Global challenges in the manufacture, regulation and international harmonization of GMP and quality standards for biopharmaceuticals

Author byline as per print journal: Adjunct Associate Professor Sia Chong Hock, BSc (Pharm), MSc; Associate Professor Sia Ming Kian, BSc (Pharm) (Hons); Chan Lai Wah, BSc (Pharm) (Hons), PhD

Abstract:
Biopharmaceuticals belong to a class of medicinal products whose active pharmaceutical ingredient (API) is manufactured using living systems such as microbial and mammalian cells. With the patent expiry of the originator biopharmaceuticals, a surge in the production of biopharmaceuticals in the form of biosimilars is to be expected. However, biopharmaceuticals are inherently more complex than conventional chemical-based pharmaceuticals, hence requiring a more complicated manufacturing process. This paper provides a brief overview of the biopharmaceutical manufacturing processes and reveals that most biopharmaceuticals share similar processes and considerations. The complex nature of biopharmaceuticals presents various manufacturing challenges such as the inherent variation in quality and demand for extensive process and product understanding. Furthermore, downstream processing bottleneck also presents another manufacturing challenge. A brief comparison of the good manufacturing practice (GMP) standards of various regulatory authorities (RAs) and international organizations (IOs) reveals that the standards are largely similar and appropriate in addressing the manufacturing challenges. This review is one of the few covering the biopharmaceutical industry and the regulatory framework of the Association of South East Asian Nations (ASEAN). However, GMP alone does not address regulatory challenges such as evaluation of biosimilarity, differing outlook on interchangeability and a growing occurrence of data integrity lapses. Solutions such as the implementation of Industry 4.0, improved harmonization of regulatory efforts and creating a culture of quality within the organization may help to address the forgoing challenges.

Submitted: 6 May 2020; Revised: 26 May 2020; Accepted: 26 May 2020; Published online first: 8 June 2020

Introduction

Biopharmaceuticals belong to a class of medicinal products whose active pharmaceutical ingredient (API) is manufactured using living systems such as microbial, mammalian, insect, plant or animal cells. According to the Pharmaceutical Inspection Co-operation Scheme (PIC/S), a medicinal product is defined as any medicine or similar product intended for human use, which is subject to control under health legislation [1]. The API in the medicinal product is responsible for furnishing a pharmacological or other direct effect in the diagnosis, cure, mitigation, treatment or prevention of the disease, or alteration of the structure or function of the body [2].

Depending on the regulatory authorities (RAs), biopharmaceuticals may be termed as ‘biologics’, ‘biological medicines’ or ‘biotherapeutics’ [35]. Biotechnological methods such as ex vivo expansion [68], recombinant deoxyribonucleic acid (rDNA) or hybridoma technologies are typically employed to produce biopharmaceuticals. Examples of biopharmaceuticals are vaccines, insulins, monoclonal antibodies (mAbs) and other therapeutic proteins [9]. Cell-based, tissue-based or gene-based therapeutic products, also known as advanced therapy medicinal products (ATMPs) in the European Union (EU), are also considered biopharmaceuticals [10]. Biosimilars, also termed ‘subsequent-entry biologics’ and ‘similar biotherapeutic products’, are biopharmaceuticals which are highly similar in terms of safety, efficacy and quality with the innovator biopharmaceutical [11]. Such similarities are demonstrated using comparability studies with the reference product, which is the innovator biopharmaceutical that has received market authorization by the relevant RAs [12].

Frost & Sullivan has estimated that US$16.83 billion worth of biopharmaceuticals in the global market would lose their patent from 2015 to 2025. The global biosimilar market is expected to grow at a compound annual growth rate of 31.5% and reach US$66.33 billion during the same period [13]. Given the highly promising outlook of the biopharmaceutical market, manufacturers are motivated to invest in the manufacturing of biopharmaceuticals. However, there are major differences between biopharmaceuticals and the conventional chemical-based pharmaceuticals which may necessitate the use of different types of manufacturing facilities and standards.

