WHITE PAPER

GMP Quality Compliance: The Good, the Bad, and the Ugly

Introduction

Good Manufacturing Practice is at the center of operations within the pharmaceutical industry. Non-compliance can carry a host of problems, including warning letters from regulatory bodies. This whitepaper discusses how establishing effective audits with fully articulated QA/QC programs will keep the bad and ugly out of GMP quality compliance.

What is GMP AND cGMP?

The public trusts that the prescription and over-the-counter therapeutic drugs that they rely on are safe, effective, and possess a well-understood risk profile. The set of regulations tasked with ensuring this pharmaceutical quality are called Good Manufacturing Practices (GMPs) or Current Good Manufacturing Practices (cGMPs). These terms are largely interchangeable, as the cGMP acronym was instituted by the FDA to impress upon drug manufacturers that beyond the mere need to rely on already existing processes, companies must strive to continually improve their standards and methods of ensuring drug safety, efficacy, and quality.

In the US, GMP standards are enforced by the FDA, which ensures that pharmaceutical companies have systems which support the proper design, monitoring, and control of manufacturing processes and facilities. In many other countries, GMP standards are established by the World Health Organization (WHO).

Likewise, the EU has similar regulations to the WHO and FDA. In the UK, the Medicines and Healthcare products Regulatory Agency (MHRA) is responsible for the regulation of medicines, ensuring that they are safe and effective before being delivered to the market. It is incumbent upon a given pharmaceutical company that the drug being manufacturing meets GMP standards and that, if there are any deviations, they are corrected immediately.

To enforce GMP standards in the US, the FDA employs auditors to inspect pharmaceutical manufacturing facilities and processes to identify non-compliance or errors in the manufacturing process. This protects consumers from purchasing a product that is either harmful or ineffective. If pharmaceutical companies do not adhere to GMP, the oversight can result in serious consequences, including drug recalls/seizures, fines, or even an order to cease production.

An audit typically includes a review of a company’s quality systems and associated documentation to demonstrate compliance, as well as an analysis of its data integrity policies and process. In addition, an audit may include a thorough investigation of laboratory instrumentation and manufacturing equipment to ensure that they are in a state of compliance. Inspectors may also ask for evidence that employees are trained in GMP. Outside of inspections, other entities, including the public, can report on suspected GMP compliance concerns.

Fortunately, the execution of GMP guidelines is left largely open to interpretation, and it is thus under the purview of individual pharmaceutical companies to incorporate the best controls and practices in order to ensure they are manufacturing a safe and effective drug. Needless to say, employing solutions, staff, and processes that support GMP compliance are critical in maintaining drug safety and efficacy.

The Good

The good news for the public and pharmaceutical companies alike is that Good Manufacturing Practices, if followed, are a strong safeguard of global human health.

These regulations require medicines to be of consistently high quality, ensure they are appropriate for their intended use, enforce the requirements of their respective marketing authorization, and, most importantly, provide consumers the assurance that they are safe and effective. GMP standards support safe practices and procedures in all stages of manufacturing, ranging from the quality of the raw materials to the shelf life of the finished product.

The Bad

Understanding and instituting cGMP controls and underlying processes is undoubtedly complex. In fact, the pharmaceutical industry operates in one of the world’s most regulated environments.

Auditors continue to ask for ever-increasing number of documentation that demonstrate the right methods are being exercised in order to maintain compliance. Cautionary tales within the industry highlight the importance of having effective control levers in place, including empowered Quality Assurance (QA) and Quality Control (QC) functions.

The importance of adhering to GMP can’t be stressed enough, as these regulations do not merely capture the attention of the FDA. In fact, in extreme cases, GMP violations can be elevated to the attention of the U.S. Department of Justice (DOJ). In such cases of egregious GMP violations, the DOJ will exert its influence to alleviate the issue.

Take the recent warnings issued to several pharmaceutical companies that manufacture medicines designed to treat high blood pressure and heart failure, including Valsartan, Losartan, and Irbesartan for example. The FDA cited several GMP deviations, such as a lack of adequately written procedures for the receipt, identification, and handling of raw materials, as well as the subsequent failure to adequately clean equipment and utensils.

In both this and other cases, steps can be taken before this degree of escalation becomes necessary. Sophisticated and empowered QA/QC can serve as the frontline in GMP compliance, helping in identifying potential non-compliance before the FDA becomes involved.

The Ugly

Millions of data points, combined with sophisticated equipment, human involvement, and omnipresent regulatory oversight, create a complicated and inherently costly environment within which to manufacture.

If a pharmaceutical company is not able to identify compliance across all of these categories, it may inadvertently jeopardize the safety or efficacy of its drug, and ultimately the company’s overall operation. Thus, a deep understanding of GMP is critical. Adding more weight is the Mutual Recognition Agreement (MRA).

Since 2014, the MRA allows the FDA and the EU to rely upon information from drug inspections conducted within each other’s territories, including waiving the need for batch testing of products upon their entry and mutually sharing information on inspections and quality defects. Compliance with GMP could quickly become a global concern if any part of your manufacturing or distribution cycle resides outside of headquarters.

If GMP standards are not followed, at least in the US, the FDA can issue Form 483 observations. After a thorough review process, if the aforementioned observations are corrected, the pharmaceutical company can resume normal manufacturing operations. If a pharmaceutical company does not respond to an FDA 483 in a manner that satisfies inspectors, however, an FDA Warning Letter will be issued.

This comes with its own list of significant and negative consequences including:

  • Safety risks: Delivering a potentially unsafe medicine that can cause unwanted side effects, injury, or even death
  • Damaged reputation: The public, shareholders, and other stakeholders will react negatively, affecting stock price and consumer confidence
  • Loss of marketing authorization: The drug can be pulled from the market, representing millions or billions in potentially lost sales
  • Competitive response: A competing pharmaceutical company can take advantage of the negative publicity in order to create a market opportunity for themselves
  • Future impact on new drug approvals: The FDA can put a hold on any new drug approvals

This process is similar in the EU where non-compliant observations are also released publicly.

