Pharmaceutical Data Integrity: issues, challenges and proposed solutions for manufacturers and inspectors

Author byline as per print journal: Adjunct Associate Professor Sia Chong Hock1, BSc (Pharm), MSc; Vernon Tay1, BSc (Pharm) (Hons); Vimal Sachdeva2, MSc; Associate Professor Chan Lai Wah1, BSc (Pharm) (Hons), PhD

Abstract:
Data Integrity, which is data deemed Attributable, Legible, Contemporaneous, Original, Accurate, Complete, Consistent, Enduring, and Available (ALCOA-plus), has been the focus of the pharmaceutical industry in recent years. With the growing use of computerized systems and rising prevalence of outsourcing manufacturing processes, ensuring data integrity is becoming more challenging in an increasingly complex pharmaceutical manufacturing industry. To address this issue, multiple legislation and guidance documents such as ‘Data Integrity and Compliance with CGMP Guidance for Industry’ from the US Food and Drug Administration (FDA), ‘GxP’ Data Integrity Guidance and Definitions from the UK Medicines & Healthcare products Regulatory Agency (MHRA), and ‘Guidance on Good Data and Record Management Practices’ from the World Health Organization (WHO), have been published in recent years. However, with rising data integrity issues observed by FDA, WHO, MHRA and other pharmaceutical inspectors even after these guidance documents have been published, their overall effectiveness is yet to be determined.
This paper compares and evaluates the legislation and guidance currently in existence; and discusses some of the potential challenges pharmaceutical manufacturers face in maintaining data integrity with such legislation and guidance in place. It appears that these legislation and guidance are insufficient in maintaining data integrity in the industry when used alone. Last, but not least, this paper also reviews other solutions, such as the need for a company culture of integrity, a good database management system, education and training, robust quality agreements between contract givers and acceptors, and performance of effective audits and inspections, to aid in maintaining data integrity in the manufacturing industry. These proposed solutions, if successfully implemented, can address the issues associated with data integrity, and raise the standard of pharmaceutical and biopharmaceutical manufacturing worldwide.

Introduction

Data Integrity (DI) in the pharmaceutical manufacturing industry is the state where data are Attributable, Legible, Contemporane­ous, Original, Accurate, Complete, Consistent, Enduring, and Available (ALCOA+) [13], as outlined in Table 1. Data altered such that it no longer fulfils these criteria is considered as falsi­fied, regardless of it being due to human error or generated deliberately [2, 4].

Current legislation, good manufacturing practice (GMP) stan­dards and guidance on data management and governance published by organizations such as the US Food and Drug Administration (FDA) [68] and World Health Organiza­tion (WHO) [1] aim to guide the industry in ensuring DI is not compromised. These include the ‘Data Integrity and Compli­ance with cGMP Guidance for Industry’ from FDA [9], ‘GxP Data Integrity Guidance and Definitions’ from the UK Medicines and Healthcare products Regulatory Agency (MHRA) [10], and ‘Guidance on Good Data and Record Management Practices’ from WHO [1], which were published in recent years. Inspectors from various organizations inspect the pharmaceuti­cal manufacturing companies to assure compliance to such leg­islation, standards and guidance, where appropriate [3, 11, 12]. If violations of regulatory significance are observed, warning let­ters containing the key violations to be rectified would be sent to the companies [13]. However, with the number of FDA warn­ing letters issued citing DI violations quintupling from 2014 to 2017 [14], and large pharmaceutical companies getting cited for falsifying data in quality control results and other manufacturing processes, the effectiveness of such legislation and guidance to maintain DI remains yet to be seen [15, 16].

Table 1

With an increasing use of computerized systems in the pharmaceutical industry [17, 18], and current regulation of physical data being more well-defined than regulation of electronic data [19], it is uncertain if the legislation and guidance are still able to maintain DI as more electronic data are generated. Furthermore, the outsourcing of pharmaceutical manufacturing activities to improve productivity and business efficiency continues unabatedly [20]. A lack of synergy and good data management between companies increases the difficulty in standardizing protocols and procedures to assure DI [21], regardless of the legislation and guidance in place [22]. Additionally, protocols which help maintain DI in parent companies may not be adopted by their subsidiary companies [23]. Failure to prevent DI violations could lead to substandard medicinal products being released into the market, thus causing harm and possibly death to patients [24, 25] and, in the case of vaccines and biosimilars, loss of public confidence.