Biopharmaceuticals consist of API molecules with a highly complex structure and very high molecular mass [14], ranging from thousands to hundred thousands of Daltons. In comparison, conventional chemical-based pharmaceuticals consist of API molecules that are significantly smaller, and possess a much simpler molecular structure, see Figure 1. As such, the characterization of biopharmaceuticals may require different analytical tools and methods such as post-translational modification characterization for recombinant therapeutic proteins [15], viral ­vector sequence analysis for gene-based therapeutic products [16] and reverse transcriptase polymerase chain reaction (RT-PCR) for stem cell therapies [17].

Figure 1

Biopharmaceuticals commonly exist as injectables [19]. This is because of the large molecular weight which hinders penetration of the molecule through the intestinal epithelium, thereby reducing systemic absorption [20]. In addition, most biopharmaceuticals are highly susceptible to degradation by the extreme pH conditions in the alimentary canal [21]. Thus, injectables remain the only viable option as they allow the molecules to bypass these obstacles. In comparison, chemical-based pharmaceuticals exist in a variety of dosage forms such as tablets, injections, nasal sprays and topical products.

Unlike conventional pharmaceuticals whose quality can be consistently assured, there exists an inherent variability in the quality of biopharmaceuticals which is largely due to their sensitivity to various conditions such as temperature, pH and mechanical stress [22]. Exposure to these factors can easily affect the quality, safety and efficacy of the end product. Therefore, monitoring these conditions is crucial to ensure that these conditions vary within appropriate specified limits. Clearly, significant challenges are encountered in the manufacture of biopharmaceuticals, and it is vital to adopt relevant GMP guidelines. According to the PIC/S, GMP ensures that ‘products are consistently produced and controlled to the quality standards appropriate for their intended use and as required by the marketing authorisation or product specification’ [23]. This perspective is also shared by the various RAs and World Health Organization (WHO) [2426].

The increasingly globalised nature of commerce allows manufacturers to outsource activities such as procurement of raw materials overseas, where different regulatory requirements may exist. Thus, there is a need to ensure that the GMP guidelines adopted by the RAs and international organizations (IOs) are harmonized and robust. A robust set of GMP guidelines helps to safeguard public health by assuring the quality, safety and efficacy of the biopharmaceuticals [26]. To date, review on the biopharmaceutical regulatory framework has been done on western countries, such as Canada and the US, as well as some Asian countries, such as Japan and Korea [27, 28]. However, few studies have been done on the regulatory framework for biopharmaceuticals in the ­Association of South East Asian Nations (ASEAN), with the exception of Singapore and Malaysia [27, 29].

ASEAN provides numerous incentives to biopharmaceutical manufacturers. The low manufacturing cost in some ASEAN Member States (AMS) enables greater cost-savings in the manufacture of biosimilars [30]. In addition, ASEAN is experiencing a general epidemiological shift from communicable to non-communicable chronic diseases [31], and biopharmaceuticals play an increasing role in managing the latter. With a combined population of 600 million, the ASEAN market will provide a sizeable patient population that attracts the importation and manufacturing of biopharmaceuticals in the region [32]. Thus, there is a need to ensure that the GMP guidelines adopted are adequate in assuring the quality of biopharmaceuticals.

Therefore, the aims of this project are firstly, to understand the challenges in the manufacture of biopharmaceuticals, excluding those derived from transgenic plants and animals due to their relatively inefficient commercial scalability [33, 34]. Secondly, this project aims to analyse the GMP standards of various RAs and IOs and determine if the regulatory frameworks adopted are suitable in addressing the challenges of biopharmaceuticals. Lastly, biopharmaceuticals also present unique regulatory challenges which will be discussed in later sections. Where necessary, solutions will be proposed to promote greater harmonization of GMP standards, with the ultimate goal of improving patient safety through better regulatory capacity.

Manufacture of biopharmaceuticals – an overview

Figure 2 shows the general processes involved in biopharmaceutical manufacturing. The processes involved are generally similar and are divided into two main stages – upstream and ­downstream processing. The upstream processes are briefly described in 2.1 to 2.3 while the downstream processes and ­formulation are described in 2.4 and 2.5, respectively. For all processes, controls on process variability and contamination should be highly ­prioritized and their risk mitigated with appropriate strategies [35].

