, so what is the acceptable level of host cell protein.
Dr Griffiths responded that protein contamination has been considered less of an issue than DNA. He also mentioned that it is important for inspectors to properly check how the cell bank has been prepared and the type of facility the manufacturer has used, as any problems with the cell bank will get translated into the product. He reiterated the importance that every vial in the cell bank is consistent.
Cell viability
The level of cell viability required for production was discussed. Dr Yusdy Pan discussed a 30% minimum level for viability. Any less than that can be dangerous, because when many cells die and break down it is more challenging to remove the host cell protein.
Dr Dinesh Khokal made the point that the viability level also depends on the cell line; for example, human cell lines can be more difficult to use than established animal cell lines. It can also depend on the method used to check viability. A higher level of viability is better, but this can be challenging when growing cells at high density using high throughput media.
The speakers also discussed the importance of knowing the product, highlighting that even small changes to increase expression such as a change of media can lead to a change in the end product, for example, by changing protein post-translational modifications. Consistent manufacturing processes are very important to ensure the consistency and quality of the product.
Sustainability of the fermentation process
How disposable technology is overtaking stainless steel in the biological drug industry was discussed. An increasing number of companies that use mammalian cells are moving towards disposable technology. A question was asked about the sustainability implications of single-use technology such as disposable columns and bioreactors.
Dr Khokal responded that manufacturers must comply with the local and environmental ministry’s requirements, which are usually incineration. He also said that the use of disposable technologies is environmentally beneficial in other ways, such as by reducing water and chemical detergent use. He said there is a balance to be struck between disposing plastics versus the volume of water used, power requirements, space and mobility. A further important issue is carryover contamination from a previous product, which is ameliorated by the use of disposable bioreactors.
Column purification
On the issue of purification, it was asked how to ensure that there is no residual product contamination when performing chromatography purification (using the same column with a different product).
Dr Anil Kuwar Chawla responded that it is important to demonstrate that the previous product has been eliminated from both the column and the environment. If purifying a live product, e.g. a virus, in a column you can use the culture method to demonstrate this, but if purifying an inactive product, e.g. a protein, a more sensitive method is necessary. He said it does not align with GMP to use the same regime for multiple different products.
Data integrity
Finally, following Mr Vimal Sachdeva’s session on data integrity, the differences between biological drugs and conventional APIs were discussed. On this issue, Mr Sachdeva said that the vaccine programme is the oldest programme in WHO prequalification of medicines programme, although inspections of vaccine manufacturers are newer.
Data integrity inspections of vaccine manufacturers began three or four years ago and in 2017, two or three sites (out of 10) have had data integrity issues. However, in past experience there have been more data integrity issues with small molecules.
Dr Dinesh Khokal mentioned ‘data integrity challenge exercises’, which are used as a reviewer training exercise. It was also emphasized that senior management has the ultimate responsibility for data integrity, but that data integrity is an issue throughout the manufacturing process – not only when performing analysis. Overall, the manufacturer must have a robust internal audit programme in place which accounts for data integrity.
The workshop included four parallel group discussions, which had several important outcomes. These are summarized below.
Group 1: WHO or PIC/S and other equivalent international GMP standards
Group 1 discussed the information required for effective GMP inspection.
Action points:
Group 2: Difficulties in GMP inspection
Group 2 discussed the difficulties associated with GMP inspection, especially regarding the effect of multiple inspections and a lack of mutual reliance, see Figure 7.
Action points:
Group 3: Viral safety
Group 3 discussed the viral contamination of biological and biosimilar drugs; the following action points were raised.
Action points:
Group 4: Processing into finished dosage forms
Group 4 focused on filling and processing biological drugs into finished dosage forms.
Action points:
The workshop was successful in bringing members of ASEAN together with experts from other nations, to discuss GMP for Biologicals and Biosimilars and improve understanding of the GMP inspection framework for biological (and biosimilar) drugs among ASEAN Member States. It highlighted many important issues surrounding GMP for biological and biosimilar drugs manufactured in ASEAN countries, including the challenges of adhering to general GMP standards, given the huge diversity of biological products; protecting the final product from host cell impurities including DNA and protein; as well as adventitious viral contamination and the importance of having robust quality control programmes in place at all levels of production. Overall, the meeting helped to clarify WHO’s requirements for GMP production of biological drugs and how manufacturers can ensure these standards are met to ensure their product is safe, effective and of high quality. It was an important step forward as the first meeting of its kind for ASEAN Member States.
