Warning letters to foreign manufacturing sites continue to make up the bulk of citations given by the Center for Drug Evaluation and Research (CDER). With data integrity ranked as one of the top three most observable trends for foreign establishments,¹ the U.S. Food and Drug Administration (FDA) has responded by publishing draft guidance on this topic to help life sciences companies ensure data is consistent and accurate.² The document defines data integrity as the “completeness, consistency, and accuracy of data,” and includes eighteen common questions with detailed answers and references to other applicable FDA guidelines. It also reaffirms the movement to digitization of content and data with acceptance of electronic copies and signatures in place of paper records and handwritten signatures.

Data integrity is crucial to ensuring the safety, efficacy, and quality of drugs. And, as outsourcing continues to increase with more and more critical manufacturing functions performed outside the company—and outside of direct oversight—ensuring data integrity is increasingly difficult. 

High demand for specialty outsourcing
The demand for manufacturing outsourcing has skyrocketed in recent years, from $800 million in 1998 to $2.5 billion in 2014, and it’s predicted to reach $4.1 billion by 2019.³ According to Pharmaceutical Manufacturing, the U.S. is the largest market for contract manufacturing worldwide.⁴ Remarkably, 80% of the active pharmaceutical ingredients consumed in the U.S. originate in India and China, and about 40% of finished products come from outside the U.S. Europe lags slightly behind in this category, but rapid growth is expected from developing regions such as Asia Pacific, with the Japanese market expected to realize a compounded annual growth rate of 13%.^5,6  

“It used to be that if a company did any outsourcing, it was primarily limited to sourcing raw materials,” said Daniel Matlis, founder and president, Axendia, a life sciences industry analyst firm. “But as a compounding number of companies began to go outside their four walls, they discovered opportunities to reduce cost and shed non-core competencies. Now, many aspects of manufacturing are handled by contract organizations.”

Even with contract responsibilities extending to development, manufacturing, and testing activities, life sciences companies remain ultimately responsible for the final product. According to the International Council for Harmonization (ICH), “The pharmaceutical company is ultimately responsible to ensure processes are in place to assure the control of outsourced activities and quality of purchased materials.”⁷ Further, the FDA holds “the owner’s quality unit ultimately responsible for approving and rejecting drug product manufactured by the contract manufacturer.”⁸

Life sciences companies need to demonstrate control over their data—whether internally or externally generated. According to FDA officials, “data that are not valid and trustworthy is a sign that an entire operation or facility is out of control and cannot assure the quality of its medicines.”⁹ Without accurate data, companies are less equipped to ensure the quality, safety, and effectiveness of their products.

FDA scrutiny intensifies
The FDA is increasing its local presence around the world. “We now have offices and inspectors in New Delhi and Mumbai, India, as well as China, Latin America, South Africa, and a growing cadre of international inspectors elsewhere,” said Dr. Margaret Hamburg, former commissioner of the FDA, during a 2014 interview. “We’re trying to achieve the same levels of inspection, enforcement, and compliance that we would expect of any company manufacturing drugs for consumption by the American public.”¹⁰
As data integrity issues continue to surface during plant inspections, FDA leaders are ramping up the rhetoric to compel manufacturers to clean up data operations.¹¹ In fact, standalone, raw data-generating systems, business processes, as well as interfaced business and production control systems that were formerly only given cursory reviews, have come under increasing scrutiny.¹² With the absence of credible data, the concern is that these companies’ products cannot be trusted. The FDA has subjected many of these companies to import alerts, refusing entry of their products into the U.S.¹³

Growing gap between systems and processes
Quality processes now span internal and external parties, however many supporting systems were designed to operate only within a company’s four walls. In addition, many of these applications do not work well together—often existing in siloes. Significant, manual overhead is necessary to bridge the gap between all parties, and between applications, in order to stitch together a continuous process—providing many opportunities for data issues.

