Compliance Challenges for Global Pharmaceutical Manufacturers
Amid the great opportunities that flow from extending their networks of facilities around the globe, pharmaceutical manufacturers are facing compliance challenges in emerging markets—especially culturally distinct ideas about safety, risk, and quality. Take, for example, the use of bamboo scaffolding in construction, which is common in parts of Asia, most notably Hong Kong. While safety issues, sourcing material difficulties, and labor shortages have led to a decline in the practice, it continues to be used to erect buildings as tall as skyscrapers.
“Workers will climb up twenty stories on bamboo scaffolding with no netting on the outside of it,” said Maurice Parlane, director at New Wayz Consulting in Auckland, New Zealand, which supports pharmaceutical companies’ compliance, quality, and operational needs. “Their norm of safety and acceptance of risk are different from Western notions.”
These differences can affect pharmaceutical manufacturing and are some of the significant compliance challenges facing global companies today, along with the ongoing need to address drug shortages and secure storage and sharing of data.
Joseph Famulare, Vice President of Global Compliance and External Collaboration at Genentech and immediate Past Chair of ISPE’s Board of Directors, sees compliance as an evolving process. “It’s living, takes work, and needs maintenance,” he said.
GMP and GDP, he noted, both require attention to data integrity and regulatory compliance with the manufacturing license. Achieving these things and modernizing processes and facilities while managing post-approval changes needs carefully planned strategies to ensure compliance. Improving processes for efficiency also influences supply, improves business sustainability, and helps prevent drug shortages. “Health care is heading toward new paradigms such as personalized medicine, and that is a positive development for the patient,” Famulare continued. “The industry is adapting new technologies for some new treatments on the horizon where the patient is now part of the supply chain.”
ISPE members are taking a page from the book written years ago by sectors like auto manufacturing and telecommunications, which sought not only to rely on guidance from regulators but to improve quality based on connections forged directly with customers.
“The food industry, automotive industry, and personal electronics are well connected to their customers,” said Parlane. “There are companies in these sectors with high quality standards and an appetite for improving their quality based on the desires of the market, rather than because a regulator told them to. Pharma is catching up in this regard, changing how it sees things.”
What Price Quality?
Pharmaceutical manufacturing requires a global approach to compliance as companies look for competitive advantages in regions such as Asia, not only for lower labor costs, but because China and India are emerging markets with huge populations of potential customers. A global company instituting a quality system must often adjust its approach, depending on the location of the facility. Regulatory authorities seeking to harmonize standards also face challenges with regional disparities in the perception of risk.
“When you export Western GMP to a place like Asia, it depends on people and their culture,” said Parlane, who is also a Director on the ISPE Australasia Affiliate Board and ISPE’s Member of the Year in 2016. “You can’t assume that everyone shares the same view of what GMP is.”
Manufacturers in emerging markets sometimes make versions of a drug for two distinct populations: an external market beyond their borders for which they must comply with international regulations, and an internal market that may be willing to tolerate reduced quality in exchange for lower-priced products. This dichotomy creates a dilemma for drug makers, regulators, and governments.
“Governments in these countries need to look after their own populations,” said Parlane. “Keeping in mind the health care pillars of affordability and accessibility, there is also a move to lift the level of quality.”
He believes that tiers of quality—and pricing—might evolve, perhaps resulting in a double standard in terms of compliance. “You can make a ten-cent tablet, for which the quality standards and cost of manufacture is lower, or you can make a dollar tablet for export. Of course, within these markets there are also consumers who are demanding higher quality, which drives production toward the dollar tablet.”
Complicating matters is the difference between mature markets—Singapore, Japan, parts of China—and places like Bangladesh or North Africa. Parlane cites Vietnam as an example where drug makers might want to raise quality, but if this makes the drug unaffordable it defeats the purpose. “The government might say they’re happy with a 60-cent drug,” he said. “From a Western perspective we might question the quality of a cheaper alternative, but they might be willing to make this risk-benefit analysis.”
Also contributing to this discrepancy is the nature of the industry in China, where many drugs are legacy products or generics, the manufacture of which, according to Parlane, lags behind the science and innovative developments in the rest of the industry.