Figure 2

Procurement and testing of biological starting materials
Starting materials used in the production of biopharmaceuticals include culture media, buffers and expression systems such as microbial or mammalian cells, and exclude packaging materials [36, 37]. The source, origin and suitability of starting materials should be clearly defined [1]. Western blotting, capillary electrophoresis and high-performance liquid chromatography (HPLC) are common analytical tools employed to assess the identity and purity of starting materials [38]. In addition, adequate controls, such as qualification of supplier through audits, screening for adventitious agents and viral reduction strategies should be in place to assure end product safety [39]. Where the starting materials are of human or animal origin, appropriate documentation on characteristics, such as general donor health status and age [40], should be demonstrated and meet relevant national legislation [1]. This requirement is especially relevant to ATMPs such as Chimeric Antigen Receptor (CAR) T cells, where the T cells are isolated from donors via apheresis [41].

Generation and characterization of cell banks/seed lots
The development of cell banks and seed lots begin with the construction of the vector and recombinant gene. Bacterial plasmids and cells are common choices for vector construction, and bacterial gene is manipulated using enzymes such as nucleases to insert the recombinant gene. Gene delivery into the host cells is achieved via transfection with replication-defective viruses, physical or chemical means. The choice of host cells is dependent on the type of biopharmaceuticals. In general, Chinese hamster ovary (CHO) cells dominate the manufacturing of mAbs [42], microbial cells such as Escherichia coli (E. coli) are commonly applied for simpler recombinant proteins that do not require post-translational modifications [43] and human embryonic kidney 293 (HEK-293) cells are commonly used to generate viral vectors [44]. The appropriate cell lines or seed lots are selected to establish the master bank of cell lines or seed lots. Extensive characterization of the master bank is crucial as it will be used to generate the working cells or seed lots. Titre amount, growth robustness, phenotypic and genetic stability are key considerations when selecting the master bank [45]. Cryopreservation is an essential strategy for prolonged storage of cell banks and seed lots [46].

Cell culturing
This process is responsible for producing the API. It is either done in a fed-batch or continuous manner, with fed-batch being more widely employed [47]. For tissue-based ATMPs, additional considerations should be given to the scaffolds where the cells will be seeded on. These scaffolds should not be immunogenic, and because they are derived from animal or human sources, measures to prevent contamination and disease transmission are crucial [48]. In fed-batch, the culture is expanded via sequential scaling up using bioreactors of increasing volumes, up to the maximum cell density. The cell culture is terminated before the death phase and the culture medium is harvested.

In comparison, continuous cell culture begins with the scaling up of cell culture to an optimum cell density. The culture medium is continuously harvested while fresh medium is added at the same rate to maintain the cell density, which should theoretically produce API of more consistent quality [49]. Continuous cell culture typically has a smaller footprint requirement than fed-batch cell culture due to the smaller bioreactors used [50]. However, it is generally more complex and costly to operate and to validate continuous fermentation [51, 52].

Isolation, concentration and purification of API
Downstream processing is commonly done batchwise [53] and entails the recovery, intermediate purification and polishing (RIPP) stages. The general guidelines governing the design of downstream processing are outlined in Table 1 [54].

Table 1

During the recovery stage, the API is separated from the harvested culture medium and subsequently concentrated. The localization of API is a crucial influence of the purification stage. For intracellular API, which is typically produced by microbial cells, cell lysis is essential for releasing the API. As such, further purification from cellular debris is necessary. In comparison, API produced by mammalian cells is typically secreted extracellularly, hence direct purification can be employed. Besides removal of impurities, viral inactivation or removal are generally necessary [55]. However, the latter is not appropriate for gene therapy API as it can damage the viral vectors [56]. Any remaining impurities are removed in the polishing stage. Table 2 lists the common methods used in each stage [57]. Where procedures that reduce bioburden cannot be applied, aseptic methods should be used [58].