Recommendations

Adhering to GMP is a company-wide effort. Embracing the critical controls and processes can help keep these regulations front and center in the manufacturing process.

Embrace the audit

If vetted and embraced, checklists can be a crucial tool in performing successful mock audits and responding to a real audit. A mock audit can identify emergent issues and allow for corrective action to be implemented. A detailed audit focuses on competencies and regulatory compliance across multiple areas including management, design, facility, equipment, materials/components, operations, and, last but not least, the finished product.

The same checklists can be leveraged during a Form 483 or Warning Letter remediation period to facilitate a corrective plan of action. These checklists, while sitting in the QA and QC arsenal, can be used throughout the manufacturing cycle by other stakeholders to maintain collective attention on safety and compliance.

Work with a knowledgeable partner

When reflecting on the complexity of manufacturing operations, companies can benefit from having a knowledgeable partner bring additional expertise to all significant processes, including those governed by QA and QC.

The added expertise can certainly be brought in after an observation, but incorporating industry-specific remedies at an earlier stage can help a pharmaceutical structure QA/QC programs, establish data integrity, support equipment calibration and testing, validate the integrity of raw materials, and offer staff training to cultivate an environment focused on compliance.

Addressing these challenges are beyond the capacity of individuals and single departments, requiring a partner that can work throughout the entire organization and create controls and programs focused primarily on compliance.

Conclusion

Good Manufacturing Practice compliance is at the core of operations within the pharmaceutical industry. Non-compliance can carry a significant host of consequences. Adhering to GMP regulations across all involved processes, including staff training, instrumentation validation, data integrity, and raw materials, requires a deep knowledge of the industry and regulatory guidelines.

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Without these acute insights, a pharmaceutical company lacks the diligence required to identify and remediate non-compliance before it is addressed by the FDA or another global regulatory body. Establishing effective audits with fully articulated QA/QC programs and supported by a knowledgeable partner will keep the bad and ugly out of GMP quality compliance.

REFERENCES:

  1. U.S. Food & Drug Administration. Facts About the Current Good Manufacturing Practices (CGMPs) as referenced at https://www.fda.gov/drugs/pharmaceutical-quality-resources/facts-about-current-good-manufacturing-practices-cgmps
  2. U.S. Food & Drug Administration. FDA warns company for putting consumers at risk with drug manufacturing data integrity violations August 20, 2019 as referenced at https://www.fda.gov/news-events/press-announcements/fda-warns-company-putting-consumers-risk-drug-manufacturing-data-integrity-violations.
  3. Pharmout. GMP vs cGMP - what's the difference? February 26, 2018 as referenced at https://www.pharmout.net/gmp-vs-cgmp-whats-difference/
  4. Medicines and Healthcare products Regulatory Agency as referenced at https://www.gov.uk/government/organisations/medicines-and-healthcare-products-regulatory-agency
  5. International Society for Pharmaceutical Engineering. What is GMP? As referenced at https://ispe.org/initiatives/regulatory-resources/gmp/what-is-gmp
  6. International Society for Pharmaceutical Engineering. GMP Audit Checklist for Drug Manufacturers as referenced at https://ispe.org/initiatives/regulatory-resources/gmp/audit-checklist
  7. U.S. Food & Drug Administration. Postmarketing Surveillance Programs as referenced at https://www.fda.gov/drugs/surveillance/postmarketing-surveillance-programs
  8. Proclinical. cGMP: What every quality assurance professional needs to know: as referenced at https://www.proclinical.com/blogs/2015-1/cgmp-what-every-quality-assurance-professional-needs-to-know
  9. European Medicines Agency. Good manufacturing practice as referenced at https://www.ema.europa.eu/en/human-regulatory/research-development/compliance/good-manufacturing-practice
  10. U.S. Food & Drug Administration. FDA Updates and Press Announcements on Angiotensin II Receptor Blocker (ARB) Recalls (Valsartan, Losartan, and Irbesartan) as referenced at https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-and-press-announcements-angiotensin-ii-receptor-blocker-arb-recalls-valsartan-losartan
  11. FiercePharma. The Top 12 GMP Violations as referenced at https://www.fiercepharma.com/special-report/top-12-gmp-violations
  12. U.S. Food & Drug Administration. Mutual Recognition Agreement (MRA) as referenced at https://www.fda.gov/international-programs/international-arrangements/mutual-recognition-agreement-mra
  13. U.S. Food & Drug Administration. Warning Letters as referenced at https://www.fda.gov/inspections-compliance-enforcement-and-criminal-investigations/compliance-actions-and-activities/warning-letters
  14. Investopedia. How does government regulation impact the drugs sector? October 22, 2018 as referenced at https://www.investopedia.com/ask/answers/032315/how-does-government-regulation-impact-drugs-sector.asp
  15. The FDA Group, LLC. Why Quality Assurance is So Important to Pharmaceuticals. September 24, 2014 as referenced at https://www.thefdagroup.com/blog/2014/09/the-importance-of-quality-assurance/
  16. Unger, Barbara. An Analysis of 2017 FDA Warning Letters on Data Integrity. Pharmaceutical Online. May 18, 2018 as referenced at https://www.pharmaceuticalonline.com/doc/an-analysis-of-fda-warning-letters-on-data-integrity-0003
  17. EudraGMDP. Non Compliance Reports. November, 22,2019 as referenced at http://.eudragmdp.ema.europa.eu/inspections/gmpc/searchGMPNonCompliance