And, while Singapore is a biologics production hub, Parlane thinks much of Asia will take a while to catch up. He believes that efforts in emerging Asian economies should be directed at things like infant vaccine programs, as they are in places like Bangladesh, India, and Vietnam, where biologics and vaccines are produced for the local market. “In Africa it will be even more challenging to get that industry to where it can supply large numbers of people at the right price,” Parlane said. “I have confidence that this will get figured out. There are very smart people and a thirst for knowledge throughout these regions.”
Parlane suggests that while ISPE is a technical organization, steeped in operations and an understanding of what makes a quality system good, there are sensitivities about addressing cultural issues. “We have this paradigm that a factory’s a factory, and GMP is GMP. But the people running the factory have a different tolerance level for things and they make tolerance and risk decisions in a different context. It can’t be only about knowledge transfer. You can’t change culture in a hurry.
“We need to respect and understand and not force a system onto others. If you want a particular way of working to fit, you have to adjust it to the environment. In a cynical way, we think ‘Here’s the QC system,’ and we assume it will be implemented the way it is in Europe. We’re forgetting that one of the big enablers is the people, and the people are different.”
One way that regulators and manufacturers are bridging the gap between regional differences in approaches to quality and compliance is to harmonize regulations and inspections globally. “Harmonization and convergence efforts are extremely important to global manufacturers in terms of having standards that meet all the various requirements,” said Famulare.
“When an area takes on learning the fundamentals of quality, GMP, quality mindset, and disposition, it will take a lot of time,” he continued. “There have been difficulties in terms of data integrity and accurate reporting, leading to a trend in FDA [US Food and Drug Administration] warning letters. Programs have to be put in place to meet these global standards. The International Conference on Harmonisation (ICH), for example, is issuing guidelines for technical standards and finding ways for health authorities from additional countries to become observers or full participants of the organization. Industry also has to be an important part of that discussion, because they have the technology and responsibility and manufacturers to drive both the discussion and the culture.”
Harmonizing Inspection Procedures
The Pharmaceutical Inspection Co-operation Scheme (PIC/S) is a nonbinding cooperative arrangement of regulatory authorities focused on GMP of medicines.
“PIC/S aims to harmonize inspection procedures worldwide by developing common standards and by providing training opportunities to inspectors,” said Paul Gustafson, Chair for the PIC/S subcommittee on harmonization of GM(D)P. “By facilitating co-operation and networking between competent authorities and regional and international organizations, it increases mutual confidence.”
PIC/S members share a comparable GMP inspection system; members include the US FDA, the UK Medicines and Healthcare Products Regulatory Agency, and 47 other regulators. Some countries have more than one participating authority in PIC/S.
“PIC/S has always taken great pride in featuring itself as a purely technical organization in the field of regulatory GMP,” explained Gustafson. “A firm belief of PIC/S is to not become politically involved, such as might occur if membership was country based.”
Gustafson points out a number of ways that a PIC/S member raises the GMP standards within its country and helps manufacturers build an internal quality culture. “Internationally harmonized guidance such as the PIC/S GMP Guide [equivalent to the EU GMP Guide] provide a solid foundation for compliance requirements.”
The participating authority also contributes to the enhancement of global and regional quality culture through participation in PIC/S meetings and training, both of which offer forums for exchanging ideas and experience with inspectors around the globe. “This helps build a culture of quality in the inspection community with common understandings,” Gustafson continued. “Regulatory authorities can then be in better positions to influence the building of a quality culture in the companies through internationally harmonized regulatory oversight.”
“Even though PIC/S isn’t a legally binding organization, it has been influential in organizing to harmonize inspection approaches and reaching into a variety of large and small countries,” said Famulare. He believes that PIC/S can promote government-to-government reliance or even mutual recognition. “The sharing of inspection reports under mutual reliance might eliminate duplicate inspections at the same plant or serve, when fully implemented, to accept inspections in each other’s territories. Inspectorates would then be free to redirect resources to other areas.”
As Gustafson sees it, membership diversity is one of PIC/S strengths. “It allows for positive influences to be considered from all of its members,” he said. “Each member has opportunities to make distinct impacts in bringing about continuous improvement in how PIC/S develops and promotes harmonized GMP standards and guidance documents, trains GMP inspectors, assesses GMP inspectorates, and facilitates co-operation and networking for regulators.
“The framework and governance under which PIC/S operates allows each participating authority the opportunity to contribute and collaborate on distinct elements that reflects upon values important to their organization and fit with their pharmaceutical industry,” he added.