Table 2

Formulation and filling
At the final stage, the API is combined with excipients such as buffers, salts and preservatives to prevent product degradation or contamination [59]. In addition, biopharmaceuticals are commonly formulated as freeze-dried powders, if immediate use is not required, due to their limited stability in liquid form [60]. Furthermore, considerations must be given to the packaging materials used. In general, the packaging material should not interact with the API in a manner that jeopardises the quality, such as leaching of materials into the product or structural alteration due to adsorption of API onto the packaging material [61].

Challenges concerning manufacture of biopharmaceuticals

Extensive process and product understanding required
As the quality of biopharmaceuticals is influenced by the processing steps [62], the latter must be designed such that the critical quality attributes (CQAs) of biopharmaceuticals remain within specifications [63]. CQAs are ‘analytical measures’ associated with the quality, safety and efficacy of a biopharmaceutical, such as absence of contaminants [64]. Inappropriate processing steps can adversely impact the quality. For instance, most recombinant glycoproteins except mAbs are prone to aggregation and dimerization in prolonged residence time hence fed-batch fermentation is inappropriate for these proteins [65]. In addition, any changes to the processes or formulation must be validated to assure that these changes do not significantly jeopardise product quality. This is exemplified by the infamous pure red cell aplasia (PRCA) incident associated with Eprex® (epoetin alfa), where the insufficiently validated formulation changes are associated with a surge in PRCA incidence amongst Eprex®-treated patients [66]. Hence, an extensive knowledge on the CQAs of biopharmaceuticals, together with appropriate validation, is crucial in assuring product quality.

Inherent variability of host cells
The inherent variability of the host cells can have unpredictable effects on the quality of biopharmaceuticals. This is exemplified by the widely employed CHO cells, whose genomic plasticity allows gene manipulation to produce the desired cell lines [67]. However, this has also contributed to cell line instability such as gene silencing [68]. In addition, the requirement for cell lines to produce high titre amount places considerable metabolic stress on the host cells, resulting in spontaneous recombinant gene deletion that may be difficult to predict [69, 70]. These factors will present obstacles in ensuring consistent product quality.

Downstream processing remains a key bottleneck
Downstream processing is commonly considered to be the key bottleneck of biopharmaceutical manufacturing, with chromatography being the most commonly cited [71]. Chromatographic separation is based on the degree of association between the individual components of the culture content and the stationary columns, and the separation efficiency can be modified by altering conditions such as ionic strength, pH and polarity. The designing of a chromatographic purification process has proven challenging owing to a lack of standardization arising from the myriad of chromatography modes and equipment to consider [72]. Thus, the designing process has traditionally taken a trial-and-error approach, which can be wasteful and time consuming [72].

Review of current GMP frameworks for biopharmaceuticals

Table 3 shows a comparison of GMP principles and guidance documents adopted by selected RAs and IOs. They are chosen because most of them are key players in regulatory harmonization or biopharmaceutical manufacturing [27, 29, 73]. In general, IOs and majority of the RAs adopt similar GMP principles. They emphasize on the implementation of quality risk management (QRM) principles: (1) risk evaluation should be scientifically sound and relevant to protection of patient; and (2) the amount of resources used for risk management should be proportional to the risk level [74]. QRM also facilitates better management of the manufacturing process by identifying and prioritizing the control on critical process parameters (CPPs) [75], as their variability can impact the CQAs and consequently the product quality [76]. Most guidelines acknowledge the inherent variability of biopharmaceutical quality and recommend using in-process controls and improving the robustness of manufacturing process to control the variability [1, 37, 77]. Table 3 also shows that most RAs and IOs adopt relatively similar GMP standards for API, suggesting a significant level of harmonization is already in place. However, there are major differences in the scope of the GMP standards. For instance, PIC/S provides guidance on all types of biopharmaceuticals within Annex 2 of its GMP guide, while the European Medicines Agency (EMA) provides recommendations for ATMPs in a dedicated guidance (Eudralex, Volume 4, Part IV) [78]. However, it is noted that PIC/S is currently drafting a dedicated GMP guide for ATMPs which may be implemented in the future [79]. In addition, PIC/S provides further guidance for selected types of biopharmaceuticals in Annex 2 Part B of its GMP guide [1] while WHO does not [37].