Speakers
Anil Kumar Chawla, PhD, India/Switzerland
Elwyn Griffiths, DSc, PhD, UK
Dinesh Khokal, PhD, Singapore
Dianliang Lei, PhD, Switzerland
Yusdy Pan, PhD, Singapore
Vimal Sachdeva, MSc, Switzerland
Adjunct Associate Professor Chong Hock Sia, BPharm, MSc, Singapore
Moderators
Kakkanang Porkaew, Thailand
Wiwin Wisma Prihatin, Indonesia
Seok Hui Teo, Singapore
Prapassorn Thanaphollert, BS, Thailand
Editor’s comment
Speakers and moderators had provided the discussion/conclusion of the group discussion, read the report and revised the content of the summary discussion.
The Generics and Biosimilars Initiative (GaBI) wishes to thank Ms Sylvia Laksmi Sardy and Ms B Lusia Herwahyu S from the ASEAN Secretariat for their support to the organization of this workshop; the moderators in clarifying the information of the parallel discussion when finalizing the meeting report; as well as Dr Elwyn Griffiths and Dr Dianliang Lei, Chair and Co-chair of the 2018 workshop, as well as Adjunct Associate Professor Chong Hock Sia for their strong support through the offering of advice and information during the preparation of the workshop.
The authors would like to acknowledge the help of all the workshop speaker faculty and participants, each of whom contributed to the success of the workshop and the content of this report, as well as the support of the moderators and co-moderators in facilitating meaningful discussion during the parallel case study working sessions, presenting the discussion findings at the meeting, and contributing in the finalization of this meeting report.
Lastly, the authors wish to thank Ms Alice Rolandini Jensen, GaBI Journal Editor, in preparing and finalizing this meeting report manuscript and providing English editing support on the group summaries.
Competing interests: The workshop was sponsored by an unrestricted educational grant to GaBI from Amgen Inc.
Provenance and peer review: Not commissioned; externally peer reviewed.
Elwyn Griffiths, DSc, PhD
Adjunct Associate Professor Chong Hock Sia, BPharm, MSc
References
1. Generics and Biosimilars Initiative. 1st ASEAN Overview Workshop on GMP for Biologicals/Biosimilars 2018. 5 August 2018; Da Nang, Vietnam. Available from: www.gabi-journal.net/about-gabi/educational-workshops/1st-asean-overview-work-shop-on-gmp-for-biologicals-biosimilars-2018
2. World Health Organization. WHO good manufacturing practices for biological Products, WHO Technical Report Series, No. 999, Annex 2 (2016) [homepage on the Internet]. [cited 2019 Jul 24]. Available from: https://www.who.int/biologicals/areas/vaccines/Annex_2_WHO_Good_manufacturing_practices_for_biological_products.pdf
3. ASEAN sectoral mutual recognition arrangement for good manufacturing practice (GMP) inspection of manufacturers of medicinal products [homepage on the Internet]. [cited 2019 Jul 24]. Available from: https://www.asean.org/uploads/archive/22481.pdf
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Author for correspondence: Adjunct Associate Professor Chong Hock Sia, Senior Consultant (Audit and Licensing) and Director (Quality Assurance), Health Products Regulation Group, Health Sciences Authority Singapore, 11 Biopolis Way, Helios, #11-01, Singapore 138667 |
Disclosure of Conflict of Interest Statement is available upon request.
Copyright © 2019 Pro Pharma Communications International
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.
Source URL: https://gabi-journal.net/1st-asean-overview-workshop-on-gmp-for-biologicals-biosimilars-2018-report.html
Copyright ©2024 GaBI Journal unless otherwise noted.
Quality standards for biopharmaceuticals: the importance of good manufacturing practice
Abstract:
Regulatory standards for recombinant DNA (rDNA)-derived medicinal products put in place over 40 years ago provided a framework for moving forward with novel biotechnologies and biosimilars leading to their success as highly eff ective medicines. As biologicals and biosimilars are increasingly developed, licensed and used worldwide less experienced manufacturers and regulatory agencies need support in dealing with these highly complex products. This Commentary highlights the need for regulatory convergence and support, notes the critical role of good manufacturing practices and draws attention to the comprehensive review by Sia Chong Hock et al. which strongly advocates improving harmonization of regulatory eff orts especially in the Association of South East Asian Nations (ASEAN).
Submitted: 23 June 2020; Revised: 29 June 2020; Accepted: 29 June 2020; Published online first: 10 July 2020
The past 40 years has seen a revolution in recombinant DNA (rDNA)-based and related biotechnologies and opened the door to new and exciting vistas of global public health, disease diagnosis, treatment, prevention and correction of defective genes. Amongst the successes of these technologies has been the development of platforms for the rapid development of candidate DNA and RNA vaccines as well as viral vector vaccines of particular interest in the current global COVID-19 pandemic [1]. rDNA-derived biotherapeutic proteins are likewise now key components of modern medical practice. They are at the cutting edge of biomedical research and a rapidly growing sector of pharmaceuticals.
