A Quality Mindset in Drug Manufacturing Thinks Beyond Just ‘21 CFR part 11’


Compliance with regulations, including 21 CFR part 11, requires in-depth knowledge of the current regulatory environment along with a strong sense of potential future updates. Preparing for changes will help minimize future downtime. A robust stability testing program with solid documentation will highlight risks and avoid potential consumer risk.


Pharmaceutical firms, drug manufacturers, and regulatory agencies share a common goal of maintaining the highest standards of public safety and health. Across the globe, regulators actively work to ensure quality in all phases of drug development, including drug manufacturing. In the United States, the Food and Drug Administration (FDA) is the primary regulatory body during this stage.1

In the United Kingdom, The Medicines and Healthcare products Regulatory Agency (MHRA) is responsible for the regulations of medicines, ensuring that they are safe and effective before going to market.2 The European Union has regulations similar to those of the World Health Organization (WHO) and the FDA. In other countries, public health is monitored by the WHO.

Among the many regulations in place to help support quality in the manufacturing process is Title 21 CFR part 11, which requires FDA-regulated industries to “implement controls, including audits, system validations, audit trails, electronic signatures, and documentation for software and systems involved in processing the electronic data that FDA predicate rules require them to maintain.”3 Pharmaceutical manufacturing must adhere to a significant number of regulations designed to support consumer safety.

To meet that goal, they need to think beyond 21 CFR part 11.4 While 21 CFR Part 11 is a critical component of maintaining public health standards, violations continue to trend upward. The FDA will exercise 483s and Warning Letters against any Current Good Manufacturing Practice (CGMP) violations including those related to data integrity, making it an important piece of the CGMP compliance puzzle.


Quality in drug manufacturing is an evolving discipline. When regulatory agencies across the globe were first tasked with regulating the drug manufacturing process, there were fewer compliance requirements and regulations, and less oversight. In yesterday’s manufacturing facility, technology was simpler and paper-based data integrity was easier to maintain.

Clearly, times have changed. The global pharmaceutical market is expected to grow to $1.5 trillion by 2023, from the $1.2 trillion of 2018, at an annual growth rate of 3-6%.5 This projected growth will impact the increasing complexity of the drug manufacturing process. The introduction of emergent technology will require pharmaceutical manufacturers to implement processes and procedures to anticipate evolving standards and regulations.

Growth such as this does not happen in a vacuum. In the US, one of the most powerful ways the FDA ensures compliance is through 483s and Warning Letters. In Europe, non-compliance reports play the same role. What is worrying however, are continued basic areas of non-compliance.

Figure 16

Year-over-year, data integrity violations have increased. For example, data integrity-associated FDA Warning Letters have significantly increased with 15 in 2015, 41 in 2016, and 56 in 2017. Most often such data integrity observations result from inadequate processes and systems, which in all cases the FDA regards as a risk to patient safety.7

Pharmaceutical manufacturers need not only to better understand current regulations and create processes and quality programs to successfully bring drugs to market, but also to plan for future regulations. This includes streamlining all processes, including data integrity, and raw materials, including excipient quality. This will enable manufacturing staff to focus on their primary tasks and not on quality and compliance activities.


As a drug enters the manufacturing stage, quality should be an inherent and established part of all processes. Data should be validated and the effect of all drug components including API and excipients understood and accounted for in the drug’s efficacy. Process validation, or simply put, documented process understanding needs to be fully realized via technology, procedures, and training.8

Overall, manufacturing facilities need to adopt a quality philosophy that is pro-active not re-active. This requires the manufacturer to have in place quality programs that prioritize data integrity and include mock audits and instrumentation validation.

Upholding a quality mindset pays dividends at any point in the lifecycle of the product. The manufacturing process can benefit from a shift in mind-set from putting out fires to one of getting it right the first time with a focus on product integrity at all stages.9

Enable computer systems to support quality

Data integrity cannot be overlooked when maintaining a quality mindset. Deviations from this focus can result in basic 21 CFR 211.165(e) regulatory violations: “Your firm failed to establish and document the accuracy, sensitivity, specificity, and reproducibility of its test methods.10

Violations that focus on data integrity and computer system validation can be avoided by implementing the systems, technologies, and expertise prior to manufacturing. When strong and clear quality practices are implemented early and exercised often, it will help significantly mitigate regulatory agency involvement and the worst-case scenario of causing consumer harm.

Design instrumentation testing to supporting quality

The manufacturing environment has evolved to one characterized by complexity, complete with disparate technology and diverse instrumentation. The FDA continues to view data integrity as a priority.