Table 3

Furthermore, the National Medical Products Administration (NMPA) of China has a GMP guideline for API that is not entirely relevant to biopharmaceutical APIs. This guideline provides recommendations on API produced by classical fermentation, which typically do not employ biotechnological processes and requires less stringent control on the manufacturing processes [80]. In addition, the APIs produced by classical fermentation, such as antibiotics, amino acids and vitamins, are generally of low molecular weights [77]. Instead, GMP pertaining to biopharmaceuticals and their APIs are covered under the Chinese GMP Annex 3 only. NMPA, being a regulatory member of the International Council for Harmonisation (ICH), is expected to implement ICH Q7 guideline – GMP Guide for API [81]. Hence, NMPA’s GMP guideline on API is likely to be harmonized with international standards. However, since NMPA is not expected to implement ICH Q5 guideline – Quality of Biotechnological Products, it is difficult to ascertain whether NMPA’s GMP standards on finished biopharmaceuticals are harmonized with international standards.

The Central Drugs Standard Control Organisation (CDSCO) of India, for instance, does not explicitly mention about the inclusion of biopharmaceuticals within the scope of its GMP guideline (Schedule M) [82]. However, the provisions appear to be adequate for biopharmaceuticals and also suggest that CDSCO adopts similar GMP principles as the well-established RAs and IOs. There is an additional guideline document for biopharmaceuticals on the CDSCO website, but it was inaccessible at the time of writing this review. It is worth mentioning that both China and India are currently undergoing regulatory reforms and have expressed interest to join PIC/S [83]. There are also reports that Chinese and Indian manufacturers are improving their product quality to meet international standards [84, 85], signalling their strong commitment to GMP.

Within ASEAN, the biopharmaceutical industry is at a nascent stage. Vaccines are the main biopharmaceuticals manufactured due to the high prevalence of infectious diseases [86]. In addition, there have been reports of vaccine shortages in ASEAN which may necessitate prioritizing vaccines over other biopharmaceuticals [87]. The review of ASEAN GMP standards reveals that the majority of AMS adopt PIC/S GMP recommendations for biopharmaceuticals [8891]. The lack of unified adoption can be attributed to the current exclusion of biopharmaceuticals from the scope of the ASEAN Mutual Recognition Arrangement (MRA) [92]. In addition, some AMS are emphasizing on generic pharmaceutical manufacturing [93, 94] and medical devices [95], which may also contribute to the lack of GMP guidelines for biopharmaceuticals. However, efforts have been made, such as the recent agreement on the ASEAN common technical requirements of biological products [96], to include biopharmaceuticals for harmonization in the future [97].

Overall, the differences in the scope of GMP standards observed is not surprising in view of the diversity of biopharmaceuticals being manufactured, and that GMP guidance is contextualised to the respective countries. It is however heartening to know that most RAs and IOs share similar GMP principles for regulating biopharmaceuticals. With concerted efforts, the outlook on harmonization is bright. Nonetheless, it must be emphasized that the adequacy of GMP and quality standards adopted by the various RAs and IOs, will ultimately depend on the extent of compliance by the biopharmaceutical manufacturers, and the robustness of enforcement of the standards by the RAs and IOs.

Challenges in the regulation of biopharmaceuticals

Resource-intensive evaluation of biosimilarity
The standard approach for approving generic conventional chemical-based pharmaceuticals, or generics, is not appropriate for biosimilars. For the approval of generics, manufacturers only need to demonstrate that the generics have identical molecular structure and is bioequivalent to the reference product [98]. However, the inherent variability of biopharmaceuticals makes it impossible for biosimilars to exactly replicate the reference product. Manufacturers may have to modify the manufacturing process based on the reference product with appropriate optimization such that the CQAs of biosimilars are highly similar to that of the reference product [99]. There will be differences, albeit slight, in the processing that can affect the end product of biological nature. Hence, a ‘totality-of-the-evidence’ approach is used to evaluate biosimilarity. This approach considers the entirety of the information submitted in the biosimilar application, such as data from analytical, preclinical, clinical studies and lot-to-lot variabilities, to evaluate the biosimilarity to the reference product [100]. The approval of biosimilars places more emphasis on extensive characterization of the API [101], with supplementary data from animal studies, clinical pharmacology or clinical trials to rule out any residual uncertainty from the characterization process [102]. Compared to chemical-based pharmaceuticals, the evaluation process clearly demands more time and expertise for the RAs. In addition, doubts have been cast on the suitability of the guidance for biosimilarity evaluation in assessing more complex biopharmaceuticals such as ATMPs [103]. Such uncertainty thus raises the need for more harmonization between different regulatory perspectives.

