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

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.


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

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 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].


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.


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

1. World Health Organization. Technical Report Series, Annex 5. Guidance on good data and record management [homepage on the Internet]. [cited 2020 Sep 15]. Available from: practices
2. Snee RD. LLC Data integrity – how to detect lack of integrity. IVT Validation Week; 25-27 October 2015; Philadelphia, PA. Available from: egrity_Validation/links/5684106b08aebccc4e0fdadb.pdf
3. Boogaard P, Haag T, Reid C, Rutherford M, Wakeham C. Data Integrity – here, large, and not going away, here, large, and not going away. Pharmaceutical Eng. 2016;36:41-67.
4. Perez JR. Field notes: maintaining Data Integrity. Quality Progress. 2017; 50(3):14-5.
5. Lydon B. Data Integrity. International Society of Automation. 2017.
6. U.S. 21 Code of Federal Regulations § 11, 1997.
7. U.S. 21 Code of Federal Regulations § 210, 1978.
8. U.S. 21 Code of Federal Regulations § 211, 1978.
9. U.S. Food and Drug Administration. Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and Research (CBER), Center for Veterinary Medicine (CVM), Data Integrity and compliance with CGMP guidance for industry. April 2016 [homepage on the Internet]. [cited 2020 Sep 15]. Available from:
10. Medicines and Healthcare products Regulatory Agency. GxP Data Integrity Guidance and Definitions. 2018 [homepage on the Internet]. [cited 2020 Sep 15]. Available from:
11. Kumar S, Tanwar D, Arora N. The role of regulatory GMP audit in pharmaceutical companies. Int J Res Dev Pharm Life Sci. 2013;2:493-8.
12. Milmo S. Harmonizing GMP inspections, Pharm Tech. 2018;42(5).
13. The FDA Group. The emergency guide to FDA warning letters and FDA 483 – How to handle inspectional observations and warning letters from the FDA. 2017 [homepage on the Internet]. [cited 2020 Sep 15]. Available from: Warning_Letters_and_FDA_483.pdf
14. Unger BW. An analysis of 2017 FDA warning letters on Data Integrity. Pharmaceutical Online. 2018.
15. Ranbaxy whistleblower reveals how he exposed massive pharmaceutical fraud, CBS This Morning. 2013.
16. Dooley B. Viral post inflames public anger in China vaccine scandal, Sino Daily. 24 July 2018.
17. Markarian J. Modernizing pharma manufacturing. Pharm Tech. 2018;42:20-5.
18. Tabersky D, Woelfle M, Ruess J-A, Brem S, Brombacher S. Recent regulatory trends in pharmaceutical manufacturing and their impact on the industry. CHIMIA Int J Chem. 2018;72(3):146-50.
19. Unger BW. Data Integrity and data management for GXP regulated firms. Unger Consulting. 2016.
20. Langer ES. Outsourcing trends in biopharmaceutical manufacturing. Pharmaceutical Outsourcing. 24 September 2017.
21. Privett N, Gonsalvez D. The top ten global health supply chain issues: perspectives from the field. Oper Res Health Care. 2014;3(4):226-30.
22. Osani JE. Supplier quality management: monitoring the quality and compliance of api suppliers, defining generic pharma as the customer [thesis]. 2010.
23. Rauschnabel J. 2018 Pharma Industry Outlook – the importance of quality and safety, especially in times of change. Contract Pharma. 2018.
24. Burns M. Management of narrow therapeutic index drugs. J Throm Throm­bolysis. 1999;7(2):137-43.
25. Eldawud R, Stueckle T, Manivannan S, Elbaz H, Chen M, Rojanasakul Y, et al. Real-time analysis of the effects of toxic, therapeutic and sub-therapeutic concentrations of digitoxin on lung cancer cells. Biosens Bioelectron. 2014;59:192-9.
26. Ruth A. Why pharmaceutical Data Integrity is more important than ever. Pharmaceutical Guidelines. 2017.
27. Mullin R. The drug industry’s data integrity problem. Chem Eng News. 2018;96(2):15-7.
28. Pharma Quality Europe. EU and US joint inspections: data as the cornerstone for the future. FDAnews’ 8th FDA Inspections Summit. 2018 [homepage on the Internet]. [cited 2020 Sep 15]. Available from:–EU-and-US-Joint-Inspections-Data-as-The-Cornerstone-for-The-Future.pdf
29. U.S. Food and Drug Administration. Warning letters. 2018 [homepage on the Internet]. [cited 2020 Sep 15]. Available from:
30. Bioprocess Online: FDA FY2019 Drug inspection observations and trends. 6 December 2019.
31. Unger BW. Warning letters 2016 – Data governance and Data Integrity.
32. U.S. Food and Drug Administration. Warning letters. Wockhardt Limited 7/18/13.
33. U.S. Food and Drug Administration. Warning letter. Marck Biosciences Ltd. July 08, 2014 [homepage on the Internet]. [cited 2020 Sep 15]. Available from:
34. U.S. Food and Drug Administration. Warning letters. Mahendra Chemicals July 13, 2015 [homepage on the Internet]. [cited 2020 Sep 15]. Available from:
35. U.S. Food and Drug Administration, Warning letters. Sri Krishna Pharmaceuticals Ltd. – Unit II. April 1, 2016 [homepage on the Internet]. [cited 2020 Sep 15]. Available from:­gletters/2016/ucm495535.htm
36. U.S. Food and Drug Administration. Warning letters. Zhejiang Ludao Technology Co., Ltd. 23 February 2018 [homepage on the Internet]. [cited 2020 Sep 15]. Available from:
37. Vandekerckhove W. Freedom of expression as the “broken promise” of whistleblower protection, Revue Des Droits De l’Homme. 2016;10. doi:10.4000/revdh.2680.
38. Kierans L, Lewis D. Using statutory guidance and codes of practice to build on whistleblowing legislation: the Irish experience. Revue Des Droits De l’Homme. 2016;10. doi:10.4000/revdh.2716.
39. U.S. Food and Drug Administration, Warning letters. Jilin Shulan Synthetic Pharmaceutical Co. Ltd. May 5, 2018 [homepage on the Internet]. [cited 2020 Sep 15]. Available from:
40. DiPalma D, Vannest J. Integrated systems aid Data Integrity, Pharmaceutical Technology. 2018;42(5):46-7.
41. McDowall RD. Data Integrity focus, Part III: what is the problem with hybrid systems? LCGC North America. 2019;37(3):180-4.
42. European Commission. Commission Directive 2003/63/EC. Official Journal of the European Union. 2003 [homepage on the Internet]. [cited 2020 Sep 15]. Available from: 1/dir_2003_63/dir_2003_63_en.pdf
43. European Commission. The rules governing medicinal products in the European Union. Office for Official Publications of the European Communities, Luxembourg, 1998. 2003 [homepage on the Internet]. [cited 2020 Sep 15]. Available from:
44. U.S. 21 Code of Federal Regulations. § 212, 2009.
45. U.S. 21 Code of Federal Regulations. § 600, 2014.
46. U.S. 21 Code of Federal Regulations. § 820, 1996.