The challenges faced by PIC/S, including capacity building and harmonization of GMP inspections among different regulatory authorities, are similar to those faced by industry in the implementation of global pharmaceutical quality systems.
“PIC/S and its members overcome many of these challenges through an effective governance structure that is based on consensus and mutual trust,” Gustafson said. “Admission of new members that have been qualified, and older members, which have been reassessed for compliance, reduces harmonization challenges across regions and cultures.
“As the pharmaceutical industry becomes increasingly globalized, no single authority can manage alone the risks related to pharmaceutical products and active pharmaceutical ingredients,” he continued. “A harmonized approach between authorities on aspects such as regulations and training is critical to face globalization.”
Data tampering, loss, or theft can lead to compliance problems.
With his expertise in Asia, Parlane has seen a change in the relationship between regulators and industry. “There is more open dialogue at conferences and meetings, and regulators are becoming more engaged in event planning and the documents that ISPE prepares,” he said. “There is still some official distance maintained, particularly in the United States and European Union, but I think that forums such as ICH and IFPAC [International Foundation Process Analytical Chemistry], and increasingly ISPE and similar organizations, where regulators and industry alike are present, are encouraging more open discussion. I think this is healthy.”
Mitigation Of Drug Shortages
Drug shortages continue to be a problem, especially for sterile injectables, which account for the great majority of shortages.1 While the US FDA Safety and Innovation Act of 2012 seems to have resulted in a reduction of new shortages, there were still 120 in the first three quarters of 2016.2 At least one-quarter of shortages are due to manufacturing problems or regulatory issues, though the number is likely much higher.
“PIC/S holds the view that noncompliance with GMP continues to contribute to the drug shortages experienced globally,” Gustafson pointed out. He said that PIC/S promotes work in this area following workshops held last year among its members and partner organizations such as the European Medicines Agency (EMA) and the World Health Organization. “With a view of mitigating drug shortages, PIC/S intends to update content in its Explanatory Notes for Pharmaceutical Manufacturers on the Preparation of a Site Master File3 in collaboration with an EMA drafting group that includes PIC/S representation.”
ISPE and the PEW Charitable Trusts recently surveyed executives from 10 pharmaceutical companies to identify the causes of drug shortages and provide recommendations.4 Their report identified the burden of meeting regulatory challenges as one of the factors preventing companies from investing in expanded capacity or updated equipment, especially for legacy products that are 10–20 years old and continue to be an essential medicine. These challenges include the time and cost of submitting an Abbreviated New Drug Application.
“This could be due to older processes or equipment that hasn’t been kept up to date due to a lack of investment because many older products, for example, have not warranted that investment for a variety of reasons as noted in the Pew report,” said Famulare. “Also the expectation of having to update all the licenses in every country that the product is approved in is one complicator in the process. Streamlining those efforts will be important to industry and health authorities.”
Cybersecurity And Compliance
Ever-increasing amounts of data are being shared across networks of facilities, with external partners, between patients and companies, and across regions with different regulatory regimes and cultures. Fully connected factories can lead to a reduction of errors, which enhances compliance.
“Advances in network connectivity to leverage data sharing and analytics provide opportunities to significantly transform drug quality and regulatory compliance to the benefit of patients who depend on these pharmaceuticals,” said Gustafson. “This increased information flow from manufacturing and testing equipment that can be collected and processed is expected to facilitate improved consistency in production, optimize equipment maintenance schedules, and provide more control and oversight to reduce human error. There may be significant financial return on such investments for manufacturers, and it is believed patients will also benefit from improved drug quality and fewer shortages.”
The rapidly growing Internet of Things further expands this connectivity to include machines, robotics, and devices that are internal to a company as well as medical devices that patients use. Connectivity across a factory and between facilities around the world mean that data is accessible to anyone unless rigorously protected. Protecting intellectual property such as proprietary drug formulas, process information, R&D data, and patient confidentiality is paramount.
“The pharmaceutical industry is not on its own when it comes to protecting data,” said Parlane. “There’s more of a threat out there. When we share the info we’re collecting on patients and on clinical trials around the globe, there are more risks.”
Data breaches, which cost the health care industry upwards of $5.6 billion each year,5 can lead to regulatory penalties, litigation, and loss of customer confidence. To make things worse, pharmaceutical companies are the main targets of UK cybercrime,6 and experts believe that the proliferation of ransomware attacks on enterprise seen in 2016 is a trend that will continue.7
Equally important to preventing theft is maintaining data integrity. Data tampering, loss, or theft can lead to compliance problems.