Hence, this paper strives to assess the prevalence and trends of recent DI violations, identify reasons why companies commit DI violations, evaluate the effectiveness of current legislation, guidance and challenges, and finally, explore solutions which can promote DI in the pharmaceutical and biopharmaceutical manufacturing industry. A systematic, scientific and comprehensive literature review, covering the websites of regulatory authorities, scientific journals, pharmaceutical fora and newsletters, national and international legislation, GMP and other good practices and guidance documents relating to DI, was conducted. Challenges and issues relating to DI were identified, and solutions to address them were proposed for the benefit of the manufacturers, inspectors and the global pharmaceutical and bio­pharmaceutical community in general.

Current trends

As reported by the Unger Consulting Incorporation [14], the prevalence of FDA warning letters that cited DI violations has been increasing exponentially, see Figure 1. This may be due to pharmaceutical inspectors proactively searching for DI violations [26], inspectors who are now better trained to detect DI issues, more companies taking risks in violating DI for various reasons, or ignorance and carelessness of operators [27]. It is not easy to analyse the root causes of DI violations as the increasing prevalence of DI issues and efforts to manage them appear to be a recent development [28].

Also, from Tables 2(a) and 2(b), it is noted that most of the DI violations cited pertain to manual, automatic, mechanical and electronic equipment, which includes ‘failure to calibrate and maintain written records’ and ‘failure to exercise appropriate controls over computer or related systems to assure that only authorized personnel institute changes in production and control records, laboratory records or other records’ [31]. The next few most cited DI violations pertain to quality control of the pharmaceutical product. The leading countries being issued DI associated warning letters include China and India [14], see Table 3, where parent pharmaceutical manufacturers in Europe and the US have been known to translocate their manufacturing plants to these countries to reduce production costs [20, 23]. It is also important to emphasize that DI violations are also routinely cited by FDA during inspections of domestic manufacturers as well.

Reasons for Data Integrity violations (inadvertent and intentional)

Pharmaceutical companies are often under pressure to improve their key performance indicators (KPIs), especially during economic downturns. Hence, data are known to be falsified to decrease the rejection of manufactured batches, with some companies deleting non-compliant records [3236], or even churning out records without legitimately performing relevant tests to expedite regulatory approval [28, 34]. Furthermore, the lack of sup­port from senior management, due to insufficient involvement and resources, can aggravate the situation. Also, some employees may fear retrenchment due to unachieved KPIs [37, 38]. Thus, they may release the product without following internal protocols requiring them to seek approvals from authorized personnel [33], or alter records if given access to the database [35, 39]. Occasionally, and in particular, for systems involving manual transfer of data to the company database using hybrid computerized systems, transcription errors can occur, leading to inaccurate data records [40].

Figure 1

Table 2a b

An example of a hybrid approach is where laboratory analysts use computerized instrument systems that create original electronic records and then print a summary of the results. Where hybrid approaches are used, appropriate controls for electronic docu­ments, such as templates, forms and master documents, that may be printed, should be available. However, during on-site inspections of the laboratory systems, it has been discovered that data were being falsified on an industrial scale, using a variety of means, such as copy and paste, manipulation of weights, and unauthorized manual integration of chromatograms. The root cause is often a chromatographic data ­system (CDS) whose audit trail had been deliberately turned off, and therefore, cannot track who had falsified what data, and when [41].