47. Directive 2011/62/EU of The European Parliament and of The Council of 8 June 2011 [homepage on the Internet]. [cited 2020 Sep 15]. Available from:
48. SFDA Drug Data Management Standard. 2016 [homepage on the Internet]. [cited 2020 Sep 15]. Available from:
49. Embrey MA. Chapter 6: Pharmaceutical legislation and regulation, in: MDS-3: Managing Access to Medicines and Health Technologies. Kumarian Press; 2013.
50. Guide to good manufacturing practice for medicinal products, Pharmaceutical Inspection Convention, Pharmaceutical Inspection Co-operation Scheme, Geneva, Switzerland, 2009.
51. Guide to good manufacturing practice for active pharmaceutical ingredients, Pharmaceutical Inspection Convention, Pharmaceutical Inspection Co-operation Scheme, Geneva, Switzerland, 2009.
52. The International Council on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients, Q7, 2000. [cited 2020 Sep 15]. Available from:
53. API cGMP facility questionnaire & audit checklist, n.d. [cited 2020 Sep 15]. Available from:
54. Pharmaceutical Inspection Convention and Pharmaceutical Inspection Co- operation Scheme. Revised PIC/S audit checklist based. 2014 [homepage on the Internet]. [cited 2020 Sep 15]. Available from:
55. Pharmaceutical Inspection Convention and Pharmaceutical Inspection Co- operation Scheme. Good practices for computerized systems in regulated GXP environment. 2007 [homepage on the Internet]. [cited 2020 Sep 15]. Available from:
56. U.S. Food and Drug Administration. Standardization of data and documentation practices for product tracing guidance for industry. 2018 [homepage on the Internet]. [cited 2020 Sep 15]. Available from:
57. U.S. Food and Drug Administration. Contract manufacturing arrangements for drugs: quality agreements. Guidance for Industry. 2016 [homepage on the Internet]. [cited 2020 Sep 15]. Available from:
58. The International Council on Harmonisation of Technical Requirements for Pharmaceuticals for Human Use, Q9 Quality risk management. 2005 [home­page on the Internet]. [cited 2020 Sep 15]. Available from: [
59. Pharmaceutical Inspection Convention and Pharmaceutical Inspection Co- operation Scheme. Good practices for data management and integrity in regulated GMP/GDP environments. 2016 [homepage on the Internet]. [cited 2020 Sep 15]. Available from:
60. Medicines and Healthcare products Regulatory Agency. ‘GXP’ Data Integrity Guidance and Definitions. 2018 [homepage on the Internet]. [cited 2020 Sep 15]. Available from: hment_data/file/687246/MHRA_GxP_data_integrity_guide_March_edited_Final.p df
61. Medicines and Healthcare products Regulatory Agency. Rules and Guidance for Pharmaceutical Manufacturers and Distributors 2017 (The Orange Guide). London: 2017.
62. Yang L, Sun G, Eppler MJ. Making strategy work: a literature review on the factors influencing strategy implementation [thesis]. Handbook of research on Strategy Process, 2010.
63. Khoja SS, Khoja SS, Chauhan PH, Khoja FS, Khoja SS. A review on creation and handling of data in accordance with cGMP requirements in pharmaceuticals. PharmaTutor. 2017;5:64-9.
64. Wingate G. Computer systems validation: quality assurance, risk management, and regulatory compliance for pharmaceutical and healthcare companies. Interpharm/CRC: Boca Raton, FL; 2004.
65. Craig R, Hickman CR, Silva MA. Creating excellence. 2018. doi:10.4324/9781351065306.
66. Guiso L, Sapienza P, Zingales L. The value of corporate culture. J Financ Econ. 2015;117:60-76.
67. Singh A, Joshi R. Analyzing the state of Data Integrity compliance in the Indian pharmaceutical industry. Ernst & Young LLP: India; 2015.
68. Bhatia S. Creating a culture of honesty and integrity in supply chains. Asian J Manag Sci Ed. 2018;7:55-61.
69. Alfred C. Maximizing leverage from an object database. IBM Systems Journal. 1994;33:280-99. doi:10.1147/sj.332.0280.
70. Nadkarni PM. Metadata-driven software systems in biomedicine. Health Informatics. London: Springer; 2011.
71. Schmidt J. How big data is transforming pharmaceutical manufacturing. Pharmaceutical Online. 2016.
72. Gandomi A, Haider M. Beyond the hype: big data concepts, methods, and analytics, Int J Inform Manage. 2015;35(2):13744.
73. Moniruzzaman ABM, Hossain SA. NoSQL Database: new era of databases for Big Data analytics – classification, characteristics and comparison. Int J Database Theory Appl. 2013;6(4):1-14.
74. Praveen S, Chandra U, Ali A. A Literature review on evolving database. Int J Comput Appl. 2017;162(9):35-41.
75. Gudivada VN, Rao D, Raghavan V. Renaissance in Data Management Systems: SQL, NoSQL, and NewSQL [thesis]. 2015.
76. Harrison G. Next generation databases: NoSQL, NewSQL, and Big Data, IOUG. Chicago; 2015.
77. Dove AP, Jundt LO, Lucas J. Using an object-oriented database as a repository for process configuration data. ISA Trans. 1997;36(4):339-43.
78. Haerder T, Reuter A. Principles of transaction-oriented database recovery. ACM Computing Surveys. 1983;15(4):287-317.
79. Jaedicke M, Mitschang B. User-defined table operators: enhancing extensibility for ORDBMS. VLDB’99, Proceedings of 25th International Conference on Very Large Data Bases. Edinburgh, Scotland, UK; 1999. p. 494-505.
80. Sahafizadeh E, Nematbakhsh MA. A survey on security issues in Big Data and NoSQL, Advances in Computer Science: an International Journal. 2015;4:69-72.
81. Bernstein D. Todays Tidbit: VoltDB. IEEE Cloud Computing. 2014;1(1):90-2.
82. Agarwal AK, Srivastava A. Study, comparison and analysis of different types of storage systems. Int J Curr Eng Tech. 2016;6(4):1392-9.
83. Hong W. Object-relational DBMS. 2015.
84. Ingolikar R, Khandal R, Mohare R. Comparison of HDBMS, NDBMS, RDBMS and OODBMS. Int J Adv Res Comp Sci Manage Studies. 2015;3(6):119-27.
85. Phaneendra VS, Reddy ME. Big Data – solutions for RDBMS problems – a survey, Int J Adv Res Comp Sc Software Eng. 2013;2:3686-91.
86. Agarwal AK, Srivastava A. Study, comparison and analysis of different types of storage systems, Int J Curr Eng Tech. 2016;6(4):1392-9.
87. Chandrasekhar R. Object Oriented DBMS (OODBMS). SQL Versity. 2014.
88. Corbellini A, Mateos C, Zunino A, Godoy D, Schiaffino S. Persisting big- data: the NoSQL landscape. Information Systems. 2017;63:1-23.
89. VoltDB, 4.2. Updating the Database Schema, 4.2. 2015.
90. Edlich S. Choose the “Right” Database and NewSQL: NoSQL Under Attack, InfoQ. 2012.
91. McCreary D, Kelly A. Making sense of NoSQL: a guide for managers and the rest of us. Manning: Shelter Island; 2014.
92. Haines S. Introduction to HBase, the NoSQL Database for Hadoop. Policy | InformIT. 2014.