Having the quality team review the data from manufacturing sites is a great first step. However, communication still often occurs via email, or some other uncontrolled method, in a non-validated environment—that could lead to an observation or warning letter. In fact, according to the FDA’s draft guidance entitled Data Integrity and Compliance with cGMP, “workflow, such as creation of an electronic master production and control record, is an intended use of a computer system to be checked through validation. If you validate the computer system, but you do not validate it for its intended use, you cannot know if your workflow runs correctly.” One common area coming under greater scrutiny with outsourcing is reviewing of the batch production and control records to support the batch release process. Companies currently use a combination of email and file sharing sites, making it almost impossible to provide a clear, consolidated audit trail, and to demonstrate chain-of-custody for the controlled data or documents.

“I feel strongly that outsourcing really starts with having your own skilled quality organization as a base,” said Kristina Zsebo of Biovest Consulting. “When outsourcing, you need to oversee each service provider’s quality systems, because ultimately you’re responsible for releasing the final drug product.”¹⁴

Cloud enables seamless and controlled processes with partners
Using cloud-based technology to orchestrate drug development and manufacturing enables parties to be incorporated into the process from end-to-end. Every move is controlled and can be overseen. This reduces the risk of data being manipulated or lost amidst fragmented processes and disparate systems.

“Providing our partners with direct access to our validated, cloud-based quality system ensures we maintain a clear chain-of-custody on manufacturing documents such as batch records and audit reports,” explained Craig Gassman, associate director of regulatory operations, Karyopharm Therapeutics.

The cloud gives life sciences companies the ability to extend data integrity across all parts of the value chain, while at the same time enabling partners to access information they need to provide valuable services. Raw materials suppliers, CROs, CMOs, brokers, and distributors can interact simultaneously under very controlled conditions to ensure that accurate, up-to-date information is always available to those that need it – whenever, wherever, however.¹⁵

Modern, cloud-based solutions are easily configured to align with business processes. Companies can standardize the flow of information, or support multiple concurrent outsourcing models in a controlled and validated manner, while always ensuring process transparency. 

Moving upstream, reducing risk
Reviewing information from manufacturing sites helps detect data integrity issues, however problems are typically more difficult to detect—and the impact greater—near the end of a process. Moving upstream and providing the quality team with direct access to the quality management system allows issues to be detected earlier and accelerates downstream decision-making. The quality team can review in process deviations and results of the investigation, so problems can be resolved proactively and approvals can be streamlined for improved efficiency. Providing all stakeholders with access to up-to-date, accurate data and content in a single, authoritative system instills greater confidence that operations are being executed compliantly.

With regulatory bodies requiring greater transparency into manufacturing data, having a quality solution that directly incorporates all parties into true end-to-end processes will be essential for assuring data quality and integrity.

There’s only one direction to look: Up
There’s no question that the industry will continue to increase its outsourcing of critical manufacturing functions. For example, leading CMOs such as Catalent and Lonza have made considerable investments in high-potency API and antibody drug conjugate production facilities in anticipation of long-term growth in demand over the next 10 years, according to Jonathan Weymer, senior pharmaceutical and healthcare industry analyst with Visiongain. 

This shift has greatly disrupted how quality is maintained. Manual processes backed by on-premise technology do not make it easy to extend visibility or process control outside of the organization, resulting in a number of large-scale quality issues and attracting regulatory scrutiny globally. In addition, the highly publicized quality concerns have tainted consumer perception, and carry the high cost of remediation. Data integrity is just a small part of the problem that cannot be solved with legacy technology.
These systems are locked inside companies that are now operating externally, forcing risky, manual processes and information exchange outside of a controlled environment.

The industry must stop looking within, and start looking for solutions elsewhere. The best place to look is up, to the cloud. Establish a cloud technology foundation to transform manufacturing and quality management … and do more than just make incremental steps forward. Cloud solutions that manage quality content and processes bring together all stakeholders on one platform, ensuring an auditable trail of all activities with partners. Plus, cloud applications offer operational efficiency while improving data integrity and compliance. For now, the cloud is the only way to externalize yet maintain internal control over quality. 