Assuring and promoting Data Integrity via legislation and guidance documents

Legislation
In this article, regulations from the FDA and the European Union (EU) EudraLex, are discussed and compared. As DI in pharmaceutical manufacturing is strongly associated with GMP, it is important to understand the GMP regulatory framework and its impact on DI. The GMP legislative framework from FDA comprise the 21 CFR 210, 211, 212, 600, and 820, while those from EU comprise Commission Directive 2003/94/EC and its regulatory statute EudraLex Volume 4 [42]. 21 CFR 210 provides a very generic regulation on the safety, identity, strength, quality and purity of pharmaceutical products [7]. EU Commission Directive 2003/94/EC gives a general overview of GMP for the pharmaceutical manufacturing companies [43]. 21 CFR 211 and EudraLex Volume 4 are similar, regulating the required documentation for personnel qualifications and training, equipment protocols, inspections and maintenance, labelling and distribution processes, and even protocols for recalls, and corrective and preventive actions (CAPA) [8, 43], with EudraLex Volume 4 dedicating Chapter 7 to contract requirements for outso­urced manufacturing activities [43], whereas such requirements are not explicitly stated in 21 CFR 211. 21 CFR 212 and 600 regulate specifically radiological [44] and biological pharmaceutical products [45], respectively. In general, they require more accurate and attributable information to be kept for a longer time to retrace and recall when issues pertaining to the manufacture of the product arise. 21 CFR 820 dictates requirements to ensure quality is maintained throughout the manufacturing process, specifying the documentations required to validate such processes [46]. Clearly, these legislations cover many aspects where proper documentation and DI should be enforced.

Table 3

There are also legislation specifically promoting DI in pharmaceutical manufacturing. For example, 21 CFR 11 specifically targets requirements for electronic documentation, stating that these electronic documentations are as significant as paper records, and in certain cases can be used in lieu of them [6]. It regulates computerized systems which have external personnel authorized to access and edit, and systems that are employed within the company. EU Falsified Medicines Directive regulates the labelling and distribution practices of drugs, namely ensuring that packaging cannot be tampered without being noticed, the identity of the contents in the packaging are accurate and attributable, and documentation that assures Internet sales of pharmaceutical products is validated by relevant authorities [47]. The Drug Data Management Standard of China, as translated by the China Working Group of Rx-360, provides regulations to promote DI [48]. It regulates documentation of various processes such as training of personnel, validation of computerized systems and data management, and CAPA when DI violations are found. One section specifically provides examples on how DI would be maintained using ALCOA+ as a guide. In Article 7, it specifically promotes whistleblowing as part of the culture for pharmaceutical manufacturing companies as well [48].

Guidance documents
As legislation tend to be generic to facilitate applica­tion to a wide variety of pharmaceutical companies, guidance documents have been published to clarify legislative requirements [49]. In general, guidance documents encourage voluntary compliance and can be adapted to suit the company’s culture and manufacturing processes. Guidance documents published to promote GMP include the WHO Guidance on Good Data and Record Management Practices (WHO Technical Report Series 996, Annex 5) [1], FDA Data Integrity and Compliance with CGMP Guidance for Industry, MHRA GxP Data Integrity Guidance and Definitions, the Pharmaceutical Inspection Convention and Pharmaceutical Inspection Co-operation Scheme (PIC/S) Guide to Good Manufacturing Practice for Medicinal Products [50], PIC/S Guide to Good Manufacturing Practice for Active Pharmaceutical Ingredients [51], the latter is equivalent to the International Council on Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Q7 – Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients [52]. The WHO Guidance on Data and Record Management Practices also promotes a company culture of integrity and provides links to relevant legislation and guidance documents [1]. The PIC/S Guide to GMP for Active Pharmaceutical Ingredients has been established for many years already and it addresses the same issues as ICH Q7 [53, 54].

There are also guidance that clarify specific portions of the GMP, including PIC/S Good Practices for Computerized Systems in Regulated GxP Environment [55], FDA Standardization of Data and Documentation Practices for Product Tracing Guidance for Industry [56], FDA Contract Manufacturing Arrangements for Drugs: Quality Agreements – Guidance for Industry [57], and ICH Q9 – Quality Risk Management [58]. These documents provide in-depth guidance to the various aspects of GMP, with due consideration for the respective country’s regu­lation. However, as mentioned earlier in this paper, there are some guidance that specifically focus on DI. These include the PIC/S Good Practices for Data Management and Integrity in Regulated GMP/GDP Environment [59], FDA Data Integrity and Compliance with cGMP Guidance for Industry [9], and MHRA ‘GxP’ Data Integrity Guidance and Definitions [60], all recently published due to increasing attention on DI [3]. Generally, these guidance documents discuss audit requirements, personnel responsibility in promoting DI, and validation of computerized systems and other GMP processes. The WHO, PIC/S and FDA further provide clarification on CAPA to be taken when DI violations are found [9, 59], with PIC/S providing added clarification on outsourced processes and promotion of quality culture [59]. Some guidance documents also help companies to understand the legal requirements. For example, the Orange Guide [61] compiles relevant legislation and guidance notes for manufacturers planning to enter the UK pharmaceutical market, increasing the ease for manufacturers to understand the regulations by providing relevant guidance and binding legislation.