A manufacturing process that does not account for robust data quality controls for both technology and instrumentation runs the risk of very basic failures that can provoke Warning Letters and non-compliance reports. Consequences cannot be overstated with risks including reputation damage, impact on new drug approvals, competitive leverage, loss of business, and potential litigation.11

One of the many challenges pharmaceutical manufacturing faces is related to the need to use accurate and robust analytical instruments and techniques to support characterization and quantification of API, excipients, drug product, primary packaging, and more. Pharmaceutical manufacturers need to incorporate instrumentation qualification and validation in their quality programs.

In the past, it has been acceptable for instrument software to not be inherently compliant but able to accommodate workarounds such as using paper to patch gaps. Regulatory agencies have identified this as a consumer safety risk and increasingly systems are being evaluated on inherent compliance. This change requires quality programs to be steps ahead of current regulations.

At the onset, manufacturers need to establish a goal of achieving enhanced instrumentation compliance with reduced manual intervention. This approach is more desirable and can be built into all relevant processes up-front.

Incorporate lead validation services

Validation of all major pharmaceutical systems and processes are essential. Solutions that ensure lead validation promote efficiencies and can support data integrity goals12. Without lead validation programs, manufacturers are at risk of Title 21 CFR part 11 violations such as 21 CFR 211.165(e): “Your firm failed to establish and document the accuracy, sensitivity, specificity, and reproducibility of its test methods”.10

Lead validation, however, is time consuming if it is to thoroughly support the full lifecycle of method development, method transfer, to method validation services. Pharmaceutical manufacturing needs to implement solutions to streamline workflows and support strong data integrity assessments and methods that establish robust quality control.

Support a strong stability program

Stability testing is an important part of the drug development and approval process, determining the safety and integrity of the drug and also its shelf life and storage conditions13. Failure to adhere to a strong stability program, including ensuring data integrity in all testing programs, comes with its own non-compliance risk.

For example:
“Your firm failed to establish and follow an adequate written testing program designed to assess the stability characteristics of drug products and to use results of such stability testing to determine appropriate storage conditions and expiration dates (21 CFR 211.166(a)) / Your firm failed to conduct a long-term room temperature stability study to support the expiration dates of your over-the-counter drug products. / Your firm did not have an adequate stability testing program to demonstrate that the chemical … properties of your OTC drug products remain acceptable throughout their labeled expiry period. For example, your stability testing program does not include an assay determination of the active ingredient(s) in your OTC drug products.”10

The complexity of adhering to current consumer safety regulations extends to the longevity of the product. It is the manufacturer's responsibility to understand the conditions in which the medication needs to be maintained once in the consumer’s hands. A robust stability testing program with solid documentation will highlight risks and avoid potential consumer risk.

Plan for the future with a knowledgeable third-party partner

Compliance with regulations, including 21 CFR part 11, requires in-depth knowledge of the current regulatory environment along with a strong sense of potential future updates. Preparing for changes will help minimize future downtime.

Working with a knowledgeable third-party partner will allow all functions in the manufacturing facility to remain focused on producing compliant, safe, and ultimately beneficial medications for the public. A third-party partner can implement SOPs, policies, and procedures to mitigate major failings or deficiencies, and establish practices and programs to support data integrity.


You own your company’s compliance. With computer system and instrumentation support you can offload the burden of many compliance activities and work streams, freeing up scientists’ time to focus on core competencies.


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  2. GOV.UK. MHRA as referenced at
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  5. Miglierini, Giuliana. PharmaWorld Magazine. Emerging trends for the pharmaceutical market. February 20, 2019 as referenced at
  6. Figure 1 as referenced at
  7. Robert Marohn, Contract Pharma. FDA & Data Integrity. January 25, 2019 as referenced at
  8. Masen, Jr., Russell E. BioPharm International. Understanding Validation and Technical Transfer, Part I. Volume 31, Issue 4, pg 26–30. April 1, 2018 as referenced at
  9. Meyers, Chet; Uydess, Ian. Pharmaceutical Technology. Developing and Sustaining a Quality Culture. December 2, 2011, Volume 35, Issue 12 as referenced at
  10. ECA Academy. Batch Release without Determination of Identity and Strength and other GMP violations – A Look at FDA’s Warning Letters over the Last Months. November 13, 2019 as referenced at
  11. Chen, Tony. Govzilla. A Bad 483 Could Cost A Company Millions. August 22, 2018 as referenced at
  12. Choudhary, Ankur. Pharmaceutical Guidelines. Importance of Validation in Pharmaceuticals as referenced at
  13. SEQENS CDMO, How to Know when to Toss your Prescription Drug or Refrigerate it. Price, Ed. June 18, 2017