“I have confidence that ISPE is keeping pace with the technology,” said Famulare. “You want to protect data not only from criminal intent or malfeasance, but from the obfuscation of a result, either intentionally or by mistake. It’s important to have a culture where, if a result is not within the meaning you want, you’re able to protect that data from being manipulated.”
“If you ignore the high-profile examples of companies that aren’t doing this well—and there are companies like this in the US and Europe as well China and India—everyone’s in the same boat in terms of data integrity and security,” said Parlane. “You have to be a lot more cautious about data than we have been. When people are involved, there will be mistakes. The amount of data we produce is one of the problems because, even if error rates are low, the amount of data means that errors do happen. For example, a batch document for a small molecule might have 1,000 data points.”
As in health care, prevention trumps the cure in terms of time, resources, and money. Security requires a multilayer approach. Indeed, adherence to regulatory compliance can enhance security of the production process.8
“Just as we need to password-protect our personal data, the same fundamentals are in play in the industry,” said Famulare. “Once a data point is created, it needs to be handled so it’s secure and not subject to alteration.”
Gustafson pointed out that data integrity is important regardless of the storage approach. “Manufacturers may wish to consider the recently published PIC/S draft guidance document ‘Good Practices for Data Management and Integrity in Regulated GMP/GDP Environments.’ 9 This document, although written for use by inspectorates, can help manufacturers establish the necessary frameworks to ensure the integrity of their data, regardless of where and how it is stored. This framework starts with the inclusion of data governance systems and good risk management approaches being built into their pharmaceutical quality system.”
When it comes to the ways that manufacturers are paying attention to quality and compliance, Parlane likes what he is seeing. “In the past ten years the focus in the industry has changed from looking inward on quality to an outward focus on the impact on patients,” he said. “Manufacturers know more about their patients now, which is a good thing, and when we encounter a manufacturing problem, it’s not just a manufacturing problem. It affects lives.”
- 1US Food and Drug Administration. “Drug Shortages.” http://www.fda.gov/Drugs/DrugSafety/DrugShortages/
- 2American Society of Health-System Pharmacists. “National Drug Shortages: New Shortagesby Year January 2001 to September 30, 2016.” http://www.ashp.org/DocLibrary/Policy/DrugShortages/OPA-National-Drug-Shortages.pdf
- 3Pharmaceutical Inspection Co-operation Scheme (PIC/S). “Explanatory Notes for Pharmaceutical Manufacturers on the Preparation of a Site Master File.” PE 008-4. https://picscheme.org/layout/document.php?id=129
- 4Pew Charitable Trusts, and International Society for Pharmaceutical Engineering. “Drug Shortages: An Exploration of the Relationship between US Market Forces and Sterile Injectable Pharmaceutical Products.” http://www.pewtrusts.org/~/media/assets/2017/01/drug_shortages.pdf
- 5Grealish, Gary. “The Five Key Cybersecurity Issues Facing the Healthcare Industry.” Pharmaceutical Compliance Monitor, 30 March 2016. http://www.pharmacompliancemonitor.com/the-five-key-cybersecurity-issues-facing-the-healthcare-industry/10666/
- 6UK Cabinet Office, and Detica Limited. “The Cost of Cyber Crime.” 2011. https://www.gov.uk/government/uploads/system/uploads/attachment_data/file/60943/the-cost-of-cybercrime-full-report.pdf
- 7Trend Micro. “2016 Midyear Security Roundup: The Reign of Ransomware.” 23 August 2016. http://www.trendmicro.com/vinfo/us/security/research-and-analysis/threat-reports/roundup
- 8Williams, M. “Regulatory Compliance and Cyber Threats: Industrial Security in the Pharmaceutical Sector.” Engineers Ireland. Engineers Journal, 1 November 2016. http://www.engineersjournal.ie/2016/11/01/regulatory-compliance-cyber-security-pharmaceutical/
- 9Pharmaceutical Inspection Co-operation Scheme (PIC/S). News. “Draft PIC/S Good Practices for Data Management and Integrity in Regulated GMP/GDP Environments.” August 2016.https://picscheme.org/en/news?itemid=33