In the early 1980s developments in molecular biology enabled genes encoding natural biologically active proteins to be identified, modified and transferred from one organism to another and to be efficiently synthesized in different host cells. These range from bacteria, yeast, continuous cell lines of mammalian origin, insect and plant cells as well as transgenic animals and plants. In addition, rDNA technology has been used to produce clinically useful biologically active proteins which do not exist in nature, such as humanized monoclonal antibodies or other engineered biologicals like fusion proteins. Over this time period there has also been considerable development in the technologies used for purifying and characterizing these biological macromolecules and the protein sequences, secondary/tertiary structures, post-translational glycosylation, phosphorylation, oxidation and lipidation can now be defined in great detail. Even so, it is not possible to fully predict the biological properties and clinical performance of these products based simply on their physicochemical characteristics. rDNA-derived biotherapeutics have unique and diverse structural and biological properties, including species specificity, immunogenicity and unpredicted pleiotropic activities. These properties pose particular problems in relation to non-clinical testing in animals. They also mean extensive clinical evaluation covering efficacy and safety, especially immunogenicity in humans, which may have varying clinical consequences ranging from none to severe.
Regulatory measures were put in place very early on in the development of these biotechnology-derived medicines and they were regulated as biologicals. Guidelines on their development, production and quality control were also issued early on by the European Medicines Agency (EMA), the US Food and Drug Administration (FDA) and, at the global level, by the World Health Organization (WHO) [2–6]. Over time, rDNA-derived proteins became the best characterized of all biological products, as well as safe and effective medicines. The basic regulatory procedures put in place reflected long-term experience with biologicals in general and, over the years, they have provided a framework for moving forward with novel biotechnologies. Emphasis was on guidelines (or points to consider), not prescription, to allow for further innovative developments. The original concepts are still in place today, updated, expanded and refined to take into account new knowledge and new technologies, and similar guidelines have been developed by many other agencies. Guidelines for assuring the quality and safety of DNA vaccines were also developed in the 1990s [7]. They are currently undergoing further revision and take into consideration the regulatory needs of public health emergencies of international concern. A useful list of WHO documents relevant to the development and evaluation of SARS-CoV-2 vaccines and other biologicals is also now available [8]. Documents relevant to the current Covid-19 pandemic are additionally available on the websites of EMA and FDA and other major regulators.
Since the majority of rDNA-derived therapeutic proteins need to be glycosylated for their activity and/or for half-life considerations, they are produced in animal cells, including continuous cell lines or insect cells, as are many viral vaccines. This involves using well-characterized master and working cell banks and paying attention to genetic stability issues. A major concern regarding the safety of such products is the possible presence of adventitious viruses in cell substrates or raw materials used in production which could find their way into the product. Detailed recommendations for the evaluation of animal cell cultures as substrates for the manufacture of biological products, for the characterization of cell banks and for the control of raw materials used in production are available from WHO [9], the International Council for Harmonization (ICH) [10] and national regulatory authorities. Guidelines on the reduction and/or inactivation of possible contaminants in rDNA-derived products are also available, although inactivation or reduction technologies cannot be applied to live viral vaccines. Together, these recommendations have enabled the field to develop and many key vaccines and biotherapeutics are produced in mammalian cells. However, viral contamination has occasionally occurred during production [11] but usually contained. Nevertheless, even if prevented from getting into a product, contamination of cell lines and intermediate production materials can have huge economic consequences for a manufacturer and might lead to supply issues with considerable public health impact [12–14]. Adherence to good manufacturing practices (GMP) and Quality by Design (QbD) principles as well as the availability of increasingly sensitive technologies for the detection of adventitious agents should make these events increasingly rare although when they happen manufacturers need to deal with them promptly. As new inexperienced manufacturers come into operation it is essential that they understand the need for great care and attention regarding the development and production of biological products. Good cell culture practice, which includes documentation and traceability, are all key aspects of this work and staff training in cell culture processes is vital to ensure that correct procedures are adhered to under GMP. The role of National Regulatory Authorities (NRAs) in overseeing these developments is critical and GMP inspection is a key aspect of this oversight.
In recent years, increasing numbers of patents/data protection on innovator products have been expiring and biopharmaceuticals ‘similar’ to the originals are increasingly coming to the market. The key question was how to handle the licensing of these products, recognizing that biologicals cannot meet the criteria for true generics. Following a period of intense consultation, guidelines on the evaluation of similar biotherapeutic products (SBP, biosimilars) were developed, first by EMA [15, 16], then by countries such as Canada, and by WHO [17]. More recently, FDA developed draft updated guidelines [18] and several other jurisdictions, such as Health Canada and EMA, have updated their guidance [19, 20]. Generally, the various guidelines and regulations reflect increasing convergence in the field. In all cases the intention is that licensing rely, in part, on data from an approved innovator product, the Reference Biological Product (RBP), and this has stimulated a lot of manufacturer and regulatory interest worldwide. Biosimilars are expected to be more affordable than the innovator products and contribute to increased access, as encouraged by the World Health Assembly Resolution of 2014 [21]. Some rDNA biotherapeutics and biosimilars are now listed in WHO’s Essential Drugs List.