Differing perspectives on interchangeability
Differences exist between FDA and EMA perspectives on interchangeability. For FDA, biopharmaceuticals that are highly similar to the reference product can be classified as biosimilar product or interchangeable product. For the product to be classified as interchangeable, additional data on the safety and efficacy of switching from the reference product must be provided [104]. Once an interchangeable product is approved, the reference product may be substituted with the interchangeable product by the pharmacist without consulting the prescriber. In comparison, EMA does not require additional studies to determine if a biosimilar is interchangeable. However, EMA distinguishes the act of interchanging between reference product and biosimilar, or between biosimilars, into switching and substitution: switching is done at the prescriber level while substitution is done at the pharmacy level [14]. Differences in definition can lead to unnecessary confusion when manufacturers want their products approved for use in different countries. While the requirement for a switching study can provide better safety assurance of the interchangeable product, this also increases the production cost and possibly negate any cost savings it has over the reference product. This may also explain why there has been no interchangeable products approved by FDA currently [105, 106]. In addition, the vast clinical experience of EMA in approving biosimilars has demonstrated that biosimilars have similar efficacy and safety profiles as their reference product [107]. This is also supported by a systematic review which did not show any safety or efficacy risk from switching between reference products and biosimilars [108]. Thus, the requirement by FDA for a switching study to demonstrate interchangeability is debatable.

Growing number of data integrity lapses
‘Data integrity is the degree to which a collection of data is complete, consistent and accurate throughout the data life cycle. The collected data should be attributable, legible, ­contemporaneously recorded, original or a true copy, and accurate (ALCOA). Assuring data integrity requires appropriate quality and risk management systems, including adherence to sound scientific principles and good documentation practices’ [109, 110]. FDA has noted an increasing number of GMP violations pertaining to data integrity in recent years [111]. Compromised data integrity can lead to missing and inaccurate information that are vital considerations in the regulatory approval for market authorization [112], as well as jeopardising product quality assurance [113]. Lapses can be due to unintentional errors such as lack of awareness as well as inadequate standard operating procedures (SOPs) [114]. In more serious cases, deliberate data manipulations, such as data falsification instructed by upper management, have been reported [115, 116]. A review of the warning letters issued by the Center for Biologics Evaluation and Research (CBER) reveals that data manipulation can occur despite the implementation of legislative guidelines, SOPs and controls [117119], hinting a possible lack of a quality-focused culture within these organizations.

Proposed solutions to challenges of biopharmaceuticals

Optimizing biopharmaceutical manufacturing with ­Industry 4.0
Industry 4.0, or the Fourth Industrial Revolution, is a broad concept that involves the amalgamation of physical and digital technologies to generate a constant flow of information, allowing real-time data access [120]. These data can then be applied to generate analytical tools such as algorithms and models to allow better process and product understanding [121]. Consequently, this allows more effective implementation of Quality-by-Design (QbD) approach in process development and optimization [122]. According to ICH, QbD is a ‘systematic approach to development that begins with predefined objectives and emphasizes product and process understanding and process control, based on sound science and quality risk management’ [76]. With QbD, process capability is improved with better product and process understanding, which in turn reduces the inherent variation in quality of biopharmaceuticals [123].

