How Ever-Changing Regulatory Demands Will Impact Small and Emerging Pharmaceutical and Medical Device Companies 

As regulations and guidelines become broader, more electronic and increasingly data driven, manufacturers must adapt with ever changing demands. Regulators are shifting more responsibility onto manufacturers to instil quality throughout their operations and throughout their product lifecycles. In the past, small and emerging life sciences companies might have functioned sufficiently with manual processes and disconnected systems, but may now be unable to satisfy the requirements of regulators whose fundamental shift is a growing focus on electronic processes, data driven decisions and increased transparency to information. 

Some examples where manufacturers will need to address their systems and processes based on recent changes in the industry, are discussed in this article: 

The IT Perspective 

From an IT perspective, the regulatory bodies were very active in 2016/2017 releasing new and updated regulations and guidance –  all of which further describe what is expected of companies to demonstrate that their systems are fit for purpose, remain fit for purpose and protect the safety of patients and the integrity of data.  

The increase in regulatory requirements introduced by legislation has put industry and regulators under strain and inter-operability of systems has become the key for efficient use of data and resources. The European Medicines Regulatory Network established a roadmap for electronic Submissions (eSubmission) aimed at establishing secure, consistent and efficient electronic submission processes for medicinal products for human and veterinary use across the European Medicines Regulatory Network. As of January 2018 eCTD (electronic common technical dossier) only will be accepted for all submissions in EU procedures (Note: baseline submissions are not required). The requirement for eCTD only applications for new MAA’s in DCP and MRP has already been implemented. All manufacturers/marketing authorisation holders have either transitioned to a digital/electronic system or are at the final stages of completing this process. For small enterprises who will be outsourcing their electronic submissions, there may be large resource and cost implications.   

The improved version of the EudraVigilance system went live on 22 November 2017. Users of the EudraVigilance system needed to ensure that their processes and IT infrastructure are compatible with the new system and with the internationally agreed format (ISO/ICH E2B (R3)) before the above-mentioned launch date. 

The FDA’s electronic Medical Device final rule (eMDR) requires manufacturers and importers to submit Medical Device Reports to the FDA in an electronic format that the FDA can process. Like all regulations, the FDA’s eMDR final rule continues to change and evolve. In the first half of 2017, the FDA made a variety of enhancements to the eMDR system stressing that “submitters should begin planning updates to comply with these eMDR changes as soon as possible”. 

As we continue to innovate with technology in the industry we will continue to see an increased focus in our regulations. ICH E6 (R2) became effective in June 2017 and within it we saw the introduction of standards regarding electronic records and computer system validation. Within the industry we’ve long been adhering to the best practices outlined within GAMP 5 (Good Automated Manufacturing Practices), but there has been a move to bring regulations more in-line with industry standards. 

The Drug Supply Chain 

Failures in the supply chain and lack of vendor oversight can lead to patient safety risks that come from counterfeit, stolen, contaminated or otherwise harmful products in the pharmaceutical supply chain. 

On June 30, 2017, the FDA issued a draft guidance for industry entitled Product Identifier Requirements Under the Drug Supply Chain Security Act – Compliance Policy, which updated the latest round of serialisation requirements. The FDA encourages manufacturers and re-packagers to serialise packages using a product identifier, serial number, lot number and expiration date by November 27th 2017, with enforcement commencing on November 27th 2018. 

In addition to the FDA, a number of other regulators around the world (e.g. EC Falsified Medicines Directive) have implemented, or are in the process of implementing, pharmaceutical serialisation regulations. It is estimated that by 2020, track and trace regulations will cover more than 80% of global drug supply. 

The pharmaceutical supply chain heavily relies upon vendors, regardless of the size or span of the organisation. The bigger the supply chain, the bigger the risk. Regulators expect companies to evaluate all suppliers in line with regulatory standards. Vendor oversight applies to both manufacturing and wholesaling and distribution. 

 

The FDA’s Quality Metrics Program 

In January 2015, the FDA established the Office of Pharmaceutical Quality (OPQ) within its Centre for Drug Evaluation and Research (CDER), which encourages pharmaceutical firms to embrace continuous improvement and foster a culture of quality by collecting and reporting manufacturing quality data. Under the OPQ, the FDA plans to leverage its authority to collect product and site specific quality metrics records in place of or in advance of an inspection, and for companies with plenty of quality metrics data that could mean reduced site inspections. 

With regards to the quality metrics themselves, the FDA requests the following primary metrics: 

Lot Acceptance Rate (LAR) as an indicator of manufacturing performance 

Product Quality Complaint Rate (PQCR) as an indicator of patient or customer feedback 

Invalidated Out-of-Specification (OOS) Rate (IOOSR) as an indicator of the operation of a laboratory 

The FDA intends to launch an electronic portal in January 2018 through which manufacturers can submit voluntary data. In the future the agency intends to develop a mandatory quality metrics reporting program. 

 

Tightening of Medical Device Regulations 

Although the EU Medical Device Regulation date of application is not until 2020, manufacturers are now focussing on their transition plans to the new regulation. Many medical device companies active in Europe have begun mapping out how the new Regulations will impact their business. Examples of new requirements of the regulation include; unannounced audits performed by Notified Bodies (NBs) at least once every five years, NBs will assess plans, procedures and results documented in CERs and other evidence, the PMCF (post-market clinical follow up) will drive the clinical performance evaluation and must be based on real-life data and finally, device equivalency claims will be limited to those manufacturers who are able to demonstrate equivalence by having access to equivalent device data, and the MDR even requires a contract between the manufacturer and the equivalent device manufacturer to access the technical documentation of that device. 

Clinical evaluation is a permanent process that must be covered by plans and reports and the PMCF results must be taken into account for clinical evaluation and risk management. 

The International Organisation for Standardisation’s ISO 13485, Medical Devices – Quality Management Systems – Requirements for Regulatory Purposes describes the requirements for a QMS specific to the medical device industry. In 2016 ISO issued ISO 13485:2016 which it “designed to respond to latest QMS practices, including changes in technology and regulatory requirements and expectations.” This latest version of the standard places “greater emphasis on risk management and risk-based decision making, as well as changes related to the increased regulatory requirements for organisations in the supply chain”. 

 

The Quality Element 

As in the past, manufacturers are expected to comply with the various applicable regulations in order to maintain their licences and market their products in their respective regions. In addition to this, manufacturers are expected to prove their ongoing commitment to continuous process improvement and quality outcomes. In order to improve quality and not simply compliance within the life science industry, manufacturers will need to become more data driven in their operations and in their documentation and collaborate closely with suppliers to ensure quality throughout the product lifecycle. Achieving enterprise-wide quality requires all parties to the process to openly and effectively communicate at every step of the process. Tracking the full cycle of corrective and preventative actions – from the identification of root cause, to actions to address it, and through to verification that actions were effective, should be performed. The provision of quality metrics (including proof that quality measures have been followed and tracked), may also be requested of third parties and suppliers who are subject to a service agreement with a larger manufacturer.  

 Conclusion

As global regulations constantly change, those companies that previously functioned sufficiently with manual processes and disconnected systems, will be unable to satisfy the requirements of regulators and 3rd party stakeholders, who increasingly want quick access to in-depth information on their quality operations. Those that implement an enterprise-wide (including suppliers and distributors) quality management system can meet current regulatory requirements, prepare for future regulatory challenges and scale their quality operations to fit their growing needs.