93. Okman L, Gal-Oz N, Gonen Y, Gudes E, Abramov J. Security issues in NoSQL Databases. IEEE 10th International Conference on Trust, Security and Privacy in Computing and Communications. 2011. p. 541-7.
94. Srinivasa KG, Hiriyannaiah S. Comparative study of different in-memory (No/New) SQL Databases, A deep dive into NoSQL Databases: the use cases and applications. Advances in Computers. 2018;109:133-156.
95. Laranjeiro N, Soydemir SN, Bernardino J. A survey on data quality: classifying poor data. 2015 IEEE 21st Pacific Rim International Symposium on Depend­able Computing (PRDC). 2015.
96. Clark B, Burstall R. Blockchain, IP and the pharma industry—how distributed ledger technologies can help secure the pharma supply chain. J Intellectual Property Law & Practice. 2018;13:531-3.
97. Conoscenti M, Vetro A, Martin JCD. Blockchain for the Internet of things: a systematic literature review, 2016 IEEE/ACS 13th International Conference of Computer Systems and Applications (AICCSA). 2016.
98. Crosby M, Nachiappan, Pattanayak P, Verma S, Kalyanaraman V. Blockchain technology: beyond Bitcoin. Applied Innovation Review. 2016.
99. British Standards Institution. Deshpande A, Stewart K, Lepetit L, Gunashekar S. Overview report distributed ledger technologies/blockchain: challenges, opportunities and the prospects for standards. 2017 [homepage on the Internet]. [cited 2020 Sep 15]. Available from:
100. Christidis K, Devetsikiotis M. Blockchains and smart contracts for the Internet of things. IEEE Access. 2016;4:2292-303.
101. Iansiti M, Lakhani KR, Mohamed H. The truth about blockchain, Harvard Business Review. 2017.
102. BlockchainHub. Blockchains & distributed ledger technologies. 2016 [homepage on the Internet]. [cited 2020 Sep 15]. Available from: ledger-technologies-in-general/
103. Bocek T, Rodrigues BB, Strasser T, Stiller B. Blockchains everywhere – a use-case of blockchains in the pharma supply-chain. 2017 IFIP/IEEE Symposium on Integrated Network and Service Management (IM). 2017. p. 772-7.
104. Wentworth S. How will blockchain impact pharma? The Pharma Letter. 2018.
105. modum. Applications – Industry Specific, Modum. 2018 [homepage on the Internet]. [cited 2020 Sep 15]. Available from:
106. Puthal D, Malik N, Mohanty SP. Everything you wanted to know about the blockchain. IEEE Consumer Electronics Magazine. 2018;7:6-14.
107. Autor D, Kaufman Z, Tetzlaff R, Gribbin M, Dole M, Glover D, et al. PDA points to consider: best practices for document/data management and control and preparing for Data Integrity inspections. PDA J Pharma Sci Technol. 2018;72:332-7.
108. Yli-Huumo J, Ko D, Choi S, Park S, Smolander K. Where is current research on blockchain technology?—a systematic review. Plos One. 2016;11.
109. Watanabe H, Fujimura S, Nakadaira A, Miyazaki Y, Akutsu A, Kishigami JJ. Blockchain contract: a complete consensus using blockchain. 2015 IEEE 4th Global Conference on Consumer Electronics (GCCE). 2015. p. 577-8.
110. Liu Y, Lu Q, Xu X, Zhu L, Yao H. Applying design patterns in Smart contracts. In: Chen S, Wang H, Zhang L.-J. (editors). Blockchain – ICBC 2018: First International Conference, Held as Part of the Services Conference Federation, SCF 2018 Seattle, WA, USA, 25-30 June 2018, Proceedings. Springer International Publishing, Cham. 2018. p. 92-106.
111. McDowall RD. Validation of chromatography data systems: ensuring data integrity, meeting business and regulatory requirements. The Royal Society of Chemistry. Cambridge; 2017.
112. Barkow S, Takahashi K. Current expectations and guidance, including data integrity and compliance with cGMP. Society of Quality Assurance Annual Meeting 2017. Available from: ow+S,+Takahashi+K,+Current+expectations+and+guidance,+including&hl=e n&as_sdt=0&as_vis=1&oi=scholart
113. Albon KI, Davis D, Brooks JL. A risk-based approach to Data Integrity. Pharma Technol. 2015;39(7):46-50.
114. Unger B. Is GMP quality system auditing fundamentally flawed? – a Data Integrity alternative. Pharmaceutical Online. 2017.
115. Morris J. Practical data migration. Bcs Learning & Development Lim. 2012.
116. Warmuth A, Dufrasne B, Appel J, Bauer W, Douglass S, Klee P, et al. Ds8870 data migration techniques. IBM Redbooks. 2015.
117. Wolfgang W, Ludwig H. Part 3: Ensuring data integrity in electronic records. BioPharm. 2000;13(11):S24-S27.
118. McDowall RD. What is Data Integrity training?, Spectroscopy. 2015;30:34-41.
119. ECA Certified Data Integrity Manager. ECA Academy.
120. Data Integrity Pharmaceutical Training Course, RSSL. 2020.
121. Vaittinen S. Supply chain management in a highly regulated environment – a case study of supplier GMP-compliance management in the pharmaceutical industry [thesis]. Aalto University; 2016.
122. Maguire J, Peng D. How to identify critical quality attributes and critical process parameters. 2nd FDA/PQRI Conference on Advancing Product Quality; 5-7 October 2015; North Bethesda, Maryland
123. Rx-360. Rx-360 Best Practices Quality Agreement Guide. 2015. Available from:
124. Lopez O. Data Integrity expectations of EU GMP inspectors. PharmTech. 2017;41(7):6-10.
125. Lazar MS. “GMP” an evolution in application. Journal of GXP Compliance. 2008;12(2):20-3. Available from:
126. Pharma Quality Europe, EU and US Joint Inspections: Data as the Cornerstone for the Future, FDAnews’ 8th FDA Inspections Summit. 2013. Available from:–EU-and-US-Joint-Inspections-Data-as-The-Cornerstone-for-The-Future.pdf
127. Sawant A, Tetzlaff R, Baker D. 2018 PDA/FDA Joint Regulatory Conference; 9 July 2018. PDA Letter. 2018. Available from:
128. Milmo S. Harmonizing GMP inspections. PharmTech. 2018;42(5):6-8.
129. ASQ. What is auditing? ASQ. 2015. Available from:
130. Pharmaceutical Inspection Convention, Pharmaceutical Inspection Co-operation Scheme. Guide to good manufacturing practice for medicinal products (Part 1). 2009 [homepage on the Internet]. [cited 2020 Sep 15]. Available from:
131. International Society for Pharmaceutical Engineering. GAMP 5 guide: compliant GxP computerized systems. 2008 [homepage on the Internet]. [cited 2020 Sep 15]. Available from:
132. van Rijmenam M, Erekhinskaya T, Schweitzer J, Williams M-A. Avoid being the Turkey: how big data analytics changes the game of strategy in times of ambiguity and uncertainty. Long Range Planning. 2018;52(5):
133. McDowall RD. What’s new with the FDA’s Data Integrity guidance? Spectroscopy. 2016;31:1-6.
134. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. Pharmaceutical Development Q8(R2). 2009 [homepage on the Internet]. [cited 2020 Sep 15]. Available from:
135. Coronel C, Morris S. 1-3a – Role and Advantages of the DBMS. Database systems: design, implementation and management. 12th ed. 2016. p. 6-11.