Real-time data access can be achieved with process analytical technologies (PAT). FDA considers PAT as ‘a system for designing, analysing, and controlling manufacturing through timely measurements, i.e. during processing, of critical quality and performance attributes of raw and in-process materials and processes, with the goal of ensuring final product quality’ [124]. The general methodology of PAT begins with the collection of data using robust, rapid and sensitive analytical tools and sensors, such as HPLC, dynamic light scattering, pressure gauge and flow meter [125]. This is followed by the modelling of these data to generate useful process-related information and ends with the goal of using the generated data to influence the manufacturing processes [126]. For instance, PAT has been used to optimize downstream processing. This is achieved by combining the screening of previously validated chromatographic conditions with scientifically sound experiments to generate a chromatographic model that is able to predict critical process parameters for downstream optimization [127, 128]. In addition, deviations captured during routine monitoring can also be used to generate algorithms that can better categorize human errors or facilitate more effective corrective actions and ­preventive actions (CAPAs), thereby reducing the occurrence of failed batches as well as the cost of implementing CAPAs [129].

Industry 4.0 has allowed greater interconnectivity through platforms such as the Internet of Things (IoT), providing worldwide access to data to facilitate better process understanding. For instance, a better understanding of the CHO cell genome is achieved by pooling data from various assemblies generated by the other researchers using sequencing technologies such as short-read Illumina and single molecule real time (SMRT) sequencing [130]. With a better understanding of the genome, manufacturers may manipulate the gene more effectively and improve host-cell stability, consequently leading to more consistent product quality.

Enhanced harmonization efforts on biosimilar guidelines
With the expected influx of biosimilars due to patent expiry of the reference product, there is a need for RAs to develop guidelines that facilitate the clinical decision to choose between the reference product and biosimilars, switching between reference product and biosimilars, or switching between biosimilars as a potential therapeutic option. Although EMA does not provide recommendations on interchangeability and leave the development of substitution policies to its Member States [131], countries such as Germany, The Netherland and Scotland have endorsed the interchangeability of biosimilars [132]. In general, these countries recommend that the decision of switching should be based on shared decision-making between the patient and prescriber on the potential risks of switching, along with appropriate monitoring for early detection of adverse event [14, 133135]. Such perspective is logically sound as it ensures that any clinical decision made is in the patient’s best interest. It is worthwhile to encourage RAs of these countries to share their regulatory experience so that other RAs can make a more informed choice when developing guidelines relating to the use of biosimilars. Such concerted efforts will promote harmonization of guidelines.

Enhancing data integrity with a culture of quality (quality culture)
Without a culture of quality, even the simplest and preventable data integrity-related violations can occur [136]. This is because the organizational culture directly impacts routine operations which have a downstream influence on data and product quality, and senior management is responsible for creating a culture of quality [137]. A critical element of quality culture is the ‘transparent and open reporting’ of data integrity-related violations at all organizational levels [109]. Measures such as an independent reporting channel, anonymous or identifiable, or rewarding employees who report quality-related issues can help to incentivise employees to voice out their concerns [138]. A culture of quality can be created by first incorporating the ‘Leader 5Vs’ that correlate with a positive influence on quality culture [139], which are further explained in Table 4 [140]. In essence, the table emphasizes on the importance of senior management in creating a vision, leading by example, empowering their employees towards quality excellence. Senior management is encouraged to look at WHO guidance on data integrity as it provides practical recommendations on building a quality ­culture [138].

Table 4

In facilitating a behavioural change, employers may consider the ABC (antecedent, behaviour, consequence) model: where an antecedent encourages a behaviour and leads to a consequence, which in turn influences the recurrence of behaviours [141], see Figure 3. While antecedents are essential in triggering a behaviour, it is the consequence that significantly motivates or demotivates the latter [142]. As such, in the implementation measures to effectively correct a behaviour, consequences should be emphasized over antecedents. In addition, a ratio of positive to negative consequences at 4:1 is recommended to sustain performance outcomes [141].

Figure 3

Employees are also crucial in transforming the organizational culture [143]. Training for employees should help them understand the organization’s quality objectives, SOPs and their individual role in achieving said objectives [144]. In addition, they should leverage on the ‘speak up’ culture to provide feedback on how the senior management can customise the quality culture messages to be more relevant to their work [145].

Developing a culture of quality excellence is not an instantaneous process as it requires a change of mindsets: senior management must drive the change while employees must be motivated to change. An effective collaboration at all organizational levels will ensure that the change can be expedited, and the culture remains sustainable in the long term.