The success of biosimilars has depended on improved technologies which can now be used to characterize complex biological macromolecules in exquisite detail “3D structures of proteins and glycans, oxidations and other post-translational modifications. Whilst there is a need to show similarity between the RBP and the biosimilar/SBP it is necessary also to identify any differences. There will be differences between an SBP and RBP since, by definition, these macromolecules are highly similar but not identical. Introducing manufacturing changes to approved biotherapeutic products may likewise result in analytical differences between the pre- and post-changes product. Predicting the impact of structural differences, and the level of differences, on biological activity and clinical performance is the difficult part, especially in the case of multifunctional products, such as monoclonal antibodies. Much work is now ongoing in the area of biotherapeutics, driven by the issues of biosimilars and the field is moving towards a better understanding of the structure/function relationships of rDNA-derived proteins. Knowing which parameters affect Critical Quality Attributes, and which do not, may help refine non-clinical or clinical supporting data needs and provide confidence in the quality, safety and efficacy of biosimilars and in the extrapolation of indications, as well as post-approval manufacturing changes to biotherapeutics. This is indicated by the increasing complexity of licensed biosimilars, the first being Omnitrope (somatropin) (21 kDa) in 2006 and from 2013 onwards several much larger and complex monoclonal antibodies, such as infliximab (144.2 kDa). Data are now available to show that, at least in the situation examined, switching from innovator to biosimilar has no negative impact on efficacy, safety or immunogenicity, enhances confidence in the use of biosimilars and reduces the cost of biotherapeutic treatment [22]. Currently, there is interest in the potential role of IL-6 antagonists, such as tocilizumab, a monoclonal antibody against the IL-6 receptor (IL-6 R), in the clinical management of severe COVID-19 infection, where some patients develop a ‘cytokine storm’ syndrome; clinical trials are ongoing [23–25]. The patents for tocilizumab have expired and several biosimilar versions are in development in a number of countries which, if successful, may offer access to more affordable treatment.
Driven by these successes and by the need for affordable biopharmaceuticals, rDNA-derived medicines, biosimilars and vaccines are increasingly being, produced and used worldwide, including in low- and middle-income countries (LMICs). This often means new manufacturers with less experience of biotherapeutics as well as NRAs with less expertise/experience and capacity to evaluate these complex products. Less experienced NRAs will therefore become the ‘first regulatory entry point’ for some complex biotherapeutics and they may need support. WHO provides support by promoting regulatory convergence at the global level by developing standards and encouraging their use through implementation workshops and the publication of case studies [6, 26–32]. GaBI also has provided support in the form of a series of interactive workshops on the regulatory assessment of biosimilars, such as the ones in Bangkok, Thailand in 2017 and Ankara, Turkey in 2018 [33, 34]. Many regulatory agencies across the globe are assessing how policy and regulations can be developed and improved to ensure that these critical and technically demanding medicines are of appropriate quality, safety and efficacy. The production of any pharmaceutical needs to be carried out using GMP and the GMP inspection is a critical and integral component of the licensing of both pharmaceutical and biological medicinal products and in ensuring their ongoing quality, safety and efficacy. However, this is especially challenging for modern day biological products which include sophisticated rDNA-derived biotherapeutics, biosimilars and vaccines. Due to the complexity of rDNA products, the inherent variability of biological production processes, depending as they do on cell culture, as well as the bioassays used in the characterization of such products, special considerations are needed in order to maintain consistency in product quality and clinical performance. A very timely and comprehensive overview of the global challenges in the manufacture, regulation and international harmonization of GMP and Quality Standards is presented by Sia CH et al. in GaBI Journal [35]. In particular, the review covers the biopharmaceutical industry and regulatory frameworks of countries in the Association of South East Asian Nations (ASEAN) and strongly advocates improving harmonization of regulatory efforts and creating a culture of quality within the organization to meet the common challenges in dealing with these innovative and critical biological medicines. This will be particularly important for dealing with novel, technically demanding cell therapies and other advanced therapy medicinal products (ATMPs) which hold much promise to health at the personal level [36].
Competing interests: None.
Provenance and peer review: Commissioned; externally peer reviewed.
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Author: Elwyn Griffiths, DSc, PhD, Consultant in Vaccines and Biotherapeutics, Kingston upon Thames, Surrey, UK
Disclosure of Conflict of Interest Statement is available upon request.
Copyright © 2020 Pro Pharma Communications International
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.
Source URL: https://gabi-journal.net/quality-standards-for-biopharmaceuticals-the-importance-of-good-manufacturing-practice.html