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

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


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


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.


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

1. Pharmaceutical Inspection Co-operation Scheme. PIC/S GMP Guide (Related annexes). 2018 [homepage on the Internet]. [cited 2020 May 26]. Available from:
2. Pharmaceutical Inspection Co-operation Scheme. PIC/S GMP Guide (Part II: Basic requirements for active pharmaceutical ingredients). 2018 [homepage on the Internet]. [cited 2020 May 26]. Available from:
3. U.S. Food and Drug Administration. Resources for you (Biologics). 2019 [homepage on the Internet]. [cited 2020 May 26]. Available from:
4. European Medicines Agency. Biological medicine [homepage on the Internet]. [cited 2020 May 26]. Available from:
5. World Health Organization. Biotherapeutic products [homepage on the Internet]. [cited 2020 May 26]. Available from:
6. European Medicines Agency. First stem-cell therapy recommended for approval in EU. 2014 [homepage on the Internet]. [cited 2020 May 26]. Available from:
7. Pellegrini G, Ardigò D, Milazzo G, Iotti G, Guatelli P, Pelosi D, et al. Navigating market authorization: the path Holoclar took to become the first stem cell product approved in the European Union. Stem Cells Transl Med. 2018;7(1):146-54.
8. Wang X, Rivière I. Clinical manufacturing of CAR T cells: foundation of a promising therapy. Mol Ther Oncolytics. 2016;5(3):1-7.
9. Center for Biologics Evaluation and Research. What are “Biologics” questions and answers. 2018 [homepage on the Internet]. [cited 2020 May 26]. Available from:
10. European Medicines Agency. Advanced therapy medicincal products: overview [homepage on the Internet]. [cited 2020 May 26]. Available from:
11. World Health Organization. WHO questions and answers: similar biotherapeutic products. 2018 [homepage on the Internet]. [cited 2020 May 26]. Available from:
12. European Medicines Agency. Biosimilar medicines: overview [homepage on the Internet]. [cited 2020 May 26]. Available from:
13. Frost & Sullivan. APAC biosimilar market, forecast 2025. [homepage on the Internet]. [cited 2020 May 26]. Available from:
14. European Medicines Agency. Biosimilars in the EU. Information guide for healthcare professionals: 2017 [homepage on the Internet]. [cited 2020 May 26]. Available from:
15. Berkowitz SA, Engen JR, Mazzeo JR, Jones GB. Analytical tools for characterizing biopharmaceuticals and the implications for biosimilars. Nat Rev Drug Discov. 2012;11(7):527-40.
16. Husain SR, Han J, Au P, Shannon K, Puri RK. Gene therapy for cancer: regulatory considerations for approval. Cancer Gene Ther. 2015;22(12):554-63.
17. U.S. Food and Drug Administration. Bauer S. Development of ­strategies to improve cell therapy product characterization. 2018 [­homepage on the Internet]. [cited 2020 May 26]. Available from:
18. National Library of Medicine. Aspirin, CID=2244 PubChem Database. 2004 [homepage on the Internet]. [cited 2020 May 26]. Available from:
19. Grenha A. Systemic delivery of biopharmaceuticals: parenteral forever? Pharm Bioallied Sci. 2012;4(2):95.
20. Morishita M, Peppas NA. Is the oral route possible for peptide and protein drug delivery? Drug Discov Today. 2006;11(19):905-10.
21. Vela Ramirez JE, Sharpe LA, Peppas NA. Current state and challenges in developing oral vaccines. Adv Drug Deliv Rev. 2017;114:116-31.
22. Krause ME, Sahin E. Chemical and physical instabilities in manufacturing and storage of therapeutic proteins. Curr Opin Biotechnol. 2019;60:159-67.
23. Pharmaceutical Inspection Co-operation Scheme. PIC/S Brochure. 2018 [homepage on the Internet]. [cited 2020 May 26]. Available from:
24. European Medicines Agency. Good manufacturing practice [homepage on the Internet]. [cited 2020 May 26]. Available from:
25. World Health Organization. Good manufacturing practices [homepage on the Internet]. [cited 2020 May 26]. Available from:
26. U.S. Food and Drug Administration. Facts about the Current Good Manufacturing Practices (CGMPs). 2018 [homepage on the Internet]. [cited 2020 May 26]. Available from:
27. Esteban E, Bustos RH, García JC, Jáuregui E. Biosimilars: an approach to some current worldwide regulation frameworks. Curr Clin Pharmacol. 2019;14(1):16-40.
28. Bas TG, Carolina Oliu C. Biosimilars in developed and developing East and Southeast Asian countries: Japan, South Korea, and Malaysia-overview, evolution, and regulations assessment. Biomed Res Int. 2016:2016:5910403.
29. Tsai W-C. Update on biosimilars in Asia. Curr Rheumatol Rep. 2017;19(8):47.
30. Tonby O, Ng J, Mancini M. Understanding ASEAN: the manufacturing opportunity. McKinsey&Company.
31. Vervisch R. The generics in Southeast Asia: market analysis and their role in shaping the future of biosimilars [thesis]. Université libre de Bruxelles; 2017.
32. Hock SC, Tribe R, Wah CL. ASEAN harmonization on GMP inspection and training of inspectors. Pharmaceut Eng. 2013;33(1):56-62.
33. Monzani PS, Adona PR, Ohashi OM, Meirelles FV, Wheeler MB. Transgenic bovine as bioreactors: challenges and perspectives. Bioengineered. 2016;7(3):123-31
34. Schillberg S, Raven N, Spiegel H, Rasche S, Buntru M. Critical analysis of the commercial potential of plants for the production of recombinant proteins. Front Plant Sci. 2019;10:720-. Epub June 11, 2019. doi: 10.3389/fpls.2019.00720.
35. Jagschies G, Łącki KM. Chapter 4 – Process capability requirements. In: Jagschies G, Lindskog E, Łącki K, Galliher P, editors. Biopharmaceutical processing: Elsevier; 2018. p. 73-94.
36. European Commission. EudraLex – Volume 4 – Good Manufacturing ­Practice (GMP) guidelines, glossary. 2004 [homepage on the Internet]. [cited 2020 May 26]. Available from:
37. World Health Organization. Annex 2. WHO good manufacturing practices for biological products. 2016 [homepage on the Internet]. [cited 2020 May 26]. Available from:
38. Challener CA. Ensuring the safety, quality, and identity of biopharmaceutical raw materials. BioPharm Int. 2014;27(8):28-9,44.
39. Chen D. Safety assurance for biologics manufactured in mammalian cell cultures: a multitiered strategy. In: Zhou W, Kantardjieff A, editors. Mammalian cell cultures for biologics manufacturing. 139. Berlin, Heidelberg: Springer; 2014. p. 167-83.
40. International Conference on Harmonisation of Technical requirements for registration of pharmaceeuticals for human use. Derivation and characterisation of cell substrates used for production of biotechnological/biological products Q5D. 1997 [homepage on the Internet]. [cited 2020 May 26]. Available from:
41. Highfill SL, Stroncek DF. Overcoming challenges in process development of cellular therapies. Curr Hematol Malig Rep. 2019;14(4):269-77.
42. Costa AR, Rodrigues ME, Henriques M, Azeredo J, Oliveira R. Guidelines to cell engineering for monoclonal antibody production. Eur J Pharm Biopharm. 2010;74(2):127-38.
43. Lindskog EK, Fischer S, Wenger T, Schulz P. Chapter 6 – Host Cells. In: Jagschies G, Lindskog E, Łącki K, Galliher P, editors. Biopharmaceutical processing. Elsevier; 2018. p. 111-30.
44. van der Loo JCM, Wright JF. Progress and challenges in viral vector manufacturing. Hum Mol Genet. 2016;25(R1):R42-R52.
45. Ng RP. Considerations for successful upstream process development. BioPharm International. 2012;25(7):48-50.
46. Gretzinger S, Limbrunner S, Hubbuch J. Automated image processing as an analytical tool in cell cryopreservation for bioprocess development. Bioprocess and Biosyst Eng. 2019;42(5):665-75.
47. Gjoka X, Gantier R, Schofield M. Platform for Integrated continuous bioprocessing. BioPharm Int. 2017;30(7):26-32.
48. Hunsberger J, Harrysson O, Shirwaiker R, Starly B, Wysk R, Cohen P, et al. Manufacturing road map for tissue engineering and regenerative medicine technologies. Stem Cells Transl Med. 2015;4(2):130-5.
49. Walther J, Lu J, Hollenbach M, Yu M, Hwang C, McLarty J, et al. Perfusion cell culture decreases process and product heterogeneity in a head-to-head comparison with fed-batch. Biotechnol J. 2019;14(2):1-10.
50. Pollock J, Ho SV, Farid SS. Fed-batch and perfusion culture processes: economic, environmental, and operational feasibility under uncertainty. Biotechnol Bioeng. 2013;110(1):206-19.
51. Klutz S, Holtmann L, Lobedann M, Schembecker G. Cost evaluation of antibody production processes in different operation modes. Chem Eng Sci. 2016;141:63-74.
52. Li F, Vijayasankaran N, Shen A, Kiss R, Amanullah A. Cell culture processes for monoclonal antibody production. Mabs. 2010;2(5):466-79.
53. Przybycien T, Titchener-Hooker N. Continuous processing in downstream operations. Chem Eng Prog. 2015;111(12):38-44.
54. Prazeres DM. An overview of downstream processing. Plasmid Biopharmaceuticals. 2011:415-25. doi: 10.1002/9780470939918.ch14.
55. Shukla A, Aranha H. Viral clearance for biopharmaceutical downstream processes. Pharm Bioprocess. 2015;3(2):127-38.
56. Carbonell R, Mukherjee A, Dordick J, Roberts CJ. A technology roadmap for today’s gene therapy manufacturing challenges. Cell & Gene. 2019 Apri 18.
57. Aires-Barros MR, Azevedo AM. 7 – Fundamentals of biological separation processes. In: Pandey A, Teixeira JAC, editors. Current developments in biotechnology and bioengineering: Elsevier; 2017. p. 187-237.
58. Dream R, Odum J. Impact of ATMP manufacturing on process equipment and facility design. BioPharm Int. 2018;31(11):30-4.
59. Alsharabasy AM. Concise review: considerations for the formulation, delivery and administration routes of biopharmaceuticals. Arch Biotechnol Biomed. 2017;1:33-53.
60. Renteria Gamiz AG, Dewulf J, De Soete W, Heirman B, Dahlin P, Jurisch C, et al. Freeze drying in the biopharmaceutical industry: an environmental sustainability assessment. Food Bioprod Process. 2019;117:213-23.
61. Bee JS, Randolph TW, Carpenter JF, Bishop SM, Dimitrova MN. Effects of surfaces and leachables on the stability of biopharmaceuticals. J Pharm Sci. 2011;100(10):4158-70.
62. Vulto AG, Jaquez OA. The process defines the product: what really matters in biosimilar design and production? Rheumatology (Oxford). 2017;56(suppl_4):iv14-iv29.
63. U.S. Food and Drug Administration. Guidance for industry. Process validation: general principles and practices. 2011 [homepage on the Internet]. [cited 2020 May 26]. Available from:
64. Siew A. Characterizing critical quality attributes in biopharmaceutical drug development. BioPharm Int. 2018;31(9):32.
65. Lalor F, Fitzpatrick J, Sage C, Byrne E. Sustainability in the biopharmaceutical industry: Seeking a holistic perspective. Biotechnol Adv. 2019;37(5):698-707.
66. Health Sciences Authority. Increase in antibody-mediated pure red cell aplasia (PRCA) cases with subcutaneous administration of Eprex® (epoetin alfa) in Singapore. 2013 [homepage on the Internet]. [cited 2020 May 26]. Available from:
67. Wurm MF, Wurm JM. Cloning of CHO cells, productivity and genetic stability—a discussion. Processes. 2017;5(2):1-13.
68. Spencer S, Gugliotta A, Koenitzer J, Hauser H, Wirth D. Stability of single copy transgene expression in CHOK1 cells is affected by histone modifications but not by DNA methylation. J Biotechnol. 2015;195:15-29.
69. Betts Z, Croxford AS, Dickson AJ. Evaluating the interaction between UCOE and DHFR-linked amplification and stability of recombinant protein expression. Biotechnol Prog. 2015;31(4):1014-25.
70. Bort JAH, Hackl M, Höflmayer H, Jadhav V, Harreither E, Kumar N, et al. Dynamic mRNA and miRNA profiling of CHO-K1 suspension cell cultures. Biotechnol J. 2012;7(4):500-15.
71. Longer ES, Rader RA. Top trends in biopharmaceutical manufacturing, 2017: innovation speeds discovery, drives down costs, and improves productivity. Pharmaceut. Technol. 2017;41(9):58-60.