Overall, the legislation and guidance documents appear to be comprehensive in assuring and promoting DI. However, they are unable to prevent DI violations alone. Most DI issues only surface during on-site audits [18] or from whistleblowing [15], and by then, non-compliant pharmaceutical products would have already been distributed, with potentially substandard products having been consumed by patients. Hence, legislation and guidance must be supplemented with other approaches to promote and assure DI at a higher level.

Proposed solutions to better promote and assure Data Integrity

Culture of integrity

A study was conducted by the Parenteral Drug Association (PDA) to assess the effectiveness of its published DI guidance document. Although more than 90% found this guidance helpful in promoting DI, some remarked that a culture of integrity is required to truly attain DI [62], Incentives, including recognition for companies if no DI issues have been found for a consecutive number of years, could be introduced to encourage companies to follow the guidance.

As mentioned in some legislation and guidance documents, a culture of integrity is required in a company to make regulations work [62]. Setting a culture of integrity is important so that management would treat DI seri­ously [3, 63], and employees would then feel obligated to do the same [64]. According to a study by Yang, Sun and Eppler, for any strategy to be implemented successfully, the formulation needs to be of a certain standard, and inter- and intra-department relationships should be cordial [62]. Middle management is noted to be the main drivers for implementation [62], and close collaboration with the top management increases its effectiveness [62]. However, if management ignores the DI issues, implementation would be hindered [65]. Open and supportive communication between employees and management aid in effective strategy implementation [62, 66]. Providing internal whistleblowing opportunities to flag any DI issues will further promote a company’s culture of integrity [67, 68]. This method is adopted by FDA, where under the Dodd-Frank Wall Street and False Claims Act, monetary rewards are used to promote whistleblowing behaviour [67].

Having a culture of integrity within the company will reduce DI issues, and ultimately bring about a positive perception of the company’s pharmaceutical products [63]. However, for a large company, it is difficult to start a culture of integrity if this culture was absent in the first place, as the implementation of such a culture requires some time before the effects are fully felt [65]. Furthermore, old habits may cause top management to resist adopting such a culture unless specific incentives are provided [65]. Therefore, some regulations should be in place to start this culture of integrity within the company [64].

Database management systems

Another proposed solution to promote DI is by having good and effective database management. A database management system (DBMS) stores data [69] and presents them in an understandable format when accessed [112]. With data becoming larger in volume and variety in the pharmaceutical manufacturing industry [70], user-friendly and efficient DBMS are in high demand [71]. With validated DBMS, manufacturers and regulators would be better able to focus on other DI-related issues.

This paper also evaluates some of these DBMS, and their effectiveness in promoting DI below. Specifically, the advantages and complications of three major categories of DBMS are ­compared, see Figure 2.

Figure 2

Table 4

Relational and non-relational database management system
Relational database management systems store data in either a two-dimensional table or a three-dimensional ‘object’ [72, 77]. Non-relational database management system on the other hand does not have a specified structure of storing data. Further elaboration is provided in Tables 4, 5 and 6.

With a wide variety of DBMSchoices currently in the ­market, adopting one that keeps data ALCOA+ throughout its lifespan would minimize the cost required to maintain it manually [95].

Blockchain technology
Blockchain is hypothesized as the next pharmaceutical manufacturing DBMS innovation [96, 97]. It is a decentralized record of digital events, with validation by the participants occurring before it is recorded [98], making manipulation of previously verified transactions including data entry or movement very hard, and cannot be deleted [99]. Blockchain has three main ways to ensure data security. Firstly, it has a hash function, which identifies blocks, and calculation of hashes involves the previous block’s hash [100]. Secondly, it has a peer-to-peer network to verify before it is added to the current blockchain as a legitimate block [97], removing the need for an authorized person for approval of transaction [98]. Once a block is added, it is added to all the copies of the verified blockchain across the entire network [101], hence remaining in the system indefinitely. Thirdly, as only pre-approved participants can participate in adding new blocks, the identity of the node adding the block would be documented [102], which ensures data attributability.