References

1. “Inspectional Findings and Trends: What Do They Really Mean?” by Rebeca Rodriguez, U.S. Food & Drug Administration, March 21, 2014. For more:  http://xavierhealth.org/wp-content/uploads/6.-Rodriguez_FDA-and-MHRA-Investigator-Insights.pdf
2. “Data Integrity and Compliance with cGMP. Draft Guidance for Industry,” U.S. Food & Drug Administration, April 2016. For more:  http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm495891.pdf
3. “Biopharmaceutical Outsourcing Continues to Grow,” by Agnes Shanley, Pharmaceutical Technology, April 2016. For more: http://www.pharmtech.com/dcat-2016-biopharmaceutical-outsourcing-continues-grow
4. “News: Global Pharmaceutical Contract Manufacturing Market to Reach US $40.7 Billion by 2015,” Pharmaceutical Manufacturing, 2011. For more: http://www.pharmamanufacturing.com/industrynews/2011/004/
5. “The Safety of Prescription Drugs Made Outside the U.S.,” The Diane Rehme Show (WAMU 88.5 radio), February 20, 2014. For more: https://thedianerehmshow.org/shows/2014-02-20/safety-prescription-drugs-made-outside-us
6. “Best Practices in Life Sciences for Avoiding Data Integrity & Quality Pitfalls,” Pharmaceutical Online, 2016. For more: http://www.pharmaceuticalonline.com/doc/best-practices-in-life-sciences-for-avoiding-data-integrity-quality-pitfalls-0001
7. “Quality Guidelines,” International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use. For more: http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q10/Step4/Q10_Guideline
8. “Guidance for Industry – Contract Manufacturing Arrangements for Drugs: Quality Agreements,” U.S. Food & Drug Administration, May 2013. For more: http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm353925
9. “Data Integrity Key to GMP Compliance,” PharmTech.com, 2014. For more: http://www.pharmtech.com/data-integrity-key-gmp-compliance-0
10. “FDA Warning Letters Rise 78% Over Six Years with Increase Expected in 2015,” The Pharma Letter, 2014. For more: http://www.thepharmaletter.com/article/fda-warning-letters-rise-78-over-six-years-with-increase-expected-in-2015
11. “New Realities of Globalization – Implications for Health, Medicine, and the Role of Regulator,” U.S. Food & Drug Administration, 2014. For more: http://www.fda.gov/NewsEvents/Speeches/ucm388388.htm
12. “Risk-based Approach to Data Integrity,” Pharmtech.com, 2015. For more: http://www.pharmtech.com/print/294776?page=full
13. “Biopharma Outsourcing Past Is Prologue,” Pharmaceutical Online, 2016. For more: http://www.pharmaceuticalonline.com/doc/biopharma-outsourcing-past…6e8238&utm_content=Biopharma%2bOutsourcing%2bPast%2bls%2bPrologue
14. “Managing Quality in a Global and Outsourced Ecosystem,” (webinar), FDANews.com with speakers Daniel Matlis and Ethan Smith, March 2016. For more: http://www.fdanews.com/qualityecosystem
15. “Best Practices in Life Sciences for Avoiding Data Integrity & Quality Pitfalls,” Pharmaceutical Online, 2016. For more: http://www.pharmaceuticalonline.com/doc/best-practices-in-life-sciences-for-avoiding-data-integrity-quality-pitfalls-0001

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Mike Jovanis is Veeva Systems’ Vice President of Vault QualityDocs, and is an accomplished executive with hands-on experience in a broad range of disciplines. Over his decades-long career in the life sciences industry, he has proven instrumental in driving rapid growth, increased market share, and industry-leading EBITDA in roles at Sparta Systems and, more recently, Medidata Solutions.