72. Wolf MW, Reichl U. Downstream processing of cell culture-derived virus particles. Expert Rev Vaccines. 2011;10(10):1451-75.
73. Han FV, Weiss K. Regulatory trends in drug development in Asia Pacific. Ther Innov Regul Sci. 2018;53(4):497-501.
74. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. Quality risk management Q9. 2005 [homepage on the Internet]. [cited 2020 May 26]. Available from:
75. Castillo FC, Cooney B, Levine HL. Biopharmaceutical manufacturing process validation and quality risk management. Pharmaceutical Engineering. 2016.
76. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. Pharmaceutical development Q8 (R2). 2009 [homepage on the Internet]. [cited 2020 May 26]. Available from:
77. Wheelwright SM. CFDA good manufacturing practice. Annexes. 2016 [home-page on the Internet]. [cited 2020 May 26]. Available from:
78. European Commission. Guidelines on good manufacturing practice specific to advanced therapy medicinal products. 2017 [homepage on the Internet]. [cited 2020 May 26]. Available from:
79. Ph`armaceutical Inspection Co-operation Scheme. Draft Annex 2A. Manufacture of ATMP) to PICS GMP Guide For Public Consultation. 2019 [homepage on the Internet]. [cited 2020 May 26]. Available from:
80. World Health Organization. Annex 2. WHO good manufacturing practices for active pharmaceutical ingredients. 2010 [homepage on the Internet]. [cited 2020 May 26]. Available from:
81. International Conference on Harmonisation of Technical requirements for registration of pharmaceeuticals for human use. Articles of Association. 2019 [homepage on the Internet]. [cited 2020 May 26]. Available from:
82. Central Drugs Standard Control Organization. Good manufacturing practices and requirements of premises, plant and equipment for pharmaceutical products [homepage on the Internet]. [cited 2020 May 26]. Available from:
83. Tribe RW. The growing influence of PIC/S in Asia Pacific. Pharmaceutical Engineering. 2017.
84. Burke E. India: from generics to biosimilars. Pharmaceutical Engineering. 2019.
85. Fotheringham S. The rise of biopharmaceutical manufacturing in Asia. Pharmaceutical Engineering. 2018.
86. Montoya JC, Rebulanan CL, Parungao NAC, Ramirez B. A look at the ASEAN-NDI: building a regional health R&D innovation network. Infectious Diseases of Poverty. 2014;3(1). doi:10.1186/2049-9957-3-15
87. Muangchana C, Thanormwat Y, Kongsiang A. Workshops advocating ASEAN Vaccine Security and Self-Reliance (AVSSR): a regional initiative. Vaccine. 2019;37(14):2034-41.
88. Health Sciences Authority. Guidelines on good manufacturing practice standard and good distribution practice standard. 2018 [homepage on the Internet]. [cited 2020 May 26]. Available from:
89. National Pharmaceutical Regulatory Agency. FAQ : good manufacturing practice/good distribution practice. 2015 [homepage on the Internet]. [cited 2020 May 26]. Available from:
90. Food and Drug Administration of the Philippines. Notice on the adoption of the PIC/S guide to GMP. 2018 [homepage on the Internet]. [cited 2020 May 26]. Available from:
91. Department of Pharmaceutical Services. Ministry of Health Brunei Darussalam. Guide to application for a licence to manufacture or assemble medicinal products. 2013 [homepage on the Internet]. [cited 2020 May 26]. Available from:
92. Association of Southeast Asian Nations. ASEAN sectoral mutual recognition arrangement for good manufacturing practice (GMP) inspection of manufacturers of medicinal products. 2009 [homepage on the Internet]. [cited 2020 May 26]. Available from:
93. Indonesia Healthcare Outlook. Frost & Sullivan. 2015.
94. Malaysia Healthcare Outlook. Frost & Sullivan. 2014.
95. Vietnam Healthcare Outlook. Frost & Sullivan. 2015.
96. Association of Southeast Asian Nations. ASEAN agrees on common requirements of biological products. 2018 [homepage on the Internet]. [cited 2020 May 26]. Available from:
97. Association of Southeast Asian Nations. Frequently asked questions on the ASEAN mutual recognition arrangement (MRA) on GMP inspection of manufacturers of medicinal products [homepage on the Internet]. [cited 2020 May 26]. Available from:
98. U.S. Food and Drug Administration. What is the approval ­process for genericdrugs? 2017 [homepage on the Internet]. [cited 2020 May 26]. Available from:
99. O’Callaghan J, Barry SP, Bermingham M, Morris JM, Griffin BT. Regulation of biosimilar medicines and current perspectives on interchangeability and policy. Eur J Clin Pharmacol. 2019;75(1):1-11.
100. U.S. Food and Drug Administration. Scientific considerations in demonstrating biosimilarity to a reference product. 2015 [homepage on the Internet]. [cited 2020 May 26]. Available from:
101. Kirchhoff CF, Wang X-ZM, Conlon HD, Anderson S, Ryan AM, Bose A. Biosimilars: key regulatory considerations and similarity assessment tools. Biotechnol Bioeng. 2017;114(12):2696-705.
102. U.S. Food and Drug Administration. Biosimilar development, review, and approval. 2017 [homepage on the Internet]. [cited 2020 May 26]. Available from:
103. Tsiftsoglou AS, Ruiz S, Schneider CK. Development and regulation of biosimilars: current status and future challenges. BioDrugs. 2013;27(3):203-11.
104. U.S. Food and Drug Administration. Biosimilar and interchangeable products. 2017 [homepage on the Internet]. [cited 2020 May 26]. Available from:
105. Center for Biologics Evaluation and Research. List of licensed biological products. with (1) reference product exclusivity and (2) biosimilarity or interchangeability evaluations to date [homepage on the Internet]. [cited 2020 May 26]. Available from:
106. Center for Drug Evaluation and Research. List of licensed biological products with (1) reference product exclusivity and (2) biosimilarity or interchangeability evaluations to date [homepage on the Internet]. [cited 2020 May 26]. Available from:
107. Wiland P, Batko B, Brzosko M, Kucharz EJ, Samborski W, Świerkot J, et al. Biosimilar switching – current state of knowledge. Reumatologia. 2018;56(4):234-42.
108. Inotai A, Prins CPJ, Csanádi M, Vitezic D, Codreanu C, Kaló Z. Is there a reason for concern or is it just hype? – a systematic literature review of the clinical consequences of switching from originator biologics to biosimilars. Expert Opin Biol Ther. 2017;17(8):915-26.
109. World Health Organization. Annex 5. Guidance on good data and record management practices. 2016 [homepage on the Internet]. [cited 2020 May 26]. Available from:
110. Medicines and Healthcare products Regulatory Agency. ‘GXP’ data integrity guidance and definitions. 2018 [homepage on the Internet]. [cited 2020 May 26]. Available from:
111. U.S. Food and Drug Administration. Data integrity and compliance with drug cGMP questions and answers. Guidance for industry. 2018 [homepage on the Internet]. [cited 2020 May 26]. Available from:
112. Scanlin A. How GMPs & data integrity align for safer products & swifter approvals. iSpeak [Internet]: Pharmaceutical Engineering. 2019.
113. Wechsler J. Data integrity key to GMP compliance. BioPharm Int. 2014;27(9).
114. Tabersky D, Woelfle M, Ruess JA, Brem S, Brombacher S. Recent regulatory trends in pharmaceutical manufacturing and their impact on the industry. Chimia (Aarau). 2018;72(3):146-50.
115. Center for Biologics Evaluation and Research. Warning letter: Instituto Bioclon, S.A. de C.V. – 04/16/2014. 2014 [homepage on the Internet]. [cited 2020 May 26]. Available from:
116. AveXis. AveXis, Inc., San Diego, CA., 483 firm response dated 08/23/2019.
117. Center for Biologics Evaluation and Research. Warning letter: Irvine Stem Cell Treatment Center – 12/30/2015. 2015 [homepage on the Internet]. [cited 2020 May 26]. Available from:
118. Center for Biologics Evaluation and Research. Warning ­letter: Amniotic Therapies LLC. – 08/17/2016. 2016 [homepage on the Internet]. [cited 2020 May 26]. Available from:
119. Center for Biologics Evaluation and Research. Warning letter: Genetech, Inc. – 561808 – 11/29/2018. 2018 [homepage on the Internet]. [cited 2020 May 26]. Available from:
120. Sniderman B, Cottleleer M, Mahto M. Industry 4.0 and manufacturing ecosystems. 2016. Deloitte.
121. Cottleleer M, Sniderman B. Forces of change: Industry 4.0. 2017. Deloitte.
122. Kim TK, Seo K-S, Kwon S-O, Little TA, Kim M, Kim C-W. Application of the Quality-by-Design (QbD) approach for erythropoietin alpha purification. Bulletin of the Korean Chemical Society. 2019;40(7):623-33.
123. Yu LX, Amidon G, Khan MA, Hoag SW, Polli J, Raju GK, et al. Understanding pharmaceutical quality by design. AAPS J. 2014;16(4):771-83.
124. U.S. Food and Drug Administration. Guidance for industry. PAT — a framework for innovative pharmaceutical development, manufacturing, and quality assurance. 2004 [homepage on the Internet]. [cited 2020 May 26]. Available from:
125. Rathore AS, Kapoor G. Application of process analytical technology for downstream purification of biotherapeutics. J Chem Technol Biotechnol. 2015;90(2):228-36.
126. Glassey J, Gernaey KV, Clemens C, Schulz TW, Oliveira R, Striedner G, et al. Process analytical technology (PAT) for biopharmaceuticals. Biotechnol J. 2011;6(4):369-77.
127. Vicente T, Fáber R, Alves PM, Carrondo MJT, Mota JPB. Impact of ligand density on the optimization of ion-exchange membrane chromatography for viral vector purification. Biotechnol Bioeng. 2011;108(6):1347-59.
128. Vicente T, Peixoto C, Alves PM, Manuel J, Carrondo MJT. Modeling electrostatic interactions of baculovirus vectors for ion-exchange process development. J Chromatogr A. 2010;1217(24):3754-64.
129. Ko P, Stein M. Design methodologies for continuous improvement. In: Rebelo F, Soares M. editors. Advances in ergonomics in design. Springer, Cham; 2019. p431-21.
130. Rupp O, MacDonald ML, Li S, Dhiman H, Polson S, Griep S, et al. A reference genome of the Chinese hamster based on a hybrid assembly strategy. Biotechnol Bioeng. 2018;115(8):2087-100.
131. European Medicines Agency. Guideline on similar biological medicinal products. 2014 [homepage on the Internet]. [cited 2020 May 26]. Available from:
132. Brennan Z. Are biosimilars ‘interchangeable’ in the EU? A new perspective. 2017 Mar 31. Regulatory Focus.
133. Biosimilars Nederland. Franken AAM. The Dutch Medicines Board opinion on biosimilars. 2015 [homepage on the Internet]. [cited 2020 May 26]. Available from:
134. Ludwig W-D, Dicheva S. Biosimilars in Germany: guidance of the Drug Commission of the German Medical Association. Generics and Biosimilars Initiative Journal (GaBI Journal). 2017;6(4):178-80. doi:10.5639/gabij.2017.0604.037.
135. Scottish Medicines Consortium. Biosimilar medicines. 2015 [homepage on the Internet]. [cited 2020 May 26]. Available from:
136. Wolf K. Why data integrity is impossible without a quality culture. Pharmaceutical Online. 2019 Feb 19.
137. Calnan NF, Davidson JG. Data integrity: beyond the lab. Pharmaceut Eng. 2019.
138. Schnedar C. 5 Steps to build a quality culture that supports data integrity. 2016 Sep 20. Pharmaceutical Online.
139. Ballman E. How leader actions and behaviors influence quality culture part 1. Pharmaceut Eng. 2016.
140. Ballman E. How leader actions and behaviors influence quality culture part 2. Pharmaceut Eng. 2016.
141. Calnan N. Leading indicators of quality: Pinpointing behaviors and measuring results. Pharmaceut Eng. 2016;36(6):64-7.
142. Walter G, Morse N, South N. The ABCs of behavioral change in biopharma manufacturing. Boston Consulting Group, 2013.
143. Giorgio AMD. Building a culture of continuous improvement & quality assurance. Pharmaceut Eng. 2016
144. Meyers C, Uydess I. Developing and sustaining a quality culture. Pharmaceutical Technology. 2011;35(12).
145. Srinivasan A, Kurey B. Creating a culture of quality. Harvard Business Review. 2014.