Furthermore, by using blockchain-utilizing smart contracts, DI can be enforced [103], using blockchain technology to ensure all components of the contract are met before transactions such as approvals occur [103, 104]. This can also be employed for auditing as well, where, if certain values deviate from the acceptable range, they would be flagged up for inspection [100]. Companies such as BlockVerify [103] and One Network Enterprises [96] have started to employ blockchain to maintain DI in the pharmaceutical market. Blockchain has also been applied in promoting DI in the distribution of pharmaceutical products through modium.io AG [105], making use of an array of sensors to ensure erroneous data would not be entered into the system in the first place [103]. In the future, blockchain could even be used to supplement guidance ­documents [106, 107].

Table 5

Table 6

However, handling large volumes of information and simultaneous transactions is slow with current blockchain technology [108], and with more data being generated in pharmaceutical manufacturing companies, this translates to lower efficiency of maintaining DI for large data stores. Furthermore, the difficulty in comprehending and using the code gives the developer the power to maintain DI [109], rendering both authorities and companies incapable of maintaining DBMS DI themselves. Additionally, having a private blockchain requires data encryption [109] to protect data from unauthorized access [107, 110].

In general, having a good DBMS promotes DI as it streamlines audits. Guidance in the form of questions are available to help companies find the best DBMS options available for them [75]. Furthermore, it is common to use multiple databases for different functions [90]. However, relying on DBMS alone will not prevent all DI issues. Firstly, DBMS is unable to ensure data entered was ALCOA-plus, and audits are required to ascertain that [111]. Secondly, unvalidated or outdated systems require upgrading, and migration of data while updating may cause errors to be carried forward unknowingly, especially for large volume of data [95, 112], leading to an inaccurate database. Therefore, DBMS alone cannot prevent all DI issues. Continually upgrading DBMS by periodically reviewing documentation and procedures which influence the quality of pharmaceutical products manufactured against established standards would aid in promoting DI in the future as well [113116]. However, audits take resources to perform, and smaller companies might not be able to perform frequent and comprehensive self-audits. Nonetheless, having such audits would ensure that the DBMS employed by the company are current and efficient, ultimately promoting DI [95, 114].

Education and training
It is important for employees to undergo DI education and training for them to understand the importance of maintaining DI and the consequences if not maintained [117, 118]. More detailed sessions should be conducted for employees with access to ­modify processes, systems and records, further explaining their responsibilities [114, 118]. Training sessions could also standardize the procedures, terminology and concepts within the company, reducing DI violations due to miscommunication [114]. Currently, DI courses from external service providers such as ECA Academy [119] and Reading Scientific Services Ltd (RSSL) [120] exist.

However, training can be costly, especially to smaller companies. To mitigate part of the cost, a representative could be trained, before training their fellow colleagues, causing a multiplying effect. Furthermore, manufacturers may form associations together, getting group discounts from DI training providers [120]. To ensure knowledge retention of the training provided, constant refreshers are needed, be it refresher courses or incentivize maintaining DI with company culture, otherwise, such knowledge might be forgotten if infrequently used [121].

Robust quality agreements
With an increase in outsourcing of pharmaceutical manufacturing processes, quality agreements, which are written contracts between companies to ensure responsibilities and expectations for both parties are agreed upon [122], must be rigorously prepared, mutually agreed and signed. However, this process can be time-consuming as reaching a consensus can be challenging. Some guides, such as one from Rx-360 [123], help expedite this process. By having a concise understanding of expectations, the contract giver would hence be able to assure that practices which promote DI would be performed by the contract acceptor, while the contract acceptor understands what is expected of them [124].

Collaboration between countries
Each country has its own set of legislation. Although the legislation of different countries generally overlaps [125, 126], individual countries may not accept specific documents that originate from another country, exacerbating DI issues. Hence, collaborative use of legislation and mutual recognition schemes can help to promote DI [127, 128], with the added benefit of efficient international transactions as DI criteria would have been fulfilled prior to application for regulatory or other transaction approvals.