List of abbreviations

Conclusion

With the patent expiry of innovator biopharmaceuticals, more biosimilars will be developed for use. In general, this paper has shown that most biopharmaceuticals share similar manufacturing processes and considerations, providing useful insights for manufacturers who are interested to include biosimilars in their pipeline. However, it is still highly advisable for manufacturers to demonstrate an extensive product and process understanding as there may be certain methods that are not suitable or relevant for their product. Due to their inherent complexity, biopharmaceuticals present challenges in assuring product quality. This can be addressed with real-time monitoring and better predictive modelling, as well as other solutions that are not discussed in this paper.

For the RAs and IOs, the outlook on GMP harmonization for biopharmaceuticals is highly promising. As countries improve and harmonize their GMP standards, there will be a greater assurance of quality and safety of biopharmaceuticals. However, more effort is needed in providing guidelines on the interchangeability of biosimilars to encourage their use. With greater collaboration among RAs and IOs, practical experience can be shared, and this can facilitate improvement of existing guidelines. The challenges presented by biopharmaceuticals, although daunting, are not insurmountable. With technological advances and better collaboration between key stakeholders, these challenges can be effectively managed.

Competing interests: None.

Provenance and peer review: Not commissioned; externally peer reviewed.

Authors

Adjunct Associate Professor Sia Chong Hock, BSc (Pharm), MSc
Sia Ming Kian, BSc (Pharm) (Hons)
Associate Professor Chan Lai Wah, BSc (Pharm) (Hons), 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, 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

Disclosure of Conflict of Interest Statement is available upon request.

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1st ASEAN overview workshop on GMP for biologicals/biosimilars 2018 – Report

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.
Methods: The workshop was held on 5 August 2018 in Da Nang, Vietnam. It was attended by 46 participants including representatives from the World Health Organization (WHO), ASEAN Joint Sectoral Committee (JSC) on GMP Inspection, ACCSQ-PPWG (ASEAN Consultative Committee for Standards and Quality-Pharmaceutical Product Working Group), as well as a range of other experts and consultants. It included a series of presentations, Q&A sessions and parallel group discussions.
Results/Processes: Topics discussed included the revised WHO GMP for biological products; cell types used for biological production; the fundamentals of fermentation and purification; the harvesting process; pharmaceutical quality systems; virus removal and inactivation technologies; batching of bulk biological products; data integrity; and the latest WHO recommendations on cell substrates.
Conclusion: The meeting highlighted many important issues surrounding GMP for biological and biosimilar drugs manufactured and/or imported into ASEAN Member States (AMS). 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 countries.

Submitted: 18 February 2019; Revised: 24 July 2019; Accepted: 25 July 2019; Published online first: 6 August 2019

Introduction

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.

Results/Processes

Expert speaker presentations

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.

GMP for biologicals and biosimilars – workshop objectives

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.

Newly revised WHO GMP for 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.

Table 1

Characterization and testing of animal cell substrates used for production of biologicals

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.

Table 2

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.

Fermentation: fundamentals, control of source materials and cell culture conditions

Focusing on fermentation, Dr Dinesh Khokal of Amgen Singapore, first described the upstream and downstream processes for biological manufacturing, see Figure 1.

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.

Figure 2

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.

Purification of vaccines and biologicals

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.

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.

Harvest process in commercial biologicals manufacturing

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.

Figure 3

Figure 4

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:

How to build an effective pharmaceutical quality system

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.

Table 4

Validation of viral removal/inactivation and bioanalytical methods

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.

Batching and storage of bulk biological products

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.

Figure 5

Table 5

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.

Data integrity, from an inspector’s point of view

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.

Figure 6

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.

WHO recommendations on cell substrates used for production

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).

Importance of GMP in controlling cell substrates and production processes for biologicals – two case studies

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.

Summary of the discussions that followed the expert presentations

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.

Action points highlighted in the discussions

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:

Figure 7

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:

Conclusion

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.

Speaker Faculty and Moderators

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.

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 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.

Authors

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 July 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 July 24]. Available from: https://www.asean.org/uploads/archive/22481.pdf

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.

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