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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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


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.


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.

Table 2

He noted that continuous mammalian cell lines are the substrate of choice for many rDNA products as they can be transfected and engineered to grow rapidly and produce glycosylated products. He outlined the three major concerns associated with using these cells to produce biological drugs:

1) Genetic stability of cell lines
2) Residual host cell DNA, which might cause cancer
3) Viruses in animal cells, including re-troviruses

Dr Griffiths introduced the concept of a Master Cell Bank (MCB, cells derived from a cell seed and frozen) and Working Cell Bank (WCB, derived from the MCB and used to provide cells for manufacturing) which provide a standardized source of production cells and are now used for all cell lines. To prevent viral contamination, WHO encourages production based on cryopreserved cell banks exhaustively screened for virus contamination; control of raw material used in production; closed systems of cell culture; testing each cell culture for contamination, and validation of viral removal/inactivation by downstream processing.

Dr Griffiths noted that cell banks require highly specialized expertise and infrastructure, and this is often contracted out to specialized testing organizations. He described good cell culture practice, including ensuring the donor is free of transmissible diseases, and confirming the absence of viral and microbial contamination. The MCB, WCB and all cell culture processes are key to consistently producing safe and effective biologicals.

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.

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.

Figure 2

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.

Dr Pan outlined the differences between mammalian and microbial cell expression systems, see Figure 3.

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.

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.

Figure 5

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.

Table 5

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.

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.

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.

Figure 6

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.

Figure 7

Action points:

Group 3: Viral safety
Group 3 discussed the viral contamination of biological and biosimilar drugs; the following action points were raised.

Action points:

Group 4: Processing into finished dosage forms
Group 4 focused on filling and processing biological drugs into finished dosage forms.

Action points:


The workshop was successful in bringing members of ASEAN together with experts from other nations, to discuss GMP for Biologicals and Biosimilars and improve understanding of the GMP inspection framework for biological (and biosimilar) drugs among ASEAN Member States. It highlighted many important issues surrounding GMP for biological and biosimilar drugs manufactured in ASEAN countries, including the challenges of adhering to general GMP standards, given the huge diversity of biological products; protecting the final product from host cell impurities including DNA and protein; as well as adventitious viral contamination and the importance of having robust quality control programmes in place at all levels of production. Overall, the meeting helped to clarify WHO’s requirements for GMP production of biological drugs and how manufacturers can ensure these standards are met to ensure their product is safe, effective and of high quality. It was an important step forward as the first meeting of its kind for ASEAN Member States.

Speaker Faculty and Moderators

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

Kakkanang Porkaew, Thailand
Wiwin Wisma Prihatin, Indonesia
Seok Hui Teo, Singapore
Prapassorn Thanaphollert, BS, Thailand

Editor’s comment
Speakers and moderators had provided the discussion/conclusion of the group discussion, read the report and revised the content of the summary discussion.


The Generics and Biosimilars Initiative (GaBI) wishes to thank Ms Sylvia Laksmi Sardy and Ms B Lusia Herwahyu S from the ASEAN Secretariat for their support to the organization of this workshop; the moderators in clarifying the information of the parallel discussion when finalizing the meeting report; as well as Dr Elwyn Griffiths and Dr Dianliang Lei, Chair and Co-chair of the 2018 workshop, as well as Adjunct Associate Professor Chong Hock Sia for their strong support through the offering of advice and information during the preparation of the workshop.

The authors would like to acknowledge the help of all the workshop speaker faculty and participants, each of whom contributed to the success of the workshop and the content of this report, as well as the support of the moderators and co-moderators in facilitating meaningful discussion during the parallel case study working sessions, presenting the discussion findings at the meeting, and contributing in the finalization of this meeting report.

Lastly, the authors wish to thank Ms Alice Rolandini Jensen, GaBI Journal Editor, in preparing and finalizing this meeting report manuscript and providing English editing support on the group summaries.

Competing interests: The workshop was sponsored by an unrestricted educational grant to GaBI from Amgen Inc.

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


Elwyn Griffiths, DSc, PhD
Adjunct Associate Professor Chong Hock Sia, BPharm, MSc

1. Generics and Biosimilars Initiative. 1st ASEAN Overview Workshop on GMP for Biologicals/Biosimilars 2018. 5 August 2018; Da Nang, Vietnam. Available from:
2. World Health Organization. WHO good manufacturing practices for biological Products, WHO Technical Report Series, No. 999, Annex 2 (2016) [homepage on the Internet]. [cited 2019 Jul 24]. Available from:
3. ASEAN sectoral mutual recognition arrangement for good manufacturing practice (GMP) inspection of manufacturers of medicinal products [homepage on the Internet]. [cited 2019 Jul 24]. Available from:

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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