Effective and efficient audits and audit trail review
Audits are defined as validation checks conducted on manufacturing protocols and systems that assure quality in the processes, products, and computerized systems at the manufacturing site [129]. This includes both internal audits self-conducted by the manufacturer in accordance with Chapter 9 of the PIC/S GMP Guide [130], and external audits conducted by regulatory auditors including FDA and MHRA. As audits are limited in duration, meaningful and efficient audits should be conducted [124]. In general, processes or data that do not affect product safety and compliance, including data on accounting and finances [131], need not be audited. The audit can be streamlined by tagging relevant items to allow the auditor to quickly sieve them out for scrutiny [132, 133]. Audit trails may be divided into two different types: Data Audit Trail (DAT), which covers the raw data recorded, and System Audit Trails (SAT), which covers the systems in place to maintain DI during documentation.

When auditing DAT, critical quality attributes (CQA) and audit trail elements must be defined before conducting the audit. CQAs are the characteristics or properties that can harm patients if not properly controlled [117]. These attributes are to be defined by the company, referring to current legislation and guidance such as ICH Q8(R2) Part 2 [134]. Audit trail elements are the items which affect CQAs and are to be audited [132]. Other items need not be audited as frequently nor meticulously [131]. When auditing SAT, assuming the current system is validated, auditing for possible indicators of DI breaches can substitute an audit of the raw SAT data [131]. These indicators include multiple login attempts and read and write errors [135]. With the recent focus of audits being more SAT-oriented, coupled with more robust systems that can detect errors in DAT [131], falsification of data points prior to documentation may not be detected. As such, both DAT and SAT must be audited in tandem to achieve a more comprehensive audit outcome.

Finally, it must be emphasized that a reliance on periodic audits from the regulator is grossly inadequate to address DI issues. On the other hand, overly frequent internal audits may inefficiently use the company’s manpower. For SAT, an approach based on the risks and implications of DI breaches and the Good Automated Manufacturing Practices (GAMP 5) Software Category [131], as tabulated in Table 7, is recommended.

Table 7

Computerized systems validation
Pharmaceutical and biopharmaceutical manufacturers should validate their computerized systems such that they are fit for their intended purpose, and to ensure that adequate controls are in place to facilitate tracking and detection of deleted or altered data. The use of hybrid (paper and computerized) systems should be discouraged. However, where legacy systems are awaiting replacement, mitigating controls should be put in place. In such cases, original records generated during the course of GxP activities must be complete and must be maintained throughout the records retention period in a manner that allows the full reconstruction of the GxP activities. Replacement of hybrid systems should be a priority [41].

Conclusion

With increasingly complex pharmaceutical manufacturing processes, maintaining DI might become more challenging, and relying merely on legislation and guidance to maintain DI might be insufficient. Some possible solutions to tackle this challenge include having a company culture of integrity, having a good DBMS, education and training, forming effective quality agreements, collaborations between countries, and performing efficient audits. Together with existing legislation and guidance, these measures can help manage DI issues in the pharmaceutical manufacturing industry, improve the standard of pharmaceutical manufacturing worldwide, and ultimately, produce safe and quality medicinal products for patients internationally.

Competing interests: None.

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

Authors

Adjunct Associate Professor Sia Chong Hock1, BSc (Pharm), MSc
Vernon Tay1, BSc (Pharm) (Hons)
Vimal Sachdeva2, MSc
Associate Professor Chan Lai Wah1, BSc (Pharm) (Hons), PhD

1Department of Pharmacy, National University of Singapore, 18 Science Drive 4, Singapore 117543
2Technical Officer (Senior Inspector), World Health Organization, Prequalification Team, Regulation of Medicines and Other Heath Technologies (RHT), Essential Medicines and Health Products (EMP), Health Systems and Innovation, 20 Avenue Appia, CH-1211 Geneva 27, Switzerland

Acronyms and abbreviation

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Author for correspondence: Adjunct Associate Professor Sia Chong Hock, BSc (Pharm), MSc, Senior Consultant (Audit and Licensing) and Director (Quality Assurance), Health Products Regulation Group, Health Sciences Authority Singapore, 11 Biopolis Way, #11-01 Helios, Singapore 138667

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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

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